SNPMiner Trials by Shray Alag


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Report for Mutation T790M

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

There are 297 clinical trials

Clinical Trials


1 A Phase 2 Study of XL647 in Subjects With Non-Small Cell Lung Cancer Who Have Progressed After Responding to Treatment With Either Gefitinib or Erlotinib

The purpose of this study is to determine the best confirmed response rate of daily administration of the multiple receptor tyrosine kinase (RTK) inhibitor (including EGFR and VEGFR2) XL647 in subjects with NSCLC who have progressed after responding to treatment with either erlotinib or gefitinib.

NCT00522145 Carcinoma, Non-Small-Cell Lung Drug: XL647
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Subjects must have: 1. documented (radiological or clinical) progressive disease (PD) following a prior response (including stable disease) to monotherapy with erlotinib or gefitinib that was administered for at least 12 weeks prior to progression OR 2. a documented T790M EGFR mutation - Measurable disease defined according to RECIST - ECOG performance status of 0 or 1. - Sexually active subjects must use an accepted method of contraception during the course of the study. --- T790M ---

Primary Outcomes

Measure: Determine the best confirmed response rate

Time: Inclusion until disease progression

Secondary Outcomes

Measure: Safety and tolerability of XL647 administered daily

Time: First treatment until 30 day post last treatment

Measure: Progression-free survival, duration of response, and overall survival

Time: Incusion until disease progression

Measure: Further characterize the pharmacokinetic (PK) parameters

Time: Every 8 weeks after Day 57 until disease progression

2 A Phase II Trial of Adjuvant Erlotinib in Patients With Resected, Early Stage Non-Small Cell Lung Cancer (NSCLC) With Confirmed Mutations in the Epidermal Growth Factor Receptor (EGFR)

In this research study erlotinib will be given to eligible participants whose lung cancer has been removed by surgery. Eligible patients have adenocarcinoma, a type of non-small lung cancer, and must have 1 or more of the following characteristics: be female, be of Asian or Pacific Rim descent and/or be a never smoker. The potential participant's tumor will be examined for Epidermal growth factor (EGFR) mutations. EGFR is a protein that is overexpressed in most non-small cell lung cancers. Some EGFR has been found to have specific mutations and the participant must have one of these mutations in his tumor. Erlotinib blocks this protein and may control tumor growth and increase survival. Previous research has shown that erlotinib is most effective for people who have these specific mutations in the EGFR.

NCT00567359 Non-small Cell Lung Cancer Drug: Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- 18 years of age or older - Tumor samples must have either exon 19 deletion mutations or the exon 21 L858R point mutation - ECOG Performance status of 0,1, or 2 - Adequate organ function as outlined in protocol Exclusion Criteria: - Radiographic evidence of recurrent NSCLC prior to erlotinib treatment - Confirmed T790M resistance mutation in the primary tumor sample - Prior exposure to EGFR tyrosine kinase inhibitors - Known hypersensitivity to erlotinib, gefitinib, or any closely related drug - Pregnant or breastfeeding women - Any evidence of clinically active interstitial lung disease - Current use of enzyme-inducing anti-epileptic drugs, including carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and primidone - Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the study - Use of any non-FDA approved or investigational agent within 2 weeks of enrolling onto the trial, or failure to recover from the side effects of any of these agents Inclusion Criteria: - Pathologically confirmed diagnosis of NSCLC of adenocarcinoma histology - Stage IA-B, IIA-B, or IIIA by the American Joint Committee on Cancer 7th edition staging criteria - Patients must have undergone surgical resection with curative intent within 6 months of enrollment - Sufficient tumor tissue available for EGFR mutation analysis - At least ONE of the following patient characteristics: previously detected deletion 19 or L858R EGFR mutation, female sex, history of never smoking, or Asian/Pacific Rim ethnicity (to be enrolled in the screening portion of trial). --- L858R --- --- T790M ---

- 18 years of age or older - Tumor samples must have either exon 19 deletion mutations or the exon 21 L858R point mutation - ECOG Performance status of 0,1, or 2 - Adequate organ function as outlined in protocol Exclusion Criteria: - Radiographic evidence of recurrent NSCLC prior to erlotinib treatment - Confirmed T790M resistance mutation in the primary tumor sample - Prior exposure to EGFR tyrosine kinase inhibitors - Known hypersensitivity to erlotinib, gefitinib, or any closely related drug - Pregnant or breastfeeding women - Any evidence of clinically active interstitial lung disease - Current use of enzyme-inducing anti-epileptic drugs, including carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and primidone - Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the study - Use of any non-FDA approved or investigational agent within 2 weeks of enrolling onto the trial, or failure to recover from the side effects of any of these agents Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung - Erlotinib is a pill taken daily and participants may continue to receive erlotinib for up to two years, as long as the cancer does not return and they do not experience any unacceptable side effects. --- L858R --- --- T790M ---

Primary Outcomes

Description: The number of participants alive and free from disease recurrence 2 years after enrollment. Participants were monitored for disease recurrence with the use of surveillance radiographs. When possible and medically appropriate, tissue biopsies were obtained to prove recurrence.

Measure: 2-year Disease-free Survival

Time: 2 years

Secondary Outcomes

Description: Adverse events were assessed using Common Terminology Criteria for Adverse Events (CTCAE 3.0) from the start of treatment until 30 days after the end of treatment. Serious adverse events were defined as adverse events that were grade 3 or greater and deemed to be possibly, probably or definitely related to the study treatment.

Measure: Number of Participants With Treat Related Serious Adverse Events

Time: From the start of treatment until 30 days after the end of treatment, up 13 months total

Description: The median amount of time from the time of registration until death due to any cause

Measure: Median Overall Survival

Time: From the time of registration until death, up to approximately 9 years

Description: The median amount of time measured from the time of registration until the time of disease recurrence or death.

Measure: Median Disease Free Survival

Time: From registration to disease recurrence or death, up to approximately 9 years

3 A Phase 2 Trial of Dasatinib in Patients With Lung Adenocarcinoma With Acquired Resistance to Erlotinib or Gefitinib

RATIONALE: Dasatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. PURPOSE: This phase II trial is studying how well dasatinib works in treating patients with advanced lung cancer that is no longer responding to erlotinib or gefitinib.

NCT00570401 Lung Cancer Drug: dasatinib
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

- To determine the overall response rate in patients with EGFR T790M lung adenocarcinomas treated with this drug. --- T790M ---

- To determine the progression-free survival and overall survival of patients with EGFR T790M lung adenocarcinomas treated with this drug. --- T790M ---

Primary Outcomes

Description: To determine the overall response rate in patients with acquired erlotinib hydrochloride- or gefitinibresistant advanced adenocarcinoma of the lung treated with dasatinib using the RECIST criteria. Response and progression will be evaluated in this study using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee.22 Changes in only the largest diameter (uni-dimensional measurement) of the tumor lesions are used in the RECIST.

Measure: Determine the Overall Objective Response

Time: 2 years

4 A Prospective Registry for Patients With Acquired Resistance to Small Molecule Kinase Inhibitors in Non-Small-Cell Lung Cancer

The purpose of this study is to try to learn more about how small molecule kinase inhibitors work in treating lung cancer. Some early studies have shown that gefitinib, erlotinib and similar drugs are more likely to work if a particular DNA change (also known as a mutation) is found in a protein that is important in lung cancer. This protein is called the epidermal growth factor receptor (EGFR). Since small molecule kinase inhibitors sometimes stop working, we would like to examine your tumor to learn why these medicines are not working as well. Your tumor will be examined for a variety of things including changes in the DNA of the EGFR. We will also sequence parts of the genes for HER2, HER3, HER4, and KRAS, other proteins thought to be important in lung cancer.

NCT00579683 Unresectable or Metastatic Non-small Cell Lung Cancer (NSCLC) Other: Tumor core biopsy for RNA isolation
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

To more precisely characterize the frequency and clinical implications of T790M in patients with acquired resistance to small molecule kinase inhibitors.. null. --- T790M ---

Primary Outcomes

Measure: To compare EGFR gene sequence in patients upon relapse with EGFR gene sequence prior to treatment with small molecule kinase inhibitors.

Time: 2 years

Secondary Outcomes

Measure: To identify novel mutations in the tyrosine kinase domain of EGFR in patients with acquired resistance to small molecule kinase inhibitors.

Time: 2 years

Measure: To more precisely characterize the frequency and clinical implications of T790M in patients with acquired resistance to small molecule kinase inhibitors.

Time: 2 years

Measure: To identify novel mechanisms of acquired resistance to EGFR small molecule kinase inhibitors.

Time: 2 years

5 A Randomized Phase 2 Trial Of Pf-00299804 Versus Erlotinib For The Treatment Of Advanced Non-small Cell Lung Cancer After Failure Of At Least One Prior Chemotherapy Regimen

This study will compare PF-00299804 given orally on continuous schedule to the approved drug, erlotinib, in patients whose non-small cell lung cancer has progressed after chemotherapy; patients will be randomized to receive one of these drugs, and followed for efficacy and tolerance of each.

NCT00769067 Non-small Cell Lung Cancer Drug: Erlotinib Drug: PF-00299804
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

OS was calculated as (the death date or last known alive date (if death date unavailable) minus the date of randomization plus 1) divided by 7.. Number of Participants With Kirsten Rat Sarcoma (KRAS) and Epidermal Growth Factor Receptor (EGFR) Status and EGFR T790M Mutation. --- T790M ---

Additionally blood specimens were analyzed at a sponsor-designated laboratory for T790M mutation in EGFR.. Soluble Protein Biomarkers Level. --- T790M ---

Primary Outcomes

Description: PFS: Time in weeks from randomization to date of objective disease progression or death due to any cause, whichever occurred first. PFS was calculated as (first event date or last known event-free date [if the event date unavailable] minus the date of randomization plus 1) divided by 7. Objective progression is defined using Response Evaluation Criteria in Solid Tumors (RECIST), as at least 20 percent (%) increase in the sum of longest dimensions (LDs) of target lesions, taking as reference the smallest sum of LD recorded since the treatment started and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.

Measure: Progression-Free Survival (PFS)

Time: Baseline until disease progression or death, assessed at Cycle 2, 3, 4, 5, 6, thereafter every other cycle up to end of treatment (121 weeks), followed by every 8 weeks >284 weeks

Secondary Outcomes

Description: EORTC QLQ-C30: included global health status/quality of life (QoL), functional (Fn) scales (physical, role, cognitive, emotional, and social), symptom scales (fatigue, pain, nausea/vomiting), and single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, and financial difficulties). Scores were averaged, transformed to 0-100 scale; higher score for Global Qol/Fn scales=better level of QoL/functioning or higher score for symptom scales/items=greater degree of symptoms. Overall scale change is categorized as Improved (if average scales change from baseline: for Global QoL/Fn scales >=10; for symptom scale/item <=-10), Worsened (if average scales change from baseline: for Global QoL/Fn scales <=-10; for symptom scale/item >=10), and Stable (if average scales change from baseline >-10 but <10 for Global QoL/Fn scales and symptom scale/item) and participants in each category are reported.

Measure: Categorical Summary of Overall Scale Change in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)

Time: Baseline up to Cycle 44 (Week 188)

Description: QLQ-LC13 consisted of 13 questions relating to disease symptoms specific to lung cancer and treatment side effects typical of treatment with chemotherapy and radiotherapy. The 13 questions comprised 1 multi-item scale for dyspnea and 10 single-item symptoms and side effects (coughing, hemoptysis, sore mouth, dysphagia, peripheral neuropathy, alopecia, chest pain, arm pain, other pain, and medicine for pain). Scores averaged, transformed to 0-100 scale; higher symptom score = greater degree of symptoms. Overall scale change is categorized as Improved (if average scales change from baseline <=-10), Worsened (if average scales change from baseline >=10), and Stable (if average scales change from baseline >-10 but <10) and participants in each category are reported.

Measure: Categorical Summary of Overall Scale Change in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer Module (EORTC QLQ-LC13)

Time: Baseline up to Cycle 44 (Week 188)

Description: DLQI: 10-item questionnaire to measure how much the participant's skin problem has impacted their life over the previous week on following 6 domains: symptoms/feelings (2 questions), daily activities (2 questions), leisure (2 questions), work/school (1 question), personal relationships (2 questions), and treatment (1 question). All questions were answered on a 4-point Likert scale ranging from 0 (not at all/not relevant) to 3 (very much/prevented work or studying). The DLQI total evaluable score was calculated by summing the score of each question and ranged from 0 to 30, where higher scores indicated more quality of life impairment.

Measure: Dermatology Life Quality Index (DLQI)

Time: Cycle (C) 1 Day (D) 1 (baseline), C1D10-14, D1 of subsequent cycles up to C44

Description: Percentage of participants with objective response based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST version 1.0. CR: disappearance of all target and non-target lesions. PR: at least 30 % decrease in sum of the LDs of target lesion, taking as reference the baseline sum LD. Confirmed responses are those that persist on repeat imaging study at least 4 weeks after initial documentation of response.

Measure: Percentage of Participants With Objective Response

Time: Baseline until disease progression or death, assessed at Cycle 2, 3, 4, 5, 6, thereafter every other cycle up to end of treatment (121 weeks), followed by every 8 weeks >284 weeks

Description: Number of participants with BOR according to RECIST version 1.0: CR= disappearance of all target and non-target lesions. PR= at least 30% decrease in sum of LDs of target lesion, taking as reference baseline sum LD. Stable/no response= neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of LDs since treatment started. Objective progression= at least a 20% increase in sum of LDs of target lesions, taking as reference the smallest sum of LDs recorded since treatment started and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.

Measure: Best Overall Response (BOR)

Time: Baseline until disease progression or death, assessed at Cycle 2, 3, 4, 5, 6, thereafter every other cycle up to end of treatment (121 weeks), followed by every 8 weeks >284 weeks

Description: Time in weeks from first documentation of objective tumor response to objective tumor progression or symptomatic deterioration or death due to any cause, whichever occurred first. Duration of tumor response was calculated as (the date of the first documentation of objective tumor progression or symptomatic deterioration or death due to any cause or last known progression-free date [if none of the event dates available] minus the date of the first CR or PR [which ever occurred first] that was subsequently confirmed plus 1) divided by 7. DR was calculated for the subgroup of participants with a confirmed objective tumor response.

Measure: Duration of Response (DR)

Time: Baseline until disease progression or death, assessed at Cycle 2, 3, 4, 5, 6, thereafter every other cycle up to end of treatment (121 weeks), followed by every 8 weeks >284 weeks

Description: Time in weeks from randomization to date of death due to any cause. OS was calculated as (the death date or last known alive date (if death date unavailable) minus the date of randomization plus 1) divided by 7.

Measure: Overall Survival (OS)

Time: Baseline until end of treatment (15 August 2014); followed up every 8 weeks after discontinuation from study treatment.

Other Outcomes

Description: Tumor tissue were analyzed at a sponsor-designated laboratory to investigate KRAS and EGFR status (wild type or mutated). Participants who did not provide samples for central laboratory analysis confirmation were classified as "unknown". Additionally blood specimens were analyzed at a sponsor-designated laboratory for T790M mutation in EGFR.

Measure: Number of Participants With Kirsten Rat Sarcoma (KRAS) and Epidermal Growth Factor Receptor (EGFR) Status and EGFR T790M Mutation

Time: Baseline

Description: Blood specimens were analyzed at a sponsor-designated laboratory for analysis of shed proteins/receptors related to Human Epidermal Growth Factor Receptor (HER) signaling (EGFR, HER-2, Epithelial-cadherin [E-cadherin]). The data collection after C12D1 was not performed, as there were too few participants across both treatment arms after C12D1.

Measure: Soluble Protein Biomarkers Level

Time: Cycle (C) 1 Day (D) 1 (baseline), D1 of each subsequent cycle up to end of treatment (up to 121 weeks)

Description: Only participants from "Dacomitinib" treatment arm were planned to be analyzed for this outcome.

Measure: Trough Plasma Concentration (Ctrough) of Dacomitinib (PF-00299804)

Time: C1D10-14, C2D1, C3D1, C4D1

6 Study of Epithelial Growth Factor Receptor Mutations in Tumor Specimens and Blood Samples From Patients With Non-Small Cell Lung Cancer Enrolled on Clinical Trial CASE-2507

RATIONALE: Studying samples of blood and tissue from patients with cancer in the laboratory may help doctors learn more about changes that occur in DNA and RNA and identify biomarkers related to cancer. PURPOSE: This laboratory study is looking at biomarkers in tumor tissue and blood samples from patients with non-small cell lung cancer.

NCT00907699 Lung Cancer Genetic: DNA analysis Genetic: RNA analysis Genetic: fluorescence in situ hybridization Genetic: gene expression analysis Genetic: mutation analysis Genetic: polymerase chain reaction Genetic: reverse transcriptase-polymerase chain reaction Other: laboratory biomarker analysis
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Predictive value of T790M mutation status of the second biopsy (before maintenance therapy on CASE-2507) on progression-free survival (PFS). --- T790M ---

Difference of PFS between those with and without T790M mutation. --- T790M ---

Difference of clinical response rate between T790M mutation statuses. --- T790M ---

Association between T790M mutation and baseline clinical-pathological factors and smoking status. --- T790M ---

Primary Outcomes

Measure: Predictive value of T790M mutation status of the second biopsy (before maintenance therapy on CASE-2507) on progression-free survival (PFS)

Time: At the time of the second biopsy or surgical procedures

Measure: Difference of PFS between those with and without T790M mutation

Time: At the time of the second biopsy or surgical procedures

Measure: Difference of clinical response rate between T790M mutation statuses

Time: At the time of the second biopsy or surgical procedures

Measure: Predictive value of mutation status on clinical response

Time: At the time of the second biopsy or surgical procedures

Measure: Association between T790M mutation and baseline clinical-pathological factors and smoking status

Time: At the time of the second biopsy or surgical procedures

7 Phase II Study of Erlotinib With or Without Hydroxychloroquine in Patients With Previously Untreated Advanced NSCLC and EGFR Mutations

The purpose of this research study is to learn if adding hydroxychloroquine (HCQ) to erlotinib helps treat non-small cell lung cancer (NSCLC). Another goal of this research study is to learn more about NSCLC and how it may respond to study treatment. Erlotinib (Tarceva) is a type of drug called a tyrosine kinase inhibitor (TKI). TKIs block a protein called the epidermal growth factor receptor (EGFR). EGFR may control tumor growth and tumor cell survival. However, although TKI drugs can work for some lung cancer patients for a period of time, eventually the tumor finds a way to resist or counteract the TKI treatment and it begins to grow again. Hydroxychloroquine (HCQ) is a drug approved by the FDA for treating malaria, rheumatoid arthritis, and several other diseases. Laboratory research suggests that when HCQ is given with a TKI, it may help delay or prevent TKI resistance from developing.

NCT00977470 Non-small Cell Lung Cancer Drug: Erlotinib Drug: Hydroxychloroquine
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Presence of the known resistance mutation T790M as detected by direct tumor sequencing is not allowed. --- T790M ---

Primary Outcomes

Description: A measure of progression-free survival in patients with advanced non small-cell lung cancer (NSCLC) and EGFR mutations treated with erlotinib as compared with patients treated with erlotinib plus hydroxychloroquine (HCQ). Disease progression is defined as at least a 20% increase in the sum of the longest diameter of target lesions, as seen on CT scan, or the appearance of one or more new lesions on CT scan.

Measure: Median Progression Free Survival

Time: From start of treatment until report of disease progression, assessed up to 10 years.

Description: This trial can detect a difference in proportions alive without progression at 9 months from 50% in the erlotinib arm to 77% in the erlotinib plus hydroxychloroquine (HCQ) arm, using an alpha of 0.15 and power of 85%, using the two-sided Likelihood Ratio test. Progression is defined as at least a 20% increase in the size of existing lesions or the appearance of one or more new lesions.

Measure: Nine-month Progression-free Survival Rate

Time: Nine months

Secondary Outcomes

Description: To evaluate the safety of treatment with erlotinib with and without hydroxychloroquine (HCQ). All participants receiving study treatment were evaluated for safety. Parameters included laboratory tests, hematological abnormalities, physical exam findings and spontaneous reports of adverse events reported by participants. Toxicities were evaluated and graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life-threatening, Grade 5 = fatal.

Measure: Treatment Related Toxicity, > 10% Frequency, Any Grade

Time: 2 years

Description: Response is assessed via spiral CT scan, done at baseline and after every 2 cycles of study treatment. Standard RECIST (Response Evaluation Criteria in Solid Tumors) was used. Complete Response (CR) = disappearance of all target lesions; Partial Response (PR) = at least a 30% decrease in the size of target lesions, as compared to baseline; Progressive Disease (PD) = at least at 20% increase in the size of target lesions, or the appearance of one or more new lesions; Stable Disease (SD) = neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease. Response rate = CR + PR. Disease control rate = CR + PR + SD

Measure: Objective Tumor Response Rate Following Treatment With Erlotinib and With Erlotinib/HCQ.

Time: 2 years

Measure: Overall Survival of Patients Treated With Erlotinib and With Erlotinib/HCQ

Time: Until death

Other Outcomes

Description: Serial circulating tumor cell (CTC) analyses will be performed on peripheral blood and correlated with disease response.

Measure: Circulating Tumor Cell Quantification

Time: Until disease progression (median of 10.8 months)

Description: Correlation of molecular and genetic tumor characteristics with disease response. Genomic DNA will be extracted from tumor tissue and direct sequencing analysis will be performed to identify additional mutations.

Measure: EGFR Mutational Status

Time: 2 years

Description: [18F]-FMISO-PET/CT was performed on a 64-slice PET/CT scanner and tracer uptake was assessed using SUV (standardized uptake value), normalizing the radioactivity measured in tissue by the injected dose and the body weight of the patient. Mean and maximum SUV and threshold volume of FMISO uptake were measured to quantify the extent of hypoxia in the primary tumor. Imaging was performed before and after initiation of therapy with erlotinib.

Measure: Percent of Participants in Which FMISO-PET ([18F]-Fluoromisonidazole-positron Emission Tomography) is Able to Detect and Quantify Changes in Tumor Hypoxia After Erlotinib.

Time: 12 weeks

8 First-Line Erlotinib Therapy and the Subsequent Development of Mechanisms of Secondary Resistance in Patients With Non-Small Cell Lung Cancer and Known Sensitizing EGFR Mutations

Erlotinib is a drug which targets non small cell lung cancer with a genetic change (mutation) in the epidermal growth factor receptor (EGFR). This drug has been used in other cancer research studies and information from those studies suggests that Erlotinib can control the growth of these cancer cells.

NCT00997334 Non-small Cell Lung Cancer Drug: Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Participants were classified into 4 potential resistant mechanism groups (4 genetic/ 1 histologic) based on evaluation of rebiopsy tissue: EGFR mutations (T790M mutation, exon 20 insertion), KRAS mutations, MET amplification or small-cell lung cancer (SCLC) transform using established methods.. Progression-Free Survival. --- T790M ---

Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE -To prospectively assess the frequency of different genetic mechanisms of secondary resistance in patients' tumors during treatment with erlotinib (e.g., T790M mutations, MET amplification). --- T790M ---

Primary Outcomes

Description: Participants were classified into 4 potential resistant mechanism groups (4 genetic/ 1 histologic) based on evaluation of rebiopsy tissue: EGFR mutations (T790M mutation, exon 20 insertion), KRAS mutations, MET amplification or small-cell lung cancer (SCLC) transform using established methods.

Measure: Resistance Mechanism

Time: Participants were evaluated for incidence of genetic mechanisms of secondary resistance at time of disease progression at which point participants stopped treatment. Progression follow up was up to 3 years in this study cohort.

Secondary Outcomes

Description: Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.

Measure: Progression-Free Survival

Time: Disease was evaluated radiologically every 8 weeks on treatment (cycle duration=4 weeks). Participants were treated until evidence of disease progression or unacceptable toxicity. Progression follow-up was up to 3 years in this study cohort.

9 Understanding Mechanisms of Acquired Resistance to BIBW2992

In this research study we are looking to see how effective BIBW 2992 is at suppressing the development of the T790M mutation in non-small cell lung cancer (NSCLC) patients. Epidermal growth factor receptors (EGFR) are proteins found on the surface of some cancer cells that promote a growth signal. Some cancer drugs for NSCLC work to block this signal from reaching its target on the cancer cells which in turn may slow or stop the cancer from growing. However, many times patients with EGFR mutations will stop responding to these cancer drugs and develop drug-resistance because they have developed a specific EGFR mutation called T790M. BIBW 2992 may prevent the T790M mutation from becoming active and therefore slow disease progression.

NCT01074177 Non-small Cell Lung Cancer EGFR Mutations Drug: BIBW 2992
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Understanding Mechanisms of Acquired Resistance to BIBW2992 In this research study we are looking to see how effective BIBW 2992 is at suppressing the development of the T790M mutation in non-small cell lung cancer (NSCLC) patients. --- T790M ---

However, many times patients with EGFR mutations will stop responding to these cancer drugs and develop drug-resistance because they have developed a specific EGFR mutation called T790M. --- T790M ---

BIBW 2992 may prevent the T790M mutation from becoming active and therefore slow disease progression. --- T790M ---

Number of Participants That Have a T790M Mutation on Their Progression Biopsy.. null. --- T790M ---

The purpose of this biopsy is to assess for the presence or the absence of the mutation T790M. --- T790M ---

Primary Outcomes

Measure: Number of Participants That Have a T790M Mutation on Their Progression Biopsy.

Time: At the time of disease progression (median duration of 11.4 months from start of treatment)

Secondary Outcomes

Description: The number of participants with either a complete response (CR) or partial response (PR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) CR: Disappearance of all target lesions. Any pathological lymph node must have reduction in short axis to < 10 mm PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Measure: Response Rate

Time: Baseline and then after the end of every two 28 day cycles until treatment is discontinued; median duration of followup of 19.3 months

Description: The progression-free and overall survival times. Overall survival is measured from the start of treatment until the time of death or until the participant is lost to follow-up. Progression free survival is measured from the start of treatment until the time of progression, death, or until the participant is lost to follow-up (whichever occurs first). Progression is defined as having at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study with at least a 5 mm absolute increase in the sum of all lesions. The appearance of one or more new lesions denotes disease progression.

Measure: Median Progression-free and Overall Survival

Time: start of treatment, at the time of disease progression, time of death

Description: The number of participants with biopsy complications from repeat tumor biopsies taken following disease progression. Biopsy complications are any adverse events considered to be potentially related to the biopsy.

Measure: Number of Participants With Biopsy Complications From Repeat Tumor Biopsies

Time: 7 days post biopsy and ≥ 30 days post-biopsy

10 A Phase Ib Open-label Clinical Trial of Continuous Once Daily Oral Treatment Using BIBW 2992 Plus Cetuximab (Erbitux®) in Patients With Non-small Cell Lung Cancer With Progression Following Prior Erlotinib (Tarceva®) or Gefitinib (Iressa®)

The primary objective of this trial is to determine the maximum tolerated dose (MTD) and recommended Phase II doses for the combination of BIBW 2992 and cetuximab in patients with non-small cell lung cancer and acquired resistance to erlotinib or gefitinib. Overall safety, pharmacokinetics and anti-tumor activity for the combination of BIBW 2992 and cetuximab in patients with non-small cell lung cancer and acquired resistance to erlotinib, gefitinib or BIBW 2992 will be evaluated as secondary objectives. Initially a standard, 3+3 dose escalation will be performed to determine the MTD of BIBW 2992 when administered together with cetuximab in patients with advanced non small cell lung cancer and acquired resistance to erlotinib or gefitinib. Subsequently, the preliminary efficacy and safety of the identified MTD of cetuximab administered with BIBW 2992 will be explored in a combo arm via a further expansion of MTD cohort up to a total of 140 EGFR mutation positive NSCLC with acquired resistance to erlotinib/gefitinib. Furthermore, the safety and preliminary anti-tumor activity of the combination therapy in EGFR mutant NSCLC patients who developed acquired resistance (AR) to BIBW 2992, will be assessed in a sequential arm. The sequential arm will use a two-stage design with an early stopping rule after 12 patients with acquired resistance to BIBW 2992 have received up to 5 courses of BIBW 2992 plus cetuximab. If no responses are seen in 12 patients during 5 courses of combination therapy, accrual in the sequential arm will stop. If 1 or more responses are observed, the sequential arm will expand up to about 40 patients.

NCT01090011 Carcinoma, Non-Small-Cell Lung Drug: Cetuximab Drug: Cetuximab Drug: BIBW 2992 Drug: BIBW 2992
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

A tumor which harbors exon 20 insertion or de novo T790M mutation is eligible for the treatment in the sequential arm 2) Objective clinical benefit from treatment with an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) as defined by either 1. Documented partial or complete response (Response Evaluation Criteria in Solid Tumors, RECIST), or 2. Stable disease >=6 months as defined by RECIST in absence of radiographic progression after initiation of gefitinib or erlotinib; or stable disease/PR/CR >=12 weeks as defined by RECIST after initiation of BIBW 2992 3. Systemic progression of disease (RECIST v1.1) while on continuous treatment with erlotinib or gefitinib or BIBW 2992 within the last 30 days. --- T790M ---

Primary Outcomes

Description: A DLT was defined as an AE or laboratory abnormality that a) related to the study regimen; b) or met any of the following criteria: CTCAE Grade 2 or higher decrease in cardiac left ventricular function CTCAE Grade 2 diarrhea lasting for 7 or more days, despite appropriate use of standard anti-diarrheal therapy CTCAE Grade ≥3 diarrhea despite appropriate use of standard anti-diarrheal therapy for at least 2 days CTCAE Grade ≥3 nausea and/or vomiting despite appropriate use of standard anti-emetics for at least 3 days CTCAE Grade ≥3 rash despite standard medical management CTCAE Grade ≥3 fatigue lasting for more than 7 days CTCAE Grade 4 hypomagnesaemia or Grade 3 hypomagnesaemia with clinical significant sequelae All other toxicities of CTCAE Grade ≥3 (except alopecia, and allergic reaction) leading to an interruption of afatinib and/or cetuximab for more than 14 days until recovery to baseline or Grade 1, whichever was higher.

Measure: The Primary Endpoint is the Occurrence of Dose Limiting Toxicity (DLT).

Time: from day 1 treatment until progression or undue toxicity, up to 28 days

Secondary Outcomes

Description: Safety of afatinib when administered together with cetuximab as indicated by intensity and incidence of adverse events, graded according to the U.S. National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version (v) 3.0

Measure: Highest CTCAE Grade

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Measure: Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Measure: Frequency (%) of Patients With Adverse Events Leading to Dose Reduction

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Description: Frequency (%) of patients with adverse events leading to treatment discontinuation

Measure: Frequency (%) of Patients With Adverse Events Leading to Treatment Discontinuation

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Measure: Frequency (%) of Patients With Adverse Events Leading to Death

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Description: Frequency (%) of patients with drug-related serious adverse events

Measure: Frequency (%) of Patients With Related Serious Adverse Events

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Description: Area Under the Concentration-time Curve (AUC) of Afatinib in plasma at steady state over a uniform dosing interval tau (15 days) (AUCtau,ss) after oral administration of Afatinib and cetuximab combination therapy

Measure: Area Under the Concentration-time Curve (AUC) on Day 15 of Plasma Afatinib for the Combination Arm

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Minimum measured concentration of Afatinib in plasma at steady state over 15 day dosing interval (Cmin,ss). Maximum measured concentration of Afatinib in plasma at steady state over 15 day dosing interval (Cmax,ss).

Measure: Concentration of Afatinib in Plasma for the Combination Arm

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Peak-trough fluctuation (PTF) of plasma afatinib for the combination arm. PTF = 100*(Cmax-Cmin)/Caverage where Caverage = AUC/time, where time equals 24 hours.

Measure: Peak-trough Fluctuation (PTF)

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Terminal half-life of Afatinib in plasma at steady state (t1/2,ss)

Measure: t1/2,ss

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: mean residence time of Afatinib in the body at steady state after oral administration (MRTpo,ss) for 15 days

Measure: MRTpo,ss

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Apparent clearance of afatinib in plasma at steady state after extravascular multiple dose administration (CL/F,ss)

Measure: CL/F,ss,15

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Apparent volume of distribution during the terminal phase λz at steady state following extravascular administration (Vz/F,ss) for 15 days

Measure: Vz/F,ss

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Predose plasma concentrations (Cpre,ss) of Afatinib at Course 1, Visit 2, 3, 4 and 5, at Course 2, Visit 1 and 2 and at Course 3, Visit 1.

Measure: Predose Plasma Concentrations of Afatinib for the Combination Arm

Time: Up to 57 days

Description: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), At least a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesion(s); Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Disease control = CR + PR + SD.

Measure: Disease Control (CR, PR and Stable Disease (SD) Determined by RECIST v1.1)

Time: up to 116 weeks

Description: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), At least a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesion(s); Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Objective tumor response = CR + PR.

Measure: Objective Tumor Response (Complete Response [CR] and Partial Response [PR]) Determined by RECIST v1.1)

Time: up to 116 weeks

Description: Duration of objective response was measured from the time measurements criteria were met for CR/PR (whichever was first recorded) until the first date that recurrent or PD was objectively documented (taking as reference for PD the smallest measurements recorded since treatment started).

Measure: Duration of Objective Response (According to RECIST v1.1)

Time: up to 116 weeks

Description: Duration of disease control was defined as the time from the start of treatment to the time of progression or death (whichever occurred first), among patients with evidence SD, PR or CR.

Measure: Duration of Disease Control (According to RECIST v1.1)

Time: up to 116 weeks

Description: Progression-Free Survival was defined as the duration of time from start of treatment until the day of objective tumour progression confirmed by tumour imaging (PD according to RECIST 1.1) or death.

Measure: Progression-Free Survival (PFS) Time

Time: up to 116 weeks

11 A Phase 2 Trial of Erlotinib Re-Challenge for Recurrent EGFR-mutant Lung Cancer in Patients Who Previously Received Adjuvant Erlotinib or Gefitinib

The purpose of this study is to measure the ability of erlotinib to effectively treat recurrent lung cancer which carries an EGFR mutation lung cancer after prior treatment with erlotinib or gefitinib received in the post-surgical or post-radiation setting.

NCT01189435 Lung Cancer Drug: erlotinib
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Inclusion Criteria: - A history of stage I-IIIB NSCLC - Previously underdone definitive surgery or radiation - Received prior adjuvant treatment or neoadjuvant with erlotinib or gefitinib for a total of at least 3 months at any time - Stopped adjuvant erlotinib or neoadjuvant at least 2 months prior to date of first imaging demonstrating recurrence - Pathologic evidence of recurrent lung cancer, confirmed at MSKCC EGFR sensitizing mutation (point mutation in exons 18 or 21, or deletion in exon 19) must be documented in the primary or recurrent tumor - Tissue from their recurrent tumor must be submitted for EGFR mutation testing, and to evaluate for the presence of the T790M mutation (results do not need to have been reported to be eligible) - Measurable disease by RECIST; if received prior irradiation, then must have a target lesion outside the irradiated field - Signed informed consent - Age > or = to 21 years old - Persons of reproductive potential must agree to use an adequate method of contraception throughout treatment and for at least 4 weeks after study drug is stopped Exclusion Criteria: - Prior progressive disease while receiving erlotinib or gefitinib therapy - Patients with known pre-existing interstitial lung disease - Total bilirubin greater than 1.8 mg/dl, excepting patients known to have Gilbert's syndrome - AST or ALT greater than five times the upper limit of normal - Pregnant or lactating women - Medically unfit for erlotinib therapy as determined by treating oncologist Inclusion Criteria: - A history of stage I-IIIB NSCLC - Previously underdone definitive surgery or radiation - Received prior adjuvant treatment or neoadjuvant with erlotinib or gefitinib for a total of at least 3 months at any time - Stopped adjuvant erlotinib or neoadjuvant at least 2 months prior to date of first imaging demonstrating recurrence - Pathologic evidence of recurrent lung cancer, confirmed at MSKCC EGFR sensitizing mutation (point mutation in exons 18 or 21, or deletion in exon 19) must be documented in the primary or recurrent tumor - Tissue from their recurrent tumor must be submitted for EGFR mutation testing, and to evaluate for the presence of the T790M mutation (results do not need to have been reported to be eligible) - Measurable disease by RECIST; if received prior irradiation, then must have a target lesion outside the irradiated field - Signed informed consent - Age > or = to 21 years old - Persons of reproductive potential must agree to use an adequate method of contraception throughout treatment and for at least 4 weeks after study drug is stopped Exclusion Criteria: - Prior progressive disease while receiving erlotinib or gefitinib therapy - Patients with known pre-existing interstitial lung disease - Total bilirubin greater than 1.8 mg/dl, excepting patients known to have Gilbert's syndrome - AST or ALT greater than five times the upper limit of normal - Pregnant or lactating women - Medically unfit for erlotinib therapy as determined by treating oncologist Lung Cancer Lung Neoplasms null --- T790M ---

Inclusion Criteria: - A history of stage I-IIIB NSCLC - Previously underdone definitive surgery or radiation - Received prior adjuvant treatment or neoadjuvant with erlotinib or gefitinib for a total of at least 3 months at any time - Stopped adjuvant erlotinib or neoadjuvant at least 2 months prior to date of first imaging demonstrating recurrence - Pathologic evidence of recurrent lung cancer, confirmed at MSKCC EGFR sensitizing mutation (point mutation in exons 18 or 21, or deletion in exon 19) must be documented in the primary or recurrent tumor - Tissue from their recurrent tumor must be submitted for EGFR mutation testing, and to evaluate for the presence of the T790M mutation (results do not need to have been reported to be eligible) - Measurable disease by RECIST; if received prior irradiation, then must have a target lesion outside the irradiated field - Signed informed consent - Age > or = to 21 years old - Persons of reproductive potential must agree to use an adequate method of contraception throughout treatment and for at least 4 weeks after study drug is stopped Exclusion Criteria: - Prior progressive disease while receiving erlotinib or gefitinib therapy - Patients with known pre-existing interstitial lung disease - Total bilirubin greater than 1.8 mg/dl, excepting patients known to have Gilbert's syndrome - AST or ALT greater than five times the upper limit of normal - Pregnant or lactating women - Medically unfit for erlotinib therapy as determined by treating oncologist Inclusion Criteria: - A history of stage I-IIIB NSCLC - Previously underdone definitive surgery or radiation - Received prior adjuvant treatment or neoadjuvant with erlotinib or gefitinib for a total of at least 3 months at any time - Stopped adjuvant erlotinib or neoadjuvant at least 2 months prior to date of first imaging demonstrating recurrence - Pathologic evidence of recurrent lung cancer, confirmed at MSKCC EGFR sensitizing mutation (point mutation in exons 18 or 21, or deletion in exon 19) must be documented in the primary or recurrent tumor - Tissue from their recurrent tumor must be submitted for EGFR mutation testing, and to evaluate for the presence of the T790M mutation (results do not need to have been reported to be eligible) - Measurable disease by RECIST; if received prior irradiation, then must have a target lesion outside the irradiated field - Signed informed consent - Age > or = to 21 years old - Persons of reproductive potential must agree to use an adequate method of contraception throughout treatment and for at least 4 weeks after study drug is stopped Exclusion Criteria: - Prior progressive disease while receiving erlotinib or gefitinib therapy - Patients with known pre-existing interstitial lung disease - Total bilirubin greater than 1.8 mg/dl, excepting patients known to have Gilbert's syndrome - AST or ALT greater than five times the upper limit of normal - Pregnant or lactating women - Medically unfit for erlotinib therapy as determined by treating oncologist Lung Cancer Lung Neoplasms null --- T790M --- --- T790M ---

Primary Outcomes

Description: in recurrent EGFR-mutant lung cancer, given to patients who previously received adjuvant erlotinib or gefitinib

Measure: To Examine the Objective Response Rate (ORR) of Single-agent Erlotinib

Time: 2 years

12 Development of Circulating Tumour Cell Molecular Diagnostics Using a Novel Microfluidic Device

1. To compare EGFR mutations between primary non-small cell lung cancer (NSCLC) tumours and corresponding CTCs isolated by a label-free microfluidic device-based system 2. To characterize the association between clinical response in NSCLC patients treated with gefitinib and serial changes in CTC EGFR mutations detected by a label-free microfluidic device-based system The investigators recently developed a label-free, microfluidic device for capturing circulating tumour cells (CTCs) and acquired a Fluidigm Biomark digital PCR instrument for reliable low-level DNA quantification. The overall aim of this study is to test the feasibility of using these state-of-the-art devices to reliably detect clinically relevant EGFR mutations in CTCs.

NCT01193829 Patients With Non-small Cell Lung Cancer
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

DNA will be extracted from the retrieved CTCs and tumour samples, and analyzed exon 19 deletion, L858R and T790M mutations by digital PCR on the Fluidigm Biomark according to methods described previously.23 --- L858R --- --- T790M ---

In particular, the frequency of T790M mutations in a relevant patient population is lacking, highlighting the lack of adequate analytical systems for its assessment such as the one proposed in this study. --- T790M ---


13 Addition of the Gamma-Secretase Inhibitor RO4929097 to Erlotinib in Patients With Advanced Non-small Cell Lung Cancer (NSCLC)

This phase I trial studies the side effects and best dose of gamma-secretase/Notch signalling pathway inhibitor RO4929097 (RO4929097) and erlotinib hydrochloride when given together in treating patients with non-small cell lung cancer that is stage IV or has come back. RO4929097 and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT01193881 Recurrent Non-Small Cell Lung Carcinoma Stage IV Non-Small Cell Lung Cancer Drug: Erlotinib Hydrochloride Drug: Gamma-Secretase Inhibitor RO4929097 Other: Laboratory Biomarker Analysis Other: Pharmacological Study
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

(Expansion cohort) SECONDARY OBJECTIVES: I. To perform a preliminary exploratory assessment of whether probability of detectable tumor shrinkage/response correlates with pre RO4929097 presence in tumor of an activating epidermal growth factor receptor (EGFR) mutation, the T790M EGFR mutation, met proto-oncogene (c-MET) gene amplification or insulin-like growth factor 1 receptor (IGF-1R) expression or activation or various Notch pathway markers. --- T790M ---

Conduct a preliminary exploratory assessment on the expansion cohort with respect to tumor shrinkage/response of the following over the first 2 cycles of erlotinib and RO4929097 treatment with and without the presence of mutation, amplification, and activation of markers: tumor IHC scores and RPPA expression of the Notch ligand jagged 1 (Jag1), and the Notch targets hairy and enhancer of split 1 (HES1), hairy/enhancer-of-split related with YRPW motif protein 1 (HEY1); tumor IHC scores and RPPA expression of putative stem cell markers cluster of differentiation (CD)24 (decreased in stem cells), CD44, CD133, dehydrogenase and of the epithelial to mesenchymal transition (EMT) markers E-cadherin and vimentin; detectability in tumor of EGFR T790M mutations, MET amplification, and IGF-1R expression and activation; and soluble markers of angiogenesis, including stromal cell-derived factor 1 alpha (SDF-1alpha), basic fibroblastic growth factor (bFGF), cryptic epitope of collagen IV, interleukin (IL)-6, IL-8, vascular endothelial growth factor (VEGF). --- T790M ---

Conduct a preliminary exploratory assessment of whether percent tumor shrinkage/response or time to progression correlates with pre-therapy IHC and RPPA expression of Notch 1, 2, 3 and 4, the above Notch pathway and stem cell markers, with baseline detectability of T790M mutations and MET amplification, and with baseline IGF-1R expression and activation, and with change in these markers from the initial biopsy to the subsequent biopsy. --- T790M ---

Primary Outcomes

Measure: Incidence of adverse events assessed using NCI CTCAE version 4.0 (Dose escalation phase)

Time: Within 30 days of last drug dose

Measure: Maximum-tolerated dose of RO4929097 and erlotinib hydrochloride defined as the highest dose tested causing dose limiting toxicity in < 2/6 patients assessed using National Cancer Institute (NCI) CTCAE version 4.0 (Dose escalation phase)

Time: At least 3 weeks after day 1 of course 1

Description: The differences before and after treatment will be assessed using a paired-t test on the log-transformed tumor sizes and a Wilcoxon signed-rank test.

Measure: Percentage of change in expression of Notch and other tumor and blood biomarkers (Expansion cohort)

Time: Baseline to 6 weeks

Description: Will be correlated with response and baseline expression of biomarkers. The differences before and after treatment will be assessed using a paired-t test on the log-transformed tumor sizes and a Wilcoxon signed-rank test.

Measure: Percentage of tumor shrinkage (Expansion cohort)

Time: Up to 6 weeks

Measure: Response rate by RECIST 1.1 (Expansion cohort)

Time: Up to 12 weeks

Description: Will be correlated with baseline expression or biomarkers.

Measure: Time to progression (Expansion cohort)

Time: Up to 12 weeks

Other Outcomes

Measure: Efficacy of this combination in unselected patients and in patients with intrinsic or acquired erlotinib resistance (Dose escalation phase)

Time: Up to 12 weeks

Description: Correlations between Notch pathway gene polymorphisms and tumor and blood biomarkers will be assessed. Correlations between Notch pathway gene polymorphisms and tumor shrinkage/response on therapy will also be assessed.

Measure: Host Notch pathway gene polymorphisms

Time: Up to 6 weeks

Description: Exploratory assessments of correlations of tumor shrinkage and response on the combination with pre-therapy tumor expression of Notch and other tumor and blood biomarkers will be conducted.

Measure: Pre-therapy tumor expression of Notch and other tumor and blood biomarkers (Dose escalation phase)

Time: Baseline

Description: Correlations between Notch pathway markers and stem cell markers will be assessed.

Measure: Stem cell markers

Time: Up to 6 weeks

14 A Phase I/II Trial of Hsp 90 Inhibitor AUY-922 in Patients With Lung Adenocarcinoma With "Acquired Resistance" to EGFR Tyrosine Kinase Inhibitors

Hsp90 inhibitor AUY922 and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. This phase I/II trial is studying the side effects and best dose of Hsp90 inhibitor AUY922 when given together with erlotinib hydrochloride and to see how well it works in treating patients with stage IIIB-IV non-small cell lung cancer.

NCT01259089 Adenocarcinoma of the Lung Non-small Cell Lung Cancer Drug: erlotinib hydrochloride Drug: Hsp90 inhibitor AUY922 Other: laboratory biomarker analysis Procedure: needle biopsy Genetic: mutation analysis Other: pharmacological study
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung Adenocarcinoma Adenocarci Adenocarcinoma of Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Overall survival (OS) is defined as the time from treatment initiation until death due to any cause.. Overall Survival Among Patients With Acquired Resistance With T790M Mutations (Phase II). --- T790M ---

Overall Survival (OS) will be measured from treatment initiation until death due to any cause for patients with acquired resistance with T790M mutations in the phase II portion of the study.. Inclusion Criteria: - All patients must have pathologic evidence of advanced lung adenocarcinoma (stage IIIB or stage IV) confirmed histologically/cytologically at NU, MSKCC, or DFCI and EITHER previous RECIST-defined response (CR or PR) to an EGFR-TKI (erlotinib or gefitinib) or an investigational EGFR TK inhibitor OR a documented mutation in the EGFR gene (G719X, exon 19 deletion, L858R, L861Q) - Radiographic progression by RECIST during treatment with erlotinib/gefitinib - Received treatment with erlotinib/gefitinib throughout the one month prior to enrollment and at least six months at any time - Measurable (RECIST) indicator lesion not previously irradiated - Must have undergone a biopsy after the development of acquired resistance - Karnofsky Performance Status >= 70% OR ECOG/WHO Performance Status 0-1 - Signed informed consent - Effective contraception and negative serum pregnancy test obtained within two weeks prior to the first administration of AUY922 in all pre-menopausal women (ie., last menstrual period =< 24 months ago) and women < 2 years after onset of menopause; menopause is defined as the time at which fertility ceases, where a woman has had no menstruation for > 24 months - Total bilirubin =< 1.5 x Upper Limit of Normal (ULN) - AST/SGOT and ALT/SGPT =< 3.0 x ULN, or =< 5.0 x ULN if liver metastasis present - Absolute neutrophil count (ANC) >= 1.5 x10^9/L - Hemoglobin (Hgb) >= 9g/dL - Platelets (plts) >= 100 x 10^9/L - Serum creatinine =< 1.5 x ULN or 24 hour clearance >= 50 mL/min Exclusion Criteria: - Symptomatic CNS metastases which are symptomatic and /or requiring escalating doses of steroids - Prior treatment with any HSP90 inhibitor compounds - Conventional chemotherapy, radiation or monoclonal antibodies within 4 weeks (erlotinib/gefitinib therapy within the past 4 weeks IS allowed) - Palliative radiation within 2 weeks - Unresolved diarrhea >= CTCAE grade 2 - Pregnant or lactating women - Women of childbearing potential (WCBP) (i.e. --- T790M ---

Primary Outcomes

Description: To determine the maximally tolerated dose (MTD), and recommended phase II dose of AUY922 when given in combination with erlotinib for patients with acquired resistance to erlotinib. (Phase I) Escalation of dose will be in a 3+3 design. If no dose limiting toxicities (DLTs) are seen in 3 patients enrolled at that dose level, then dose will be escalated to the next dose level and the next 3 patients will be enrolled at that dose. Alternatively, if 1 DLT is seen in 3 patients at that dose level, 3 more patients will be added at that same dose level. If 1 DLT is seen in 6 patients at that dose level, MTD will be determined to be at that dose. If more than 1 DLT is seen at that dose level, then the prior lower dose level will be the considered the MTD. DLT is defined as any of the following related to the investigational agent: Death and grade 3 and 4 specific hematological and non-hematological toxicities defined in the protocol.

Measure: Maximally Tolerated Dose (MTD) of AUY922 and Erlotinib Treatment Combination (Phase I)

Time: During the first 4 weeks of treatment for each patient.

Description: Overall response rate (ORR) will be measured per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT scan or MRI: Complete response (CR) defined as disappearance of all target lesions. Partial Response (PR), defined as >=30% decrease in the sum of the longest diameter of target lesions. Stable Disease (SD) defined as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study. Progressive Disease (PD) defined as having at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions

Measure: Overall Response Rate (ORR), Defined as Complete Response(CR) + Partial Response (PR) Using the Modified RECIST 1.1 Criteria for All Patients Treated at Dose of 70mg/m2 AUG922

Time: At 8 weeks from treatment initiation

Secondary Outcomes

Description: To characterize the toxicity profile for the combination of erlotinib and AUY922. Toxicity data will be collected every week for the first 28 day cycle and then every two weeks during treatment and up to 28 days after the last treatment. Adverse events will be graded according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 4.0 (CTCAE v4.0). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE

Measure: Toxicity as Assessed by NCI CTCAE Version 4.00 When AUG922 Administered at Its MTD (Phase I and II)

Time: At weeks 1 through 4 and then every 2 weeks during treatment and 30 days post last treatment for up to 2 years and half years

Description: Adverse events will be collected weekly for the first 28 day cycle and then every two weeks during treatment and up to 28 days after the last treatment. Adverse events will be graded according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 4.0 (CTCAE v4.0). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE

Measure: Incidence of Reported Adverse Events in Phase I

Time: At weeks 1 through 4 and then every 2 weeks during treatment and 30 days post last treatment, for up to 2 years and half years

Description: Median Progression Free Survival (PFS) will be calculated from time of treatment initiation until the first documentation of progressive disease. Patients will be considered to have progressive disease when CT scan or MRI show at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Measure: Progression-free Survival (Phase II)

Time: From the time of first treatment with AUY922 to disease progression for up to 2 years post treatment

Description: Overall survival (OS) is defined as the time from treatment initiation until death due to any cause.

Measure: Overall Survival (Phase II)

Time: From the time of first treatment with AUY922 to death, followed up to 2 years post treatment

Description: Overall Survival (OS) will be measured from treatment initiation until death due to any cause for patients with acquired resistance with T790M mutations in the phase II portion of the study.

Measure: Overall Survival Among Patients With Acquired Resistance With T790M Mutations (Phase II)

Time: From the time of first treatment with AUY922 to death, followed for up to 2 years

15 Pilot Trial of Molecular Profiling and Targeted Therapy for Advanced Non-Small Cell Lung Cancer, Small Cell Lung Cancer, and Thymic Malignancies

Background: - The current standard of care for advanced lung cancer and cancers of the thymus consists primarily of chemotherapy treatment. The drugs used for chemotherapy depend on the classification of the cancer in different categories that are based on the appearance of the cancer in the microscope. Though this approach has been proved to be useful in some ways, the survival rates of individuals with lung cancer and cancers of the thymus are still very poor. Recent research has shown that several genetic abnormalities play an important role in the development and growth of lung cancer and cancers of the thymus, and that it is possible to improve treatment success rates with drugs that specifically target some of the abnormal genes. Researchers are interested in determining whether it is possible to analyze the genes of patients with lung cancer and cancers of the thymus in order to provide personalized treatment with drugs that target the specific gene abnormalities. Objectives: - To evaluate the effectiveness of genetic analysis in determining targeted therapy for individuals with advanced non-small cell lung cancer, small cell lung cancer, and thymic cancer. Eligibility: - Individuals at least 18 years of age who have been diagnosed with either lung cancer or a cancer of the thymus that is not considered to be curable with the use of surgery or radiation therapy. Design: - Participants will be screened with a full medical history and physical examination, blood and urine tests, and tumor imaging studies. Participants will have a tumor biopsy or provide previously collected tumor tissue for study. - Based on the results of the tumor biopsy study, participants will be separated into different treatment groups: - Participants with EGFR gene mutation will receive a drug called erlotinib, which inhibits a protein called EGFR that is thought to be a key factor in the development and progression of some cancers. - Participants with KRAS, BRAF, HRAS, or NRAF gene mutations will receive a drug called AZD6244, which inhibits a protein called MEK that is thought to be a key factor in the development and progression of some cancers. - Participants with PIK3CA, AKT, or PTEN gene mutations will receive a drug called MK-2206, which inhibits a protein called AKT that is thought to be a key factor in the development and progression of some cancers. - Participants with KIT or PDGFRA gene mutations will receive a drug called sunitinib, which inhibits some proteins that are thought to be key factors in the development and progression of some cancers, including kidney cancer. - Participants who have ERBB2 gene mutation or amplification will receive a drug called lapatinib, which inhibits some proteins that are thought to be key factors in the development and progression of some cancers, including breast cancer. - Participants who do not have any of the genetic abnormalities described above will be offered different options for treatment, including standard of care chemotherapy or treatment with investigational agents in a different research protocol. - After 6 weeks of treatment, participants will have imaging studies to evaluate the status of their cancer. Treatment will continue as long as participants tolerate the drugs and the disease does not progress. - Participants who benefit from the first treatment but eventually develop resistance and progression of their cancer will be offered the chance to have a second tumor biopsy and undergo a different treatment for their cancer.

NCT01306045 Carcinoma, Non-Small-Cell Lung Carcinoma, Small Cell Lung Carcinoma, Thymic Drug: AZD6244 Drug: MK-2206 Drug: Lapatinib Drug: Erlotinib Drug: Sunitinib Procedure: Molecular Profiling
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung Small Cell Lung Carcinoma Carcinoma, Small Cell Thymoma
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma Small cell lung carcinoma Thymoma

- Individuals are eligible for EGFR germline mutation testing if they have: - a personal history of invasive lung cancer or one of the pre-invasive histologies associated with the development of lung cancer and more than two affected family members with invasive lung cancer or one of the pre-invasive histologies associated with the development of lung cancer; OR - a first-degree relative with a known EGFR germline mutation (EGFR exon 20 T790M, exon 21 V843I, exon 21 R831C and exon 20 R776G). --- T790M ---

Primary Outcomes

Description: The feasibility rate for the trial will be evaluated by determining the percentage of enrolled patients with a successful molecular profile determined.

Measure: To determine the feasibility of the use of tumor molecular profiling and targeted therapies in the treatment of NSCLC, SCLC, and Thymic Malignancies

Time: 5 years

Description: Efficacy will be determined by assessing if patients who have treatment assigned on the basis of their molecular profiling results will exhibit reasonable response rates to the drug selected for their particular profile.

Measure: To estimate the response rate of molecular-profile directed treatments in NSCLC, SCLC, and Thymic Malignancies

Time: 5 years

16 An Open-Label Multicenter Study of Erlotinib (Tarceva®) as First Line Therapy Until and Beyond RECIST Progression in NSCLC Patients Who Harbour EGFR Mutations

This open-label, single arm study will evaluate the safety and efficacy of Tarceva (erlotinib) as first-line therapy in participants with stage IV or recurrent non-small cell lung cancer who harbour epidermal growth factor receptor (EGFR) mutations. All participants will receive Tarceva 150 mg daily orally until disease progression or unacceptable toxicity occurs. At the investigator's discretion, participants may receive Tarceva beyond disease progression.

NCT01310036 Non-Squamous Non-Small Cell Lung Cancer Drug: Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

This outcome measure was not assessed.. Inclusion Criteria: - Adult participants, >/= 18 years of age - Stage IV or recurrent non-small cell lung cancer (NSCLC) - Presence of mutation(s) in exon 18 through exon 21 of epidermal growth factor receptor (EGFR), (except T790M single mutation only) - Measurable disease (at least one lesion >= 10 mm in longest diameter) - Eastern Cooperative Oncology Group (ECOG) performance status 0-2 - Adequate hematological, renal and liver function Exclusion Criteria: - Patients with T790M single mutation only - Prior exposure to agents directed at the human epidermal receptor (HER) axis, e.g. --- T790M ---

This outcome measure was not assessed.. Inclusion Criteria: - Adult participants, >/= 18 years of age - Stage IV or recurrent non-small cell lung cancer (NSCLC) - Presence of mutation(s) in exon 18 through exon 21 of epidermal growth factor receptor (EGFR), (except T790M single mutation only) - Measurable disease (at least one lesion >= 10 mm in longest diameter) - Eastern Cooperative Oncology Group (ECOG) performance status 0-2 - Adequate hematological, renal and liver function Exclusion Criteria: - Patients with T790M single mutation only - Prior exposure to agents directed at the human epidermal receptor (HER) axis, e.g. --- T790M --- --- T790M ---

erlotinib, gefitinib, cetuximab, trastuzumab - Prior chemotherapy or systemic anti-cancer therapy for advanced NSCLC disease - Symptomatic or uncontrolled central nervous system (CNS) metastases - Other malignancy within the last 5 years, except for carcinoma in situ of the cervix, or basal or squamous cell carcinoma of the skin, or surgically treated localized prostate cancer, or surgically treated ductal cell carcinoma in situ of the breast - Any significant ophthalmologic abnormality - Pre-existing parenchymal lung disease such as pulmonary fibrosis - Use of coumarins (for anti-coagulation therapy the use of low molecular weight heparin is recommended instead) Inclusion Criteria: - Adult participants, >/= 18 years of age - Stage IV or recurrent non-small cell lung cancer (NSCLC) - Presence of mutation(s) in exon 18 through exon 21 of epidermal growth factor receptor (EGFR), (except T790M single mutation only) - Measurable disease (at least one lesion >= 10 mm in longest diameter) - Eastern Cooperative Oncology Group (ECOG) performance status 0-2 - Adequate hematological, renal and liver function Exclusion Criteria: - Patients with T790M single mutation only - Prior exposure to agents directed at the human epidermal receptor (HER) axis, e.g. --- T790M ---

erlotinib, gefitinib, cetuximab, trastuzumab - Prior chemotherapy or systemic anti-cancer therapy for advanced NSCLC disease - Symptomatic or uncontrolled central nervous system (CNS) metastases - Other malignancy within the last 5 years, except for carcinoma in situ of the cervix, or basal or squamous cell carcinoma of the skin, or surgically treated localized prostate cancer, or surgically treated ductal cell carcinoma in situ of the breast - Any significant ophthalmologic abnormality - Pre-existing parenchymal lung disease such as pulmonary fibrosis - Use of coumarins (for anti-coagulation therapy the use of low molecular weight heparin is recommended instead) Inclusion Criteria: - Adult participants, >/= 18 years of age - Stage IV or recurrent non-small cell lung cancer (NSCLC) - Presence of mutation(s) in exon 18 through exon 21 of epidermal growth factor receptor (EGFR), (except T790M single mutation only) - Measurable disease (at least one lesion >= 10 mm in longest diameter) - Eastern Cooperative Oncology Group (ECOG) performance status 0-2 - Adequate hematological, renal and liver function Exclusion Criteria: - Patients with T790M single mutation only - Prior exposure to agents directed at the human epidermal receptor (HER) axis, e.g. --- T790M --- --- T790M ---

Primary Outcomes

Description: PFS1 was defined as time from first dose until documented progressive disease (PD), assessed per Response Evaluation Criteria in Solid Tumors RECIST, v. 1.1, or death from any cause, whichever occurred first. PD was defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; and the appearance of one or more new lesions.

Measure: Progression-free Survival Per RECIST, v. 1.1 (PFS1)

Time: Approximately 68 months

Secondary Outcomes

Description: PFS2 was defined as time from first study dose to off-erlotinib progressive disease (PD), assessed by the investigator based on overall clinical evaluation.

Measure: Progression-free Survival Per Investigator (PFS2)

Time: Approximately 68 months

Description: ORR was defined as the occurrence of either a confirmed complete (CR) or a partial response (PR, as a best overall response), as determined by RECIST, v. 1.1 criteria. CR was defined as disappearance of all target lesions. PR was defined as least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.

Measure: Objective Response Rate (ORR) for All Participants and Participants With EGFR Mutation E19del or L858R

Time: Approximately 68 months

Description: DCR was defined as CR + PR + Stable disease (SD). CR was defined as disappearance of all target lesions. PR was defined as least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. PD was defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; and the appearance of one or more new lesions.

Measure: Disease Control Rate (DCR) for All Participants and Participants With EGFR Mutation E19del or L858R

Time: Approximately 68 months

Description: PFS1 was defined as time from first dose until documented progressive disease (PD), assessed per Response Evaluation Criteria in Solid Tumors RECIST, v. 1.1, or death from any cause, whichever occurred first. PD was defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; and the appearance of one or more new lesions.

Measure: Progression-free Survival for Participants With EGFR Mutation E19del or L858R Per RECIST, v. 1.1 (PFS1)

Time: Approximately 68 months

Description: OS was defined as the time from baseline to the date of death from any cause.

Measure: Overall Survival (OS) for All Participants and Participants With EGFR Mutation E19del or L858R

Time: Approximately 68 months

Description: An adverse event is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not considered related to the study drug.

Measure: Number of Participants With Adverse Events

Time: Approximately 68 months

Description: This outcome measure was not assessed.

Measure: Correlation Between EGFR Mutations in Plasma and Clinical Outcome (ORR/PFS/OS)

Time: Approximately 68 months

17 A Randomized, Open-label Trial of Gefitinib Versus Combination of Vinorelbine Plus Platinum as Adjuvant Treatment in Pathological Stage II-IIIA(N1-N2) Non-small Cell Lung Cancer With EGFR Mutation

Activating somatic mutations of the tyrosine kinase domain of epidermal growth factor receptor (EGFR) have been characterized in a subset of patients with advanced NSCLC.The EGFR mutation rate was 30% in Chinese Non-small Cell Lung Cancer(NSCLC). Patients harboring these mutations in their tumors show excellent response to EGFR tyrosine kinase inhibitors (EGFR-TKIs). This randomized phase III trial is studying gefitinib to see how well it works compared to cisplatin-based chemotherapy in treating patients who have undergone surgery for stage II-IIIA(N1-N2) NSCLC with EGFR activating mutation in Asian population.

NCT01405079 Non-small Cell Lung Cancer Drug: Gefitinib Drug: Vinorelbine+Cisplatin
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

pyrexia of or 38.0℃ over) - Patients who harbouring exon 20 T790M mutation. --- T790M ---

Primary Outcomes

Description: To evaluate the disease free survival of gefitinib versus combination of vinorelbine plus platinum as adjuvant treatment for pathological stage II-IIIA(N1-N2) NSCLC with EGFR mutation.Disease free survival (DFS)- defined as the time from randomization to the first documented disease progression or death, whichever occurs first.

Measure: Disease free survival

Time: Pts after surgery will receive long-term follow-up including chest CT scan, abdominal ultrasound every 3 months, brain MRI every 6 months, bone scan every 12 months for up to 3 years. The survival after 3 years will be followed up with telephone.

Secondary Outcomes

Description: To evaluate the overall survival of gefitinib versus combination of vinorelbine plus platinum as adjuvant treatment for stage II-IIIA(N1-N2) NSCLC with EGFR mutation.

Measure: Overall survival

Time: Pts after surgery will receive long-term follow-up including chest CT scan, abdominal ultrasound every 3 months, brain MRI every 6 months, bone scan every 12 months for up to 3 years. The survival after 3 years will be followed up with telephone.

Description: To compare the randomized treatment arms in terms of 3 yeas DFS rate, 5 years DFS rate, 5 years OS rate.

Measure: 3 yeas DFS rate, 5 years DFS rate, 5 years OS rate

Time: Pts after surgery will receive long-term follow-up including chest CT scan, abdominal ultrasound every 3 months, brain MRI every 6 months, bone scan every 12 months for up to 3 years. The survival after 3 years will be followed up with telephone.

Description: The safety and tolerability profile of gefitinib at a 250 mg daily dose relative to that of Chemotherapy.

Measure: Number of Participants with Adverse Events

Time: In the period of Gefitinib 250 mg/day oral daily for 24 months.Vinorelbine 25 mg/m2 intravenous infusion on day 1 and day 8, Cisplatin 75 mg/m2 on day 1 for 4 cycles.

Description: Quality of life as measured by the total score and Trial Outcome Index (TOI) of the Functional Assessment of Cancer Therapy - Lung Cancer (FACT-L) questionnaire.

Measure: The Total Score and TOI of FACT-L to Measure Quality of life

Time: In the period of Gefitinib 250 mg/day oral daily for 24 months.Vinorelbine 25 mg/m2 intravenous infusion on day 1 and day 8, Cisplatin 75 mg/m2 on day 1 for 4 cycles.

18 Trial of Afatinib (BIBW 2992) in Suspected or Confirmed Mutant EGFR Lung Cancer Patients Unfit for Chemotherapy

The purpose of this study is to examine the efficacy and safety of using afatinib (BIBW 2992) to treat non-small cell lung cancer patients considered unfit for chemotherapy and have either suspected or confirmed Epidermal Growth Factor Receptor (EGFR) mutation.

NCT01415011 Carcinoma, Non-Small-Cell Lung Drug: Afatinib (BIBW 2992)
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

L858R, exon 19 deletions, exon 20 insertions, T790M, list is not exhaustive), and WHO PS 0-3 Or No tissue suitable for EGFR genotyping, failed genotype, or EGFR genotyping unavailable, and NSCLC Adenocarcinoma sub-type, and Eligible smoking history: Never smoker (<100 cigarettes in lifetime), or Former smoker (stopped >1year ago and ≤10 pack-years) and WHO PS 0-2 - Unsuitable for or patient declining chemotherapy due to significant co-morbidity - Measurable disease according to RECIST version 1.1 - Adequate haematopoietic, hepatic and renal function defined as follows: Absolute neutrophil count (ANC) ≤1.5 x 109/L and platelet count ≤100 x 109/L - Bilirubin ≤1.5 x ULN, ALT (SGPT) ≤3 x ULN (or ≤ 5 x ULN in cases of liver metastases) - Serum creatinine clearance ≥45 ml/min - Palliative radiotherapy allowed unless to a solitary target lesion - Age 18 or over (no upper age limit) - Written informed consent that is consistent with ICH-GCP guidelines Exclusion Criteria: - Previous treatment with afatinib (BIBW 2992), or any EGFR-directed inhibitor - Any concurrent anticancer systemic therapy - Prior chemotherapy for relapsed and/or metastatic NSCLC - Neoadjuvant/adjuvant chemotherapy is permitted if at least 12 months has elapsed between the end of chemotherapy and registration - Suitable for radical radiotherapy - Palliative radiotherapy within 2 weeks prior to registration - Palliative radiotherapy to a solitary target lesion - Surgery (other than biopsy) within 4 weeks prior to registration - Inability to take oral medication, requirement for intravenous feeding, active peptic ulcer, prior surgical procedures affecting absorption, any medical co- morbidity affecting gastrointestinal absorption - Patients with current or pre-existing interstitial lung disease - Active or uncontrolled infections or serious illnesses or medical conditions that could interfere with the patient's participation in the trial - Significant or recent acute gastrointestinal abnormalities with diarrhoea as a major symptom e.g., Crohn's disease, mal-absorption, or CTCAE version 4.0 Grade ≥3 diarrhoea of any etiology at baseline - Active brain metastases (defined as stable for <4 weeks and/or symptomatic and/or requiring treatment with anticonvulsants and/or leptomeningeal disease). --- L858R --- --- T790M ---

In ~50% of cases this is due to the gefitinib/erlotinib-resistant T790M genotype acquired through either secondary somatic mutation or clonal expansion. --- T790M ---

Primary Outcomes

Description: Progression free survival will be determined by measurement of tumour size using RECIST version 1.1 at progression or date of patient death.

Measure: Progression free survival

Time: At 6 months

Secondary Outcomes

Measure: Overall response

Time: CT scan of chest & abdomen 4 weeks after registartion, then every 8 calender weeks until disease progression. CT scans every 12 weeks if patient is still on BIBW 2992 after 1 year of treatment.

Measure: Overall survival

Time: This will be measured in days, from the first day of treatment to the day of death.

Measure: Change in performance status

Time: At 1 month

Description: For each type of adverse event, the maximum toxicity grade will be obtained for each patient using CTCAE version 4.0 to closely monitor tolerability to BIBW 2992. Focus will be on those with a grade 3 or 4 BIBW 2992 related toxicities. The proportion of patients with any grade 3 or 4 event will also be examined.

Measure: Safety

Time: To be assessed at every timepoint i.e. baseline, fortnightly for the first 2 cycles and then monthly for 12 months and 2 monthly thereafter

Measure: Progression free survival in patients aged 70 and over

Time: At progression or patient death

Measure: Treatment compliance

Time: Compliance will be examined based on the time between starting treatment and stopping it completely

19 A Phase 1, Open-Label, Dose Escalation Study to Evaluate Safety, Pharmacokinetics and Pharmacodynamics of Combined Oral C-Met/ALK Inhibitor (PF-02341066) and Pan-Her Inhibitor (PF-0299804) in Patients With Advanced Non-Small Cell Lung Cancer

Background: - PF-02341066 and PF-00299804 are drugs that specifically target certain proteins that may be more active in cancer cells than normal cells, in particular in non-small cell lung cancer. Both drugs seem to be able to stop the growth of or kill cancer cells. Researchers want to combine them to see if they are a safe and effective treatment for advanced non-small cell lung cancer. Objectives: - To test the safety and effectiveness of PF-02341066 and PF-00299804 for advanced non-small cell lung cancer. Eligibility: - Individuals at least 18 years of age with advanced non-small cell lung cancer that has not responded to standard treatments. Design: - Participants will be screened with a medical history and physical exam. They will also have blood and urine tests, and imaging studies. Heart and lung function tests and an eye exam may also be given. - The first cycle of treatment will be 28 days. Every cycle after the first will be 21 days. Participants may have up to 17 cycles of treatment. - Participants will take both study drugs as tablets. Twelve hours after the first dose, participants will take only the PF-02341066. This dose schedule will remain the same throughout the study. - Participants will be monitored with frequent blood and urine tests and imaging studies. Tumor biopsies will be taken as needed. Those in the study will keep a diary to record any symptoms or side effects of taking the study drugs. - After 17 cycles of treatment, or after stopping the study drugs early for any other reason, participants will have a final followup visit.

NCT01441128 Carcinoma, Non-Small Cell Lung Adenocarcinoma Carcinoma, Squamous Cell Carcinoma, Large Cell Drug: PF-02341066/PF-00299804 Drug: PF-02341066/PF-00299804
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung Adenocarcinoma Carcinoma, Squamous Cell Carcinoma, Large Cell
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma Squamous cell carcinoma

Biomarkers in tumor and blood that are potentially predictive for drug activity: for example, KRAS mutations, EGFR mutations (eg, T790M), EGFR and HER2 amplifications, c Met amplification and mutations, ALK, PTEN and PIK3A status in tumor biopsi.... null. --- T790M ---

- Despite the dramatic initial response to gefitinib and erlotinib, about 50% of NSCLC tumors develop resistance due to secondary activating mutations in EGFR itself, including the EGFR T790M gatekeeper mutation, and more than 20% of acquired resistance is due to an increase in mesenchymal-epithelial transition factor (c-Met) signaling. --- T790M ---

- There is evidence from a limited number of tumors from patients with acquired resistance to EGFR-TKIs that both T790M and cMET resistance mechanisms can occur in the same patient at different metastatic sites and even in different fractions of the same lesion. --- T790M ---

- Tumors with acquired resistance to erlotinib and gefitinib might be vulnerable to a combination of PF-00299804 a second generation EGFR TKI which is also an inhibitor of T790M mutation, and PF-02341066 which is an inhibitor of c- Met/Hepatocyte Growth Factor Receptor (HGFR). --- T790M ---

Primary Outcomes

Measure: Overall safety profile of combined PF 02341066 plus PF 00299804 including adverse events (AE), as defined and graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], and first cycle Dose Limiting Tox...

Time: 18 months

Secondary Outcomes

Measure: Plasma concentrations and pharmacokinetic (PK) parameters of PF 02341066 and PF 00299804 including AUCtau, Cmax, Ctrough, Tmax, and CLss/F

Time: 18 months

Measure: Clinical activity of combined PF 02341066 plus PF 00299804 including objective response (OR) and stable disease (SD) as defined by RECIST version 1.1, duration of response (DR) and progression free survival (PFS).

Time: 18 months

Measure: Biomarkers in tumor and blood that are potentially predictive for drug activity: for example, KRAS mutations, EGFR mutations (eg, T790M), EGFR and HER2 amplifications, c Met amplification and mutations, ALK, PTEN and PIK3A status in tumor biopsi...

Time: 12 months

Measure: Pharmacodynamic biomarkers in tumor biopsies (e.g., phospho c Met, c Met, EGFR, phospho EGFR) and in blood (e.g., HGF and s Met) that are modulated following drug exposure.

Time: 12 months

20 A Phase 1/2 Study of the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-Tumor Activity of the Oral ALK/EGFR Inhibitor AP26113

The purpose of this study is 2-fold: initially, in the dose escalation phase, the goal is to determine the safety profile of orally administered brigatinib, including: the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), recommended phase 2 dose (RP2D), and pharmacokinetic (PK) profile. Then, once the RP2D is established, an expansion phase will assess the preliminary anti-tumor activity of brigatinib, both in non-small cell lung cancer (NSCLC) with ALK gene rearrangement (including participants with active brain metastases) or mutated EGFR, and in other cancers with abnormal targets against which brigatinib is active.

NCT01449461 Lymphoma, Large-Cell, Anaplastic Carcinoma, Non-Small-Cell Lung Drug: Brigatinib
MeSH:Lymphoma Carcinoma, Non-Small-Cell Lung Lymphoma, Large-Cell, Anaplastic
HPO:Anaplastic large-cell lymphoma Lymphoma Non-small cell lung carcinoma

Resistant to crizotinib (and have not received any other prior ALK inhibitor therapy); 3. Expansion cohort 3: NSCLC participants whose tumors exhibit an epidermal growth factor receptor EGFR-T790M mutation and who are resistant to 1 prior EGFR TKI: i. Histologically or cytologically confirmed NSCLC ii. --- T790M ---

Documented evidence of an EGFR-T790M mutation following disease progression on the most recent EGFR TKI therapy; iv. --- T790M ---

Primary Outcomes

Description: The RP2D is the maximum tolerated dose (MTD) or less. The MTD is defined as the dose range at which ≤ 1 of 6 evaluable participants experience dose limiting toxicities (DLT) within the first 28 days of treatment (end of cycle 1).

Measure: Recommended Phase 2 Dose of Brigatinib

Time: 28 days

Description: ORR assessed by the investigator, is defined as the proportion of the participants with complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid tumors (RECIST) v1.1 after the initiation of study treatment. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and normalization of tumor marker level. PR: at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline sum diameters. Crzb=Crizotinib.

Measure: Objective Response Rate (ORR)

Time: Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)

Secondary Outcomes

Description: An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.

Measure: Number of Participants Who Had at Least One Treatment-Emergent Adverse Event (TEAE)

Time: Any adverse event reported on or after the day of first dose of study drug (approximately up to 50 months)

Description: The MTD is defined as the highest dose at which ≤ 1 of 6 evaluable participants experience a DLT within the first 28 days of treatment (end of cycle 1). Evaluable participants must complete at least 75% of their planned doses, unless missed doses are due to AEs. The cohort may be expanded to better define the safety profile for confirmation of the MTD. The maximum administered dose in the trial will likely exceed the MTD.

Measure: Maximum Tolerated Dose (MTD) Assessed in Dose Escalation Phase of the Study

Time: Up to Cycle 1 (28 days)

Description: DLT include any toxicity that is possibly, probably, or definitely drug-related. Toxicity grades will be defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 4.0. DLTs are defined by the following: A) Non-hematologic toxicities: Any grade ≥3 non-hematologic toxicity, with the exception of self-limiting or medically controllable toxicities (eg, nausea, vomiting, fatigue, electrolyte disturbances, hypersensitivity reactions) lasting < 3 days, and excluding alopecia. B) Hematologic toxicities: Febrile neutropenia not related to underlying disease (fever, > 101°F; ANC<500); Prolonged grade 4 neutropenia (> 7 days); Neutropenic infection: ≥ grade 3 neutropenia with ≥ grade 3 infection; Thrombocytopenia ≥ grade 3 with bleeding or grade 4 lasting ≥ 7 days. C) Missed ≥ 25% of planned doses of brigatinib over 28 days due to treatment-related AEs in the first cycle.

Measure: Number of Participants With Dose Limiting Toxicities (DLTs) Assessed in Dose Escalation Phase of the Study

Time: Up to Cycle 1 (28 days)

Measure: Cmax: Maximum Observed Plasma Concentration for Brigatinib

Time: Cycle 1 Day 1

Measure: Cmax: Maximum Observed Plasma Concentration for Brigatinib

Time: Cycle 2 Day 2

Measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Brigatinib

Time: Cycle 1 Day 1

Measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Brigatinib

Time: Cycle 2 Day 1

Measure: AUC(0-24): Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours Post-dose for Brigatinib

Time: Cycle 1 Day 1, 8, 15 and 22 pre-dose and Day 1 multiple timepoints (up to 48 hours) post-dose; Cycle 2 Day 1 and 3 pre-dose and Day 1 multiple time points (up to 48 hours) post-dose

Measure: Terminal Phase Elimination Half-life (T1/2) for Brigatinib

Time: Cycle 2 Day 1

Description: Best overall response is defined as proportion of participants with CR, PR, stable disease (SD) or progressive disease (PD) as per of RECIST v1.1 as evaluated by investigator. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and normalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters. Disease progression for target lesion: SLD increased by at least 20% from smallest value on study and SLD must also demonstrate an absolute increase of at least 5 mm or development of any new lesion. PD for non-target lesion: unequivocal progression of existing non-target lesions. SD for neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Measure: Best Overall Response

Time: Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)

Description: Duration of response is defined as time interval from the time that measurement criteria are first met for CR/PR (whichever is first recorded) until first date that progressive disease is objectively documented or death due to any cause. Participants who did not progress nor die were censored at last valid response assessment. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and normalization of tumor marker level. PR: at least a 30% decrease in SLD of target lesions. PD for target lesion: SLD increased by at least 20% from smallest value and must also demonstrate an absolute increase of at least 5 mm or development of any new lesion. PD for non-target lesion: unequivocal progression of existing non-target lesions.

Measure: Duration of Response

Time: Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)

Description: PFS is defined as the time interval from the date of the first dose of the study treatment until the first date at which disease progression is objectively documented, or death due to any cause, whichever occurs first. Disease progression for target lesion: SLD increased by at least 20% from the smallest value on study (including baseline, if that is the smallest) and SLD must also demonstrate an absolute increase of at least 5 mm or development of any new lesion. Disease progression for non-target lesion: Unequivocal progression of existing non-target lesions. (Subjective judgment by experienced reader). PFS was calculated by Kaplan-Meier estimation.

Measure: Progression Free Survival (PFS)

Time: Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)

Description: OS is defined as the time interval from the date of the first dose of the study treatment until death due to any cause.

Measure: Overall Survival (OS)

Time: Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)

Description: Intracranial objective response rate is defined as the proportion of the participants with CR or PR in the intracranial CNS per modification of RECIST v1.1 after the initiation of study drug. CR for target lesion: disappearance of all extranodal lesions. CR for non-target lesion: disappearance of all extranodal non-target lesions and normalization of tumor marker level. PR: at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline sum diameters. Meta.=Metastases.

Measure: Intracranial Objective Response Rate

Time: Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)

Description: Intracranial duration of response is defined as the time interval from the time that the measurement criteria are first met for CR/PR in brain metastases (whichever is first recorded) until the first date that progressive disease is objectively documented or death due to any cause. Participants who did not progress nor die were censored at the last valid response assessment. Duration intracranial of response was calculated by Kaplan-Meier estimation.

Measure: Duration of Intracranial Response

Time: Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)

Description: PFS is defined as the time interval from the date of the first dose of the study treatment until the first date at which disease progression in brain, or death due to any cause, whichever occurs first. Intracranial PFS was calculated by Kaplan-Meier estimation.

Measure: Intracranial Progression Free Survival (PFS)

Time: Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)

21 A Phase II Trial of Gefitinib in Squamous NSCLC Patients Who Failed First-Line Chemotherapy

Gefitinib was the first epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC). Results from two randomised phase II trials (IDEAL 1 and 2) suggested that gefitinib was efficacious and less toxic, compared with previous results, than was chemotherapy in patients with previously-treated non-small-cell lung cancer. Two phase III trials of gefitinib in advanced non-small-cell lung cancer followed on from the IDEAL phase II studies: Iressa Survival Evaluation in Lung cancer (ISEL) and Iressa NSCLC Trial Evaluating REsponse and Survival versus Taxotere (INTEREST). Although the phase III ISEL trial failed to prove the superiority of gefitinib treatment compared to placebo in previously treated patients, a subgroup analysis demonstrated improved survival in particular populations (Asians and non-smokers). The INTEREST study compared an EGFR tyrosine kinase inhibitor with chemotherapy in pretreated advanced non-small-cell lung cancer. In INTEREST, survival was similar for gefitinib and docetaxel in almost all subgroups; no EGFR-related biomarker or any clinical factor (including female sex, adenocarcinoma histology, never-smoker, and Asian ethnicity) appeared to be predictive of a greater survival benefit for gefitinib versus docetaxel. However, these factors may still be predictive of a greater survival benefit for gefitinib and/or docetaxel versus best supportive care; alternatively, they may just be good prognostic factors. Progression free survival and overall response rate was no statistically significant difference between gefitinib and docetaxel. This suggests gefitinib can provide similar overall survival to docetaxel in pretreated advanced non-small-cell lung cancer patients. These studies have demonstrated that gefitinib is effective for the second-line treatment of NSCLC. Now, gefitinib is recommended in advanced and metastatic NSCLC as second-line chemotherapy. But, there was no prospective study with gefitinib in NSCLC wih squamous cell histology. This trial will investigate the efficacy and safety of gefitinib in locally advanced, metastatic NSCLC patients with squamous cell histology who have failed first-line chemotherapy.

NCT01485809 Squamous Cell Carcinoma of Bronchus Drug: Gefitinib
MeSH:Carcinoma, Bronchogenic

Presence of EGFR mutation reported to confer resistance to EGFR TKI: exon 20 point mutation (T790M or S768I EGFR) or exon 20 insertion 11. --- T790M ---

Primary Outcomes

Measure: Disease control rate (complete response, partial response, or stable disease) at 8 weeks

Time: 8 weeks

Secondary Outcomes

Description: safety & tolerability: NCI CTCAE version 4.0

Measure: number of participants with adverse events as a measure of safety and tolerability

Time: 2 years

22 Phase II Trial of Erlotinib and BKM120 in Patients With Advanced Non Small Cell Lung Cancer Previously Sensitive to Erlotinib

Preclinical data in lung cancer cell lines showed that EGFR mutation can potentially be a positive predictor for sensitivity to BKM120. Furthermore, when the erlotinib-resistant model H1975 (LR858 and T790M mutation) was treated with BKM120, significant tumor control was observed (Novartis internal data). Therefore, combining BKM120 with erlotinib could potentially down-modulate PI3K-Akt activity resulting in a synergistic effect on cell growth inhibition and enhancing the response to erlotinib.

NCT01487265 Non Small Cell Lung Cancer Drug: BKM120 and Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Furthermore, when the erlotinib-resistant model H1975 (LR858 and T790M mutation) was treated with BKM120, significant tumor control was observed (Novartis internal data). --- T790M ---

Primary Outcomes

Description: Percentage of patients who are alive and progression-free at 3 months (APF3) from first treatment.

Measure: Progression Free Survival at 3 Months

Time: 3 months

Secondary Outcomes

Description: Defined as the time from first treatment until death from any cause.

Measure: Overall Survival

Time: every 3 months after study treatment, projected 24 months

Description: Defined as the time from complete or partial response (CR or PR) until objective tumor progression. Tumor measurements will be obtained using CT scans of chest, abdomen and pelvis and assessed per RECIST v 1.1. Complete response (CR) is defined as a disappearance of all lesions; partial response (PR) is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking the baseline sum LD as reference. Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for progressive disease, taking as reference the smallest (nadir) sum LD since start of treatment.

Measure: Duration of Response

Time: every 8 weeks for 12 months, then every 12 weeks thereafter, estimated 18 months

Description: Defined as the percentage of complete and partial responses (CR + PR) among all patients. Complete response (CR) is defined as a disappearance of all lesions; partial response (PR) is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking the baseline sum LD as reference. Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for progressive disease, taking as reference the smallest (nadir) sum LD since start of treatment.

Measure: Objective Response Rate

Time: every 8 weeks for 12 months, then every 12 weeks thereafter, estimated 18 months

Description: Adverse events will be graded using CTCAE v4.3. and will be collected until 30 days after the discontinuation of study treatment for each participant. A non-serious adverse event is any untoward medical occurrence. A serious adverse event (SAE) is an event that meets one or more of the following: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; requires intervention to prevent permanent impairment or damage. Specific AE and SAE terms are provided in the Adverse event module.

Measure: Number of Participants With Serious and Non-serious Adverse Events as a Measure of Safety.

Time: Every 2 weeks for 8 weeks, then every 8 weeks thereafter, estimated 24 months

23 Multicenter, Randomized, Phase Ib/IIb Study to Evaluate the Efficacy and Tolerability of Gefitinib in Combination With Olaparib (AZD2281) Versus Gefitinib Alone, in Patients With EGFR Mutation Positive Advanced Non-small-cell Lung Cancer

This is a study of gefitinib plus olaparib gefitinib in combination with olaparib (AZD2281) versus gefitinib alone, in patients with Epidermal Growth Factor Receptor (EGFR) mutation positive advanced non-small-cell lung cancer.

NCT01513174 Non Small Cell Lung Cancer Drug: Gefitinib Drug: Gefitinib plus olaparib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

4. Tumor tissue available (according to the criterion of the specimen-processing laboratory) for EGFR mutation assessment: to be included in the study patients should present at least one EGFR mutation (exon 19 deletion or L858R with or without T790M). --- L858R --- --- T790M ---

Primary Outcomes

Measure: MTD (Maximum Tolerated Dose) defined as the highest dose level at which < 2 out of 6 patients experience a DLT

Time: 5 weeks

Secondary Outcomes

Measure: Progression-free survival

Time: An expected average of 2 years

Measure: Overall response rate

Time: An expected average of 2 years

Measure: Overall survival

Time: An expected average of 2 years

Measure: Peak Plasma Concentration

Time: Predose, half an hour, 1, 2, 4, 6 and 12 hours post-dose

24 A Phase 1/2, Open-Label, Safety, Pharmacokinetic and Preliminary Efficacy Study of Oral Rociletinib in Patients With Previously Treated Mutant EGFR Non-Small Cell Lung Cancer (NSCLC)

Rociletinib is a novel, potent, small molecule irreversible tyrosine kinase inhibitor (TKI) that selectively targets mutant forms of the epidermal growth factor receptor (EGFR) while sparing wild-type (WT) EGFR. The purpose of the study is to evaluate the pharmacokinetic (PK) and safety profile of oral rociletinib; to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of oral rociletinib; to assess the safety and efficacy of rociletinib in previously treated NSCLC patients known to have the T790M EGFR mutation.

NCT01526928 Locally Advanced or Metastatic Non Small Cell Lung Cancer Drug: Rociletinib Drug: Rociletinib Drug: Rociletinib Drug: Rociletinib Drug: Rociletinib Drug: Rociletinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

The purpose of the study is to evaluate the pharmacokinetic (PK) and safety profile of oral rociletinib; to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of oral rociletinib; to assess the safety and efficacy of rociletinib in previously treated NSCLC patients known to have the T790M EGFR mutation. --- T790M ---

Percentage of T790M Positive Patients With Confirmed Response Per Investigator. --- T790M ---

Percentage of patients with a T790M mutation (determined by central lab) with a best overall confirmed response of partial response (PR) or complete response (CR) recorded from the start of the treatment until disease progression or recurrence. --- T790M ---

Partial Response (PR),at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter.. Duration of Response (DOR) in T790M Positive Patients According to RECIST Version 1.1 as Determined by Investigator Assessment. --- T790M ---

Duration of Response in patients with a T790M mutation (determined by central lab) with confirmed response per investigator. --- T790M ---

Adequate hematological and biological function 7. Written consent on an IRB/IEC-approved Informed Consent Form (ICF) prior to any study-specific evaluation Phase 2 Cohorts must also meet the following inclusion criteria: - Disease progression confirmed by radiologic assessment while on treatment with EGFR- TKI Or - Disease progression confirmed by radiologic assessment while on treatment with the first single agent EGFR TKI and - Documented evidence of T790M mutation in EGFR following disease progression on the first single agent EGFR TKI. - Measureable disease according to RECIST Version 1.1 Exclusion Criteria - Any of the following criteria will exclude patients from study participation: 1. Documented evidence of an Exon 20 insertion activating mutation in the EGFR gene 2. Active second malignancy 3. Known pre-existing interstitial lung disease 4. Patients with Leptomeningeal carcinomatosis are excluded. --- T790M ---

Other CNS metastases are only permitted if treated, asymptomatic and stable (not requiring steroids for at least 4 weeks prior to start of study treatment). 5. Treatment with prohibited medications less than or equal to 14 days prior to treatment with rociletinib 6. Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication before starting rociletinib 7. Prior treatment with rociletinib or other drugs that target T790M positive mutant EGFR with sparing of wild type EGFR 8. Certain cardiac abnormalities or history 9. Non-study related surgical procedures less than or equal to 7 days prior to administration of rociletinib 10. --- T790M ---

However, patients on TKIs eventually progress, and in approximately 50% of cases, progression is due to development of an additional mutation called T790M. --- T790M ---

Nonclinical data demonstrate that rociletinib inhibits T790M. --- T790M ---

It is anticipated that rociletinib may promote cell death in tumor cells with the T790M mutation, thus providing possible therapeutic benefit in patients who have developed T790M-mediated resistance to first generation TKIs. --- T790M ---

It is anticipated that rociletinib may promote cell death in tumor cells with the T790M mutation, thus providing possible therapeutic benefit in patients who have developed T790M-mediated resistance to first generation TKIs. --- T790M --- --- T790M ---

This study will include 2 parts: Phase 1: Dose-escalation Period with 21-day cycles; optional Treatment Extension Period starting on Day 22 Phase 2: Evaluation of activity and safety in patients with the T790M EGFR mutation who have: Cohort A - Progressed on EGFR directed therapy (irrespective of the number and order of previous lines of NSCLC therapy) or Cohort B - Progression on the first single agent EGFR directed therapy received and also had no more than one previous line of chemotherapy or Cohort C - Patients with discordance between local (T790M positive) and central (T790M negative) T790M results, or had no central test result due to inadequacy of the tissue specimen and known to be T790M positive by local test --- T790M ---

This study will include 2 parts: Phase 1: Dose-escalation Period with 21-day cycles; optional Treatment Extension Period starting on Day 22 Phase 2: Evaluation of activity and safety in patients with the T790M EGFR mutation who have: Cohort A - Progressed on EGFR directed therapy (irrespective of the number and order of previous lines of NSCLC therapy) or Cohort B - Progression on the first single agent EGFR directed therapy received and also had no more than one previous line of chemotherapy or Cohort C - Patients with discordance between local (T790M positive) and central (T790M negative) T790M results, or had no central test result due to inadequacy of the tissue specimen and known to be T790M positive by local test --- T790M --- --- T790M ---

This study will include 2 parts: Phase 1: Dose-escalation Period with 21-day cycles; optional Treatment Extension Period starting on Day 22 Phase 2: Evaluation of activity and safety in patients with the T790M EGFR mutation who have: Cohort A - Progressed on EGFR directed therapy (irrespective of the number and order of previous lines of NSCLC therapy) or Cohort B - Progression on the first single agent EGFR directed therapy received and also had no more than one previous line of chemotherapy or Cohort C - Patients with discordance between local (T790M positive) and central (T790M negative) T790M results, or had no central test result due to inadequacy of the tissue specimen and known to be T790M positive by local test --- T790M --- --- T790M --- --- T790M ---

This study will include 2 parts: Phase 1: Dose-escalation Period with 21-day cycles; optional Treatment Extension Period starting on Day 22 Phase 2: Evaluation of activity and safety in patients with the T790M EGFR mutation who have: Cohort A - Progressed on EGFR directed therapy (irrespective of the number and order of previous lines of NSCLC therapy) or Cohort B - Progression on the first single agent EGFR directed therapy received and also had no more than one previous line of chemotherapy or Cohort C - Patients with discordance between local (T790M positive) and central (T790M negative) T790M results, or had no central test result due to inadequacy of the tissue specimen and known to be T790M positive by local test --- T790M --- --- T790M --- --- T790M --- --- T790M ---

This study will include 2 parts: Phase 1: Dose-escalation Period with 21-day cycles; optional Treatment Extension Period starting on Day 22 Phase 2: Evaluation of activity and safety in patients with the T790M EGFR mutation who have: Cohort A - Progressed on EGFR directed therapy (irrespective of the number and order of previous lines of NSCLC therapy) or Cohort B - Progression on the first single agent EGFR directed therapy received and also had no more than one previous line of chemotherapy or Cohort C - Patients with discordance between local (T790M positive) and central (T790M negative) T790M results, or had no central test result due to inadequacy of the tissue specimen and known to be T790M positive by local test --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Primary Outcomes

Description: Percentage of patients with a T790M mutation (determined by central lab) with a best overall confirmed response of partial response (PR) or complete response (CR) recorded from the start of the treatment until disease progression or recurrence. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: Complete Response (CR), is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR),at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter.

Measure: Percentage of T790M Positive Patients With Confirmed Response Per Investigator

Time: Cycle 1 Day 1 to End of Treatment, up to approximately 42 months

Description: Duration of Response in patients with a T790M mutation (determined by central lab) with confirmed response per investigator. The DOR for complete response (CR) and partial response (PR) was measured from the date that any of these best responses is first recorded until the first date that progressive disease (PD) is objectively documented. For patients who continue treatment post-progression, the first date of progression was used for the analysis.

Measure: Duration of Response (DOR) in T790M Positive Patients According to RECIST Version 1.1 as Determined by Investigator Assessment

Time: Cycle 1 Day 1 to End of Treatment, up to approximately 36 months

Description: The number of Phase 1 patients who experienced dose limiting toxicities after one cycle (21 days) of study drug.

Measure: Dose Limiting Toxicity (DLT) Incidence

Time: Cycle 1 Day 1 to Cycle 1 Day 21

Secondary Outcomes

Description: Overall survival was calculated as 1+ the number of days from the first dose of study drug to death due to any cause. Patients without a documented date of death were censored on the date the patient was last known to be alive.

Measure: Overall Survival (OS) Determined by Investigator Assessment

Time: Cycle 1 Day 1 to date of death, assessed up to 42 months

Description: Progression-free survival was calculated as the number of days from the date of the first dose of study drug to the date of disease progression or death due to any cause + 1. Patients without a documented event of disease progression were censored on the date of their last adequate tumor assessment (i.e., radiologic assessment) or date of first dose of study drug if no tumor assessments have been performed. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.

Measure: Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by Investigator Review (invPFS)

Time: Cycle 1 Day 1 to End of Treatment, up to approximately 42 months

Description: Cmax = maximum concentration following administration of rociletinib

Measure: PK Profile of Rociletinib - Cmax

Time: Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days

Description: Tmax = time to maximum concentration following administration of rociletinib

Measure: PK Profile of Rociletinib - Tmax

Time: Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days

Description: AUC 0-24 = area under the curve from 0 to 24 hours

Measure: PK Profile of Rociletinib - AUC 0-24

Time: Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days

Description: T 1/2 = elimination half-life following administration of rociletinib

Measure: PK Profile of Rociletinib - T 1/2

Time: Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days

Description: Cmax = maximum concentration following administration of rociletinib. The effect of food on rociletinib PK parameters was assessed over a 24-hour period in blood samples from a subset of 3 patients. These patients were given a single dose of rociletinib 150mg FB 1 week prior (Day -7) to the start of continuous daily dosing after fasting. On Day 1 of Cycle 1, patients consumed a high-fat, high-calorie breakfast at the study site prior to receiving rociletinib. On each day, patients underwent blood sampling for PK at the specified time points.

Measure: Food Effect on PK of Rociletinib - Cmax

Time: Day -7 prior to Cycle 1 Day 1, or approximately 7 days

Description: Tmax = time to maximum concentration following administration of rociletinib. The effect of food on rociletinib PK parameters was assessed over a 24-hour period in blood samples from a subset of 3 patients. These patients were given a single dose of rociletinib 150mg FB 1 week prior (Day -7) to the start of continuous daily dosing after fasting. On Day 1 of Cycle 1, patients consumed a high-fat, high-calorie breakfast at the study site prior to receiving rociletinib. On each day, patients underwent blood sampling for PK at the specified time points.

Measure: Food Effect on PK of Rociletinib - Tmax

Time: Day -7 prior to Cycle 1 Day 1, or approximately 7 days

Description: AUC 0-24 = area under the curve from 0 to 24 hours. The effect of food on rociletinib PK parameters was assessed over a 24-hour period in blood samples from a subset of 3 patients. These patients were given a single dose of rociletinib 150mg FB 1 week prior (Day -7) to the start of continuous daily dosing after fasting. On Day 1 of Cycle 1, patients consumed a high-fat, high-calorie breakfast at the study site prior to receiving rociletinib. On each day, patients underwent blood sampling for PK at the specified time points.

Measure: Food Effect on PK of Rociletinib - AUC 0-24

Time: Day -7 prior to Cycle 1 Day 1, or approximately 7 days

Description: C24 = rociletinib plasma concentration at 24 hours post the morning dose. The effect of food on rociletinib PK parameters was assessed over a 24-hour period in blood samples from a subset of 3 patients. These patients were given a single dose of rociletinib 150mg FB 1 week prior (Day -7) to the start of continuous daily dosing after fasting. On Day 1 of Cycle 1, patients consumed a high-fat, high-calorie breakfast at the study site prior to receiving rociletinib. On each day, patients underwent blood sampling for PK at the specified time points.

Measure: Food Effect on PK of Rociletinib - C24

Time: Day -7 prior to Cycle 1 Day 1, or approximately 7 days

Description: T 1/2 = elimination half-life following administration of rociletinib. The effect of food on rociletinib PK parameters was assessed over a 24-hour period in blood samples from a subset of 3 patients. These patients were given a single dose of rociletinib 150mg FB 1 week prior (Day -7) to the start of continuous daily dosing after fasting. On Day 1 of Cycle 1, patients consumed a high-fat, high-calorie breakfast at the study site prior to receiving rociletinib. On each day, patients underwent blood sampling for PK at the specified time points.

Measure: Food Effect on PK of Rociletinib - T 1/2

Time: Day -7 prior to Cycle 1 Day 1, or approximately 7 days

Description: Frequency of QT interval prolongation by daily dose (corrected using Fridericia's method, QTcF). To evaluate the effects of rociletinib on the QT (interval from Q wave to T wave)/QTc (interval corrected for heart rate) interval, all patients underwent serial ECG monitoring at Baseline, on Cycle 1 Day 1, Cycle 1 Day 15, on Day 1 of all subsequent cycles, at the EOT Visit, and as clinically indicated. Worst post-baseline QTcF value was used to categorize each patient.

Measure: QTcF Values Post Baseline by Daily Dose

Time: Screening to End of Treatment, up to approximately 42 months

Description: QTcF value change from baseline by daily dose (corrected using Fridericia's method, QTcF). To evaluate the effects of rociletinib on the QT (interval from Q wave to T wave)/QTc (interval corrected for heart rate) interval, all patients underwent serial ECG monitoring at Baseline, on Cycle 1 Day 1, Cycle 1 Day 15, on Day 1 of all subsequent cycles, at the EOT Visit, and as clinically indicated. Worst post-baseline QTcF value was used to categorize each patient.

Measure: QTcF Value Change From Baseline

Time: Screening to End of Treatment, up to approximately 42 months

Description: Objective response rate (ORR), duration of response (DOR) and progression-free survival (PFS) per RECIST Version 1.1 as determined by independent radiology review (IRR)

Measure: Objective Response Rate (ORR), Duration of Response (DOR) and Progression-Free Survival (PFS) Per RECIST Version 1.1 as Determined by IRR

Time: Cycle 1 Day 1 to End of Treatment / End of Follow-up

25 A Phase I Dose-Escalation Study of Erlotinib in Combination With Pralatrexate in Subjects With Advanced Cancer

The goal of this clinical research study is to find the highest tolerable dose of the combination of erlotinib and pralatrexate that can be given to patients with advanced cancer. The safety of the drug combination will also be studied. Pralatrexate is designed to block the body's ability to make folic acid, a protein that may help cancer tissue to develop and spread. Erlotinib hydrochloride is designed to block proteins that are thought to cause cancer cells to grow. Erlotinib may help slow the growth of tumors.

NCT01532011 Advanced Cancers Solid Tumors Drug: Erlotinib Drug: Pralatrexate
MeSH:Neoplasms
HPO:Neoplasm

Have an EGFR-resistant mutation (as T790M in exon 20), OR III. --- T790M ---

Primary Outcomes

Description: MTD defined by dose limiting toxicities (DLTs) that occur in the first cycle. DLT defined as any Grade 3 or 4 non-hematologic toxicity as defined in the NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v3.0. Grade 4 hematologic toxicity lasting 2 weeks or longer despite supportive care. Grade 4 nausea or vomiting > 5 days despite maximum anti-nausea regimens, and any other Grade 3 non-hematologic toxicity, including symptoms/signs of vascular leak or cytokine release syndrome; or any severe or life-threatening complication or abnormality not defined in NCI-CTCAE as attributable to therapy.

Measure: Maximum Tolerated Dose (MTD) of Erlotinib with Pralatrexate

Time: 8 weeks

Secondary Outcomes

Description: Tumor response defined as one or more of the following: (1) stable disease for more than or equal to 4 months, (2) decrease in measurable tumor (sentinel lesions) by more than or equal to 20% by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, (3) decrease in tumor markers by more than or equal to 25% (for example, a >/= 25% decrease in CA125 for patients with ovarian cancer), or (4) a partial response according to the Choi criteria, i.e. decrease in size by 10% or more, or a decrease in tumor density, as measured in Hounsfield units (HU), by more than or equal to 15% (28).

Measure: Tumor Response

Time: 8 weeks

26 A Randomized Phase II Trial of Erlotinib Alone or in Combination With Bevacizumab in Patients With Non-Small Cell Lung Cancer and Activating Epidermal Growth Factor Receptor Mutations

This randomized phase II trial studies how well erlotinib hydrochloride (Tarceva) with or without bevacizumab (Avastin) works in treating patients with stage IV non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, may block tumor growth in different ways by targeting certain cells. Bevacizumab may also stop the growth of NSCLC by blocking the growth of new blood vessels necessary for tumor growth. It is not yet known whether erlotinib hydrochloride is more effective when given alone or with bevacizumab in treating patients with NSCLC.

NCT01532089 EGFR Exon 19 Deletion Mutation EGFR NP_005219.2:p.L858R Lung Non-Squamous Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Biological: Bevacizumab Drug: Erlotinib Drug: Erlotinib Hydrochloride Other: Laboratory Biomarker Analysis
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Agreement of EGFR mutations detected in plasma DNA with those detected in tumor DNA will be evaluated.. Prevalence of EGFR T790M Resistance Mutations From Pretreatment > Tumor Biopsies Using More Sensitive Mutation Detection Methods. --- T790M ---

The robustness of treatment effect in different subgroups will be examined in a Forest plot.. EGFR T790M Mutations. --- T790M ---

The PFS of patients with EGFR T790M mutations will be estimated and the survival difference will be tested using Cox proportional hazard model after adjusting for treatment effect. --- T790M ---

To estimate the prevalence of EGFR T790M resistance mutations from pretreatment tumor biopsies using more sensitive mutation detection methods. --- T790M ---

To investigate progression free survival of EGFR mutant NSCLC patients with and without concurrent EGFR T790M detected from pre-treatment tumor specimen using allele specific quantitative polymerase chain reaction (PCR). --- T790M ---

Primary Outcomes

Description: Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as at least a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.

Measure: Progression Free Survival (PFS)

Time: Time from randomization to disease progression and death of any cause, whichever comes first, assessed up to 6 years

Secondary Outcomes

Description: Overall survival time is defined as the time from randomization to death due to any cause. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.

Measure: Overall Survival

Time: Time from randomization to death of any causes, assessed up to 6 years

Description: The response rate (percentage) is the percent of patients whose best response was Complete Response (CR) or Partial Response (PR) as defined by RECIST 1.1 criteria. Percentage of successes will be estimated by 100 times the number of successes divided by the total number of evaluable patients. (CR: Disappearance of all evidence of disease, PR: Regression of measurable disease and no new sites).

Measure: Response Rate (Complete or Partial) to Each Treatment, Evaluated Using the New International Criteria Proposed by the Revised Response Evaluation Criteria in Solid Tumors Guidelines (Version 1.1)

Time: Up to 6 years

Description: Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as at least a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator by mutation type.

Measure: Progression Free Survival of Patients With Different Mutation Types (Exon Deletion 19 Versus Exon 21 L858R)

Time: From the date of randomization to the date of disease progression or death of any cause, whichever comes first, assessed up to 6 years

Description: The number of patients experiencing toxicity defined as grade 3 or higher adverse events (using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0) considered at least possibly related to treatment is reported below.

Measure: Number of Patients Experiencing Toxicity

Time: Up to 42 days after treatment discontinuation

Other Outcomes

Description: Agreement of EGFR mutations detected in plasma DNA with those detected in tumor DNA will be evaluated.

Measure: EGFR Mutations Detected in Plasma Deoxyribonucleic Acid (DNA)

Time: Up to 6 years

Description: Agreement of EGFR mutations detected in plasma DNA with those detected in tumor DNA will be evaluated.

Measure: EGFR Mutations Detected in Tumor Deoxyribonucleic Acid (DNA)

Time: Up to 6 years

Description: Tested using Cox proportional hazard model after adjusting for treatment effect. The robustness of treatment effect in different subgroups will be examined in a Forest plot.

Measure: Prevalence of EGFR T790M Resistance Mutations From Pretreatment > Tumor Biopsies Using More Sensitive Mutation Detection Methods

Time: Baseline

Description: Detected from pre-treatment tumor specimen using allele specific quantitative polymerase chain reaction (PCR). The PFS of patients with EGFR T790M mutations will be estimated and the survival difference will be tested using Cox proportional hazard model after adjusting for treatment effect. The robustness of treatment effect in different subgroups will be examined in a Forest plot.

Measure: EGFR T790M Mutations

Time: Up to 6 years

Description: Evaluated using time-dependent receiver operating characteristic curve and area under curve.

Measure: Predictive Value of Plasma VEGF-A Levels on Progression Free Survival in Patients Treated With Erlotinib Hydrochloride Alone or in Combination With Bevacizumab

Time: Baseline

27 An Open-label Phase II Trial of Erlotinib and Bevacizumab in Patients With Advanced Non-small Cell Lung Cancer and Activating EGFR Mutations

Rationale: Advanced non-small-cell lung cancer (NSCLC) patients harbouring epidermal growth factor receptor (EGFR) mutations (del19 or L858R) show an impressive progression-free survival between 9 and 14 months when treated with erlotinib. However, the presence of EGFR mutations can only imperfectly predict outcome. The investigators hypothesize that progression-free survival could be influenced both by the pretreatment EGFR T790M mutation and by components of DNA repair pathways. The investigators propose a model of treatment whereby patients with EGFR mutations (single or with T790M) can attain a benefit with longer overall PFS when treated with erlotinib plus bevacizumab. When the patients are grouped by BRCA1 mRNA levels and T790M the hypothesis is that the combination of erlotinib plus bevacizumab can improve the PFS in all subgroups.

NCT01562028 Lung Cancer Drug: Erlotinib Drug: Bevacizumab
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

The investigators hypothesize that progression-free survival could be influenced both by the pretreatment EGFR T790M mutation and by components of DNA repair pathways. --- T790M ---

The investigators propose a model of treatment whereby patients with EGFR mutations (single or with T790M) can attain a benefit with longer overall PFS when treated with erlotinib plus bevacizumab. --- T790M ---

When the patients are grouped by BRCA1 mRNA levels and T790M the hypothesis is that the combination of erlotinib plus bevacizumab can improve the PFS in all subgroups. --- T790M ---

To determine long-term outcome of patients with advanced non-squamous NSCLC harbouring EGFR mutations with or without T790M mutation at diagnosis and treated with the combination of erlotinib and bevacizumab. --- T790M ---

Primary endpoint: progression-free survival 2. To evaluate the efficacy and tolerability of the combination 3. To evaluate the correlation of BRCA1 mRNA and AEG-1 mRNA expression and T790M with progression-free survival 4. To monitor EGFR mutations (including T790M) in serum and plasma longitudinally 5. To evaluate molecular biomarkers related to EGFR TKI and bevacizumab Design: This is a multinational, multi-center phase II trial of erlotinib plus bevacizumab in patients with advanced non-squamous NSCLC harbouring EGFR mutations confirmed by central re-assessment. --- T790M ---

Primary endpoint: progression-free survival 2. To evaluate the efficacy and tolerability of the combination 3. To evaluate the correlation of BRCA1 mRNA and AEG-1 mRNA expression and T790M with progression-free survival 4. To monitor EGFR mutations (including T790M) in serum and plasma longitudinally 5. To evaluate molecular biomarkers related to EGFR TKI and bevacizumab Design: This is a multinational, multi-center phase II trial of erlotinib plus bevacizumab in patients with advanced non-squamous NSCLC harbouring EGFR mutations confirmed by central re-assessment. --- T790M --- --- T790M ---

Patients will be stratified into two subgroups, with and without EGFR T790M mutation. --- T790M ---

Primary Outcomes

Description: Time from the date of enrollment until an investigator-documented progression or death, whichever occurs first. Assessment of Progressive Disease (PD) is based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1): at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Measure: Progression Free Survival

Time: From the date of enrollment until documented progression or death, whichever occurs first, assessed up to 48 months.

Secondary Outcomes

Description: Time from the date of enrollment until death from any cause.

Measure: Overall Survival

Time: From the date of enrollment until death, assessed up to 48 months.

Description: Time from the date of enrollment to discontinuation of treatment for any reason including progression of disease (based on RECIST v1.1), treatment toxicity (adverse events classified according to NCI CTCAE version 4.), refusal and death.

Measure: Time to Treatment Failure

Time: From the date of enrollment until discontinuation of treatment, assessed up to 48 months.

Description: Objective response is defined as best overall response (CR or PR) across all assessment time-points during the period from enrollment to termination of trial treatment. Objective response, along with progressive and stable disease, will be determined using RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters recorded on the trial.

Measure: Objective Response

Time: Assessed across all time-points from enrollment to termination of trial treatment (max 48 months).

Description: Disease control is defined as achieving objective response (CR or PR, across all time-points from enrollment to termination of trial treatment) or stable disease for at least 6 weeks. Objective response, along with SD (disease control) and PD (no disease control), will be determined using RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters.Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters recorded on the trial.

Measure: Disease Control

Time: Assessed across all time-points from enrollment to termination of trial treatment (max 48 months).

Description: Interval from the date of first documentation of objective response (CR or PR) to the date of first documented progression or relapse. Assessment of Objective response and Progressive Disease (PD) is based on the RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters recorded on the trial.

Measure: Duration of Response

Time: Assessed across all time-points from enrollment to to the date of first documented progression or relapse (max 48 months).

Description: Adverse events graded according to NCI CTCAE V4.

Measure: Adverse Events

Time: Assessed across all time-points until end of treatment (30 +/-5 days following the last dose of study drug) (max 48 months).

28 An Open Label, Randomized, Multicenter, Phase II Study to Compare Efficacy and Safety of Gefitinib/ Pemetrexed With Pemetrexed Alone as Maintenance Therapy in Patients With Advanced (Stage IV) EGFR Mutation Negative or T790M Single Mutation Nonsquamous NSCLC Who Respond to 4 Cycles of Pemetrexed/ Platinum as First-line Therapy

The study aims to randomize 52 patients with advanced (Stage IV) EGFR mutation negative nonsquamous non-small cell lung cancer (NSCLC) who respond (CR/PR/SD) to 4 cycles of pemetrexed / cisplatin or pemetrexed/carboplatin as first-line therapy. In order to achieve that, approximately 144 treatment naïve patients with advanced nonsquamous NSCLC need to be enrolled from around 6 investigational sites in Taiwan that have expertise in lung cancer diagnosis.

NCT01579630 NSCLC Drug: Pemetrexed 500mg/m2 iv Drug: Pemetrexed 500mg/m2 iv and Gefitinib 250 mg

An Open Label, Randomized, Multicenter, Phase II Study to Compare Efficacy and Safety of Gefitinib/ Pemetrexed With Pemetrexed Alone as Maintenance Therapy in Patients With Advanced (Stage IV) EGFR Mutation Negative or T790M Single Mutation Nonsquamous NSCLC Who Respond to 4 Cycles of Pemetrexed/ Platinum as First-line Therapy. --- T790M ---

Genius Study Study to Compare Efficacy and Safety of Gefitinib/ Pemetrexed With Pemetrexed Alone as Maintenance Therapy in Patients With Stage IV EGFR Mutation Negative or T790M Single Mutation Who Respond to Pemetrexed/ Platinum as First-line Therapy The study aims to randomize 52 patients with advanced (Stage IV) EGFR mutation negative nonsquamous non-small cell lung cancer (NSCLC) who respond (CR/PR/SD) to 4 cycles of pemetrexed / cisplatin or pemetrexed/carboplatin as first-line therapy. --- T790M ---

5. Measurable disease according to RECIST (Version 1.1) criteria 6. World Health Organization (WHO) performance status (PS) of 0 to 1 7. Provision of cancer tissue sample for mutation testing or the result of EGFR mutation test is negative (single T790M mutation positive patients can also be enrolled) Exclusion Criteria summary 1. Newly diagnosed Central Nervous System (CNS) metastases that have not yet been definitively treated with surgery and/or radiation. --- T790M ---

Primary Outcomes

Description: Progression of disease will be calculated from the tumour measurements collected at each tumour assessment per the RECIST (V1.1) criteria and/or the date of patient death.

Measure: Progression free survival

Time: up to 4 months

Secondary Outcomes

Description: The RECIST (V1.1) criteria will be used to assess objective tumour response. Details of target and non-target lesions will be collected on the appropriate CRF pages and used to calculate tumour response. Post-baseline tumour evaluations should use the same modality (CT scan or magnetic resonance imaging [MRI]) as used at baseline and should preferably be undertaken at the same institution.

Measure: Overall objective tumour response

Time: up to 1 year

29 Phase I/II Study to Assess the Safety, Tolerability, Pharmacokinetics and Anti-tumor Activity of HM61713 in NSCLC Patients With EGFR Mutation

The main objective of this study is to evaluate the safety and tolerability of HM61713.

NCT01588145 Non Small Cell Lung Cancer Drug: HM61713
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

※ For subjects with a liver metastases, AST/ALT/ALP≤ 5 x ULN is allowed; and for subjects with bone marrow metastases, ALP≤ 5 x ULN is allowed - Patients with amylase level ≤ 1.5 x ULN - Subjects who have provided voluntary consent to participate in the study, and signed the written consent document - Malignancy that has progressed after at least two prior chemotherapy regimens, including EGFR-TKI - Patients with disease progression despite anticancer therapy with EGFR-TKI (e.g., erlotinib, gefitinib, neratinib, afatinib, dacomitinib) - Patients who have provided voluntary consent for collection of tumor tissue taken and archived after the last anticancer therapy or collection of new tissue specimen and signed the written consent document & - Patients with disease progression despite anticancer therapy with EGFR TKI (e.g., erlotinib, gefitinib, neratinib, afatinib, dacomitinib) (Except treatment with EGFR mutation selective inhibitor, the same class of drug as investigational drug in this study) - T790M mutation-positive confirmed in tissue collected after PD is confirmed during or after the last anticancer therapy - At least one measurable target lesion allowing repeated measurement according to RECIST ver1.1 as of screening - Patients with disease progression despite anticancer therapy with EGFR TKI (e.g., erlotinib, gefitinib, neratinib, afatinib, dacomitinib) (Except treatment with EGFR mutation selective inhibitor, the same class of drug as investigational drug in this study) - T790M mutation-negative confirmed in tissue collected after progressive disease (PD) is confirmed during or after the last anticancer therapy - At least one measurable target lesion allowing repeated measurement according to RECIST ver1.1 as of screening Exclusion Criteria: - Hematologic malignancies - Symptomatic or uncontrolled central nervous system metastases - Interstitial lung disease, including pulmonary fibrosis - LVEF < 40% or NYHA Class III or IV heart failure - History of pancreatitis - History or current evidence, of any psychiatric or congenital disorder, including dementia or epilepsy - Compromised organ function, infection or allergy - Pregnant or breast-feeding women, or women of child-bearing potential who do not use an appropriate method of contraception (male patients should also use an appropriate method of contraception during the study period) - Patients who had received other investigational product within 30 days prior to screening Inclusion Criteria: - Patients with histologically or cytologically confirmed diagnosis of advanced NSCLC - Patients with EGFR mutation-positive tumor - Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less - Estimated life expectancy of at least 12 weeks - Subjects with adequate bone marrow (WBC ≥4,000/mm3, Platelet ≥100,000/mm3, Hemoglobin≥9.0g/dL, --- T790M ---

※ For subjects with a liver metastases, AST/ALT/ALP≤ 5 x ULN is allowed; and for subjects with bone marrow metastases, ALP≤ 5 x ULN is allowed - Patients with amylase level ≤ 1.5 x ULN - Subjects who have provided voluntary consent to participate in the study, and signed the written consent document - Malignancy that has progressed after at least two prior chemotherapy regimens, including EGFR-TKI - Patients with disease progression despite anticancer therapy with EGFR-TKI (e.g., erlotinib, gefitinib, neratinib, afatinib, dacomitinib) - Patients who have provided voluntary consent for collection of tumor tissue taken and archived after the last anticancer therapy or collection of new tissue specimen and signed the written consent document & - Patients with disease progression despite anticancer therapy with EGFR TKI (e.g., erlotinib, gefitinib, neratinib, afatinib, dacomitinib) (Except treatment with EGFR mutation selective inhibitor, the same class of drug as investigational drug in this study) - T790M mutation-positive confirmed in tissue collected after PD is confirmed during or after the last anticancer therapy - At least one measurable target lesion allowing repeated measurement according to RECIST ver1.1 as of screening - Patients with disease progression despite anticancer therapy with EGFR TKI (e.g., erlotinib, gefitinib, neratinib, afatinib, dacomitinib) (Except treatment with EGFR mutation selective inhibitor, the same class of drug as investigational drug in this study) - T790M mutation-negative confirmed in tissue collected after progressive disease (PD) is confirmed during or after the last anticancer therapy - At least one measurable target lesion allowing repeated measurement according to RECIST ver1.1 as of screening Exclusion Criteria: - Hematologic malignancies - Symptomatic or uncontrolled central nervous system metastases - Interstitial lung disease, including pulmonary fibrosis - LVEF < 40% or NYHA Class III or IV heart failure - History of pancreatitis - History or current evidence, of any psychiatric or congenital disorder, including dementia or epilepsy - Compromised organ function, infection or allergy - Pregnant or breast-feeding women, or women of child-bearing potential who do not use an appropriate method of contraception (male patients should also use an appropriate method of contraception during the study period) - Patients who had received other investigational product within 30 days prior to screening Inclusion Criteria: - Patients with histologically or cytologically confirmed diagnosis of advanced NSCLC - Patients with EGFR mutation-positive tumor - Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less - Estimated life expectancy of at least 12 weeks - Subjects with adequate bone marrow (WBC ≥4,000/mm3, Platelet ≥100,000/mm3, Hemoglobin≥9.0g/dL, --- T790M --- --- T790M ---

※ For subjects with a liver metastases, AST/ALT/ALP≤ 5 x ULN is allowed; and for subjects with bone marrow metastases, ALP≤ 5 x ULN is allowed - Patients with amylase level ≤ 1.5 x ULN - Subjects who have provided voluntary consent to participate in the study, and signed the written consent document - Malignancy that has progressed after at least two prior chemotherapy regimens, including EGFR-TKI - Patients with disease progression despite anticancer therapy with EGFR-TKI (e.g., erlotinib, gefitinib, neratinib, afatinib, dacomitinib) - Patients who have provided voluntary consent for collection of tumor tissue taken and archived after the last anticancer therapy or collection of new tissue specimen and signed the written consent document & - Patients with disease progression despite anticancer therapy with EGFR TKI (e.g., erlotinib, gefitinib, neratinib, afatinib, dacomitinib) (Except treatment with EGFR mutation selective inhibitor, the same class of drug as investigational drug in this study) - T790M mutation-positive confirmed in tissue collected after PD is confirmed during or after the last anticancer therapy - At least one measurable target lesion allowing repeated measurement according to RECIST ver1.1 as of screening - Patients with disease progression despite anticancer therapy with EGFR TKI (e.g., erlotinib, gefitinib, neratinib, afatinib, dacomitinib) (Except treatment with EGFR mutation selective inhibitor, the same class of drug as investigational drug in this study) - T790M mutation-negative confirmed in tissue collected after progressive disease (PD) is confirmed during or after the last anticancer therapy - At least one measurable target lesion allowing repeated measurement according to RECIST ver1.1 as of screening Exclusion Criteria: - Hematologic malignancies - Symptomatic or uncontrolled central nervous system metastases - Interstitial lung disease, including pulmonary fibrosis - LVEF < 40% or NYHA Class III or IV heart failure - History of pancreatitis - History or current evidence, of any psychiatric or congenital disorder, including dementia or epilepsy - Compromised organ function, infection or allergy - Pregnant or breast-feeding women, or women of child-bearing potential who do not use an appropriate method of contraception (male patients should also use an appropriate method of contraception during the study period) - Patients who had received other investigational product within 30 days prior to screening Non Small Cell Lung Cancer Carcinoma, Non-Small-Cell Lung Besides the main objective, there are 3 other objectives as follows: - To evaluate the anti-cancer effect of HM61713 in NSCLC patients with EGFR mutation - To investigate the pharmacokinetic profile of HM61713 and its metabolites after oral administration - To investigate biomarkers related to the safety and efficacy of HM61713 --- T790M ---

※ For subjects with a liver metastases, AST/ALT/ALP≤ 5 x ULN is allowed; and for subjects with bone marrow metastases, ALP≤ 5 x ULN is allowed - Patients with amylase level ≤ 1.5 x ULN - Subjects who have provided voluntary consent to participate in the study, and signed the written consent document - Malignancy that has progressed after at least two prior chemotherapy regimens, including EGFR-TKI - Patients with disease progression despite anticancer therapy with EGFR-TKI (e.g., erlotinib, gefitinib, neratinib, afatinib, dacomitinib) - Patients who have provided voluntary consent for collection of tumor tissue taken and archived after the last anticancer therapy or collection of new tissue specimen and signed the written consent document & - Patients with disease progression despite anticancer therapy with EGFR TKI (e.g., erlotinib, gefitinib, neratinib, afatinib, dacomitinib) (Except treatment with EGFR mutation selective inhibitor, the same class of drug as investigational drug in this study) - T790M mutation-positive confirmed in tissue collected after PD is confirmed during or after the last anticancer therapy - At least one measurable target lesion allowing repeated measurement according to RECIST ver1.1 as of screening - Patients with disease progression despite anticancer therapy with EGFR TKI (e.g., erlotinib, gefitinib, neratinib, afatinib, dacomitinib) (Except treatment with EGFR mutation selective inhibitor, the same class of drug as investigational drug in this study) - T790M mutation-negative confirmed in tissue collected after progressive disease (PD) is confirmed during or after the last anticancer therapy - At least one measurable target lesion allowing repeated measurement according to RECIST ver1.1 as of screening Exclusion Criteria: - Hematologic malignancies - Symptomatic or uncontrolled central nervous system metastases - Interstitial lung disease, including pulmonary fibrosis - LVEF < 40% or NYHA Class III or IV heart failure - History of pancreatitis - History or current evidence, of any psychiatric or congenital disorder, including dementia or epilepsy - Compromised organ function, infection or allergy - Pregnant or breast-feeding women, or women of child-bearing potential who do not use an appropriate method of contraception (male patients should also use an appropriate method of contraception during the study period) - Patients who had received other investigational product within 30 days prior to screening Non Small Cell Lung Cancer Carcinoma, Non-Small-Cell Lung Besides the main objective, there are 3 other objectives as follows: - To evaluate the anti-cancer effect of HM61713 in NSCLC patients with EGFR mutation - To investigate the pharmacokinetic profile of HM61713 and its metabolites after oral administration - To investigate biomarkers related to the safety and efficacy of HM61713 --- T790M --- --- T790M ---

Primary Outcomes

Measure: Safety and tolerability

Time: Dose limiting Toxicity will be evaluated on Day 24 during Cycle 1

30 A Phase I/II, Multi-Center, Open-Label, Dose Escalation Trial of the Safety and Pharmacokinetics of Intravenous PR610 Given Weekly in Subjects With Solid Tumors

The purpose of this study is to determine the Maximum Tolerated Dose and the Dose-Limiting Toxicity of the drug to further evaluate safety and antitumor activity.

NCT01631279 Unspecified Adult Solid Tumor, Protocol Specific Drug: PR610
MeSH:Neoplasms
HPO:Neoplasm

Inclusion Criteria: - Signed informed consent - Age 18 years or more - Histologically-confirmed, progressive cancer with the following diagnosis: 1. Phase I: locally advanced or metastatic solid tumor that may respond to an EGFR inhibitor; 2. Phase II: Stage IIIB or IV, non-squamous, non-small cell lung cancer (NSCLC) with known sensitizing mutations in EGFR, and the T790M resistance mutation - Failed, refused, or not eligible for standard of care therapy - ECOG performance status of 0, 1, or 2 - Life expectancy of at least 12 weeks - At least 4 weeks from prior anticancer therapy including chemotherapy, hormonal, investigational, and/or biological therapies and irradiation. --- T790M ---

- Recovered from prior treatment related toxicity 1. except for grade 1 fatigue, grade 1 peripheral sensory neuropathy and grade 1 or 2 alopecia during the phase I portion of the study 2. except for grade 1 toxicity, and grade 2 peripheral neuropathy during the phase II portion of the study - At least four (4) weeks from prior major surgery - Women of child-bearing potential must be willing to use an acceptable contraceptive method and must have a negative urine or serum pregnancy test within 2 weeks prior to beginning treatment on this trial - Sexually active men must be willing to use an acceptable contraceptive method - Adequate hematological and biological function - Willingness to participate in PK sampling during cycles 1 and 2 - Willingness to provide permission to access archived tumor samples for evaluation of EGFR mutation status - Willingness to provide samples for storage of normal tissue containing wild-type DNA Additional Inclusion Criteria during Expansion Phase - At least one target lesion as defined by RECIST 1.1 that allows for evaluation of tumor response Exclusion Criteria: - Pregnant or nursing women - Any uncontrolled medical illness including, but not limited to, significant gastrointestinal disorders, cardiovascular disease, or interstitial lung disease - History of clinically significant cardiovascular abnormalities, eg., uncontrolled hypertension, CHF (NYHA classification ≥2), unstable angina, poorly controlled arrhythmias, myocardial infarction within 6 months of study entry, implantable pacemaker or implantable cardioverter defibrillator - Clinically significant abnormal 12-lead ECG with QTcF >450 msec - Use of any medications known to produce QT prolongation - Family history of Long QT Syndrome - Prior treatment with anthracyclines with a cumulative dose of doxorubicin (or equivalent) ≥400 mg/m2 - Cardiac left ventricular function with resting ejection fraction of less than 50% - Symptomatic CNS lesions or known CNS lesions that require therapy - Prior history of an allergic reaction to a tyrosine kinase inhibitor Additional Exclusion Criteria during Expansion Phase - Any other malignancy likely to effect the assessment of toxicity or efficacy of PR610 Inclusion Criteria: - Signed informed consent - Age 18 years or more - Histologically-confirmed, progressive cancer with the following diagnosis: 1. Phase I: locally advanced or metastatic solid tumor that may respond to an EGFR inhibitor; 2. Phase II: Stage IIIB or IV, non-squamous, non-small cell lung cancer (NSCLC) with known sensitizing mutations in EGFR, and the T790M resistance mutation - Failed, refused, or not eligible for standard of care therapy - ECOG performance status of 0, 1, or 2 - Life expectancy of at least 12 weeks - At least 4 weeks from prior anticancer therapy including chemotherapy, hormonal, investigational, and/or biological therapies and irradiation. --- T790M ---

Primary Outcomes

Description: The first cohort of three subjects will receive PR610 at Dose Level 1. Subsequent cohorts will receive PR610 at a dose levels determined as per dose escalation criteria. The MTD will be defined as the dose level at which one (1) or fewer subject in six exhibit DLT with the next highest dose level demonstrating two (2) or more of six (6) subjects with DLT (or for which more than ≥33% of subjects exhibit DLT if the cohort size exceeds 6 subjects).

Measure: Determine the Maximum Tolerated Dose (MTD) of PR610 for Both a 1-hour and a 24-hour Weekly IV Infusion

Time: 3 weeks (1 cycle)

Description: DLT is defined as the following: Occurs during the first cycle of PR610 Is considered PR610-related, as defined by "Definitely-related", "Probably-related" or "Possibly-related" Is clinically significant, as determined by the Principal Investigator In addition, DLT will meet at least one of the criteria listed below using grading criteria from the CTCAEv4. Grade 4 hematologic toxicity Any drug-related toxicity that prevents administration of 100% of all doses of PR610 planned for Cycle 1 Grade 3 or higher non-hematologic toxicity

Measure: Determine the Dose-Limiting Toxicity (DLT) of PR610 for Both a 1-hour and a 24-hour Weekly IV Infusion

Time: 3 weeks (1 Cycle)

Secondary Outcomes

Description: The number of adverse events experienced by participants will be measured.

Measure: Evaluate the safety profile of PR610: Adverse Events

Time: 30 days following the last administration of study treatment

Measure: Peak Plasma Concentration (Cmax) of PR610 and PR610E for Both a 1-hour and a 24-hour Weekly Infusion

Time: pre, 30 minutes into infusion, end of infusion, 1, 2, 4, 24, 48, and 72 hours post-infusion on Cycles 1 and 2

Description: Efficacy will be determined for each subject that received at least one dose of PR610 and had at least one post-baseline disease assessment. The following four outcomes will be tabulated: Tumor response Time to response Duration of response Progression-free survival

Measure: Evaluate the activity of PR610 in a general phase I population and in a subset of subjects with NSCLC genetically resistant to reversible EGFR inhibitors

Time: 30 days following the last administration of study treatment

Measure: Time of Peak Plasma Concentration (tmax) of PR610 and PR610E for Both a 1-hour and a 24-hour Weekly Infusion

Time: pre, 30 minutes into infusion, end of infusion, 1, 2, 4, 24, 48, and 72 hours post-infusion on Cycles 1 and 2

Measure: Half life (t1/2) of PR610 and PR610E for Both a 1-hour and a 24-hour Weekly Infusion

Time: pre, 30 minutes into infusion, end of infusion, 1, 2, 4, 24, 48, and 72 hours post-infusion on Cycles 1 and 2

Measure: Area Under the Curve (AUC) of PR610 and PR610E for Both a 1-hour and a 24-hour Weekly Infusion

Time: pre, 30 minutes into infusion, end of infusion, 1, 2, 4, 24, 48, and 72 hours post-infusion on Cycles 1 and 2

Measure: Clearance (CL) of PR610 and PR610E for Both a 1-hour and a 24-hour Weekly Infusion

Time: pre, 30 minutes into infusion, end of infusion, 1, 2, 4, 24, 48, and 72 hours post-infusion on Cycles 1 and 2

31 A Phase 1b Study of Intermittent Administration of High Doses of the Irreversible EGFR Inhibitor Afatinib as a Means of Achieving Plasma Levels Active Against Non-small Cell Lung Cancer With Known T790M Mutations

This trial is divided into Part A and Part B. The primary objective of Part A is to establish the Maximal Tolerated Dose of intermittent high dose afatinib. The primary objective of Part B is to assess the response rate of patients with non-small cell lung cancer with EGFR T790M mutations to a dose of intermittent afatinib established in Part A. The secondary objective is to explore tumor response and tumor-derived biological markers of response to afatinib, as well as pharmacokinetic parameters of afatinib.

NCT01647711 Carcinoma, Non-Small-Cell Lung Drug: Dose escalation followed by treatment with MTD
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

A Phase 1b Study of Intermittent Administration of High Doses of the Irreversible EGFR Inhibitor Afatinib as a Means of Achieving Plasma Levels Active Against Non-small Cell Lung Cancer With Known T790M Mutations. --- T790M ---

A Study of Intermittent, High-dose Afatinib to Determine the Maximal Tolerated Dose and Assess Activity of This Dose Against Non-small Cell Lung Cancer With T790M Mutations This trial is divided into Part A and Part B. The primary objective of Part A is to establish the Maximal Tolerated Dose of intermittent high dose afatinib. --- T790M ---

The primary objective of Part B is to assess the response rate of patients with non-small cell lung cancer with EGFR T790M mutations to a dose of intermittent afatinib established in Part A. The secondary objective is to explore tumor response and tumor-derived biological markers of response to afatinib, as well as pharmacokinetic parameters of afatinib. --- T790M ---

Maximum Tolerated Dose (MTD) was defined as the dose in which less than 2 of up to 6 patients developed a Dose Limiting Toxicity (DLT).. Objective Response Rate for Patients With EGFR T790M Mutations. --- T790M ---

Objective response rate for patients with Epidermal Growth Factor Receptor (EGFR) T790M mutations. --- T790M ---

Part B only: 2. Pathologically confirmed diagnosis of Stage IV (M1a or b) non-small cell lung cancer 3. Documented Epidermal Growth Factor Receptor (EGFR) T790M mutation 4. Progression of disease on a reversible tyrosine kinase inhibitor within 30 days of starting study drug. --- T790M ---

Primary Outcomes

Description: Percentage of participants with Dose Limiting Toxicities (DLTs), based on investigator assessment, for determination of Maximum Tolerated Dose (MTD). MTD was defined as the dose in which less than 2 of up to 6 patients developed a DLT.

Measure: Percentage of Participants With Dose Limiting Toxicities

Time: 28 days

Description: Maximum Tolerated Dose (MTD) was defined as the dose in which less than 2 of up to 6 patients developed a Dose Limiting Toxicity (DLT).

Measure: Maximum Tolerated Dose

Time: 28 days

Secondary Outcomes

Description: Objective response rate for patients with Epidermal Growth Factor Receptor (EGFR) T790M mutations. Objective response was defined as Complete Response (CR): Disappearance of all target lesion or Partial Response and (PR): >=30% decrease in the sum of the longest diameter of target lesions, according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. This endpoint was originally planned to be analysed in part B of the study, however as no participants were treated in part B the analysis was performed on the part A participants.

Measure: Objective Response Rate for Patients With EGFR T790M Mutations

Time: From first drug administration until last drug administration, up to 420 days

Description: Maximum measured concentration (Cmax) of afatinib as determined on day 3 of course 1 for patients in Part A

Measure: Cmax of Afatinib on Day 3 of Course 1

Time: 47 hours (h) 55 minutes (min), 49h, 50h, 51h, 52h, 53h, 54h, 55h after first dose administration (on day 3 of course 1)

Description: Determination of dosage for expansion cohort in Part B. Dosage was the MTD or less depending on tolerability.

Measure: Determination of Dosage for Expansion Cohort in Part B

Time: 28 days

32 French National Observatory of the Patients With Non-small Cell Lung (NSCLC) Benefiting From a Molecular Test on the Hospital Platforms of Molecular Genetics.

The French National Cancer Institute (INCa) support a 28 hospital platforms network for molecular testing of cancer patients. These platforms routinely assess a panel of biomarkers in order to speed up access of French cancer patients to targeted therapies (commercially available or through clinical trials). The objective of the BIOMARKERS-France study is to describe the epidemiological, clinical and molecular characteristics of these patients and their tumors and to assess the impact of these analyzes on their treatment (ie bio-guided therapy) as well as outcomes (response rate, progression free and overall survival).

NCT01700582 Carcinoma, Non-Small-Cell Lung ALK Gene Mutation KRAS Gene Mutation BRAF Gene Mutation
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Regarding stage IV non-squamous NSCLC patients, 7 biomarkers are assessed including activating EGFR mutations, EML4-ALK translocation and EGFR T790M, KRAS, BRAF, HER2 and PI3KCA mutations. --- T790M ---

Primary Outcomes

Description: Number of patients with EGF-R gene mutation

Measure: EGF-R gene mutation in nationwide cohort

Time: 1 Year

Secondary Outcomes

Description: Number of patients with K-RAS gene mutation

Measure: K-RAS gene mutation in nationwide cohort

Time: 1 year

Description: Number of patients with EML4-ALK translocation

Measure: EML4-ALK translocation in nationwide cohort

Time: 1 year

Description: Number of patients with BRAF gene mutation

Measure: BRAF gene mutation in nationwide cohort

Time: 1 year

Description: Number of patients with HER2 gene mutation

Measure: HER2 gene mutation in nationwide cohort

Time: 1 year

Description: Number of patients with PI3K gene mutation

Measure: PI3K gene mutation in nationwide cohort

Time: 1 year

33 Detecting EGFR T790M Mutations From Circulating Tumor Cells

The purpose of this research study is to determine if the EGFR mutation can be detected in CTCs. CTCs are cancer cells that are shed from solid tumors and float freely in the bloodstream. A device called the CTC-chip has been developed to find CTCs in the blood of patients with cancer. This is an experimental device. Using this device, the investigators will test participants' blood to try and find CTCs with the EGFR mutation and compare them with the results from the biopsy your doctor has recommended. The long-term goal of this research is to develop a way to test for the EGFR mutation that is less invasive than a tumor biopsy.

NCT01734915 Non Small Cell Lung Cancer Device: Circulating tumor cell chip
MeSH:Neoplastic Cells, Circulating

Detecting EGFR T790M Mutations From Circulating Tumor Cells. --- T790M ---

Detecting EGFR T790M Mutations From Circulating Tumor Cells The purpose of this research study is to determine if the EGFR mutation can be detected in CTCs. --- T790M ---

Primary Outcomes

Description: Calculate the number of patients in the study population with detectable EGFR mutations in the CTCs in order to demonstrate the feasibility of testing for EGFR mutations from captured CTCs

Measure: Number of patients with detectable EGFR mutations in their CTCs

Time: 2 years

Description: Determine the concordance of EGFR genotyping from CTCs compared to tumor tissue

Measure: Number of patients with CTC-derived EGFR genotyping matching their tumor-derived EGFR genotyping

Time: 2 yearss

Secondary Outcomes

Description: Explore the feasibility of EGFR genotyping from plasma circulating free DNA (cfDNA)

Measure: Number of patients with EGFR gentoype results detectable from plasma cfDNA

Time: 2 years

34 INHERIT EGFR - INvestigating HEreditary RIsk From T790M: A Multi-Centered Study to Identify and Characterize Individuals Carrying Germline EGFR Mutations

Lung cancer is a common malignancy that is associated with cigarette smoking but can also affect individuals who never smoked. It is not well understood whether there are hereditary risk factors that influence the risk of lung cancer. It has been recently found that a small number of families have an inherited (passed from parent to child) change in one of their genes that may contribute to an increased tendency to develop lung cancers, even in never smokers. In some lung cancer patients this gene, called "EGFR", contains a DNA change known as an "inherited EGFR mutation". Early data indicate that these inherited EGFR mutations may be associated with an increased risk of lung cancer. So far, only a small number of families have been found to carry inherited EGFR mutations. For this reason the risk of lung cancer associated with inherited EGFR mutations is not well understood. Understanding the risk may help investigators find ways of detecting lung cancer sooner or reducing the risk of developing lung cancer. It was recently discovered that lung cancer patients who are found to carry one rare EGFR mutation in their cancer cells, called "T790M", have an increased risk of carrying an inherited EGFR mutation in their normal cells as well. This represents a new strategy for finding individuals and families carrying inherited EGFR mutations. This research study is designed to find cancer patients whose tumors have this EGFR mutation, T790M, to find out if they also have an inherited EGFR mutation. Subjects will not have to undergo a biopsy to participate in this research study. Investigators will collect a saliva specimen from patients with a T790M in their cancer to find out if they also have an inherited EGFR mutation. Study participants found or known to carry an inherited EGFR mutation will have the option of offering their close relative the opportunity to also participate in this study. Close relatives can consider testing to see if they also carry the inherited mutation in their normal cells. Once investigators have identified individuals and relatives that carry inherited EGFR mutations in their genes, investigators will then try to understand the risk of lung cancer and other cancers. Individuals with inherited EGFR mutations will also have the opportunity to participate in future studies related to cancer and other diseases. This study is being funded in part by the Conquer Cancer Foundation of ASCO and the Bonnie J. Addario Lung Cancer Foundation.

NCT01754025 Lung Cancer

INHERIT EGFR - INvestigating HEreditary RIsk From T790M: A Multi-Centered Study to Identify and Characterize Individuals Carrying Germline EGFR Mutations. --- T790M ---

It was recently discovered that lung cancer patients who are found to carry one rare EGFR mutation in their cancer cells, called "T790M", have an increased risk of carrying an inherited EGFR mutation in their normal cells as well. --- T790M ---

This research study is designed to find cancer patients whose tumors have this EGFR mutation, T790M, to find out if they also have an inherited EGFR mutation. --- T790M ---

Investigators will collect a saliva specimen from patients with a T790M in their cancer to find out if they also have an inherited EGFR mutation. --- T790M ---

To determine the prevalence of germline EGFR mutations in lung cancer patients with EGFR T790M mutations in their tumor and in relatives of carriers of germline EGFR mutations. --- T790M ---

Explore Relationship Between High Allelic Fraction T790M in plasma genotyping and germline mutations. --- T790M ---

To explore the relationship between high allelic fraction T790M on plasma genotyping and presence of an underlying germline EGFR T790M mutation. --- T790M ---

To explore the relationship between high allelic fraction T790M on plasma genotyping and presence of an underlying germline EGFR T790M mutation. --- T790M --- --- T790M ---

Inclusion Criteria: To participate in this study a subject must meet the eligibility of one of the following cohorts: Cohort 1 - Cancer patients with T790M in their tumor must both: - Have a diagnosis of cancer of any type (lung cancer or other) - Have an EGFR mutation identified. --- T790M ---

Either EGFR T790M identified on tumor genotyping of their cancer OR on quantitative plasma genotyping with evidence of high level (>40% allelic fraction) EGFR T790M OR - Another EGFR mutation previously reported as germline detected on tumor genotyping of their cancer Cohort 2 - Relatives of carriers of germline EGFR mutations are eligible as follows: - First-degree or second-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) - Third-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) if the relative has a personal history of lung cancer or another malignancy Cohort 3 - Individuals already known to carry a germline EGFR mutation must: - Have a known germline EGFR mutation (either T790M or other novel germline EGFR mutation) Exclusion Criteria: - Subjects with lung cancer and an acquired T790M mutation first detected after exposure to an EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib - Subjects who are too ill to complete the study questionnaire or provide the necessary specimen for testing - Subjects who are unable to give informed consent - Subjects who are unable to speak or read English or Brazilian Portuguese - Subjects under the age of 18 Inclusion Criteria: To participate in this study a subject must meet the eligibility of one of the following cohorts: Cohort 1 - Cancer patients with T790M in their tumor must both: - Have a diagnosis of cancer of any type (lung cancer or other) - Have an EGFR mutation identified. --- T790M ---

Either EGFR T790M identified on tumor genotyping of their cancer OR on quantitative plasma genotyping with evidence of high level (>40% allelic fraction) EGFR T790M OR - Another EGFR mutation previously reported as germline detected on tumor genotyping of their cancer Cohort 2 - Relatives of carriers of germline EGFR mutations are eligible as follows: - First-degree or second-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) - Third-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) if the relative has a personal history of lung cancer or another malignancy Cohort 3 - Individuals already known to carry a germline EGFR mutation must: - Have a known germline EGFR mutation (either T790M or other novel germline EGFR mutation) Exclusion Criteria: - Subjects with lung cancer and an acquired T790M mutation first detected after exposure to an EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib - Subjects who are too ill to complete the study questionnaire or provide the necessary specimen for testing - Subjects who are unable to give informed consent - Subjects who are unable to speak or read English or Brazilian Portuguese - Subjects under the age of 18 Inclusion Criteria: To participate in this study a subject must meet the eligibility of one of the following cohorts: Cohort 1 - Cancer patients with T790M in their tumor must both: - Have a diagnosis of cancer of any type (lung cancer or other) - Have an EGFR mutation identified. --- T790M --- --- T790M ---

Either EGFR T790M identified on tumor genotyping of their cancer OR on quantitative plasma genotyping with evidence of high level (>40% allelic fraction) EGFR T790M OR - Another EGFR mutation previously reported as germline detected on tumor genotyping of their cancer Cohort 2 - Relatives of carriers of germline EGFR mutations are eligible as follows: - First-degree or second-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) - Third-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) if the relative has a personal history of lung cancer or another malignancy Cohort 3 - Individuals already known to carry a germline EGFR mutation must: - Have a known germline EGFR mutation (either T790M or other novel germline EGFR mutation) Exclusion Criteria: - Subjects with lung cancer and an acquired T790M mutation first detected after exposure to an EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib - Subjects who are too ill to complete the study questionnaire or provide the necessary specimen for testing - Subjects who are unable to give informed consent - Subjects who are unable to speak or read English or Brazilian Portuguese - Subjects under the age of 18 Inclusion Criteria: To participate in this study a subject must meet the eligibility of one of the following cohorts: Cohort 1 - Cancer patients with T790M in their tumor must both: - Have a diagnosis of cancer of any type (lung cancer or other) - Have an EGFR mutation identified. --- T790M --- --- T790M --- --- T790M ---

Either EGFR T790M identified on tumor genotyping of their cancer OR on quantitative plasma genotyping with evidence of high level (>40% allelic fraction) EGFR T790M OR - Another EGFR mutation previously reported as germline detected on tumor genotyping of their cancer Cohort 2 - Relatives of carriers of germline EGFR mutations are eligible as follows: - First-degree or second-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) - Third-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) if the relative has a personal history of lung cancer or another malignancy Cohort 3 - Individuals already known to carry a germline EGFR mutation must: - Have a known germline EGFR mutation (either T790M or other novel germline EGFR mutation) Exclusion Criteria: - Subjects with lung cancer and an acquired T790M mutation first detected after exposure to an EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib - Subjects who are too ill to complete the study questionnaire or provide the necessary specimen for testing - Subjects who are unable to give informed consent - Subjects who are unable to speak or read English or Brazilian Portuguese - Subjects under the age of 18 Inclusion Criteria: To participate in this study a subject must meet the eligibility of one of the following cohorts: Cohort 1 - Cancer patients with T790M in their tumor must both: - Have a diagnosis of cancer of any type (lung cancer or other) - Have an EGFR mutation identified. --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Either EGFR T790M identified on tumor genotyping of their cancer OR on quantitative plasma genotyping with evidence of high level (>40% allelic fraction) EGFR T790M OR - Another EGFR mutation previously reported as germline detected on tumor genotyping of their cancer Cohort 2 - Relatives of carriers of germline EGFR mutations are eligible as follows: - First-degree or second-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) - Third-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) if the relative has a personal history of lung cancer or another malignancy Cohort 3 - Individuals already known to carry a germline EGFR mutation must: - Have a known germline EGFR mutation (either T790M or other novel germline EGFR mutation) Exclusion Criteria: - Subjects with lung cancer and an acquired T790M mutation first detected after exposure to an EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib - Subjects who are too ill to complete the study questionnaire or provide the necessary specimen for testing - Subjects who are unable to give informed consent - Subjects who are unable to speak or read English or Brazilian Portuguese - Subjects under the age of 18 Inclusion Criteria: To participate in this study a subject must meet the eligibility of one of the following cohorts: Cohort 1 - Cancer patients with T790M in their tumor must both: - Have a diagnosis of cancer of any type (lung cancer or other) - Have an EGFR mutation identified. --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Either EGFR T790M identified on tumor genotyping of their cancer OR on quantitative plasma genotyping with evidence of high level (>40% allelic fraction) EGFR T790M OR - Another EGFR mutation previously reported as germline detected on tumor genotyping of their cancer Cohort 2 - Relatives of carriers of germline EGFR mutations are eligible as follows: - First-degree or second-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) - Third-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) if the relative has a personal history of lung cancer or another malignancy Cohort 3 - Individuals already known to carry a germline EGFR mutation must: - Have a known germline EGFR mutation (either T790M or other novel germline EGFR mutation) Exclusion Criteria: - Subjects with lung cancer and an acquired T790M mutation first detected after exposure to an EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib - Subjects who are too ill to complete the study questionnaire or provide the necessary specimen for testing - Subjects who are unable to give informed consent - Subjects who are unable to speak or read English or Brazilian Portuguese - Subjects under the age of 18 Inclusion Criteria: To participate in this study a subject must meet the eligibility of one of the following cohorts: Cohort 1 - Cancer patients with T790M in their tumor must both: - Have a diagnosis of cancer of any type (lung cancer or other) - Have an EGFR mutation identified. --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Either EGFR T790M identified on tumor genotyping of their cancer OR on quantitative plasma genotyping with evidence of high level (>40% allelic fraction) EGFR T790M OR - Another EGFR mutation previously reported as germline detected on tumor genotyping of their cancer Cohort 2 - Relatives of carriers of germline EGFR mutations are eligible as follows: - First-degree or second-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) - Third-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) if the relative has a personal history of lung cancer or another malignancy Cohort 3 - Individuals already known to carry a germline EGFR mutation must: - Have a known germline EGFR mutation (either T790M or other novel germline EGFR mutation) Exclusion Criteria: - Subjects with lung cancer and an acquired T790M mutation first detected after exposure to an EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib - Subjects who are too ill to complete the study questionnaire or provide the necessary specimen for testing - Subjects who are unable to give informed consent - Subjects who are unable to speak or read English or Brazilian Portuguese - Subjects under the age of 18 Inclusion Criteria: To participate in this study a subject must meet the eligibility of one of the following cohorts: Cohort 1 - Cancer patients with T790M in their tumor must both: - Have a diagnosis of cancer of any type (lung cancer or other) - Have an EGFR mutation identified. --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Either EGFR T790M identified on tumor genotyping of their cancer OR on quantitative plasma genotyping with evidence of high level (>40% allelic fraction) EGFR T790M OR - Another EGFR mutation previously reported as germline detected on tumor genotyping of their cancer Cohort 2 - Relatives of carriers of germline EGFR mutations are eligible as follows: - First-degree or second-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) - Third-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) if the relative has a personal history of lung cancer or another malignancy Cohort 3 - Individuals already known to carry a germline EGFR mutation must: - Have a known germline EGFR mutation (either T790M or other novel germline EGFR mutation) Exclusion Criteria: - Subjects with lung cancer and an acquired T790M mutation first detected after exposure to an EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib - Subjects who are too ill to complete the study questionnaire or provide the necessary specimen for testing - Subjects who are unable to give informed consent - Subjects who are unable to speak or read English or Brazilian Portuguese - Subjects under the age of 18 Lung Cancer If a subject have lung cancer or another cancer carrying a T790M mutation in the EGFR gene, he/she may be eligible to participate in this research study. --- T790M ---

Either EGFR T790M identified on tumor genotyping of their cancer OR on quantitative plasma genotyping with evidence of high level (>40% allelic fraction) EGFR T790M OR - Another EGFR mutation previously reported as germline detected on tumor genotyping of their cancer Cohort 2 - Relatives of carriers of germline EGFR mutations are eligible as follows: - First-degree or second-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) - Third-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) if the relative has a personal history of lung cancer or another malignancy Cohort 3 - Individuals already known to carry a germline EGFR mutation must: - Have a known germline EGFR mutation (either T790M or other novel germline EGFR mutation) Exclusion Criteria: - Subjects with lung cancer and an acquired T790M mutation first detected after exposure to an EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib - Subjects who are too ill to complete the study questionnaire or provide the necessary specimen for testing - Subjects who are unable to give informed consent - Subjects who are unable to speak or read English or Brazilian Portuguese - Subjects under the age of 18 Lung Cancer If a subject have lung cancer or another cancer carrying a T790M mutation in the EGFR gene, he/she may be eligible to participate in this research study. --- T790M --- --- T790M ---

Either EGFR T790M identified on tumor genotyping of their cancer OR on quantitative plasma genotyping with evidence of high level (>40% allelic fraction) EGFR T790M OR - Another EGFR mutation previously reported as germline detected on tumor genotyping of their cancer Cohort 2 - Relatives of carriers of germline EGFR mutations are eligible as follows: - First-degree or second-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) - Third-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) if the relative has a personal history of lung cancer or another malignancy Cohort 3 - Individuals already known to carry a germline EGFR mutation must: - Have a known germline EGFR mutation (either T790M or other novel germline EGFR mutation) Exclusion Criteria: - Subjects with lung cancer and an acquired T790M mutation first detected after exposure to an EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib - Subjects who are too ill to complete the study questionnaire or provide the necessary specimen for testing - Subjects who are unable to give informed consent - Subjects who are unable to speak or read English or Brazilian Portuguese - Subjects under the age of 18 Lung Cancer If a subject have lung cancer or another cancer carrying a T790M mutation in the EGFR gene, he/she may be eligible to participate in this research study. --- T790M --- --- T790M --- --- T790M ---

Either EGFR T790M identified on tumor genotyping of their cancer OR on quantitative plasma genotyping with evidence of high level (>40% allelic fraction) EGFR T790M OR - Another EGFR mutation previously reported as germline detected on tumor genotyping of their cancer Cohort 2 - Relatives of carriers of germline EGFR mutations are eligible as follows: - First-degree or second-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) - Third-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) if the relative has a personal history of lung cancer or another malignancy Cohort 3 - Individuals already known to carry a germline EGFR mutation must: - Have a known germline EGFR mutation (either T790M or other novel germline EGFR mutation) Exclusion Criteria: - Subjects with lung cancer and an acquired T790M mutation first detected after exposure to an EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib - Subjects who are too ill to complete the study questionnaire or provide the necessary specimen for testing - Subjects who are unable to give informed consent - Subjects who are unable to speak or read English or Brazilian Portuguese - Subjects under the age of 18 Lung Cancer If a subject have lung cancer or another cancer carrying a T790M mutation in the EGFR gene, he/she may be eligible to participate in this research study. --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Either EGFR T790M identified on tumor genotyping of their cancer OR on quantitative plasma genotyping with evidence of high level (>40% allelic fraction) EGFR T790M OR - Another EGFR mutation previously reported as germline detected on tumor genotyping of their cancer Cohort 2 - Relatives of carriers of germline EGFR mutations are eligible as follows: - First-degree or second-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) - Third-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) if the relative has a personal history of lung cancer or another malignancy Cohort 3 - Individuals already known to carry a germline EGFR mutation must: - Have a known germline EGFR mutation (either T790M or other novel germline EGFR mutation) Exclusion Criteria: - Subjects with lung cancer and an acquired T790M mutation first detected after exposure to an EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib - Subjects who are too ill to complete the study questionnaire or provide the necessary specimen for testing - Subjects who are unable to give informed consent - Subjects who are unable to speak or read English or Brazilian Portuguese - Subjects under the age of 18 Lung Cancer If a subject have lung cancer or another cancer carrying a T790M mutation in the EGFR gene, he/she may be eligible to participate in this research study. --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Either EGFR T790M identified on tumor genotyping of their cancer OR on quantitative plasma genotyping with evidence of high level (>40% allelic fraction) EGFR T790M OR - Another EGFR mutation previously reported as germline detected on tumor genotyping of their cancer Cohort 2 - Relatives of carriers of germline EGFR mutations are eligible as follows: - First-degree or second-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) - Third-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) if the relative has a personal history of lung cancer or another malignancy Cohort 3 - Individuals already known to carry a germline EGFR mutation must: - Have a known germline EGFR mutation (either T790M or other novel germline EGFR mutation) Exclusion Criteria: - Subjects with lung cancer and an acquired T790M mutation first detected after exposure to an EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib - Subjects who are too ill to complete the study questionnaire or provide the necessary specimen for testing - Subjects who are unable to give informed consent - Subjects who are unable to speak or read English or Brazilian Portuguese - Subjects under the age of 18 Lung Cancer If a subject have lung cancer or another cancer carrying a T790M mutation in the EGFR gene, he/she may be eligible to participate in this research study. --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Either EGFR T790M identified on tumor genotyping of their cancer OR on quantitative plasma genotyping with evidence of high level (>40% allelic fraction) EGFR T790M OR - Another EGFR mutation previously reported as germline detected on tumor genotyping of their cancer Cohort 2 - Relatives of carriers of germline EGFR mutations are eligible as follows: - First-degree or second-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) - Third-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) if the relative has a personal history of lung cancer or another malignancy Cohort 3 - Individuals already known to carry a germline EGFR mutation must: - Have a known germline EGFR mutation (either T790M or other novel germline EGFR mutation) Exclusion Criteria: - Subjects with lung cancer and an acquired T790M mutation first detected after exposure to an EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib - Subjects who are too ill to complete the study questionnaire or provide the necessary specimen for testing - Subjects who are unable to give informed consent - Subjects who are unable to speak or read English or Brazilian Portuguese - Subjects under the age of 18 Lung Cancer If a subject have lung cancer or another cancer carrying a T790M mutation in the EGFR gene, he/she may be eligible to participate in this research study. --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

This information will be used to answer additional questions about cancers carrying EGFR T790M mutations. --- T790M ---

Primary Outcomes

Description: To determine the prevalence of germline EGFR mutations in lung cancer patients with EGFR T790M mutations in their tumor and in relatives of carriers of germline EGFR mutations

Measure: Prevalence of EGFR mutations

Time: 2 years

Secondary Outcomes

Description: To make a preliminary assessment of the natural history of lung cancers occurring in patients with germline EGFR mutations

Measure: Preliminary Assessment of History of Lung Cancers

Time: 2 years

Description: To generate an initial estimate of the prevalence of CT-detected lung nodules in individuals with germline EGFR mutations

Measure: Estimate of Prevalence of Lung Nodules

Time: 2 years

Description: To study EGFR expression in skin biopsies from patients on study

Measure: Study EGFR Expression in Skin Biopsies

Time: 2 years

Description: To explore the relationship between high allelic fraction T790M on plasma genotyping and presence of an underlying germline EGFR T790M mutation

Measure: Explore Relationship Between High Allelic Fraction T790M in plasma genotyping and germline mutations

Time: 2 years

Description: To study individuals and families with rare germline mutations, such as EGFR V843I and EGFR R776H

Measure: Examine Lung Cancer Risk Associated with Other Germline Mutations

Time: 2 years

35 ARCHER 1050: A Randomized, Open-Label Phase 3 Efficacy and Safety Study Of Dacomitinib (PF-00299804) Vs. Gefitinib For The First-Line Treatment Of Locally Advanced or Metastatic NSCLC In Subjects With EGFR-Activating Mutations

This is a multinational, multicenter, randomized, open-label, Phase 3 study comparing the efficacy and safety of treatment with dacomitinib (PF-00299804) to treatment with gefitinib in patients with locally advanced or metastatic non-small cell lung cancer, with epidermal growth factor receptor EGFR-activating mutation (s). Analyses of primary objective (Progression Free Survival) will be done as defined in the protocol.

NCT01774721 Non-small Cell Lung Cancer With EGFR-Activating Mutations Drug: Dacomitinib (PF-00299804) Drug: Gefitinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- It is acceptable for subjects with the presence of the exon 20 T790M mutation together with either EGFR-activating mutation (exon 19 deletion or the L858R mutation in exon 21) to be included in this study - Minimum of 12 months disease free interval between completion of systemic therapy and recurrence of NSCLC - Adequate tissue sample must be available for central analyses. --- T790M ---

- Any other mutation other than exon 19 deletion or L858R in exon 21, with or without the presence of the exon 20 T790M mutation. --- L858R --- --- T790M ---

Primary Outcomes

Description: PFS: time from randomization to date of progression of disease (PD) as determined by IRC review as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria or death due to any cause, whichever occurred first. PD for target lesions: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, with minimum absolute increase of 5 mm; for non-target lesions: unequivocal progression of pre-existing lesions. Overall tumor burden increased sufficiently to merit discontinuation of therapy. In presence of stable disease (did not achieve partial response, complete response or PD) or partial response (>=30% decrease under baseline of sum of diameters of all target measurable lesions, short diameter used in the sum for target nodes, longest diameter used in sum for all other target lesions) in target disease; for new lesions: appearance of any new unequivocal malignant lesion indicated PD.

Measure: Progression Free Survival (PFS) Based on Independent Radiologic Central (IRC) Review

Time: Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression or death due to any cause, whichever occurred first (up to 48 months)

Secondary Outcomes

Description: PFS: time from randomization to date of PD as determined by investigator assessment as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria or death due to any cause, whichever occurred first. PD for target lesions: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, with minimum absolute increase of 5 mm; for non-target lesions: unequivocal progression of pre-existing lesions. Overall tumor burden increased sufficiently to merit discontinuation of therapy. In presence of stable disease (did not achieve partial response, complete response or PD) or partial response (>=30% decrease under baseline of sum of diameters of all target measurable lesions, short diameter used in the sum for target nodes, longest diameter used in sum for all other target lesions) in target disease; for new lesions: appearance of any new unequivocal malignant lesion indicated PD.

Measure: Progression Free Survival (PFS) Based on Investigator Assessment

Time: Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression or death due to any cause, whichever occurred first (up to 48 months)

Description: Number of participants with BOR based on IRC review(complete response[CR] or confirmed partial response[PR]) was recorded from randomization until disease progression based on RECISTv1.1. CR for target lesion: disappearance of all target lesions with exception of nodal disease. All target nodes must decreased to normal size(short axis <10 mm); for non-target lesions: disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be 'normal' in size(=30% decrease under baseline of sum of all target measurable lesions, short diameter was used in sum for target nodes, longest diameter was used in sum for all other target lesions. PD was defined as 20% increase in sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm.

Measure: Number of Participants With Best Overall Response (BOR) Based on IRC Review

Time: Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression (up to 48 months)

Description: Number of participants with BOR based on investigator assessment (CR or confirmed PR) was recorded from randomization until disease progression based on RECIST v1.1. CR for target lesion: disappearance of all target lesions with exception of nodal disease. All target nodes must decreased to normal size (short axis <10 mm); for non-target lesions: disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be 'normal' in size (=30% decrease under baseline of sum of all target measurable lesions, short diameter was used in sum for target nodes, longest diameter was used in sum for all other target lesions. PD was defined as 20% increase in sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm.

Measure: Number of Participants With Best Overall Response (BOR) Based on Investigator Assessment

Time: Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression (up to 48 months)

Description: Percentage of participants with a BOR of either CR or PR based on IRC review recorded from the start of treatment until disease progression based on RECIST v1.1. CR for target lesion: disappearance of all target lesions with exception of nodal disease. All target nodes must decreased to normal size (short axis <10 mm); for non-target lesions: disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be 'normal' in size (=30% decrease under baseline of sum of all target measurable lesions, short diameter was used in sum for target nodes, longest diameter was used in sum for all other target lesions. PD was defined as 20% increase in sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm.

Measure: Objective Response Rate (ORR) Based on IRC Review

Time: Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression (up to 48 months)

Description: Percentage of participants with a BOR of either CR or PR based on investigator assessment recorded from the start of treatment until disease progression based on RECIST v1.1. CR for target lesion: disappearance of all target lesions with exception of nodal disease. All target nodes must decreased to normal size (short axis <10 mm); for non-target lesions: disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be 'normal' in size (=30% decrease under baseline of sum of all target measurable lesions, short diameter was used in sum for target nodes, longest diameter was used in sum for all other target lesions. PD was defined as 20% increase in sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm.

Measure: Objective Response Rate (ORR) Based on Investigator Assessment

Time: Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression (up to 48 months)

Description: DoR was defined as time from first documentation of objective response(CR or PR, whichever occurred first)to date of PD or death from any cause, whichever occurred first. CR for target lesion: disappearance of all target lesions with exception of nodal disease. All target nodes decreased to normal size(short axis <10 mm); for non-target lesions: disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be 'normal' in size(=30% decrease under baseline of sum of all target measurable lesions, short diameter used in sum for target nodes, longest diameter used in sum for all other target lesions. PD: 20% increase in sum of diameters of target measurable lesions above the smallest sum observed(over baseline if no decrease in sum is observed),with a minimum absolute increase of 5 mm. DoR was recorded based on IRC review and investigator's assessment.

Measure: Duration of Response (DoR)

Time: Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression or death due to any cause, whichever occurred first (up to 48 months)

Description: An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs were events between first dose of study drug and up to 28-35 days after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non- serious adverse events.

Measure: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Time: From baseline up to 28-35 days after last dose of study drug (up to 48 months)

Description: Laboratory parameters included haematological and biochemistry parameters. Haematology parameters included anaemia, activated partial thromboplastin time, haemoglobin, international normalized ratio, lymphocyte count, lymphopenia, neutrophils (absolute), platelets, prothrombin time and white blood cells. Biochemistry parameters included alanine aminotransferase (increased), alkaline phosphatase (increased), aspartate aminotransferase (increased), bilirubin (total), creatinine (increased), hypercalcaemia, hyperglycaemia, hyperkalaemia, hypermagnesaemia, hypernatraemia, hypoalbuminaemia, hypocalcaemia, hypoglycaemia, hypokalaemia, hypomagnesaemia, hyponatraemia. Test abnormalities were graded by AEs according to the Common Terminology Criteria for Adverse Events(NCI CTCAE) version 4.03 as Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Only categories with at least 1 participant with abnormality are reported in this outcome measure.

Measure: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI CTCAE Version 4.03: Biochemistry and Haematology

Time: From baseline up to 28-35 days after last dose of study drug (up to 48 months)

Description: Urinalysis parameter included urine protein, urine blood/haemoglobin, urine glucose and urine sediment. Test abnormalities was defined as deviation from normal range (higher or lower). Normal range of 24-hour urine protein test: less than 150 mg of protein per day, urine glucose: 0 to 0.8 mmol/L (millimole per liter), urine protein: 0 to 20 mg/dL (milligrams per deciliter). Urine blood/haemoglobin abnormality was defined as presence and absence of blood/haemoglobin in urine of participants. Urine sediment abnormality was defined as the presence of any bacteria, casts, crystals, and epithelial cells. Only categories with at least 1 participant with abnormality are reported in this outcome measure.

Measure: Number of Participants With Laboratory Test Abnormalities: Urinalysis

Time: From baseline up to 28-35 days after last dose of study drug (up to 48 months)

Description: Criteria for vital signs abnormalities: systolic pulse rate less than (<) 50 beats per minute (bpm) or greater than (>)130 bpm and maximum increase or decrease from baseline in pulse rate of 30 bpm. Systolic blood pressure of maximum increase from baseline (MIB) >=40 millimeters of mercury (mmHg), maximum decrease from baseline (MDB) in systolic blood pressure =<60 mmHg. Diastolic blood pressure of MIB >=20 mmHg and MDB in diastolic blood pressure >40 and =<20 mm Hg. Only categories with at least 1 participant with abnormality are reported in this outcome measure.

Measure: Number of Participants With Clinically Significant Abnormalities in Vital Signs

Time: From baseline up to 28-35 days after last dose of study drug (up to 48 months)

Description: ECG parameters included corrected QT interval using Bazett's formula (QTcB) and corrected QT interval using Fridericia's formula (QTcF). ECG criteria for abnormality: absolute value 450 - <480 msec, 480 - <500 msec >=500. The number of participants with potentially clinically significant ECG findings at any visit were reported.

Measure: Number of Participants With Clinically Significant Abnormality in Electrocardiogram (ECG)

Time: From baseline up to 28-35 days after last dose of study drug (up to 48 months)

Description: An ejection fraction (EF) was the volumetric fraction of blood ejected from a ventricle of the heart with each heartbeat; it was a measure of the pumping efficiency of the heart. The EF of the left heart, known as the left ventricular ejection fraction, was a measure of the efficiency of pumping into the body's systemic circulation.

Measure: Number of Participants With Maximum Relative Decrease From Baseline >20% in Left Ventricular Ejection Fraction (LVEF)

Time: From baseline up to 7 days of Cycle 4 (up to 91 days)

Description: HRQOL was measured by standardized questionnaires (European Organization for Research and Treatment of Cancer (EORTC)) quality of life questionnaires (OLQ-C30) and its lung cancer module (QLQ-LC13). TTD in pain (chest, arm/shoulder), dyspnea, fatigue or cough was defined as time between baseline and first occurrence of increase in score of 10 points or greater from baseline in any of these 4 symptoms for at least two consecutive cycles. For those who had not shown deterioration, the data was censored at the last date when the participants completed an assessment for pain, dyspnea, fatigue or cough.

Measure: Health Related Quality of Life (HRQOL): Time to Deterioration (TTD) in Pain, Dyspnea, Fatigue or Cough

Time: Baseline until the end of treatment (up to 48 months)

Description: The Euro Quality of Life-5 dimension (EQ-5D) is a brief self-administered, validated reliable generic health status instrument. EQ-5D general health status can also be measured by a visual analog scale (EQ-5D VAS). EQ-5D VAS measures the participant's self-rated health status on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state).

Measure: Overall Mean Scores of Euro Quality of Life-5 Dimension Visual Analog Scale (EQ-5D VAS)

Time: From Cycle 1 to 41 (up to 48 months)

Measure: Maximum Observed Plasma Concentration (Cmax) of Dacomitinib and Its Metabolite PF-05199265

Time: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Dacomitinib and Its Metabolite PF-05199265

Time: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Measure: Area Under the Plasma Concentration-Time Curve From Time 0 to End of Dosing Interval (AUCtau) of Dacomitinib and Its Metabolite PF-05199265

Time: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Measure: Averaged Plasma Concentration at Steady State (Cavg) of Dacomitinib and Its Metabolite PF-05199265

Time: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Measure: Minimum Observed Plasma Concentration (Cmin) of Dacomitinib and Its Metabolite PF-05199265

Time: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Description: Fluctuation coefficient between trough and peak plasma concentration was determined as Cmax-Ctrough divided by Cavg, where Cmax was the maximum observed concentration within the dosing interval, Ctrough was the observed concentration prior to dose administration and Cavg was averaged plasma concentration at steady state.

Measure: Fluctuation Coefficient Between Trough and Peak Plasma Concentration (DF) of Dacomitinib and Its Metabolite PF-05199265

Time: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Description: Drug clearance was a quantitative measure of the rate at which a drug substance was removed from the blood (rate at which a drug is metabolized or eliminated by normal biological processes).

Measure: Apparent Clearance (CL) of Dacomitinib

Time: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Description: Trough plasma concentration was defined as the measured concentration at the end of a dosing interval at steady state (taken directly before next administration).

Measure: Pre-dose Plasma Concentrations (Ctrough) of Dacomitinib and Its Metabolite PF-05199265

Time: Pre-dose on Day 1 of Cycle 2, 3, 4, 5 and 6

36 Detection of Resistance Genes From Serially Collected Plasma DNA in Non-small Cell Lung Cancer Patients Harboring EGFR Activating Mutation Who Are Being Treated With EGFR TKIs

To detect resistance gene from serially collected plasma DNA in non-small cell lung cancer harbouring EGFR activating mutation who are being treated with EGFR TKIs by using castPCR method.

NCT01776684 EGFR Mutation Positive Non-small Cell Lung Cancer Drug: EGFR TKIs (gefitinib, erlotinib, afatinib, et al)
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

To evaluate the efficiency of castPCR method for detection of resistance genes, especially, T790M mutation from serially collected plasma DNA in non-small cell lung cancer patients harboring EGFR activating mutation who are being treated with EGFR TKIs. --- T790M ---

Primary Outcomes

Description: To evaluate the efficiency of castPCR method for detection of resistance genes, especially, T790M mutation from serially collected plasma DNA in non-small cell lung cancer patients harboring EGFR activating mutation who are being treated with EGFR TKIs

Measure: detection of resistant gene

Time: 24 months

37 Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of AZD9291 in Patients With Advanced Non Small Cell Lung Cancer Who Progressed on Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent

This study will treat patients with advanced NSCLC who have already received at least one course of specific anti-cancer treatment but the tumour has started to re-grow following that treatment. This is the first time this drug has ever been tested in patients, and so it will help to understand what type of side effects may occur with the drug treatment, it will measure the levels of drug in the body, it will also measure the anti-cancer activity. By using these pieces of information together the best dose of this drug to use in further clinical trials will be selected.

NCT01802632 Advanced Non Small Cell Lung Cancer Advanced (Inoperable) Non Small Cell Lung Cancer Drug: AZD9291
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- For dose expansion and extension cohorts, patients must also have confirmation of tumour T790M mutation status (confirmed positive or negative) from a biopsy sample taken after disease progression on the most recent treatment regimen (irrespective of whether this is EGFR TKI or chemotherapy). --- T790M ---

Prior to entry a result from the central analysis of the patient's T790M mutation status must be obtained. --- T790M ---

Primary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (by investigator assessment) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR) for Dose Expansion Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. Not evaluable (NE): TL response is missing and there is no evidence of progression of NTLs and no new lesions. BOR is the best response (by investigator assessment) a patient has achieved where the order of best to worst is CR, PR, SD, PD, NE prior to or at progression and prior to further anti-cancer therapy.

Measure: Best Objective Response (BOR) for Dose Escalation Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 25 months (at time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (by independent central review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR) for Extension Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 12 months (at the time of analysis)

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. DoR was defined as the time from the date of first documented response (CR or PR that was subsequently confirmed) until the date of documented progression (PD) or death in the absence of disease progression (by investigator assessment).

Measure: Duration of Response (DoR) for Dose Expansion Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. PFS is the time from date of first dose until the date of PD (by independent central review) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from AZD9291 therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.

Measure: Progression-Free Survival (PFS) for Dose Expansion Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. Not evaluable (NE): TL response is missing and there is no evidence of progression of NTLs and no new lesions. BOR is the best response (by investigator assessment) a patient has achieved where the order of best to worst is CR, PR, SD, PD, NE prior to or at progression and prior to further anti-cancer therapy.

Measure: Best Objective Response (BOR) for 80mg AZD9291 Extension Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 12 months (at the time of analysis)

38 A Prospective, Open-label, Single Arm, Multi-center, Phase II Exploratory Trial to Evaluate the Efficacy and Safety of NOV120101 (Poziotinib) as the First-line Treatment Medication in Patients With Harboring EGFR Mutations

The purpose of this open-label, single-arm, multi-center phase II trial is to evaluate the efficacy and safety of novel pan-HER inhibitor, NOV120101 (Poziotinib), as a first-line monotherapeutic agent in patients with lung adenocarcinoma harboring EGFR mutation.

NCT01819428 Adenocarcinoma of Lung Stage IIIB Adenocarcinoma of Lung Stage IV Drug: NOV120101 (Poziotinib)
MeSH:Adenocarcinoma Adenocarcinoma of Lung

to observe HGF expression status in plasma and T790M mutation induction status from plasma DNA. --- T790M ---

Primary Outcomes

Description: the proportion of patients with complete response (CR) and/or partial response (PR)

Measure: Objective response rate (ORR)

Time: about 3 years

Secondary Outcomes

Description: the proportion of patients with complete response (CR) and/or partial response (PR) at 12 months following start of study drug administration.

Measure: Progression free survival (PFS) rate at 12 months

Time: 12 months after enrollment of the last subject

Description: the proportion of patients with CR, PR and/or stable disease (SD)

Measure: Disease control rate (DCR)

Time: 3 years

Description: The length of time during and after medication or treatment during which the disease being treated (usually cnacer) does not get worse.

Measure: Progression free survival (PFS)

Time: 3 years

Description: the time from study drug administration until death from any cause

Measure: Overall survival (OS)

Time: 3 years

Description: Change means the end of treatment minus baseline in each patient

Measure: Change of quality of life (QoL) measured by EQ-5D questionnaire

Time: 3 years

Other Outcomes

Description: to observe pharmacokinetic parameter, inter-individual variability and intra-individual variability considering covariates, demographic factors, influencing PK profile.

Measure: Population pharmacokinetics (PK) of NOV120101 (Poziotinib)

Time: 3 months after enrollment of the last subject

Description: to observe HGF expression status in plasma and T790M mutation induction status from plasma DNA

Measure: Subgroup analyses according to the genetic information

Time: 3 years

39 A Randomized Phase II Study of Individualized Combined Modality Therapy for Stage III Non-small Cell Lung Cancer (NSCLC)

This randomized phase II trial studies how well erlotinib hydrochloride or crizotinib with chemoradiation therapy works in treating patients with stage III non-small cell lung cancer. Radiation therapy uses high energy x rays to kill tumor cells. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs used in chemotherapy, such as cisplatin, etoposide, paclitaxel, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving erlotinib hydrochloride is more effective than crizotinib with chemoradiation therapy in treating patients with non-small cell lung cancer.

NCT01822496 Stage III Non-Small Cell Lung Cancer AJCC v7 Stage IIIA Non-Small Cell Lung Cancer AJCC v7 Stage IIIB Non-Small Cell Lung Cancer AJCC v7 Radiation: Radiation Therapy Drug: Carboplatin Drug: Cisplatin Drug: Crizotinib Drug: Erlotinib Drug: Etoposide Drug: Paclitaxel
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Histologically or cytologically confirmed, newly diagnosed non-squamous NSCLC - Unresectable stage IIIA or IIIB disease; patients must be surgically staged to confirm N2 or N3 disease; patients may have invasive mediastinal staging by mediastinoscopy, mediastinotomy, endobronchial ultrasound transbronchial aspiration (EBUS-TBNA), endoscopic ultrasound (EUS), or video-assisted thoracoscopic surgery (VATS) - Patients with any tumor (T) with node (N)2 or N3 are eligible; patients with T3, N1-N3 disease are eligible if deemed unresectable; patients with T4, any N are eligible - Patients must have measurable disease, i.e., lesions that can be accurately measured in at least 1 dimension (longest dimension in the plane of measurement is to be recorded) with a minimum size of 10 mm by computed tomography (CT) scan (CT scan slice thickness no greater than 5 mm) - Patients with a pleural effusion, which is a transudate, cytologically negative and non-bloody, are eligible if the radiation oncologist feels the tumor can be encompassed within a reasonable field of radiotherapy - If a pleural effusion can be seen on the chest CT but not on chest x-ray and is too small to tap, the patient will be eligible; patients who develop a new pleural effusion after thoracotomy or other invasive thoracic procedure will be eligible - The institution's pre-enrollment biomarker screening at a Clinical Laboratory Improvement Amendments (CLIA) certified lab documents presence of known "sensitive" mutations in epidermal growth factor receptor tyrosine kinase (EGFR TK) domain (exon 19 deletion, L858) and/or EML4-anaplastic lymphoma kinase (ALK) fusion arrangement; either the primary tumor or the metastatic lymph node tissue may be used for testing of mutations - The institution's pre-enrollment biomarker screening at a CLIA certified lab documents absence of T790M mutation in the EGFR TK domain - Appropriate stage for protocol entry, including no distant metastases, based upon the following minimum diagnostic workup: - History/physical examination, including recording of pulse, blood pressure (BP), weight, and body surface area, within 45 days prior to registration - Whole body fludeoxyglucose-positron emission tomography (FDG-PET)/CT (orbits to mid-thighs) within 30 days prior to registration; PET/CT must be negative for distant metastasis - CT scan with contrast of the chest and upper abdomen to include liver and adrenals (unless medically contraindicated) within 30 days prior to registration - Magnetic resonance imaging (MRI) of the brain with contrast (or CT scan with contrast, if MRI medically contraindicated) within 30 days prior to registration - Zubrod performance status 0-1 within 14 days prior to registration - Absolute neutrophil count (ANC) >= 1,000 cells/mm^3 - Platelets >= 100,000 cells/mm^3 - Hemoglobin >= 8.0 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 8.0 g/dl is acceptable) - Serum creatinine < 1.5 mg/dL or calculated creatinine clearance >= 50 ml/min (by Cockcroft-Gault formula) within 14 days prior to registration - Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN) within 14 days prior to registration - Bilirubin within normal institutional limits within 14 days prior to registration - Negative serum pregnancy test within 14 days prior to registration for women of childbearing potential - Patient must provide study specific informed consent prior to study entry, including consent for mandatory screening of tissue Exclusion Criteria: - Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 730 days (2 years) (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible) - Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable - Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields - Atelectasis of the entire lung - Contralateral hilar node involvement - Exudative, bloody, or cytologically malignant effusions - Severe, active co-morbidity, defined as follows: - Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months - Transmural myocardial infarction within the last 6 months - Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration - Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration; hepatic insufficiency resulting in clinical jaundice and/or coagulation defects - Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol; protocol-specific requirements may also exclude immuno-compromised patients - Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception - Prior allergic reaction to the study drug(s) involved in this protocol Inclusion Criteria: - Histologically or cytologically confirmed, newly diagnosed non-squamous NSCLC - Unresectable stage IIIA or IIIB disease; patients must be surgically staged to confirm N2 or N3 disease; patients may have invasive mediastinal staging by mediastinoscopy, mediastinotomy, endobronchial ultrasound transbronchial aspiration (EBUS-TBNA), endoscopic ultrasound (EUS), or video-assisted thoracoscopic surgery (VATS) - Patients with any tumor (T) with node (N)2 or N3 are eligible; patients with T3, N1-N3 disease are eligible if deemed unresectable; patients with T4, any N are eligible - Patients must have measurable disease, i.e., lesions that can be accurately measured in at least 1 dimension (longest dimension in the plane of measurement is to be recorded) with a minimum size of 10 mm by computed tomography (CT) scan (CT scan slice thickness no greater than 5 mm) - Patients with a pleural effusion, which is a transudate, cytologically negative and non-bloody, are eligible if the radiation oncologist feels the tumor can be encompassed within a reasonable field of radiotherapy - If a pleural effusion can be seen on the chest CT but not on chest x-ray and is too small to tap, the patient will be eligible; patients who develop a new pleural effusion after thoracotomy or other invasive thoracic procedure will be eligible - The institution's pre-enrollment biomarker screening at a Clinical Laboratory Improvement Amendments (CLIA) certified lab documents presence of known "sensitive" mutations in epidermal growth factor receptor tyrosine kinase (EGFR TK) domain (exon 19 deletion, L858) and/or EML4-anaplastic lymphoma kinase (ALK) fusion arrangement; either the primary tumor or the metastatic lymph node tissue may be used for testing of mutations - The institution's pre-enrollment biomarker screening at a CLIA certified lab documents absence of T790M mutation in the EGFR TK domain - Appropriate stage for protocol entry, including no distant metastases, based upon the following minimum diagnostic workup: - History/physical examination, including recording of pulse, blood pressure (BP), weight, and body surface area, within 45 days prior to registration - Whole body fludeoxyglucose-positron emission tomography (FDG-PET)/CT (orbits to mid-thighs) within 30 days prior to registration; PET/CT must be negative for distant metastasis - CT scan with contrast of the chest and upper abdomen to include liver and adrenals (unless medically contraindicated) within 30 days prior to registration - Magnetic resonance imaging (MRI) of the brain with contrast (or CT scan with contrast, if MRI medically contraindicated) within 30 days prior to registration - Zubrod performance status 0-1 within 14 days prior to registration - Absolute neutrophil count (ANC) >= 1,000 cells/mm^3 - Platelets >= 100,000 cells/mm^3 - Hemoglobin >= 8.0 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 8.0 g/dl is acceptable) - Serum creatinine < 1.5 mg/dL or calculated creatinine clearance >= 50 ml/min (by Cockcroft-Gault formula) within 14 days prior to registration - Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN) within 14 days prior to registration - Bilirubin within normal institutional limits within 14 days prior to registration - Negative serum pregnancy test within 14 days prior to registration for women of childbearing potential - Patient must provide study specific informed consent prior to study entry, including consent for mandatory screening of tissue Exclusion Criteria: - Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 730 days (2 years) (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible) - Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable - Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields - Atelectasis of the entire lung - Contralateral hilar node involvement - Exudative, bloody, or cytologically malignant effusions - Severe, active co-morbidity, defined as follows: - Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months - Transmural myocardial infarction within the last 6 months - Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration - Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration; hepatic insufficiency resulting in clinical jaundice and/or coagulation defects - Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol; protocol-specific requirements may also exclude immuno-compromised patients - Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception - Prior allergic reaction to the study drug(s) involved in this protocol Stage III Non-Small Cell Lung Cancer AJCC v7 Stage IIIA Non-Small Cell Lung Cancer AJCC v7 Stage IIIB Non-Small Cell Lung Cancer AJCC v7 Lung Neoplasms Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVES: I. To assess whether patients with unresectable local-regionally advanced non-small cell lung cancer (NSCLC) treated with targeted agents based on molecular characteristics have a longer progression-free survival than those treated with standard care therapy alone. --- T790M ---

Inclusion Criteria: - Histologically or cytologically confirmed, newly diagnosed non-squamous NSCLC - Unresectable stage IIIA or IIIB disease; patients must be surgically staged to confirm N2 or N3 disease; patients may have invasive mediastinal staging by mediastinoscopy, mediastinotomy, endobronchial ultrasound transbronchial aspiration (EBUS-TBNA), endoscopic ultrasound (EUS), or video-assisted thoracoscopic surgery (VATS) - Patients with any tumor (T) with node (N)2 or N3 are eligible; patients with T3, N1-N3 disease are eligible if deemed unresectable; patients with T4, any N are eligible - Patients must have measurable disease, i.e., lesions that can be accurately measured in at least 1 dimension (longest dimension in the plane of measurement is to be recorded) with a minimum size of 10 mm by computed tomography (CT) scan (CT scan slice thickness no greater than 5 mm) - Patients with a pleural effusion, which is a transudate, cytologically negative and non-bloody, are eligible if the radiation oncologist feels the tumor can be encompassed within a reasonable field of radiotherapy - If a pleural effusion can be seen on the chest CT but not on chest x-ray and is too small to tap, the patient will be eligible; patients who develop a new pleural effusion after thoracotomy or other invasive thoracic procedure will be eligible - The institution's pre-enrollment biomarker screening at a Clinical Laboratory Improvement Amendments (CLIA) certified lab documents presence of known "sensitive" mutations in epidermal growth factor receptor tyrosine kinase (EGFR TK) domain (exon 19 deletion, L858) and/or EML4-anaplastic lymphoma kinase (ALK) fusion arrangement; either the primary tumor or the metastatic lymph node tissue may be used for testing of mutations - The institution's pre-enrollment biomarker screening at a CLIA certified lab documents absence of T790M mutation in the EGFR TK domain - Appropriate stage for protocol entry, including no distant metastases, based upon the following minimum diagnostic workup: - History/physical examination, including recording of pulse, blood pressure (BP), weight, and body surface area, within 45 days prior to registration - Whole body fludeoxyglucose-positron emission tomography (FDG-PET)/CT (orbits to mid-thighs) within 30 days prior to registration; PET/CT must be negative for distant metastasis - CT scan with contrast of the chest and upper abdomen to include liver and adrenals (unless medically contraindicated) within 30 days prior to registration - Magnetic resonance imaging (MRI) of the brain with contrast (or CT scan with contrast, if MRI medically contraindicated) within 30 days prior to registration - Zubrod performance status 0-1 within 14 days prior to registration - Absolute neutrophil count (ANC) >= 1,000 cells/mm^3 - Platelets >= 100,000 cells/mm^3 - Hemoglobin >= 8.0 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 8.0 g/dl is acceptable) - Serum creatinine < 1.5 mg/dL or calculated creatinine clearance >= 50 ml/min (by Cockcroft-Gault formula) within 14 days prior to registration - Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN) within 14 days prior to registration - Bilirubin within normal institutional limits within 14 days prior to registration - Negative serum pregnancy test within 14 days prior to registration for women of childbearing potential - Patient must provide study specific informed consent prior to study entry, including consent for mandatory screening of tissue Exclusion Criteria: - Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 730 days (2 years) (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible) - Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable - Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields - Atelectasis of the entire lung - Contralateral hilar node involvement - Exudative, bloody, or cytologically malignant effusions - Severe, active co-morbidity, defined as follows: - Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months - Transmural myocardial infarction within the last 6 months - Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration - Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration; hepatic insufficiency resulting in clinical jaundice and/or coagulation defects - Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol; protocol-specific requirements may also exclude immuno-compromised patients - Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception - Prior allergic reaction to the study drug(s) involved in this protocol Inclusion Criteria: - Histologically or cytologically confirmed, newly diagnosed non-squamous NSCLC - Unresectable stage IIIA or IIIB disease; patients must be surgically staged to confirm N2 or N3 disease; patients may have invasive mediastinal staging by mediastinoscopy, mediastinotomy, endobronchial ultrasound transbronchial aspiration (EBUS-TBNA), endoscopic ultrasound (EUS), or video-assisted thoracoscopic surgery (VATS) - Patients with any tumor (T) with node (N)2 or N3 are eligible; patients with T3, N1-N3 disease are eligible if deemed unresectable; patients with T4, any N are eligible - Patients must have measurable disease, i.e., lesions that can be accurately measured in at least 1 dimension (longest dimension in the plane of measurement is to be recorded) with a minimum size of 10 mm by computed tomography (CT) scan (CT scan slice thickness no greater than 5 mm) - Patients with a pleural effusion, which is a transudate, cytologically negative and non-bloody, are eligible if the radiation oncologist feels the tumor can be encompassed within a reasonable field of radiotherapy - If a pleural effusion can be seen on the chest CT but not on chest x-ray and is too small to tap, the patient will be eligible; patients who develop a new pleural effusion after thoracotomy or other invasive thoracic procedure will be eligible - The institution's pre-enrollment biomarker screening at a Clinical Laboratory Improvement Amendments (CLIA) certified lab documents presence of known "sensitive" mutations in epidermal growth factor receptor tyrosine kinase (EGFR TK) domain (exon 19 deletion, L858) and/or EML4-anaplastic lymphoma kinase (ALK) fusion arrangement; either the primary tumor or the metastatic lymph node tissue may be used for testing of mutations - The institution's pre-enrollment biomarker screening at a CLIA certified lab documents absence of T790M mutation in the EGFR TK domain - Appropriate stage for protocol entry, including no distant metastases, based upon the following minimum diagnostic workup: - History/physical examination, including recording of pulse, blood pressure (BP), weight, and body surface area, within 45 days prior to registration - Whole body fludeoxyglucose-positron emission tomography (FDG-PET)/CT (orbits to mid-thighs) within 30 days prior to registration; PET/CT must be negative for distant metastasis - CT scan with contrast of the chest and upper abdomen to include liver and adrenals (unless medically contraindicated) within 30 days prior to registration - Magnetic resonance imaging (MRI) of the brain with contrast (or CT scan with contrast, if MRI medically contraindicated) within 30 days prior to registration - Zubrod performance status 0-1 within 14 days prior to registration - Absolute neutrophil count (ANC) >= 1,000 cells/mm^3 - Platelets >= 100,000 cells/mm^3 - Hemoglobin >= 8.0 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 8.0 g/dl is acceptable) - Serum creatinine < 1.5 mg/dL or calculated creatinine clearance >= 50 ml/min (by Cockcroft-Gault formula) within 14 days prior to registration - Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN) within 14 days prior to registration - Bilirubin within normal institutional limits within 14 days prior to registration - Negative serum pregnancy test within 14 days prior to registration for women of childbearing potential - Patient must provide study specific informed consent prior to study entry, including consent for mandatory screening of tissue Exclusion Criteria: - Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 730 days (2 years) (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible) - Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable - Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields - Atelectasis of the entire lung - Contralateral hilar node involvement - Exudative, bloody, or cytologically malignant effusions - Severe, active co-morbidity, defined as follows: - Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months - Transmural myocardial infarction within the last 6 months - Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration - Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration; hepatic insufficiency resulting in clinical jaundice and/or coagulation defects - Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol; protocol-specific requirements may also exclude immuno-compromised patients - Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception - Prior allergic reaction to the study drug(s) involved in this protocol Stage III Non-Small Cell Lung Cancer AJCC v7 Stage IIIA Non-Small Cell Lung Cancer AJCC v7 Stage IIIB Non-Small Cell Lung Cancer AJCC v7 Lung Neoplasms Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVES: I. To assess whether patients with unresectable local-regionally advanced non-small cell lung cancer (NSCLC) treated with targeted agents based on molecular characteristics have a longer progression-free survival than those treated with standard care therapy alone. --- T790M --- --- T790M ---

Primary Outcomes

Description: Progression is defined using the Response Evaluation Criteria In Solid Tumors Criteria (RECIST) guideline v1.1 as a 20% increase in the sum of the longest diameter of target lesions, a measurable increase in a non-target lesion, or the appearance of new lesions at any location. Progression-free survival time is measured from the date of randomization to the date of first progression, death, or last known follow-up (censored). No statistical testing was done due to early study termination.

Measure: Progression-free Survival

Time: From randomization to study termination. Maximum follow-up was 39.0 months

Secondary Outcomes

Description: Per the RECIST guideline v1.1 complete response is defined as the disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. No statistical testing was done due to early study termination.

Measure: Percentage of Patients With Complete or Partial Response

Time: From randomization to study termination. Maximum follow-up was 39.0 months

Description: Adverse events (AE) are graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE.

Measure: Number of Patients With Grade 3-5 Adverse Events

Time: From randomization to study termination. Maximum follow-up was 39.0 months

Description: Overall survival time is defined as time from randomization to the date of death from any cause. Overall survival rates are estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact.

Measure: Overall Survival

Time: From randomization to study termination. Maximum follow-up was 39.0 months

Description: Progression is defined using the RECIST guideline v1.1 as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new regional lesions. Local progression is defined as progression within the planning target volume (PTV). Regional progression is defined as progression outside of the PTV but within the same lobe of the lung as the primary tumor or in regional lymph nodes as defined by the American Joint Committee on Cancer (AJCC) 7th edition nodal stations. Local-regional progression-free survival time is measured from the date of randomization to the date of first local-regional progression, death, or last known follow-up (censored). Local-regional progression-free survival rates are estimated using the Kaplan-Meier method. No testing was done due to early study termination.

Measure: Local-regional Progression-free Survival

Time: From randomization to study termination. Maximum follow-up was 39.0 months

Description: Distant progression is defined as the first occurrence of distant metastasis. Distant progression-free survival time is measured from the date of randomization to the date of first distant progression, death, or last known follow-up (censored). Distant progression-free survival rates are estimated using the Kaplan-Meier method. No testing was done due to early study termination.

Measure: Distant Progression-free Survival

Time: From randomization to study termination. Maximum follow-up was 39.0 months

Measure: Correlation Between Clinical Outcomes and Tumor Molecular Aberrations

Time: Baseline

40 A Single-arm, Phase II Study of Preoperative Gefitinib for Stage II-IIIa NSCLC With Activating EGFR Mutation

This is an open-label, single-arm, phase II interventional clinical trial. The investigators hypothesize that the application of EGFR-TKI, like gefitinib will be efficient and safe in a neo-adjuvant setting. 42 resectable stage II-IIIa NSCLC patients with EGFR activating (19/21) mutations will be eligible to be enrolled. EGFR mutation will be prospectively tested in all the participants' biopsy samples and confirmed in surgical resected samples. Eligible patients will be given gefitinib 250mg for 42days followed with surgical resection of tumor. Efficacy of preoperative gefitinib is based on radiographic (CT response/ORR), pathologic (pathologic response), surgical (complete resection) evaluations, and safety is based on adverse effect evaluations.

NCT01833572 Non-small-cell Lung Cancer Drug: Gefitinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Patients who harbouring exon 20 T790M mutation. --- T790M ---

Primary Outcomes

Measure: Objective response rate (ORR)

Time: at day 42 of gefitinib treatment

Secondary Outcomes

Measure: Pathologic response rate

Time: Pathologic response rate is depended on the pathology dignosis after surgery, an expected average of 8 weeks from enrollment.

Measure: Complete resection rate

Time: Complete resection rate is depended on the pathology dignosis after surgery, an expected average of 8 weeks from enrollment.

Measure: Number of participants with adverse events

Time: During the neoadjuvant and perioperative period, an expected average of 10 weeks from enrollment

Measure: Quality of life (QoL)

Time: During the neoadjuvant period, an expected average of 6 weeks from enrollment

Measure: Disease free survival (DFS)

Time: Participants after surgery will receive long-term follow-up for up to 5 years

Measure: Overall survival (OS)

Time: Participants after surgery will receive long-term follow-up for up to 5 years

41 Phase 2 Open Label Trial Of Oral Intermittent Dacomitinib In Patients With Advanced Nsclc

This is a Phase 2 study of oral dacomitinib given every 12 hours over days 1-4 of each two-week cycle to patients with Non-small cell lung cancer. The study includes two groups of patients, those whose tumor has a documented T790M mutation, and those without this mutation. All patients will receive repeated cycles of dacomitinib until disease progression, occurrence of unacceptable toxicity, or other withdrawal criteria are met.

NCT01858389 Non-small Cell Lung Cancer Drug: Dacomitinib Drug: Dacomitinib
MeSH:Lung Neoplasms Carcinoma, Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

The study includes two groups of patients, those whose tumor has a documented T790M mutation, and those without this mutation. --- T790M ---

Best Overall Response (BOR) in Participants With T790M Mutation. --- T790M ---

BOR was analyzed only for participants with T790M mutation according to the primary study objective.. Objective Response Rate (ORR) in Participants With T790M Mutation. --- T790M ---

BOR was analyzed only for participants with T790M mutation according to the primary study objective.. Objective Response Rate (ORR) in Participants With T790M Mutation. --- T790M --- --- T790M ---

ORR was analyzed only for participants with T790M mutation according to the primary study objective.. Disease Control Rate (DCR) for Participants With T790M Mutation. --- T790M ---

ORR was analyzed only for participants with T790M mutation according to the primary study objective.. Disease Control Rate (DCR) for Participants With T790M Mutation. --- T790M --- --- T790M ---

DCR was analyzed only for participants with T790M mutation according to the study objective.. Duration of Response in Participants With T790M Mutation. --- T790M ---

DCR was analyzed only for participants with T790M mutation according to the study objective.. Duration of Response in Participants With T790M Mutation. --- T790M --- --- T790M ---

DR was only calculated and summarized for the subgroup of participants with an objective tumor response in the cohort of participants with T790M mutation.. Progression-free Survival. --- T790M ---

- Evidence of T790M mutation to enroll in Cohort A. - Evidence of measurable disease by radiographic technique. --- T790M ---

Exclusion Criteria: - Patients with T790M mutation who stopped any prior EGFR-directed therapy without evidence of disease progression. --- T790M ---

Primary Outcomes

Description: BOR was best response from start of treatment until disease progression, according to the RECIST,v1.1. CR=disappearance of all preexisting lesions except nodal disease, with all nodal lesions decreased to normal size (short axis <10 mm) and no appearance of new unequivocal malignant lesions. PR= ≥30% decrease from baseline of sum of diameters of all target lesions with no unequivocal progression of preexisting non-target lesions or appearance of new lesions. CR and PR were confirmed on a follow-up imaging assessment ≥4 weeks after the initial response documentation. Progression= ≥20% increase in the sum of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm or unequivocal progression of pre-existing non-target lesions or appearance of any new unequivocal malignant lesions. Stable disease=not qualify for CR, PR or progression. BOR was analyzed only for participants with T790M mutation according to the primary study objective.

Measure: Best Overall Response (BOR) in Participants With T790M Mutation

Time: From baseline until disease progression, up to 61 weeks.

Description: ORR was calculated as the percentage of participants with a confirmed CR or PR relative to the total number of participants enrolled. Response Evaluation Criteria in Solid Tumors (RECIST), version (v) 1.1 were used to define CR and PR. CR=disappearance of all preexisting lesions except nodal disease, with all nodal lesions decreased to normal size (short axis <10 mm) and no appearance of new unequivocal malignant lesions. PR= ≥30% decrease from baseline of sum of diameters of all target lesions with no unequivocal progression of preexisting non-target lesions or appearance of new lesions. CR and PR were confirmed on a follow-up imaging assessment ≥4 weeks after the initial response documentation. ORR was analyzed only for participants with T790M mutation according to the primary study objective.

Measure: Objective Response Rate (ORR) in Participants With T790M Mutation

Time: From baseline to disease progression, up to 61 weeks.

Secondary Outcomes

Description: DCR was calculated as the percentage of participants with an objective response (CR or PR) or stable disease, based on the RECIST, v1.1, relative to the total number of participants enrolled in the cohort. If baseline tumor assessment was inadequate for a participant, and the participant could not be assessed for RECIST responses and had no objective status of stable disease documented at least 6 weeks after the start date and before the progression, the participant was only counted in the denominator. CR=disappearance of all preexisting lesions except nodal disease, with all nodal lesions decreased to normal size (short axis <10 mm) and no appearance of new unequivocal malignant lesions. PR= ≥30% decrease from baseline of sum of diameters of all target lesions with no unequivocal progression of preexisting non-target lesions or appearance of new lesions. DCR was analyzed only for participants with T790M mutation according to the study objective.

Measure: Disease Control Rate (DCR) for Participants With T790M Mutation

Time: From baseline to baseline to disease progression, up to 61 weeks.

Description: Duration of response was defined as the time from first documentation of response (CR or PR, whichever occurred first) to the date of disease progression or to death due to any cause, whichever occurred first. CR and PR were defined using RECIST, v1.1. CR=disappearance of all preexisting lesions except nodal disease, with all nodal lesions decreased to normal size (short axis <10 mm) and no appearance of new unequivocal malignant lesions. PR= ≥30% decrease from baseline of sum of diameters of all target lesions with no unequivocal progression of preexisting non-target lesions or appearance of new lesions. CR and PR were confirmed on a follow-up imaging assessment ≥4 weeks after the initial response documentation. DR was only calculated and summarized for the subgroup of participants with an objective tumor response in the cohort of participants with T790M mutation.

Measure: Duration of Response in Participants With T790M Mutation

Time: From baseline to date of disease progression or death, up to 61 weeks.

Description: Progression-free survival was defined as the time from the date of first dosing of dacomitinib to the date of disease progression by RECIST v1.1, per the investigators' assessment, or death due to any cause, whichever occurred first. Objective progression= ≥20% increase in the sum of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm or unequivocal progression of pre-existing non-target lesions or appearance of any new unequivocal malignant lesions.

Measure: Progression-free Survival

Time: From baseline to disease progression or death, up to 61 weeks.

Description: Progression-free survival at 4 months was defined as the percentage of participants who were alive without disease progression at 4 months relative to all participants enrolled. Disease progression was defined by RECIST v1.1. Objective progression= ≥20% increase in the sum of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm or unequivocal progression of pre-existing non-target lesions or appearance of any new unequivocal malignant lesions.

Measure: Progression-free Survival at 4 Months

Time: Month 4

Description: Cmax was observed directly from data. Whole blood for pharmacokinetic analysis was collected immediately after completion of electrocardiograms, blood pressure, and pulse rate.

Measure: Maximum Plasma Concentration (Cmax) for Dacomitinib and PF-05199265

Time: Pre-dose (hour 0), 2, 4, 6, 8, and 10 hours post-dose on Day 4, Cycle 0.

Description: Tmax was observed directly from data as time of first occurrence. Whole blood for pharmacokinetic analysis was collected immediately after completion of electrocardiograms, blood pressure, and pulse rate.

Measure: Time to Maximum Plasma Concentration (Tmax) for Dacomitinib and PF-05199265

Time: Pre-dose (hour 0), 2, 4, 6, 8, and 10 hours post-dose on Day 4, Cycle 0.

Description: ECGs recorded on Day 1 of Cycle 0 were used as baseline. For the ECGs assessments, the following directions were followed by the ECG central laboratory: Blinding of ECG readers to treatment, time, and day identifiers. Review of ECGs from a particular participant was performed by a single reader. Prespecification of the lead for internal measurements. Baseline and on-treatment ECG assessments were based on the same lead.

Measure: Changes From Time-matched Baseline in Adjusted Fridericia Corrected QT Interval (QTcF) on Echocardiogram (ECG)

Time: From Baseline to Cycle 0, Day 4

42 Phase II Trial of XL184 (Cabozantinib) Plus Erlotinib in Patients With Advanced EGFR-Mutant Non-small Cell Lung Cancer (NSCLC) Who Have Progressed on Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) Therapy

This phase II trial studies how well cabozantinib-s-malate and erlotinib hydrochloride works in treating patients with previously treated metastatic non-small cell lung cancer. Cabozantinib-s-malate and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Cabozantinib-s-malate may also stop the growth of non-small cell lung cancer by blocking blood flow to the tumor. Giving cabozantinib-s-malate together with erlotinib hydrochloride may be an effective treatment for non-small cell lung cancer.

NCT01866410 Recurrent Non-Small Cell Lung Carcinoma Stage IV Non-Small Cell Lung Cancer AJCC v7 Drug: Cabozantinib S-malate Drug: Erlotinib Hydrochloride Other: Laboratory Biomarker Analysis
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Estimated using the product-limit method of Kaplan and Meier.. Progression-free Survival by T790M Mutation Status. --- T790M ---

DNA was analyzed for the presence of the T790M point mutation.. Overall Survival by T790M Mutation Status. --- T790M ---

DNA was analyzed for the presence of the T790M point mutation.. Overall Survival by T790M Mutation Status. --- T790M --- --- T790M ---

V. Correlate outcome with tumor biomarkers such as met proto-oncogene (MET) amplification, T790M mutation, and serum markers of the vascular endothelial growth factor (VEGF) and MET pathways in a preliminary manner. --- T790M ---

Primary Outcomes

Description: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR

Measure: Objective Response Rate

Time: Up to 2 years

Secondary Outcomes

Description: Tumor doubling time was estimated using an exponential growth model. Specifically, the pre-progression scan, and the baseline scan were used to estimate the doubling time prior to enrollment, td = log(2)∗1time/1log(tumor size) [derivation, S(t) = S(to)∗2∧[(t−to)/td] for a parameterization of exponential growth with a doubling time of td. Taking the logarithm on both sides: log(S(t))-log(S(to)) = log(2)∗(t − to)/td or td = log(2)∗(t − to)/[log(S(t))-log(S(to))] = log(2)∗1time/1log(S)], the baseline scan and first evaluation scan were used to determine the doubling time. Based on pre-planned protocol assessment, we estimated the percent of patients that experienced a slowing of tumor kinetics (a 30% increase in the length of time for tumor doubling) based on RECIST v1.1 measurements. Patients who did not get a scan on study, and patients whose pre-progression scans were missing or whose pre-progression tumor size was zero or whose tumor was decreasing prior to enrollment were excluded.

Measure: Percentage of Patients With a Greater Than 30% Increase in Tumor Doubling Time

Time: Up to 2 years

Description: Grade 3 & 4 adverse events attributed to treatment agents. Events are graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.

Measure: Number of Adverse Events

Time: Up to 2 years

Description: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), ≥ 20% increase in the sum of the longest diameter of target lesions compared with the smallest-sum longest diameter recorded or the appearance of one or more new lesions; Stable Disease (SD), Neither CR, PR or PD.

Measure: Best Response Patient Count

Time: Up to 2 years

Description: Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Measure: Progression-free Survival

Time: Until disease progression or death from any cause, up to 2 years

Description: Estimated using the product-limit method of Kaplan and Meier.

Measure: Overall Survival

Time: Until death from any cause, up to 2 years

Other Outcomes

Description: Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. DNA was analyzed for the presence of the T790M point mutation.

Measure: Progression-free Survival by T790M Mutation Status

Time: Until disease progression or death from any cause, up to 2 years

Description: Estimated using the product-limit method of Kaplan and Meier.

Measure: Overall Survival by T790M Mutation Status

Time: Until death from any cause, up to 2 years

Measure: Changes in VEGF Levels

Time: Baseline up to 6 months after last study treatment

Measure: Changes in HGF Levels

Time: Baseline up to 6 months after last study treatment

43 A Multi-center Phase II Study of AUY922 in Patients With Stage IV Non-small Cell Lung Cancer (NSCLC) With Driver Molecular Alterations Other Than Sensitive EGFR Mutation, Who Have Progressed After One Line of Systemic Therapy

This is an open-label, single-arm, multicenter phase II trial in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC.

NCT01922583 Non-small Cell Lung Cancer (NSCLC) Drug: AUY922
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

AUY922 in Patient With Stage IV NSCLC This is an open-label, single-arm, multicenter phase II trial in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC. --- T790M ---

To define the by RECIST 1.1 of AUY922 in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC. --- T790M ---

- One of the molecular alterations as follows: - EGFR mutations in exon 20 T790M. --- T790M ---

A767_V769dupASV or H773_V774insH) or point mutations other than T790M; or other uncommon mutations. --- T790M ---

Non-small Cell Lung Cancer (NSCLC) Lung Neoplasms Carcinoma, Non-Small-Cell Lung Study Design: This is an open-label, single-arm, multicenter phase II trial in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC (n = 9 x 7) Objectives: Primary objective(s): To define the objective response rate by RECIST 1.1 of AUY922 in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC Secondary objective(s): (1) To define the disease control rate (complete response + partial response + stable disease >=24 weeks) of AUY922 in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC. --- T790M ---

Non-small Cell Lung Cancer (NSCLC) Lung Neoplasms Carcinoma, Non-Small-Cell Lung Study Design: This is an open-label, single-arm, multicenter phase II trial in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC (n = 9 x 7) Objectives: Primary objective(s): To define the objective response rate by RECIST 1.1 of AUY922 in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC Secondary objective(s): (1) To define the disease control rate (complete response + partial response + stable disease >=24 weeks) of AUY922 in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC. --- T790M --- --- T790M ---

Non-small Cell Lung Cancer (NSCLC) Lung Neoplasms Carcinoma, Non-Small-Cell Lung Study Design: This is an open-label, single-arm, multicenter phase II trial in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC (n = 9 x 7) Objectives: Primary objective(s): To define the objective response rate by RECIST 1.1 of AUY922 in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC Secondary objective(s): (1) To define the disease control rate (complete response + partial response + stable disease >=24 weeks) of AUY922 in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC. --- T790M --- --- T790M --- --- T790M ---

(2) To determine the progression-free survival of AUY922 in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, KRAS, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC. --- T790M ---

(3) To determine the overall survival of AUY922 in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, KRAS, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC. --- T790M ---

2. EGFR T790M mutation; EGFR exon 20 and other uncommon mutation; HER2 mutation; BRAF mutation; ALK translocation; ROS1 translocation; or RET translocation in tumor samples. --- T790M ---

Primary Outcomes

Description: To define the by RECIST 1.1 of AUY922 in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC

Measure: Objective response rate

Time: Patients will be followed up for 2 years(post disease progression)

Secondary Outcomes

Description: Patients will be followed for progression-free survival (PFS) and overall survival (OS) which will be analyzed by using a Kaplan-Meier curve. Patients will be followed up for PFS and OS for 2 years.

Measure: Efficacy, progression-free survival (PFS)

Time: Patients will be followed up for PFS and OS for 2 years.(post disease progression)

Description: Patients will be followed for overall survival (OS)

Measure: overall survival (OS)

Time: Patients will be followed up for OS for 2 years.(post disease progression)

44 A Randomized Open-Label Phase II Trial of Pemetrexed and a Platinum (Carboplatin or Cisplatin) With or Without Erlotinib in Patients With Non-Small Cell Lung Cancer Harboring Activating Epidermal Growth Factor Receptor Mutations and Acquired Resistance to First-Line EGFR TKIs, Erlotinib or Gefitinib

This randomized phase II trial studies how well pemetrexed disodium and carboplatin or cisplatin with or without erlotinib hydrochloride work in treating patients with epidermal growth factor receptor (EGFR) mutant positive stage IV non-small cell lung cancer and acquired resistance to first-line therapy with erlotinib hydrochloride or gefitinib. In patients that develop resistance to first-line therapy with EGFR tyrosine kinase inhibitors (TKIs) the drug is usually stopped and the patient is switched to chemotherapy. Drugs used in chemotherapy, such as pemetrexed disodium, carboplatin, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether pemetrexed disodium and carboplatin or cisplatin is more effective with or without erlotinib hydrochloride in treating patients with EGFR mutant non-small cell lung cancer and acquired resistance to EGFR TKIs.

NCT01928160 Recurrent Non-small Cell Lung Cancer Stage IV Non-small Cell Lung Cancer Drug: pemetrexed disodium Drug: carboplatin Drug: cisplatin Drug: erlotinib hydrochloride Other: laboratory biomarker analysis
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

TERTIARY OBJECTIVES: I. To determine whether presence of the T790M resistance mutation can be used to predict which patients will benefit from the addition of erlotinib to chemotherapy. --- T790M ---

Primary Outcomes

Description: The Kaplan-Meier approach will be used to estimate the time-to-PFS distribution (and median PFS times) for each treatment arm. The stratified log-rank test will be used to compare the PFS distributions between the two treatment arms. The stratified Cox-regression model will be used to estimate the hazard ratio (erlotinib plus chemotherapy vs chemotherapy alone) and corresponding 80% confidence interval (CI).

Measure: Progression free survival using the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1

Time: From randomization to the first occurrence of disease progression or death from any cause, whichever occurs earlier, assessed up to 1 year

Secondary Outcomes

Description: The Kaplan-Meier approach will be used. The stratified log-rank test will be used to compare the Overall Survival (OS) distributions between the two treatment arms. The stratified Cox-regression model will be used to estimate the hazard ratio (erlotinib plus chemotherapy vs chemotherapy alone) and corresponding 80% confidence interval (CI).

Measure: Overall survival

Time: From the date of randomization to the date of death from any cause, assessed up to 1 year

Description: An estimate of the objective response rate and its 95% CI (Blyth-Still-Casella) will be calculated for each treatment arm. The Mantel-Haenszel chi-squared test stratified according to the factors specified by EGFR activating mutation type (exon 19 deletion vs. exon 21 single point mutation), time to progression on first-line EGFR TKI (≤ 1 year vs. > 1 year), and ECOG performance status (0 vs. 1) will be used to compare the response rates between the two treatment arms. An unadjusted Fisher's exact test result will also be provided.

Measure: Objective response rate defined as partial response (PR) and complete response (CR) using RECIST version 1.1

Time: Up to 1 year

Description: Safety will be assessed through summaries of Adverse Events (AEs), Serious Adverse Events (SAEs), deaths, grade 3 or 4 AEs, AEs with incidence rates greater than 10% (all grades), AE of grade 3 or 4 with incidence rates greater 2%, and changes in laboratory test results. Verbatim descriptions of AEs will be mapped to Medical Dictionary for Regulatory Activities (MedDRA) thesaurus terms

Measure: Number of patients with each worst grade toxicity grades 3-5 based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4

Time: Up to 45 days post-treatment

45 A Retrospective, Non-interventional Study to Evaluate EGFR-Tyrosine Kinase Inhibitor Retreatment in Patients With Locally Advanced or Metastatic EGFR Mutated NSCLC Who Previously Treated With EGFR-TKI as First-line Therapy and Chemotherapy as Second-line Therapy - SEQUENCE Study

This is a retrospective, non-interventional, multicenter, observational chart review study to explore the clinical benefits of retreatment with TKI in the real world.

NCT01955681 Locally Advanced or Metastatic EGFR Mutated NSCLC.

Exclusion Criteria: 1. Patients with EGFR mutation status of positive exon 20 T790M mutation only. --- T790M ---

Primary Outcomes

Description: The median duration of re-administration of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor will be summarized by days or months, if applicable. The range of this treatment duration will also be presented. All analyses will be performed on all eligible patients in this study.

Measure: The treatment duration of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor re-administration

Time: From the start of re-administration of EGFR-TKI to data cut-off date, assessed approximately up to 6 months.

Secondary Outcomes

Description: The outcome of progression-free survival will be presented with median values and associated 95% CIs by Kaplan-Meier curve. PFS is defined as the time interval (in weeks) from the start date of a given treatment to the date of disease progression or death, respectively, which one is observed first. Subjects who did not progress or die without a reported progression will be censored on the date of their last tumor assessment.

Measure: Assessment of progression-free survival for initial, second EGFR-TKI treatment and chemotherapy between two Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor treatments.

Time: From the start of administration of EGFR-TKI to data cut-off date, assessed approximately up to 6 months.

Description: The outcome of overall survival will be presented with median values and associated 95% CIs by Kaplan-Meier curve. OS is defined as the time interval (in weeks) from the beginning of treatment until the date when death or lost to follow up is observed. For those subjects who have not died or lost to follow-up, survival duration will be censored at the last date the subject was known to be alive.

Measure: Assessment of overall survival for initial, second EGFR-TKI treatment and chemotherapy between two Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor treatments.

Time: From the start of administration of EGFR-TKI to data cut-off date, assessed approximately up to 6 months.

Description: The outcome about response rate and the proportion of response rate are estimated by all evaluable patients. The 95% exact confidence interval will be constructed around the rates. The best response during treatment sequences is determined in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines.

Measure: Assessment of response rate for initial, second EGFR-TKI treatment and chemotherapy between two Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor treatments.

Time: From the start of administration of EGFR-TKI to data cut-off date, assessed approximately up to 6 months.

Description: The outcome of disease control rate are estimated by all evaluable patients. The 95% exact confidence interval will be constructed around the rates. Disease Control Rate is defined as patients who are respond to treatment (including CR-complete respond, PR-partial respond or SD- Stable Disease).

Measure: Assessment of disease control rate for initial, second EGFR-TKI treatment and chemotherapy between two Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor treatments.

Time: From the start of administration of EGFR-TKI to data cut-off date, assessed approximately up to 6 months.

Description: Treatment duration in the initial EGFR-TKI therapy and first time chemotherapy.

Measure: Record treatment duration in the initial EGFR-TKI therapy and first time chemotherapy.

Time: Between the initial EGFR-TKI therapy and first time chemotherapy.

Description: Record the reason(s) for treatment change for initial and re-administration of EGFR-TKI therapy and first time chemotherapy (second-line treatment).

Measure: Record the reason(s) for treatment change for initial and re-administration of EGFR-TKI therapy and first time chemotherapy (second-line treatment).

Time: From the start of administration of EGFR-TKI to data cut-off date, assessed approximately up to 6 months.

Description: Explore relationships between efficacy of EGFR-TKI initial and re-administration and patient characteristics (including demographics, histology, disease stage, sites of metastasis, ECOG PS) or EGFR TKI treatment characteristics (including EGFR mutation pattern, response to initial EGFR TKI or not, length of duration between first and second EGFR-TKI treatment)

Measure: Explore relationships between efficacy of EGFR-TKI initial and re-administration and patient characteristics or EGFR TKI treatment characteristics.

Time: EGFR-TKI initial and re-administration

Description: Explore overall survival (OS), plasma CEA level and chemotherapy regimens ever used between first time chemotherapy and EGFR-TKI re-administration (including the types and number of chemotherapy regimens, and treatment duration) for those patients who have the above data available.

Measure: overall survival (OS), plasma CEA level and chemotherapy regimens ever used.

Time: between first time chemotherapy and EGFR-TKI re-administration

Description: If the images are available, conduct image peer review to evaluate tumour size retrospectively in different sequences of treatment: (1) initial and re-administration of EGFR-TKI therapy, (2) first time chemotherapy ever used (second-line treatment) after initial EGFR-TKI treatment. Peer review time point includes baseline, best response and progression of last image while stopping treatment at each treatment mentioned above.

Measure: image peer review to evaluate tumour size retrospectively in different sequences of treatment

Time: (1) initial and re-administration of EGFR-TKI therapy, (2) first time chemotherapy ever used (second-line treatment) after initial EGFR-TKI treatment.

Description: Evaluate the reason(s) for the treatment change for initial and re-administration of EGFR-TKI therapy and first time chemotherapy (second-line treatment) after peer review and compare the difference of reason(s) for the treatment change between initiatial evaluation and after peer review.

Measure: The reason(s) for the treatment change for initial and re-administration of EGFR-TKI therapy and first time chemotherapy (second-line treatment) after peer review

Time: Initial and re-administration of EGFR-TKI therapy and first time chemotherapy (second-line treatment) after peer review.

46 A Phase Ib/II Multicenter, Randomized, Open Label Trial to Compare Tepotinib (MSC2156119J) Combined With Gefitinib Versus Chemotherapy as Second‑Line Treatment in Subjects With MET Positive, Locally Advanced or Metastatic Non‑Small Cell Lung Cancer (NSCLC) Harboring EGFR Mutation and Having Acquired Resistance to Prior EGFR-Tyrosine Kinase Inhibitor (EGFR‑TKI) Therapy

This is a multi-center, open-label, randomized, Phase 1b/2 trial to determine the recommended phase 2 dose (RP2D) and to evaluate the efficacy in terms of progression free survival (PFS) of Tepotinib when used in combination with gefitinib in subjects with T790M negative, MET positive locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation and having acquired resistance to Prior EGFR-Tyrosine Kinase Inhibitor (EGFR-TKI) Therapy. This study has 2:1 randomization (Tepotinib/Gefitinib arm versus Chemotherapy arm).

NCT01982955 Non-small Cell Lung Cancer Drug: Tepotinib Drug: Gefitinib Drug: Pemetrexed Drug: Cisplatin Drug: Carboplatin
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Tepotinib With Gefitinib in Subjects With Locally Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC) This is a multi-center, open-label, randomized, Phase 1b/2 trial to determine the recommended phase 2 dose (RP2D) and to evaluate the efficacy in terms of progression free survival (PFS) of Tepotinib when used in combination with gefitinib in subjects with T790M negative, MET positive locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation and having acquired resistance to Prior EGFR-Tyrosine Kinase Inhibitor (EGFR-TKI) Therapy. --- T790M ---

PFS (assessed by investigator/site radiologist) time is defined as the time (in months) from randomization to either the first disease progression (PD) per RECIST Version 1.1 or death in T790M negative, MET+ subjects due to any cause within 84 days of either randomization or last tumor assessment. --- T790M ---

Phase II Inclusion criteria: - Locally advanced or metastatic NSCLC other than predominantly squamous histology (confirmed by either histology or cytology); - Activating mutation of the epidermal growth factor (EGFR) receptor (documented, or as determined by the central laboratory) - Acquired resistance on first-line EGFR-Tyrosine Kinase Inhibitors (EGFR-TKI) therapy including gefitinib, erlotinib, icotinib, or afatinib - EGFR T790M status after acquired resistance to first line EGFR-TKI therapy including gefitinib, erlotinib, icotinib, or afatinib treatment (as determined by the central laboratory, using a validated PCR test); - T790M negative status for the randomized part - T790M positive status for the single-arm cohort (mainland China sites only) - Availability of a fresh or archived tumor tissue (excluding fine needle aspiration and cytology samples) obtained between documentation of acquired resistance to gefitinib, erlotinib, icotinib, or afatinib and enrollment is mandatory - MET+ status, as determined by the central laboratory i.e. c-Met overexpression as determined by IHC (i.e., IHC 2+ or IHC 3+) and/or c-Met amplification and/or increased c-Met gene copy number (GCN), both determined by ISH; - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Other protocol defined inclusion criteria could apply Exclusion Criteria (Phase I and II): - Estimated life expectancy less than (<) 3 months - Inadequate bone marrow, liver or renal functions - Prior chemotherapy, biological therapy, radiation therapy, or other investigational anticancer therapy (not including palliative radiotherapy at focal sites) within 21 days prior to the first dose of trial treatment (Phase 1b only) - Prior systemic anticancer treatment with chemotherapy or other agents targeting the EGFR pathway excluding gefitinib, erlotinib, icotinib, and afatinib for advanced NSCLC (one course of chemotherapy regimen for [neo] adjuvant purpose, or one course of chemoradiation for Stage IIIa disease is allowed) (Phase 2 only) - Other protocol defined exclusion criteria could apply. --- T790M ---

Phase II Inclusion criteria: - Locally advanced or metastatic NSCLC other than predominantly squamous histology (confirmed by either histology or cytology); - Activating mutation of the epidermal growth factor (EGFR) receptor (documented, or as determined by the central laboratory) - Acquired resistance on first-line EGFR-Tyrosine Kinase Inhibitors (EGFR-TKI) therapy including gefitinib, erlotinib, icotinib, or afatinib - EGFR T790M status after acquired resistance to first line EGFR-TKI therapy including gefitinib, erlotinib, icotinib, or afatinib treatment (as determined by the central laboratory, using a validated PCR test); - T790M negative status for the randomized part - T790M positive status for the single-arm cohort (mainland China sites only) - Availability of a fresh or archived tumor tissue (excluding fine needle aspiration and cytology samples) obtained between documentation of acquired resistance to gefitinib, erlotinib, icotinib, or afatinib and enrollment is mandatory - MET+ status, as determined by the central laboratory i.e. c-Met overexpression as determined by IHC (i.e., IHC 2+ or IHC 3+) and/or c-Met amplification and/or increased c-Met gene copy number (GCN), both determined by ISH; - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Other protocol defined inclusion criteria could apply Exclusion Criteria (Phase I and II): - Estimated life expectancy less than (<) 3 months - Inadequate bone marrow, liver or renal functions - Prior chemotherapy, biological therapy, radiation therapy, or other investigational anticancer therapy (not including palliative radiotherapy at focal sites) within 21 days prior to the first dose of trial treatment (Phase 1b only) - Prior systemic anticancer treatment with chemotherapy or other agents targeting the EGFR pathway excluding gefitinib, erlotinib, icotinib, and afatinib for advanced NSCLC (one course of chemotherapy regimen for [neo] adjuvant purpose, or one course of chemoradiation for Stage IIIa disease is allowed) (Phase 2 only) - Other protocol defined exclusion criteria could apply. --- T790M --- --- T790M ---

Phase II Inclusion criteria: - Locally advanced or metastatic NSCLC other than predominantly squamous histology (confirmed by either histology or cytology); - Activating mutation of the epidermal growth factor (EGFR) receptor (documented, or as determined by the central laboratory) - Acquired resistance on first-line EGFR-Tyrosine Kinase Inhibitors (EGFR-TKI) therapy including gefitinib, erlotinib, icotinib, or afatinib - EGFR T790M status after acquired resistance to first line EGFR-TKI therapy including gefitinib, erlotinib, icotinib, or afatinib treatment (as determined by the central laboratory, using a validated PCR test); - T790M negative status for the randomized part - T790M positive status for the single-arm cohort (mainland China sites only) - Availability of a fresh or archived tumor tissue (excluding fine needle aspiration and cytology samples) obtained between documentation of acquired resistance to gefitinib, erlotinib, icotinib, or afatinib and enrollment is mandatory - MET+ status, as determined by the central laboratory i.e. c-Met overexpression as determined by IHC (i.e., IHC 2+ or IHC 3+) and/or c-Met amplification and/or increased c-Met gene copy number (GCN), both determined by ISH; - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Other protocol defined inclusion criteria could apply Exclusion Criteria (Phase I and II): - Estimated life expectancy less than (<) 3 months - Inadequate bone marrow, liver or renal functions - Prior chemotherapy, biological therapy, radiation therapy, or other investigational anticancer therapy (not including palliative radiotherapy at focal sites) within 21 days prior to the first dose of trial treatment (Phase 1b only) - Prior systemic anticancer treatment with chemotherapy or other agents targeting the EGFR pathway excluding gefitinib, erlotinib, icotinib, and afatinib for advanced NSCLC (one course of chemotherapy regimen for [neo] adjuvant purpose, or one course of chemoradiation for Stage IIIa disease is allowed) (Phase 2 only) - Other protocol defined exclusion criteria could apply. --- T790M --- --- T790M --- --- T790M ---

Primary Outcomes

Measure: Phase 1b: Number of subjects experiencing at least one dose limiting toxicity (DLT)

Time: Up to Day 21 of Cycle 1

Measure: Phase 1b: Percentage of subjects with adverse events (AEs)

Time: Baseline up to Day 30 after the last dose of study treatment

Description: PFS (assessed by investigator/site radiologist) time is defined as the time (in months) from randomization to either the first disease progression (PD) per RECIST Version 1.1 or death in T790M negative, MET+ subjects due to any cause within 84 days of either randomization or last tumor assessment. If no progression or death is observed, or if death without previously documented PD is observed after more than 84 days of last tumor assessment without progression, the PFS time will be censored on the date of last tumor assessment/date of randomization, whatever occurs later.

Measure: Phase 2 (randomized): Progression free survival (PFS) time: Investigator assessments or site radiologist assessment

Time: Up to 8 months

Secondary Outcomes

Description: PFS time is defined as the time (in months) from randomization either the first observation of PD (as assessed by the independent review committee) or occurrence of death due to any cause within 84 days of either randomization or the last tumor assessment.

Measure: Phase 2 (randomized): Progression free survival (PFS) time: Independent review assessments

Time: Time from randomization to the date of death or up to 8 months whichever occur first

Description: PFS time is defined as the time (in months) from the first administration of the trial treatment to either the first observation of documented PD per RECIST Version 1.1 or occurrence of death due to any cause within 84 days of either the first administration of the trial treatment or the last tumor assessment.

Measure: Phase 2 (single arm cohort): Progression free survival (PFS) time: Investigator and Independent review assessment

Time: Time from first administration of trial treatment to the date of death or up to 8 months whichever occur first

Description: OS time is defined as the time (in months) from randomization/the first administration of the trial treatment to the date of death in the randomized part of Phase 2/the single-arm cohort of Phase 2

Measure: Overall Survival (OS) Time

Time: Time from randomization to the date of death or up to 10 months whichever occur first

Description: Objective response is defined as complete response (CR) or partial response (PR) as the best overall response according to local radiological assessments from randomization/the first administration of the trial treatment to the first observation of PD.

Measure: Percentage of subjects with objective response according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v 1.1) criteria

Time: Every 6 weeks until Week 72 and every 12 weeks after Week 72 until radiologically documented progressive disease, death, end of trial, or starting a new treatment, whichever occurs first (assessed up to 3.5 years)

Description: Disease control is defined as CR, PR, or stable disease (SD) as the best overall response according to local radiological assessments from the date of randomization/the first administration of the trial treatment to the first observation of PD. In the case of SD, measurements must have met the SD criteria at least once after entry at a minimum interval of 42 days after randomization/the first administration of the trial treatment;

Measure: Percentage of subjects with disease control according to RECIST version 1.1 criteria

Time: Time Frame: Every 6 weeks until Week 72 and every 12 weeks after Week 72 until radiologically documented progressive disease, death, end of trial, or starting a new treatment, whichever occurs first (assessed up to 3.5 years)

Measure: Phase 1b: Area Under the Plasma Concentration Versus Time Curve from Time Zero to the Last Sampling Time AUC (0-t)

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1

Measure: Percentage of subject with treatment emergent adverse events (TEAEs), treatment related TEAEs, SAEs, treatment related SAEs, TEAEs with toxicity >= 3, treatment related TEAEs >= 3, and TEAEs leading to permanent treatment discontinuation

Time: Baseline up to Day 30 after the last dose of study treatment

Measure: Phase 1b: Area Under the Plasma Concentration Versus Time Curve within 1 dosing interval (AUC 0-tau)

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1

Measure: Phase 1b: Maximum Observed Plasma Concentration (Cmax)

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1

Measure: Phase 1b: Average Plasma Concentration (Cavg)

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1

Measure: Phase 1b: Minimum Concentration (Cmin)

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1

Measure: Phase 1b:Time to Maximum Concentration (Tmax)

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1

Measure: Phase 1b: Area Under the Curve From Time Zero to Infinity (AUC 0-inf)

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1

Measure: Phase 1b: Apparent Body Clearance of the drug from Plasma (CL/F)

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1

Measure: Phase 1b: Apparent Volume of Distribution (Vz/F)

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1

Measure: Phase 1b: Volume of Distribution at Steady State (Vss/F)

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1

Measure: Phase 1b: Apparent Terminal Rate Constant (λ z)

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1

Measure: Phase 1b: Apparent Terminal Half-Life (t1/2)

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1

Measure: Percentage of subjects with death with reasons within 30 (±3) days after the last dose of study drug

Time: 30 days after the last dose of study drug

Measure: Percentage of subjects with abnormalities in safety laboratory tests as graded by NCI-CTCAE (Version 4.0)

Time: Baseline up to Day 30 after the last dose of study treatment

Measure: Percentage of subjects with abnormalities incl. vital signs, 12-lead ECG changes, physical examination, body weight, and Eastern Cooperative Oncology Group (ECOG) PS

Time: Baseline up to Day 30 after the last dose of study treatment

Measure: Health related quality of life (HRQoL)

Time: Day 1 of Cycles 1, 3, 5, 7, 9, 11, 13, 15, 17 and every 4 cycles thereafter until disease progression or end of treatment (up to 14 days after the last dose of study drug, assessed up to 3.5 years)

Measure: Time-to-Symptom Progression (TTSP) measured by Lung Cancer Symptom Scale (LCSS)

Time: Day 1 of Cycles 1, 3, 5, 7, 9, 11, 13, 15, 17 and every 4 cycles thereafter until disease progression or end of treatment (up to 14 days after the last dose of study drug, assessed up to 3.5 years)

47 Phase I Trial Evaluating Safety and Tolerability of the Irreversible Epidermal Growth Factor Receptor Inhibitor Afatinib (BIBW 2992) in Combination With the SRC Kinase Inhibitor Dasatinib for Patients With Non-small Cell Lung Cancer (NSCLC)

The purpose of this study is to: - Find out if the study drugs Afatinib and Dasatinib can be safely given together to patients with lung cancer - Learn how these two drugs work in cancer cells when they are combined - Learn more about the side effects of these two drugs when combined - Find the highest doses of the study drugs Afatinib and Dasatinib that can be given safely without causing serious side effects

NCT01999985 Lung Cancer Non-small Cell Lung Cancer (NSCLC) Drug: Dasatinib - 1A Drug: Afatinib - 1A Drug: Dasatinib - 1B Drug: Afatinib - 1B
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Either or both of the following: Progression or recurrence of disease after receiving prior continuous gefitinib, afatinib, or erlotinib; A tumor known to harbor a de novo T790M mutation, which is known to confer EGFR TKI resistance. --- T790M ---

Primary Outcomes

Description: The MTD for this combined treatment will be defined as either: The highest dosage cohort in which six patients had been treated and there were less than two dose limiting toxicities (DLTs) or, Afatinib at the highest tolerated dose investigated (40 mg by mouth [PO] daily) plus dasatinib at the highest tolerated dose investigated (cohort 3, 140 mg PO daily).

Measure: Maximum Tolerated Dose (MTD) of Afatinib (BIBW 2992) in Combination With Dasatinib

Time: Up to 6 Months

Secondary Outcomes

Description: Estimates objective response rate (complete response [CR] and partial response [PR]) in participants with acquired EGFR resistance

Measure: Number of Participants With Objective Response

Time: Up to 6 Months

Description: Estimate the 6-month progression free survival (PFS) rate in participants with acquired EGFR resistance. Response Criteria for Phase 1B will follow RECIST v.1.1: Progressive Disease (PD) is defined as at least a 20% increase in the sum of LD of target lesions taking as references the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Measure: Median Progression Free Survival

Time: Up to 6 Months

48 A Phase IB/II, Open Label, Multicenter Study of Selumetinib Administered Orally in Combination With Gefitinib in Patients With EGFR-mutated Non-small Cell Lung Cancer Who Have Developed Acquired Resistance of EGFR Inhibitor Treatment

This is an open-label, non-randomized, multicenter phase Ib/II study, which is composed of a phase Ib dose escalation part and a phase II dose expansion part. Patients will receive selumetinib in combination with gefitinib 250mg daily. This study will enroll EGFR-mutated NSCLC patients who have developed acquired resistance to EGFR TKI treatment.

NCT02025114 Non-small Cell Lung Cancer (NSCLC) Drug: selumetinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

In the expansion phase, 10 patients with T790M and 10 patients without T790M will be enrolled. --- T790M ---

In the expansion phase, 10 patients with T790M and 10 patients without T790M will be enrolled. --- T790M --- --- T790M ---

Primary Outcomes

Description: Frequency and characteristics of DLTs to the selumetinib and gefitinib combination using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4.0. (an expected average of 18 weeks) If one patient experiences a DLT in a group of 3 or more evaluable patients, then the cohort will be expanded to include 6 evaluable patients. If only one DLT is observed in the complete cohort of 6 evaluable patients, then dose escalation may occur.

Measure: To determine the MTD and/or RP2D

Time: an expected average of 18 weeks

Secondary Outcomes

Description: to estimate overall clinical activity of selumetinib combined with gefitinib in EGFR-mutated NSCLC patients who have acquired resistance to EGFR TKIs

Measure: Overall Response Rate (ORR)

Time: Patients will be followed up for 2 years(post disease progression)

49 Ph1 Study of the Safety, PK, and PDn of Escalating Oral Doses of the Glutaminase Inhibitor CB-839, as a Single Agent and in Combination With Standard Chemotherapy in Patients With Advanced and/or Treatment-Refractory Solid Tumors

Many tumor cells, in contrast to normal cells, have been shown to require the amino acid glutamine to produce energy for growth and survival. To exploit the dependence of tumors on glutamine, CB-839, a potent and selective inhibitor of the first enzyme in glutamine utilization, glutaminase, will be tested in this Phase 1 study in patients with solid tumors. This study is an open-label Phase 1 evaluation of CB-839 in patients with advanced solid tumors. The study will be conducted in 2 parts. Part 1 is a dose escalation study enrolling patients with locally-advanced, metastatic and/or refractory solid tumors to receive CB-839 capsules orally twice or three times daily. In Part 2, patients with each of the following diseases will be enrolled: A) Triple-Negative Breast Cancer, B) Non-Small Cell Lung Cancer (adenocarcinoma), C) Renal Cell Cancer, D) Mesothelioma, E) Fumarate hydratase (FH)-deficient tumors, F) Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GIST), G) SDH-deficient non-GIST tumors, H) tumors harboring mutations in isocitrate dehydrogenase-1 (IDH1) or IDH2, and I) cMyc mutation tumors. As an extension of Parts 1 & 2, patients will be treated with CB-839 in combination with standard chemotherapy. Combination groups include: Pac-CB, CBE, CB-Erl, CBD, and CB-Cabo. Pac-CB: patients with locally-advanced or metastatic TNBC will be treated with paclitaxel and CB-839. CBE: patients with advanced clear cell RCC or papillary RCC will be treated with everolimus in combination with CB-839. CB-Erl: patients with advanced NSCLC lacking the T790M EGFR mutation will be treated with erlotinib and CB-839. CBD: patients with NSCLC harboring KRAS mutation will be treated with docetaxel and CB-839. CB-Cabo: patients with histologically confirmed diagnosis of locally-advanced, inoperable or metastatic RCC treated with cabozantinib in combination with CB-839. All patients will be assessed for safety, pharmacokinetics (plasma concentration of drug), pharmacodynamics (inhibition of glutaminase), biomarkers (biochemical markers that may predict responsiveness in later studies), and tumor response.

NCT02071862 Solid Tumors Triple-Negative Breast Cancer Non Small Cell Lung Cancer Renal Cell Carcinoma Mesothelioma Fumarate Hydratase (FH)-Deficient Tumors Succinate Dehydrogenase (SDH)-Deficient Gastrointestinal Stromal Tumors (GIST) Succinate Dehydrogenase (SDH)-Deficient Non-gastrointestinal Stromal Tumors Tumors Harboring Isocitrate Dehydrogenase-1 (IDH1) and IDH2 Mutations Tumors Harboring Amplifications in the cMyc Gene Drug: CB-839 Drug: Pac-CB Drug: CBE Drug: CB-Erl Drug: CBD Drug: CB-Cabo
MeSH:Carcinoma, Renal Cell Mesothelioma Triple Negative Breast Neoplasms Gastrointestinal Stromal Tumors Neoplasms
HPO:Clear cell renal cell carcinoma Gastrointestinal stroma tumor Neoplasm Papillary renal cell carcinoma Renal cell carcinoma

CB-Erl: patients with advanced NSCLC lacking the T790M EGFR mutation will be treated with erlotinib and CB-839. --- T790M ---

Primary Outcomes

Measure: Safety and tolerability of CB-839: Incidence of adverse events

Time: Every 21 days from study start until disease progression or unacceptable toxicity, assessed for an expected average of 6 months

Secondary Outcomes

Measure: Pharmacokinetics: Area under the Curve (AUC) of CB-839 concentration in blood

Time: Study Days 1, 15, and 22

Measure: Pharmacodynamics: % inhibition of glutaminase in blood

Time: Study Days 1 and 15

Measure: Clinical activity: Change in tumor volume from baseline

Time: Every 9 weeks until disease progression or unacceptable toxicity, assessed for an expected average of 6 months

50 Feasibility of New Biological and Histological Samples at Progression for Patients With Advanced or Metastatic Non Small Cell Lung Cancer (NSCLC)

Feasibility of new biological and histological samples at progression in patients with advanced or metastatic Non Small Cell Lung Cancer (NSCLC). A recent paper from Professor Sequist and coll. has depicted the resistance mechanisms as Thréonine790Methionine (T890M) mutation oncogene cMet (CMet) amplification. Re-biopsies showed in 14% of cases the transition between NSCLC to Small Cells Lung Cancer (SCLC). In 3 patients, resistance mechanisms have disappeared and they became again sensitive to Tyrosine Kinase Inhibitors (TKIs). It is mandatory to have a better description to natural history of the disease. This study will be conducted by the French Group of Pneumology-Oncology (Groupe Français de Pneumo Cancérologie (GFPC)) up to 100 patients during 18 Months. Each center will have to define if re-biopsies are possible or not and explain why not.

NCT02086071 Lung Cancer Procedure: re biopsy
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

One of the major resistance mechanisms is the onset of T790M mutation, which induces a non sensitivity to TKIs. --- T790M ---

has depicted the resistance mechanisms as mutation T790M or oncogene cMet (CMet) amplification. --- T790M ---

Primary Outcomes

Description: Feasibility of re-biopsies in patients with advanced or metastatic NSCLC after progression of disease under treatment. If the re-biopsy could not be performed : reason of no re-biopsy. If the biopsy could be performed : site and method of rebiopsy.

Measure: Feasibility of re-biopsies

Time: 18 months / 100 patients

Secondary Outcomes

Description: Comparison of types and numbers of resistances before treatment (on the first biopsy) and after treatment (on the re-biopsy). Appearance and/or disappearance of some resistances.

Measure: Type of resistance

Time: 18 months/100 patients

Description: Description of population: age, performance status, smoking status, sex (number, medium, maximum, minimum). Description of treatment: chemotherapy (type and products), radiotherapy (site), surgery (site)

Measure: Disease management

Time: 18 months / 100 patients

Description: Description and comparison of histology on the first biopsy and on the rebiopsy

Measure: Biological history of the disease

Time: 18 months / 100 patients

51 Phase II, Open Label, Single-arm Study to Assess Safety and Efficacy of AZD9291 in Patients With Locally Advanced/Metastatic NSCLC Whose Disease Has Progressed With Previous EGFR TKI and Whose Tumours Are EGFR and T790M Mutation Positive

A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Patients with Locally Advanced/Metastatic Non Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours are Epidermal Growth Factor Receptor Mutation and T790M Mutation Positive

NCT02094261 Non Small Cell Lung Cancer Drug: AZD9291
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Phase II, Open Label, Single-arm Study to Assess Safety and Efficacy of AZD9291 in Patients With Locally Advanced/Metastatic NSCLC Whose Disease Has Progressed With Previous EGFR TKI and Whose Tumours Are EGFR and T790M Mutation Positive. --- T790M ---

Phase II AZD9291 Open Label Study in NSCLC After Previous EGFR TKI Therapy in EGFR and T790M Mutation Positive Tumours A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Patients with Locally Advanced/Metastatic Non Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours are Epidermal Growth Factor Receptor Mutation and T790M Mutation Positive Objective Response Rate (ORR). --- T790M ---

Phase II AZD9291 Open Label Study in NSCLC After Previous EGFR TKI Therapy in EGFR and T790M Mutation Positive Tumours A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Patients with Locally Advanced/Metastatic Non Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours are Epidermal Growth Factor Receptor Mutation and T790M Mutation Positive Objective Response Rate (ORR). --- T790M --- --- T790M ---

Patients must have central confirmation of tumour T790M mutation positive status from a biopsy sample taken after confirmation of disease progression on the most recent treatment regimen. --- T790M ---

Non Small Cell Lung Cancer Carcinoma, Non-Small-Cell Lung This is a phase II, open label, single arm study assessing the safety and efficacy of AZD9291 (80 mg, orally, once daily) in patients with a confirmed diagnosis of Epidermal Growth Factor Receptor mutation positive and T790M mutation positive NSCLC,who have progressed following prior therapy with an approved Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) agent. --- T790M ---

Patients must agree to provide a biopsy for central confirmation of T790M mutation status following confirmed disease progression on the most recent treatment regimen. --- T790M ---

Primary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR)

Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. DoR was defined as the time from the date of first documented response (CR or PR that was subsequently confirmed) until the date of documented progression (PD) or death in the absence of disease progression (by investigator assessment).

Measure: Duration of Response (DoR)

Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. DCR is the percentage of patients with best response of CR, PR or SD (according to independent review), prior to progression (PD) or further anti-cancer therapy.

Measure: Disease Control Rate (DCR)

Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. PFS is the time from date of first dose until the date of PD (by independent review) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from AZD9291 therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.

Measure: Progression-Free Survival (PFS)

Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)

52 An Open-label, Phase 1 Dose Escalation Study of Oral ASP8273 in Subjects With Non-Small-Cell Lung Cancer (NSCLC) Who Have Epidermal Growth Factor Receptor (EGFR) Mutations

The purpose of this study is to assess the safety and tolerability of ASP8273 and to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D). This study will also determine the pharmacokinetics (PK) of ASP8273, evaluate the potential inhibition of CYP3A4 by ASP8273 and the antitumor activity of ASP8273 as well as determine the effect of food on the bioavailability of ASP8273.

NCT02113813 Non-Small-Cell Lung Cancer (NSCLC) Epidermal Growth Factor Receptor Mutations Drug: naquotinib Drug: midazolam
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Defined as the time from the start of the study treatment until death from any cause or radiographic disease progression assessed according to RECIST 1.1, whichever occurs first.. Inclusion Criteria: - Non-child bearing potential or able to follow birth control requirements - Eastern Cooperative Oncology Group (ECOG) ≤ 1 - Life expectancy ≥ 12 weeks - Laboratory criteria as: - Neutrophil count ≥ 1,500/mm3 - Platelet count ≥ 7.5 x 104 /mm3 - Hemoglobin ≥ 9.0 g/dL - Lymphocyte count ≥ 500/mm3 - Serum creatinine < 1.5 x institutional Upper Limit of Normal (ULN) or an estimated glomerular filtration rate (eGFR) of > 50 ml/min as calculated by the Modification of Diet in Renal Disease (MDRD) equation - Total bilirubin < 1.5 x ULN (except for subjects with documented Gilbert's syndrome) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x ULN - Dose escalation subjects: Epidermal Growth Factor Receptor (EGFR) activating mutation by local testing: exon 18 G719X, exon 19 deletion, exon 21 L861Q, exon 21 L858R or exon 20 insertion; and received prior treatment with EGFR Tyrosine Kinase Inhibitor (TKI) - Response expansion/RP2D expansion/ FE Cohort subjects: disease progression on or was intolerant to prior EGFR TKI; activating mutation as above AND T790M mutation; tumor sample subsequent to EGFR TKI is available for central testing; at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Inclusion Criteria for Exon 20 cohort: - Subject on any line of treatment and has an EGFR exon 20 insertion mutation on examination of an NSCLC tissue or cellular specimen. --- L861Q --- --- L858R --- --- T790M ---

Exclusion Criteria: - Any ongoing toxicity ≥ Grade 2 attributable to prior Non-Small-Cell Lung Cancer (NSCLC) treatment - Prior EGFR inhibitor within 6 days; received prior treatment with any other agent with antitumor activity chemotherapy, radiotherapy, or immunotherapy within 14 days; any investigational therapy within 28 days or 5 half-lives, whichever is shorter; blood transfusion or hemopoietic factor within 14 days; major surgery within 14 days; any strong CYP3A4 inhibitors within 7 days - Positive hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-HCV) or Human Immunodeficiency Virus (HIV) - Symptomatic Central Nervous System (CNS) metastasis - Active infection requiring systemic therapy within 14 days - Severe or uncontrolled systemic diseases including uncontrolled hypertension - History of or active interstitial lung disease - Screening QTcF >450 msec or current medication known to prolong QT - ≥ Grade 2 cardiac arrhythmia or uncontrolled atrial fib of any grade; Class 3 or 4 New York Heart Association congestive heart failure; history of severe/unstable angina, myocardial infarction or cerebrovascular accident within 6 months - History of gastrointestinal ulcer or bleeding within 3 months; any digestive tract dysfunction - Concurrent corneal disorder or ophthalmologic condition making subject unsuitable - RP2D cohort subjects: contraindications to midazolam, any other midazolam within 7 days, or any medications or supplements known to be strong CYP3A inhibitors within 7 days or inducers within 12 days - Any other malignancy requiring treatment Inclusion Criteria: - Non-child bearing potential or able to follow birth control requirements - Eastern Cooperative Oncology Group (ECOG) ≤ 1 - Life expectancy ≥ 12 weeks - Laboratory criteria as: - Neutrophil count ≥ 1,500/mm3 - Platelet count ≥ 7.5 x 104 /mm3 - Hemoglobin ≥ 9.0 g/dL - Lymphocyte count ≥ 500/mm3 - Serum creatinine < 1.5 x institutional Upper Limit of Normal (ULN) or an estimated glomerular filtration rate (eGFR) of > 50 ml/min as calculated by the Modification of Diet in Renal Disease (MDRD) equation - Total bilirubin < 1.5 x ULN (except for subjects with documented Gilbert's syndrome) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x ULN - Dose escalation subjects: Epidermal Growth Factor Receptor (EGFR) activating mutation by local testing: exon 18 G719X, exon 19 deletion, exon 21 L861Q, exon 21 L858R or exon 20 insertion; and received prior treatment with EGFR Tyrosine Kinase Inhibitor (TKI) - Response expansion/RP2D expansion/ FE Cohort subjects: disease progression on or was intolerant to prior EGFR TKI; activating mutation as above AND T790M mutation; tumor sample subsequent to EGFR TKI is available for central testing; at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Inclusion Criteria for Exon 20 cohort: - Subject on any line of treatment and has an EGFR exon 20 insertion mutation on examination of an NSCLC tissue or cellular specimen. --- L861Q --- --- L858R --- --- T790M ---

Primary Outcomes

Description: A DLT is defined as any pre-determined toxicity that is related to study drug per the investigator and which occurs during Cycle 0 and Cycle 1 using NCI CTCAE v4.03.

Measure: Safety and tolerability as assessed by Dose Limiting Toxicities (DLTs)

Time: up to 18 months

Description: An AE is defined as any untoward medical occurrence in a subject administered a study drug or has undergone study procedures and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.

Measure: Safety and tolerability as assessed by adverse events (AEs)

Time: up to 18 months

Description: Laboratory tests to be conducted are hematology, biochemistry, urinalysis, coagulation profile, lipid panel and lymphocyte subpopulation.

Measure: Safety and tolerability as assessed by laboratory tests

Time: up to 18 months

Description: Vital signs to be measured includes blood pressure, pulse rate and temperature.

Measure: Safety and tolerability as assessed by vital signs

Time: up to 18 months

Measure: Safety and tolerability as assessed by 12-lead electrocardiograms (ECGs)

Time: up to 18 months

Secondary Outcomes

Description: Maximum concentration (Cmax), the time after dosing when Cmax occurs (tmax), area under the concentration - time curve from time 0 up to the last quantifiable concentration (AUClast), area under the concentration - time curve from time 0 extrapolated to infinity (AUCinf), apparent terminal elimination half-life (t1/2), apparent oral systemic clearance (CL/F), Apparent volume of distribution (Vz/F)

Measure: Composite of pharmacokinetics of ASP8273 concentration and its metabolites (plasma): Cmax, tmax, AUClast, AUCinf, t1/2, CL/F, and Vz/F

Time: Cycle 0: Dose Escalation Days 1-2, FE Days 1-6; Cycle 1: Dose Escalation/Response Expansion/RP2D/FE Days 1,8,15, RP2D Day 21, Exon 20 Days 8,15; Cycle 2 & 3: Dose Escalation/Response Expansion/RP2D Days 1,2, FE Day 1; Exon 20 days 1, 2 & Cycle 3

Measure: Composite of pharmacokinetics of midazolam concentration and its metabolites (plasma): Cmax, tmax, AUClast, AUCinf, t1/2, CL/F, and Vz/F

Time: Day -1 and Day 1 of cycle 1; Day 1 and Day 2 of cycle 2

Description: Defined as proportion of subjects whose best overall response is Complete Response (CR) or Partial Response (PR) among all analyzed subjects.

Measure: Best overall response rate

Time: Up to 18 months

Description: Defined as the proportion of subjects whose best overall response is rated as CR, PR or Stable Disease (SD) among all analyzed subjects.

Measure: Disease control rate

Time: Up to 18 months

Description: Defined as the time from the start of the study treatment until death from any cause or radiographic disease progression assessed according to RECIST 1.1, whichever occurs first.

Measure: Progression free survival

Time: Up to 18 months

53 A Phase I/Pharmacokinetic Study of Erlotinib for Advanced Non-small Cell Lung Cancer in Persons With HIV Infection

This phase I trial studies the side effects and best dose of erlotinib hydrochloride in treating non-small cell lung cancer that has spread to other parts of the body or cannot be removed by surgery in patients with human immunodeficiency virus (HIV) infection. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Erlotinib hydrochloride is a standard drug used for treating lung cancer, however, it is not yet known whether it is safe to give erlotinib hydrochloride to patients who also have HIV infection or not.

NCT02134886 HIV Infection Recurrent Non-Small Cell Lung Carcinoma Stage IIIA Non-Small Cell Lung Cancer Stage IIIB Non-Small Cell Lung Cancer Stage IV Non-Small Cell Lung Cancer Drug: Erlotinib Hydrochloride Other: Laboratory Biomarker Analysis Other: Pharmacological Study Other: Quality-of-Life Assessment
MeSH:Infection Communicable Diseases HIV Infections Acquired Immunodeficiency Syndrome Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

m^2 for participants with creatinine levels above institutional normal - A cluster of differentiation (CD)4+ lymphocyte count > 50/mcL will be required within 2 weeks of study participation - Women of childbearing potential must have a negative pregnancy test within 7 days of enrollment; women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal; postmenopause is defined as amenorrhea >= 12 consecutive months; note: women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, ovarian suppression, or any other reversible reason - Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of erlotinib administration - Participants MUST receive appropriate care and treatment for HIV infection, including antiretroviral medications, when clinically indicated and should be under the care of a physician experienced in HIV management; participants will be eligible regardless of antiretroviral medication (including no antiretroviral medication) provided there is no intention to initiate therapy or the regimen has been stable for at least 4 weeks with no intention to change the regimen within 8 weeks following study entry; as study-specific (antiretroviral-based) strata fill, however, only participants who are receiving the therapies eligible for the remaining open strata will be accrued - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Participants who received prior treatment with erlotinib or other EGFR-targeted agents - Participants who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier - Participants who are receiving any other investigational agents - The participant has active brain metastases or epidural disease; participants with stable brain metastases previously treated with whole brain radiation or radiosurgery or participants with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 4 weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment; baseline brain imaging with contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) scans for participants with known brain metastases is required to confirm eligibility - History of allergic reactions attributed to compounds of similar chemical or biologic composition to erlotinib - The participant has prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test >= 1.3 the laboratory ULN within 7 days before the first dose of study treatment - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Participants with history of chronic diarrhea, grade >= 2 prior to study participation; persons with up to grade 1 diarrhea will be eligible - The participant requires chronic concomitant treatment with the following strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducers OTHER than antiretroviral agents: dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, primidone, modafinil, and other enzyme inducing anti-convulsant drugs (EIACD), and St. John's Wort; use of efavirenz or etravirine is permitted for participants considered for the CYP3A4-inducer based antiretroviral therapy (ART) regimen arm (Stratum B) of the trial - Although study participants will be eligible regardless of smoking history, smokers should be strongly advised to stop smoking while on erlotinib; smoking induces cytochrome P450, family 1, subfamily A, polypeptide 2 (CYP1A2) enzymes and alters erlotinib exposure by 64% - Participants who take medications that are not recommended for concomitant use with their current antiretroviral regimen - The participant requires concomitant treatment with the following inhibitors of CYP3A4: - Antibiotics: clarithromycin, erythromycin, telithromycin, troleandomycin - Antifungals: itraconazole, ketoconazole, voriconazole, fluconazole, posaconazole - Antidepressants: nefazodone - Antidiuretic: conivaptan - Gastrointestinal (GI): cimetidine, aprepitant - Hepatitis C: boceprevir, telaprevir - Miscellaneous: Seville oranges, grapefruit, or grapefruit juice and/or pummelos, star fruit, exotic citrus fruits, or grapefruit hybrids); use of any of anti-retrovirals (delavirdine) or protease inhibitors (ritonavir, indinavir, lopinavir/ritonavir, saquinavir, nelfinavir) is permitted; specifically, ritonavir and cobicistat is permitted for participants considered for the CYP3A4-inhibitor based ART regimen arm (Stratum A) of the trial - Participants should not have significant abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjogren's syndrome), congenital abnormality (e.g., Fuch's dystrophy), abnormal slit-lamp examination using a vital dye (e.g., fluorescein, Bengal-Rose), and/or an abnormal corneal sensitivity test (Schirmer test or similar tear production test) - Female participants may not be pregnant or breastfeeding; women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately - Persons with tumors known to have biomarkers predictive of resistance to erlotinib therapy (specifically Kirsten rat sarcoma viral oncogene homolog [KRAS] mutations, anaplastic lymphoma receptor tyrosine kinase [ALK] gene rearrangements, and EGFR T790M mutations) will be ineligible for study participation; if the results of molecular studies are not available or known at the time of study registration and subsequently become available, such participants will be considered eligible and if deriving clinical benefit may continue receiving erlotinib at the discretion of the investigator and study chair Inclusion Criteria: - Participants must have known HIV infection and histologically confirmed non-small cell lung cancer that is metastatic or unresectable; patients will be eligible regardless of tumor EGFR mutation status - Participants may have received any number of prior lines of chemotherapy (other than erlotinib or other EGFR-targeted therapy) for incurable non-small cell lung cancer; (first line platinum-doublet based chemotherapy plus switch maintenance chemotherapy counts as one line of therapy; prior adjuvant chemotherapy for early stage disease does not count as one line of therapy if 12 months or greater elapsed between completion of adjuvant therapy and initiation of first-line systemic therapy; if less than 12 months elapsed, adjuvant chemotherapy counts as one line of therapy) - PARTICIPANTS WITH NO PRIOR THERAPY FOR INCURABLE LUNG CANCER: trial eligibility will be restricted to those participants whose tumors harbor known EGFR activating mutations - PARTICIPANTS WITH PRIOR LINES OF THERAPY: all other participants (those whose tumors harbor wild-type EGFR or unknown EGFR status, or those with EGFR mutations not previously treated with erlotinib/EGFR-targeted therapy) - At least 4 weeks must have elapsed since prior chemotherapy or biological therapy, 6 weeks if the regimen included carmustine (BCNU) or mitomycin C; prior radiation therapy to the thoracic cavity, abdomen, or pelvis must be completed at least 3 months prior to registration; radiotherapy to any other site (including bone or brain metastases) must be completed at least 28 days prior to registration - Molecular characterization of non-squamous non-small cell lung cancer will be recommended prior to enrollment per standard of care/institutional guidelines; consistent with current National Comprehensive Cancer Network (NCCN) guidelines and the recent Food and Drug Administration (FDA)-approval indication of erlotinib for first-line treatment of advanced non-small cell lung cancer in persons with tumor EGFR mutations, participants who have known EGFR sensitizing mutations in tumors will be permitted to enter the study and receive erlotinib as initial monotherapy; for participants who have received one or more prior lines of chemotherapy, molecular characterization of tumors is required whenever possible with an understanding that inability to obtain sufficient tissue specimen for characterization will not preclude enrollment into the study - Participants must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria; baseline measurements and evaluation of ALL sites of disease must be obtained within 4 weeks prior to registration - Serologic documentation of HIV infection at any time prior to study entry, as evidenced by positive enzyme-linked immunosorbent assay (ELISA), positive Western blot, or any other federally approved licensed HIV test; alternatively, this documentation may include a record that another physician has documented that the participant has HIV infection based on prior ELISA and Western blot, or other approved diagnostic tests - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Life expectancy of greater than 12 weeks - Leukocytes: >= 3,000/mm^3 - Absolute neutrophil count: >= 1,500/mm^3 - Platelets: >= 100,000/mm^3 - Total bilirubin: within normal institutional limits; if, however, the participant has Gilbert's disease or unconjugated hyperbilirubinemia which is felt to be secondary to with atazanavir or indinavir therapy, then the total bilirubin must be =< 3 x upper limit of normal [ULN]) - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) / alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]): =<2.5 x institutional upper limit of normal - Hemoglobin: >= 9 g/dL - Creatinine: - Creatinine levels within normal institutional limits (< 1.5 x ULN); or, - Creatinine clearance >= 60 mL/min/1.73 --- T790M ---

m^2 for participants with creatinine levels above institutional normal - A cluster of differentiation (CD)4+ lymphocyte count > 50/mcL will be required within 2 weeks of study participation - Women of childbearing potential must have a negative pregnancy test within 7 days of enrollment; women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal; postmenopause is defined as amenorrhea >= 12 consecutive months; note: women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, ovarian suppression, or any other reversible reason - Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of erlotinib administration - Participants MUST receive appropriate care and treatment for HIV infection, including antiretroviral medications, when clinically indicated and should be under the care of a physician experienced in HIV management; participants will be eligible regardless of antiretroviral medication (including no antiretroviral medication) provided there is no intention to initiate therapy or the regimen has been stable for at least 4 weeks with no intention to change the regimen within 8 weeks following study entry; as study-specific (antiretroviral-based) strata fill, however, only participants who are receiving the therapies eligible for the remaining open strata will be accrued - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Participants who received prior treatment with erlotinib or other EGFR-targeted agents - Participants who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier - Participants who are receiving any other investigational agents - The participant has active brain metastases or epidural disease; participants with stable brain metastases previously treated with whole brain radiation or radiosurgery or participants with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 4 weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment; baseline brain imaging with contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) scans for participants with known brain metastases is required to confirm eligibility - History of allergic reactions attributed to compounds of similar chemical or biologic composition to erlotinib - The participant has prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test >= 1.3 the laboratory ULN within 7 days before the first dose of study treatment - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Participants with history of chronic diarrhea, grade >= 2 prior to study participation; persons with up to grade 1 diarrhea will be eligible - The participant requires chronic concomitant treatment with the following strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducers OTHER than antiretroviral agents: dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, primidone, modafinil, and other enzyme inducing anti-convulsant drugs (EIACD), and St. John's Wort; use of efavirenz or etravirine is permitted for participants considered for the CYP3A4-inducer based antiretroviral therapy (ART) regimen arm (Stratum B) of the trial - Although study participants will be eligible regardless of smoking history, smokers should be strongly advised to stop smoking while on erlotinib; smoking induces cytochrome P450, family 1, subfamily A, polypeptide 2 (CYP1A2) enzymes and alters erlotinib exposure by 64% - Participants who take medications that are not recommended for concomitant use with their current antiretroviral regimen - The participant requires concomitant treatment with the following inhibitors of CYP3A4: - Antibiotics: clarithromycin, erythromycin, telithromycin, troleandomycin - Antifungals: itraconazole, ketoconazole, voriconazole, fluconazole, posaconazole - Antidepressants: nefazodone - Antidiuretic: conivaptan - Gastrointestinal (GI): cimetidine, aprepitant - Hepatitis C: boceprevir, telaprevir - Miscellaneous: Seville oranges, grapefruit, or grapefruit juice and/or pummelos, star fruit, exotic citrus fruits, or grapefruit hybrids); use of any of anti-retrovirals (delavirdine) or protease inhibitors (ritonavir, indinavir, lopinavir/ritonavir, saquinavir, nelfinavir) is permitted; specifically, ritonavir and cobicistat is permitted for participants considered for the CYP3A4-inhibitor based ART regimen arm (Stratum A) of the trial - Participants should not have significant abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjogren's syndrome), congenital abnormality (e.g., Fuch's dystrophy), abnormal slit-lamp examination using a vital dye (e.g., fluorescein, Bengal-Rose), and/or an abnormal corneal sensitivity test (Schirmer test or similar tear production test) - Female participants may not be pregnant or breastfeeding; women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately - Persons with tumors known to have biomarkers predictive of resistance to erlotinib therapy (specifically Kirsten rat sarcoma viral oncogene homolog [KRAS] mutations, anaplastic lymphoma receptor tyrosine kinase [ALK] gene rearrangements, and EGFR T790M mutations) will be ineligible for study participation; if the results of molecular studies are not available or known at the time of study registration and subsequently become available, such participants will be considered eligible and if deriving clinical benefit may continue receiving erlotinib at the discretion of the investigator and study chair HIV Infection Recurrent Non-Small Cell Lung Carcinoma Stage IIIA Non-Small Cell Lung Cancer Stage IIIB Non-Small Cell Lung Cancer Stage IV Non-Small Cell Lung Cancer Infection Communicable Diseases HIV Infections Acquired Immunodeficiency Syndrome Lung Neoplasms Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of erlotinib (erlotinib hydrochloride) as a single agent in non-small cell lung cancer participants with HIV infection and to determine the maximum tolerated dose of erlotinib in combination with antiretroviral therapy in this participant population. --- T790M ---

Primary Outcomes

Measure: Incidence of toxicities evaluated with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (v4.0)

Time: Up to 30 days

Measure: Maximum tolerated dose of erlotinib hydrochloride defined as the dose level in which less than or equal to 1 out of 6 participants experiences dose-limiting toxicity evaluated with NCI CTCAE v4.0

Time: 28 days

Secondary Outcomes

Description: A repeated measures analysis of variance will be used to assess the effect of erlotinib hydrochloride on CD4+ across time points. Analyses will be done per stratum, where the data are sufficient. If the data do not meet the assumptions of normality, the data will either be transformed or Friedman's test (i.e. nonparametric analogue to a repeated measures analysis of variance) will be used.

Measure: CD4+ counts

Time: Up to 30 days

Description: A repeated measures analysis of variance will be used to assess the effect of erlotinib hydrochloride on CD8+ across time points. Analyses will be done per stratum, where the data are sufficient. If the data do not meet the assumptions of normality, the data will either be transformed or Friedman's test (i.e. nonparametric analogue to a repeated measures analysis of variance) will be used.

Measure: CD8+ counts

Time: Up to 30 days

Description: A repeated measures analysis of variance will be used to assess the effect of erlotinib hydrochloride on HIV viral loads across time points. Analyses will be done per stratum, where the data are sufficient. If the data do not meet the assumptions of normality, the data will either be transformed or Friedman's test (i.e. nonparametric analogue to a repeated measures analysis of variance) will be used.

Measure: HIV viral load

Time: Up to 30 days

Description: Spearman rank correlation coefficients will be used to investigate erlotinib-associated skin rash with immune competence. Fisher's exact tests will be used to investigate erlotinib-associated skin rash with participant response outcomes. Analyses will be done per stratum, where the data are sufficient.

Measure: Incidence of erlotinib hydrochloride-associated skin rash

Time: Up to 30 days

Description: The pharmacokinetic variables will be tabulated and descriptive statistics (e.g., geometric means and coefficients of variation) calculated for each dose level. Pharmacokinetic parameters (i.e., T1/2, Cl, and AUC) will be compared across relevant antiretroviral therapies using nonparametric statistical testing techniques.

Measure: Pharmacokinetic parameters of erlotinib hydrochloride, including half-life (T1/2), clearance (Cl), and area under the curve (AUC)

Time: Pre-treatment, 1, 2, 3, 4, 6, 8, and 24 hours post treatment

Measure: Response assessed via RECIST 1.1

Time: Up to 30 days

54 A Multi-arm, Phase Ib, Open-Label, Multicentre Study to Assess the Safety,Tolerability, Pharmacokinetics and Preliminary Anti-tumour Activity of AZD9291 in Combination With Ascending Doses of Novel Therapeutics in Patients With EGFRm+ Advanced NSCLC Who Have Progressed Following Therapy With an EGFR TKI (TATTON).

The purpose of this study is to determine the safety, tolerability and preliminary anti-tumour activity of AZD9291 when given together with AZD6094 or selumetinib in patients with EGFR mutation positive advanced lung cancer.

NCT02143466 Advanced Non Small Cell Lung Cancer Drug: Part A - AZD9291 in combination with AZD6094 Drug: Part A - AZD9291 in combination with continuous selumetinib (Asian subjects) Drug: Part A - AZD9291 in combination with continuous selumetinib (non-Asian subjects) Drug: Part A - AZD9291 in combination with intermittent selumetinib Drug: Part A - AZD9291 in combination with MEDI4736 Drug: Part B - AZD9291 in combination with AZD6094 Drug: Part B - AZD9291 in combination with selumetinib Drug: Part B - AZD9291 in combination with MEDI4736 Drug: Part C - AZD6094 monotherapy (Japan only) Drug: Part C - AZD9291 in combination with AZD6094 (Japan only) Drug: Part D - AZD9291 in combination with AZD6094
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Local confirmation of tumour T790M status is acceptable if performed with an approved test and agreed by AstraZeneca. --- T790M ---

Prior treatment with a 3rd generation (T790M-directed) therapy (eg, AZD9291, rociletinib or HM61713) outside of this study is permitted if allocated to the 3rd generation EGFR TKI cohort. --- T790M ---

Primary Outcomes

Description: Part A: To investigate the safety and tolerability of AZD9291 when given in combination with AZD6094 or selumetinib who have progressed following prior therapy with an EGFR TKI agent, and define the combination dose(s) for further clinical evaluation.

Measure: Number of participants with Adverse Events and/or Dose Limiting Toxicities as a Measure of Safety and Tolerability of AZD9291 when given in combination with AZD6094 or selumetinib

Time: Adverse events will be collected from baseline until 28 days after the last dose in the AZD6094 or selumetinib arms.

Description: Part B: To investigate the safety and tolerability of AZD9291 when given in combination with AZD6094 or selumetinib in patients with locally advanced or metastatic NSCLC, who have progressed on prior therapy with an EGFR TKI agent. Part C monotherapy cohort (Japan only): To investigate and confirm the safety and tolerability of AZD6094 when given orally to Japanese patients with advanced solid malignancies. Part C combination cohort (Japan only): To investigate the safety and tolerability of AZD9291 when given orally to Japanese patients with EGFRm+ NSCLC in combination with AZD6094 who have progressed following prior therapy with an EGFR TKI agent, and define the combination dose(s) for further clinical evaluation. Part D: To investigate the safety and tolerability of AZD9291 when given in combination with AZD6094 (300 mg OD) in patients with locally advanced or metastatic EGFRm+ NSCLC.

Measure: Number of participants with Adverse Events as a measure of Safety and Tolerability of AZD9291 when given in combination with AZD6094 or selumetinib

Time: Adverse events: baseline until 28 days after the last dose in the AZD6094 or selumetinib arms.

Secondary Outcomes

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Cmax after single dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Tmax after single dosing

Time: Blood samples will be collected from each subject at pre-specified on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: AUC after single dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: AUC0-t after single dosing

Time: Blood samples will be collected from each subject at pre-specified on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: AUC0-24 after single dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Terminal half life after single dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: CL/f after single dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Volume of distribution after single dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Cssmax after multiple dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Tssmax after multiple dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Cssmin after multiple dosing

Time: Blood samples will be collected from each subject at pre-specified times for the duration of treatment.

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: AUCss after multiple dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: CLss/f after multiple dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Rac after multiple dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 and cycle 2 day 1

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Time dependency of PK after multiple dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 and cycle 2 day 1

Description: To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1.

Measure: Objective response rate

Time: At baseline and every 6 weeks until disease progression or withdrawal from study.

Description: To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1

Measure: Disease control rate

Time: At baseline and every 6 weeks until disease progression or withdrawal from study.

Description: To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1

Measure: Duration of response

Time: At baseline and every 6 weeks until disease progression or withdrawal from study.

Description: To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1

Measure: Percentage change in tumour size

Time: At baseline and every 6 weeks until disease progression or withdrawal from study.

Description: To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1 Expansion phase only

Measure: Progression free survival

Time: At baseline and every 6 weeks until disease progression or withdrawal from study.

Description: To obtain a preliminary assessment of overall survival in the AZD9291+AZD6094 combination arms of the study for Parts B and D.

Measure: Overall survival

Time: Confirmed during the FUP period and at least every 12 weeks until the data cut-off for the primary analysis and determination that no further OS collection is needed, approximately 5 years, death, or full withdrawal of consent, whichever comes first.

55 A Phase II Study to Assess Efficacy of Combined Treatment With Erlotinib (Tarceva) and Silybin-phytosome (Siliphos) in Patients With EGFR(Epidermal Growth Factor Receptor) Mutant Lung Adenocarcinoma

1. Title and stage of study A Phase II Study to Assess Efficacy of Combined Treatment with Erlotinib (Tarceva) and Silybin-phytosome (Siliphos) in Patients with EGFR mutant lung adenocarcinoma 2. Endpoints Primary Endpoint : tumour response rate Secondary Endpoint : progression-free survival, overall survival, and safety assessment 3. Study Rationale Even though it is commonly accepted that EGFR TKIs are effective to EGFR mutation positive lung cancer patients, still remains its resistance issue. The Silybin which is extract from mugwort bean Thistle and used for hepatoprotective drug for a long time with very low adverse events in Eastern countries. Recently, there are some reports regarding its anti-cancer effects through several preclinical studies. The safety of Siliphos which is developed agent from silybin for improving intestinal absorption was demonstrated in PhaseⅠtrial. Recently investigators found out Silybin is effective for blocking EGFR signal in different mechanism from Erlotinib and it can be expected additional impact with combination therapy with preclinical data. Our research team can expect to improve Lung cancer treatment if the combination therapy (Silybin_Erlotinib) improves patients' response and Overall survivor. 4. Treatment method Erlotinib (Tarceva 150 mg/day) and Silybin (Siliphos 1g bid/day) q 4 weeks 5. Assessment criteria For toxicity assessment, posttreatment recurrence and survival rates will be investigated based on NCI-CTCAE ver 4.0 and RTOG. Efficacy assessment will be conducted through measurement of lesions by CT and RECIST criteria. Overall survival (OS), progression-free survival (PFS), and time to tumour progression (TTP) will be estimated using a Kaplan-Meier analysis. In addition, effect of pre-treatment T790M on response and PFS will be analyzed.

NCT02146118 Carcinoma, Non-Small-Cell Lung Drug: Erlotinib Dietary Supplement: Silybin-phytosome
MeSH:Adenocarcinoma Carcinoma, Non-Small-Cell Lung Adenocarcinoma of Lung
HPO:Non-small cell lung carcinoma

In addition, effect of pre-treatment T790M on response and PFS will be analyzed. --- T790M ---

In addition, effect of pre-treatment T790M on response and PFS will be analyzed. --- T790M ---

Primary Outcomes

Description: Efficacy assessment will be conducted through measurement of lesions by CT and RECIST criteria.

Measure: Tumour response rate

Time: 12 months

Secondary Outcomes

Description: For toxicity assessment, posttreatment recurrence and survival rates will be investigated based on NCI-CTCAE ver 4.0 and RTOG.

Measure: Safety assessment

Time: 12 months

56 TIGER-2: A Phase 2, Open-label, Multicenter, Safety and Efficacy Study of Oral CO-1686 as 2nd Line EGFR-directed TKI in Patients With Mutant EGFR Non-small Cell Lung Cancer (NSCLC)

The purpose of this study is to evaluate the safety and anti-tumor effect of rociletinib. The trial is open-ended, which means patients will continue to take rociletinib until the study doctor determines it is no longer beneficial for them.

NCT02147990 Non-small Cell Lung Cancer Drug: Rociletinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria - Histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC - Documented evidence of a tumor with 1 or more EGFR mutations excluding exon 20 insertion - Disease progression confirmed by radiologic assessment while receiving treatment with the first single agent EGFR-TKI - EGFR TKI treatment discontinued less than or equal to 30 days prior to planned initiation of rociletinib - The washout period for an EGFR inhibitor is a minimum of 3 days - No intervening treatment between cessation of single agent EGFR TKI and planned initiation of rociletinib - Previous treatment with less than or equal to 1 prior chemotherapy (excluding prior neo-adjuvant or adjuvant chemotherapy or chemoradiotherapy with curative intent) - Any toxicity related to prior EGFR inhibitor treatment must have resolved to Grade 1 or less - Central laboratory confirmation of the presence of the T790M mutation in tumor tissue in Cohort A and the presence or absence of the T790M mutation in tumor tissue in Cohort B. Centrally indeterminate, unknown or invalid specimens are not acceptable. --- T790M ---

Inclusion Criteria - Histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC - Documented evidence of a tumor with 1 or more EGFR mutations excluding exon 20 insertion - Disease progression confirmed by radiologic assessment while receiving treatment with the first single agent EGFR-TKI - EGFR TKI treatment discontinued less than or equal to 30 days prior to planned initiation of rociletinib - The washout period for an EGFR inhibitor is a minimum of 3 days - No intervening treatment between cessation of single agent EGFR TKI and planned initiation of rociletinib - Previous treatment with less than or equal to 1 prior chemotherapy (excluding prior neo-adjuvant or adjuvant chemotherapy or chemoradiotherapy with curative intent) - Any toxicity related to prior EGFR inhibitor treatment must have resolved to Grade 1 or less - Central laboratory confirmation of the presence of the T790M mutation in tumor tissue in Cohort A and the presence or absence of the T790M mutation in tumor tissue in Cohort B. Centrally indeterminate, unknown or invalid specimens are not acceptable. --- T790M --- --- T790M ---

- Treatment with prohibited medications less than or equal to 14 days prior to treatment with rociletinib - Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication before starting rociletinib - Prior treatment with rociletinib, or other drugs that target T790M positive mutant EGFR with sparing of wild type EGFR - Any of the following cardiac abnormalities or history - Clinically significant abnormal 12-lead ECG, QT interval corrected using Fridericia's method (QTCF) greater than 450 msec - Inability to measure QT interval on ECG - Personal or family history of long QT syndrome - Implantable pacemaker or implantable cardioverter defibrillator - Resting bradycardia less than 55 beats/min - Non-study related surgical procedures less than or equal to 7 days prior to administration of rociletinib. --- T790M ---

In all cases, the patient must be sufficiently recovered and stable before treatment administration - Females who are pregnant or breastfeeding - Refusal to use adequate contraception for fertile patients (females and males) while on treatment and for 12 weeks after the last dose of rociletinib - Presence of any serious or unstable concomitant systemic disorder incompatible with the clinical study - Any other reason the investigator considers the patient should not participate in the study Inclusion Criteria - Histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC - Documented evidence of a tumor with 1 or more EGFR mutations excluding exon 20 insertion - Disease progression confirmed by radiologic assessment while receiving treatment with the first single agent EGFR-TKI - EGFR TKI treatment discontinued less than or equal to 30 days prior to planned initiation of rociletinib - The washout period for an EGFR inhibitor is a minimum of 3 days - No intervening treatment between cessation of single agent EGFR TKI and planned initiation of rociletinib - Previous treatment with less than or equal to 1 prior chemotherapy (excluding prior neo-adjuvant or adjuvant chemotherapy or chemoradiotherapy with curative intent) - Any toxicity related to prior EGFR inhibitor treatment must have resolved to Grade 1 or less - Central laboratory confirmation of the presence of the T790M mutation in tumor tissue in Cohort A and the presence or absence of the T790M mutation in tumor tissue in Cohort B. Centrally indeterminate, unknown or invalid specimens are not acceptable. --- T790M ---

In all cases, the patient must be sufficiently recovered and stable before treatment administration - Females who are pregnant or breastfeeding - Refusal to use adequate contraception for fertile patients (females and males) while on treatment and for 12 weeks after the last dose of rociletinib - Presence of any serious or unstable concomitant systemic disorder incompatible with the clinical study - Any other reason the investigator considers the patient should not participate in the study Inclusion Criteria - Histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC - Documented evidence of a tumor with 1 or more EGFR mutations excluding exon 20 insertion - Disease progression confirmed by radiologic assessment while receiving treatment with the first single agent EGFR-TKI - EGFR TKI treatment discontinued less than or equal to 30 days prior to planned initiation of rociletinib - The washout period for an EGFR inhibitor is a minimum of 3 days - No intervening treatment between cessation of single agent EGFR TKI and planned initiation of rociletinib - Previous treatment with less than or equal to 1 prior chemotherapy (excluding prior neo-adjuvant or adjuvant chemotherapy or chemoradiotherapy with curative intent) - Any toxicity related to prior EGFR inhibitor treatment must have resolved to Grade 1 or less - Central laboratory confirmation of the presence of the T790M mutation in tumor tissue in Cohort A and the presence or absence of the T790M mutation in tumor tissue in Cohort B. Centrally indeterminate, unknown or invalid specimens are not acceptable. --- T790M --- --- T790M ---

Cohort A will enroll approximately 125 eligible patients who are centrally confirmed T790M-positive. --- T790M ---

Cohort B will be a continuation of the study and will enroll up to approximately 100 eligible patients who will be either centrally confirmed T790M-positive or T790M-negative. --- T790M ---

Cohort B will be a continuation of the study and will enroll up to approximately 100 eligible patients who will be either centrally confirmed T790M-positive or T790M-negative. --- T790M --- --- T790M ---

Primary Outcomes

Measure: Objective Response rate (ORR) according to RECIST Version 1.1 as determined by independent radiology review (IRR).

Time: Every 8 weeks until disease progression, up to approximately 24 months

Secondary Outcomes

Measure: Duration of Response (DR), Disease Control Rate (DCR) and Progression Free Survival (PFS) according to RECIST Version 1.1 as determined by IRR

Time: Every 8 weeks until disease progression, up to approximately 24 months

Measure: Objective Response Rate (ORR), Duration of Response (DR), Progression Free Survival (PFS), Disease Control Rate (DCR) as determined by Investigator Assessment

Time: Every 8 weeks until disease progression, up to approximately 24 months

Measure: Overall Survival

Time: Every 4-8 weeks until date of death, up to approximately 60 months

Measure: Change from baseline in patient reported outcomes using EORTC QLQ C30, EORTC Quality of Life Questionnaire Lung Cancer module (EORTC QLQ LC13), and the Dermatology Life Quality Index (DLQI)

Time: Every 8-12 weeks until disease progression, up to approximately 24 months

Measure: Treatment emergent adverse events (AEs), laboratory abnormalities and ECG abnormalities

Time: Every 4 weeks until treatment discontinuation, up to approximately 24 months

Measure: Plasma PK parameters for rociletinib based on sparse sampling

Time: Every 4 weeks for approximately 6 months

57 Phase I of Vorinostat-Iressa Combined Therapy on Resistance by BIM Polymorphysim in EGFR Mutant Lung Cancer

- Gefitinib is an orally active epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). However, 20-30% of patients with EGFR-activating mutations show intrinsic resistance to EGFR-TKI. - EGFR-mutant non-small cell lung cancer (NSCLC) cells with BIM (BCL2L11) deletion polymorphism show the impaired generation of BIM with the proapoptotic BH3 domain, as well as resistance to EGFR-TKI-induced apoptosis. - Both BIM polymorphism (12.9%) and EGFR mutations (50% in lung adenocarcinoma) are more prevalent in the East Asian than in Caucasian populations. BIM is a BH3-only proapoptotic member of the Bcl-2 protein family. BIM upregulation is required for apoptosis induction by EGFR-TKI in EGFR-mutant NSCLC. - Vorinostat (suberoylanilide hydroxamic acid [SAHA]) is a small-molecule inhibitor of histone deacetylase (HDAC) and induces cell differentiation, cell cycle arrest, and apoptosis in several tumor cells. HDAC inhibition can epigenetically restore BIM function and death sensitivity of EGFR-TKI in patients with EGFR-mutant NSCLC in whom resistance to EGFR-TKI is associated with a common BIM polymorphism. EGFR-TKI resistance due to the BIM polymorphism may be able to be circumvented in combination with HDAC inhibition of vorinostat with gefitinib in NSCLC.

NCT02151721 Non-Small-Cell Lung Carcinoma Drug: Vorinostat, gefitinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Having a large volume of or uncontrollable pleural effusion, ascites, or pericardial effusion - Detection of known EGFR-TKI resistance acquired by mutations of the genes, e.g., T790M. --- T790M ---

Primary Outcomes

Description: MTD (Maximum Tolerated Dose)defined as the highest dose level at which < 2 out of 6 patients experienced a DLT.

Measure: MTD (Maximum Tolerated Dose)

Time: Second cycle (Day 28)

58 A Phase III, Open Label, Randomized Study of AZD9291 Versus Platinum-Based Doublet Chemotherapy for Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed With Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Whose Tumours Harbour a T790M Mutation Within the Epidermal Growth Factor Receptor Gene (AURA3).

A Phase III, Open Label, Randomized Study of Osimertinib versus Platinum-Based Doublet Chemotherapy for Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours harbour a T790M mutation within the Epidermal Growth Factor Receptor Gene

NCT02151981 Anticancer Treatment Drug: Chemotherapy Drug: Cross-over to Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

A Phase III, Open Label, Randomized Study of AZD9291 Versus Platinum-Based Doublet Chemotherapy for Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed With Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Whose Tumours Harbour a T790M Mutation Within the Epidermal Growth Factor Receptor Gene (AURA3).. AZD9291 (Osimertinib) Versus Platinum-Based Doublet-Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer A Phase III, Open Label, Randomized Study of Osimertinib versus Platinum-Based Doublet Chemotherapy for Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours harbour a T790M mutation within the Epidermal Growth Factor Receptor Gene Progression Free Survival (PFS) by Investigator Assessment. --- T790M ---

A Phase III, Open Label, Randomized Study of AZD9291 Versus Platinum-Based Doublet Chemotherapy for Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed With Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Whose Tumours Harbour a T790M Mutation Within the Epidermal Growth Factor Receptor Gene (AURA3).. AZD9291 (Osimertinib) Versus Platinum-Based Doublet-Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer A Phase III, Open Label, Randomized Study of Osimertinib versus Platinum-Based Doublet Chemotherapy for Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours harbour a T790M mutation within the Epidermal Growth Factor Receptor Gene Progression Free Survival (PFS) by Investigator Assessment. --- T790M --- --- T790M ---

- At least 14 days since last dose of platinum-based doublet chemotherapy Anticancer Treatment Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a phase III, open label, randomized study assessing Osimertinib (80 mg, orally, once daily) versus platinum-based doublet chemotherapy (standard of care) in subjects with confirmed diagnosis of Epidermal Growth Factor Receptor (EGFR) mutation positive NSCLC, who have progressed following prior therapy with an approved Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) agent and whose tumours harbour a T790M mutation within the EGFR Gene. --- T790M ---

Primary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. PFS is the time from date of randomisation until the date of PD (by investigator assessment) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from randomised therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.

Measure: Progression Free Survival (PFS) by Investigator Assessment

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of analysis).

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR prior to progression or any further therapy.

Measure: Objective Response Rate (ORR) by Investigator Assessment

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of analysis).

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. DoR is the time from the date of first documented response until the date of documented progression or death in the absence of disease progression.

Measure: Duration of Response (DoR) by Investigator Assessment

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of analysis).

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. DCR is the percentage of patients with best response of CR, PR or SD at >=6 weeks, prior to any progressive disease (PD).

Measure: Disease Control Rate (DCR) by Investigator Assessment

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of analysis).

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Tumour size was calculated as the sum of the longest diameters (SLD) of the Target Lesions. Tumour shrinkage is percentage change in tumour size from baseline using RECIST v1.1 tumour response.

Measure: Tumour Shrinkage by Investigator Assessment

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of analysis).

Other Outcomes

Description: Total number of deaths at the time of the analysis

Measure: Number of Deaths

Time: From randomisation until death, up to 19 months (at the time of analysis).

59 A Phase 1/2 Trial of Ruxolitinib and Erlotinib in Patients With EGFR-mutant Lung Adenocarcinoma With Acquired Resistance to Erlotinib

This is a phase 2 study. The goal of this study is to find out what effects, good and/or bad, taking erlotinib and ruxolitinib has on the patients and on lung cancer. Erlotinib and ruxolitinib are FDA approved for other indications, but the use of erlotinib and ruxolitinib together has not been studied before and is not FDA-approved.

NCT02155465 Lung Cancer Drug: Ruxolitinib Drug: Erlotinib
MeSH:Adenocarcinoma Adenocarcinoma of Lung

- Received erlotinib or other EGFR TK treatment for at least 2 weeks prior to enrollment - Measurable (RECIST 1.1) indicator lesion not previously irradiated - Must have undergone biopsy after development of acquired resistance to erlotinib (which is performed as standard of care) with adequate tissue to determine EGFR T790M and tumor histology. --- T790M ---

Primary Outcomes

Measure: Maximally Tolerated Dose (MTD) (Phase I)

Time: 1 year

Description: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), at least a 30% decrease in the sum of the longest diameter of target lesions; Progressive disease (PD), at least a 20% increase in the sum of the diameter of the target lesions or the appearance of one or more new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD

Measure: Assess Overall Response Rate

Time: 1 year

Secondary Outcomes

Description: Toxicity grading will be performed in accordance with NCI CTCAE, version 4.0.

Measure: Number of Participants With NCI CTCAE Toxicity

Time: 2 years

Measure: Progression-free Survival

Time: 2 years

60 TIGER 1: A Randomized, Open-Label, Phase 2/3 Study of CO-1686 or Erlotinib as First-Line Treatment of Patients With EGFR-Mutant Advanced/Metastatic NSCLC

The purpose of this study is to compare the safety and anti-tumor effect of rociletinib with erlotinib in patients whose tumors have specific EGFR mutations and who have not previously received any treatment for advanced/metastatic EGFR mutated NSCLC. This study is a 'Randomized' Study. This means that upon entering the study, patients will be randomly assigned to be dosed with either rociletinib twice a day or erlotinib once a day. Patients will continue to take either rociletinib or erlotinib until it is no longer beneficial.

NCT02186301 Non-Small Cell Lung Cancer Drug: Rociletinib Mono-Therapy Drug: Erlotinib Mono-Therapy
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

In the Phase 2 part only, patients initially randomized to erlotinib may be eligible to participate in an optional crossover phase to receive rociletinib if they demonstrate the T790M resistance mutation after radiographic progression on erlotinib treatment among other eligibility requirements. --- T790M ---

Primary Outcomes

Description: To compare the antitumor efficacy of oral single-agent rociletinib with that of erlotinib as measured by progression-free survival (PFS), when administered as a first-line targeted treatment to patients with EGFR-mutated, advanced NSCLC.Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.The appearance of one or more new lesions is also considered progression.

Measure: Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by Investigator Review (invPFS)

Time: Cycle 1 Day 1 to End of Treatment, up to approximately 35 months

Secondary Outcomes

Description: Proportion of patients with a best overall confirmed response of partial response (PR) or complete response (CR) recorded from the start of the treatment until disease progression or recurrence. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: Complete Response (CR), is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR),at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Overall Response (OR),is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment was dependent on the achievement of both measurement and confirmation criteria.

Measure: Confirmed Response Rate

Time: Cycle 1 Day 1 to End of Treatment, up to approximately 35 months.

Description: Duration of Response in Patients with Confirmed Response per Investigator

Measure: Duration of Response

Time: Cycle 1 Day 1 to End of Treatment, up to approximately 35 months

61 A Phase Ib Open-label Clinical Trial of Once Daily Oral Treatment of Afatinib Plus Weekly Intravenous Infusion of Xentuzumab (BI 836845) in Patients With EGFR Mutant Non-small Cell Lung Cancer With Progression Following Prior EGFR Tyrosine Kinase Inhibitors

Part A: To determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of Xentuzumab (BI 836845) in combination with afatinib in patients with non-small cell lung cancer with progression following prior treatment (EGFR TKI or platinum-based chemotherapy). Part B: To evaluate the early anti-tumour activity of Xentuzumab (BI 836845) in combination with afatinib in patients with EGFR mutant non-small cell lung cancer with progression following prior irreversible EGFR TKIs. Part A and B: To evaluate the safety and pharmacokinetics of BI 836845 in combination with afatinib in patients with non-small cell lung cancer

NCT02191891 Carcinoma, Non-Small-Cell Lung Drug: BI 836845 Drug: afatinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion criteria: - Aged 18 years or older - Pathologically confirmed of advanced and/or metastatic stage IIIb/IV non-small cell carcinoma of lung - Activating EGFR mutation (exon 19 deletion, L858R, G719X, L861X) - Presence of EGFR activating mutation and absence of EGFR T790M in the tumour associated with the latest disease progression. --- L858R --- --- T790M ---

AZD9291 or CO-1686) Inclusion criteria: - Aged 18 years or older - Pathologically confirmed of advanced and/or metastatic stage IIIb/IV non-small cell carcinoma of lung - Activating EGFR mutation (exon 19 deletion, L858R, G719X, L861X) - Presence of EGFR activating mutation and absence of EGFR T790M in the tumour associated with the latest disease progression. --- L858R --- --- T790M ---

Primary Outcomes

Measure: Maximum tolerated dose (MTD) of BI 836845 in combination with afatinib - part A

Time: up to 12 months

Measure: Dose limiting toxicity (DLT) during the first treatment course - part A

Time: up to 28 days

Measure: Objective response (OR), defined as complete response (CR) or partial response (PR)

Time: up to 12 months

Secondary Outcomes

Measure: Disease control (DC), defined as complete response (CR), partial response (PR) or stable disease (SD)

Time: up to 12 months

Measure: Time to objective response, defined as the duration of time from the date of first treatment administration until objective response

Time: up to 12 months

Measure: Duration of objective response, defined as the duration of time from first objective response to the date of first objective tumour progression or death due to any cause

Time: up to 12 months

62 An Open-label Study of the Oral Administration of ASP8273 in Patients With Non-small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor (EGFR) Mutations

Purpose of the study is to determine the following in patients with non-small cell lung cancer (NSCLC) harboring EGFR activating mutations. - the safety and tolerability of ASP8273. - the pharmacokinetics (PK) of ASP8273. - the antitumor activity of ASP8273.

NCT02192697 Non-small Cell Lung Cancer Drug: ASP8273
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- *Erlotinib, gefitinib, and EGFR-TKIs under clinical investigation (e.g., neratinib, afatinib, dacomitinib) - Expression of the EGFR-T790M mutation as confirmed by a tumor biopsy of the primary or metastatic lesions after confirmation of PD following previous treatment with EGFR-TKIs and before enrollment, or by a tumor tissue sample that had been collected and archived after confirmation of PD following previous treatment with EGFR-TKIs. --- T790M ---

- Previously received treatment with EGFR-TKIs (e.g., CO-1686, AZD9291) that can inhibit EGFR with the T790M mutation. --- T790M ---

Primary Outcomes

Description: A DLT is defined as any pre-determined toxicity that is related to study drug per the investigator and which occurs during Cycle 0 and Cycle 1 using the Japan Clinical Oncology Group (JCOG) Japanese translation of the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE ver 4.0 - JCOG)

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by Dose Limiting Toxicities (DLTs)

Time: Up to Day 23

Description: The overall response rate, which is defined as the proportion of subjects whose best overall response is rated as complete response (CR) or partial response (PR) according to RECIST Version 1.1, will be calculated

Measure: Phase II: Overall response rate (CR+PR) at Week 24

Time: Week 24

Secondary Outcomes

Description: An AE is defined as any untoward medical occurrence in a subject administered a study drug or has undergone study procedures and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by adverse events (AEs)

Time: Up to 18 months

Description: Laboratory tests to be conducted are hematology, biochemistry, urinalysis, coagulation profile, lipid panel and lymphocyte subpopulation

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by laboratory tests

Time: Up to 18 months

Description: Vital signs to be measured includes blood pressure, pulse rate and temperature

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by vital signs

Time: Up to 18 months

Description: including the assessment of QT intervals

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by 12-lead ECG

Time: Up to 18 months

Measure: Phase I: Plasma concentrations of unchanged ASP8273

Time: Up to Day 1 of Cycle 3

Measure: Phase I: Urine concentrations of unchanged ASP8273

Time: Up to Day 1 of Cycle 3

Description: The overall response rate is defined as the proportion of subjects whose best overall response is rated as complete response (CR) or partial response (PR) according to RECIST Version 1.1, will be calculated

Measure: Phase I: Overall response rate (CR+PR)

Time: Up to 18 months

Description: The disease control rate is defined as the proportion of subjects whose best overall response is rated as CR, PR, or stable disease (SD) according to RECIST Version 1.1, will be calculated.

Measure: Phase I: Disease control rate (CR+PR+SD)

Time: Up to 18 months

Measure: Phase II: Plasma concentrations of unchanged ASP8273

Time: Up to Day 1 of Cycle 3

Measure: Phase II: Urine concentrations of unchanged ASP8273

Time: Up to Day 1 of Cycle 3

Description: An AE is defined as any untoward medical occurrence in a subject administered a study drug or has undergone study procedures and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product

Measure: Phase II: Safety and tolerability of ASP8273 as assessed by adverse events (AEs)

Time: Up to 18 months

Description: Laboratory tests to be conducted are hematology, biochemistry, urinalysis, coagulation profile, lipid panel and lymphocyte subpopulation

Measure: Phase II: Safety and tolerability of ASP8273 as assessed by laboratory tests

Time: Up to 18 months

Description: Vital signs to be measured includes blood pressure, pulse rate and temperature

Measure: Phase II: Safety and tolerability of ASP8273 as assessed by vital signs

Time: Up to 18 months

Description: including the assessment of QT intervals

Measure: Phase II: Safety and tolerability of ASP8273 as assessed by 12-lead ECG

Time: Up to 18 months

Description: The disease control rate is defined as the proportion of subjects whose best overall response is rated as CR, PR, or stable disease (SD) according to RECIST Version 1.1, will be calculated.

Measure: Phase II: Disease control rate

Time: Up to 18 months

Measure: Phase II: Progression-free survival (PFS)

Time: Up to 18 months

Measure: Phase II: Overall survival (OS)

Time: Up to 18 months

Description: The overall response rate, which is defined as the proportion of subjects whose best overall response is rated as complete response (CR) or partial response (PR) according to RECIST Version 1.1, will be calculated

Measure: Phase II: Overall response rate (CR+PR)

Time: Up to 18 months

63 Randomized Study of Erlotinib vs Observation in Patients With Completely Resected Epidermal Growth Factor Receptor (EGFR) Mutant Non-Small Cell Lung Cancer (NSCLC)

This phase III ALCHEMIST trial studies how well erlotinib hydrochloride compared to observation works in treating patients with stage IB-IIIA non-small cell lung cancer that has been completely removed by surgery. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02193282 Stage IB Lung Non-Small Cell Carcinoma AJCC v7 Stage II Lung Non-Small Cell Cancer AJCC v7 Stage IIA Lung Non-Small Cell Carcinoma AJCC v7 Stage IIB Lung Non-Small Cell Carcinoma AJCC v7 Stage IIIA Lung Non-Small Cell Cancer AJCC v7 Other: Clinical Observation Drug: Erlotinib Hydrochloride Other: Laboratory Biomarker Analysis Other: Placebo Administration
MeSH:Carcinoma Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Non-small cell lung carcinoma

Analysis of the overall adverse event rates, as well as specific events of interest will involve chi-square tests or Fisher's exact tests.. Inclusion Criteria: - Previously registered to A151216, with the result of lung cancer harboring an EGFR exon 19 deletion or L858R mutation; the testing must have been performed by one of the following criteria: 1. Patient registered to A151216 and the assessment performed centrally by the protocol-specified laboratory 2. By a local Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; the report must indicate the result as well as the CLIA number of the laboratory that performed the assay; these patients will also have been registered to A151216, but can be enrolled on A081105 regardless of the central lab results - Patients with known resistant mutations in the EGFR tyrosine-kinase (TK) domain (T790M) are not eligible - Patients that are both EGFR mutant and anaplastic lymphoma kinase (ALK) rearrangements will be registered to A081105 - Completely resected stage IB (>= 4 cm), II or IIIA non-squamous NSCLC with negative margins; patients may not have received neoadjuvant therapy (chemo- or radio-therapy) for this lung cancer - Complete recovery from surgery and standard post-operative therapy (if required); patients must be completely recovered from surgery at the time of randomization; the minimum time requirement between date of surgery and randomization must be at least 28 days, the maximum time requirement between surgery and randomization must be 90 days if no adjuvant chemotherapy was administered, 240 days if adjuvant chemotherapy was administered, and 300 days if adjuvant chemotherapy and radiation therapy was administered - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - No locally advanced or metastatic cancer requiring systemic therapy within 5 years prior to registration; no secondary primary lung cancer diagnosed concurrently or within 2 years prior to registration - Non-pregnant and non-lactating - No history of cornea abnormalities - Granulocytes >= 1,500/ul - Platelets >= 100,000/ul - Total bilirubin =< 1.5 x upper limit of normal (ULN) - Serum glutamic oxaloacetic transaminase (SGOT) =< 1.5 x ULN - Serum creatinine =< 1.5 x ULN Inclusion Criteria: - Previously registered to A151216, with the result of lung cancer harboring an EGFR exon 19 deletion or L858R mutation; the testing must have been performed by one of the following criteria: 1. Patient registered to A151216 and the assessment performed centrally by the protocol-specified laboratory 2. By a local Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; the report must indicate the result as well as the CLIA number of the laboratory that performed the assay; these patients will also have been registered to A151216, but can be enrolled on A081105 regardless of the central lab results - Patients with known resistant mutations in the EGFR tyrosine-kinase (TK) domain (T790M) are not eligible - Patients that are both EGFR mutant and anaplastic lymphoma kinase (ALK) rearrangements will be registered to A081105 - Completely resected stage IB (>= 4 cm), II or IIIA non-squamous NSCLC with negative margins; patients may not have received neoadjuvant therapy (chemo- or radio-therapy) for this lung cancer - Complete recovery from surgery and standard post-operative therapy (if required); patients must be completely recovered from surgery at the time of randomization; the minimum time requirement between date of surgery and randomization must be at least 28 days, the maximum time requirement between surgery and randomization must be 90 days if no adjuvant chemotherapy was administered, 240 days if adjuvant chemotherapy was administered, and 300 days if adjuvant chemotherapy and radiation therapy was administered - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - No locally advanced or metastatic cancer requiring systemic therapy within 5 years prior to registration; no secondary primary lung cancer diagnosed concurrently or within 2 years prior to registration - Non-pregnant and non-lactating - No history of cornea abnormalities - Granulocytes >= 1,500/ul - Platelets >= 100,000/ul - Total bilirubin =< 1.5 x upper limit of normal (ULN) - Serum glutamic oxaloacetic transaminase (SGOT) =< 1.5 x ULN - Serum creatinine =< 1.5 x ULN Stage IB Lung Non-Small Cell Carcinoma AJCC v7 Stage II Lung Non-Small Cell Cancer AJCC v7 Stage IIA Lung Non-Small Cell Carcinoma AJCC v7 Stage IIB Lung Non-Small Cell Carcinoma AJCC v7 Stage IIIA Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To assess whether adjuvant therapy with erlotinib (erlotinib hydrochloride) will result in improved overall survival (OS) over observation for patients with completely resected stage IB (>= 4 cm)-IIIA epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) (confirmed centrally) following complete resection and standard post-operative therapy. --- L858R --- --- T790M ---

Analysis of the overall adverse event rates, as well as specific events of interest will involve chi-square tests or Fisher's exact tests.. Inclusion Criteria: - Previously registered to A151216, with the result of lung cancer harboring an EGFR exon 19 deletion or L858R mutation; the testing must have been performed by one of the following criteria: 1. Patient registered to A151216 and the assessment performed centrally by the protocol-specified laboratory 2. By a local Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; the report must indicate the result as well as the CLIA number of the laboratory that performed the assay; these patients will also have been registered to A151216, but can be enrolled on A081105 regardless of the central lab results - Patients with known resistant mutations in the EGFR tyrosine-kinase (TK) domain (T790M) are not eligible - Patients that are both EGFR mutant and anaplastic lymphoma kinase (ALK) rearrangements will be registered to A081105 - Completely resected stage IB (>= 4 cm), II or IIIA non-squamous NSCLC with negative margins; patients may not have received neoadjuvant therapy (chemo- or radio-therapy) for this lung cancer - Complete recovery from surgery and standard post-operative therapy (if required); patients must be completely recovered from surgery at the time of randomization; the minimum time requirement between date of surgery and randomization must be at least 28 days, the maximum time requirement between surgery and randomization must be 90 days if no adjuvant chemotherapy was administered, 240 days if adjuvant chemotherapy was administered, and 300 days if adjuvant chemotherapy and radiation therapy was administered - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - No locally advanced or metastatic cancer requiring systemic therapy within 5 years prior to registration; no secondary primary lung cancer diagnosed concurrently or within 2 years prior to registration - Non-pregnant and non-lactating - No history of cornea abnormalities - Granulocytes >= 1,500/ul - Platelets >= 100,000/ul - Total bilirubin =< 1.5 x upper limit of normal (ULN) - Serum glutamic oxaloacetic transaminase (SGOT) =< 1.5 x ULN - Serum creatinine =< 1.5 x ULN Inclusion Criteria: - Previously registered to A151216, with the result of lung cancer harboring an EGFR exon 19 deletion or L858R mutation; the testing must have been performed by one of the following criteria: 1. Patient registered to A151216 and the assessment performed centrally by the protocol-specified laboratory 2. By a local Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; the report must indicate the result as well as the CLIA number of the laboratory that performed the assay; these patients will also have been registered to A151216, but can be enrolled on A081105 regardless of the central lab results - Patients with known resistant mutations in the EGFR tyrosine-kinase (TK) domain (T790M) are not eligible - Patients that are both EGFR mutant and anaplastic lymphoma kinase (ALK) rearrangements will be registered to A081105 - Completely resected stage IB (>= 4 cm), II or IIIA non-squamous NSCLC with negative margins; patients may not have received neoadjuvant therapy (chemo- or radio-therapy) for this lung cancer - Complete recovery from surgery and standard post-operative therapy (if required); patients must be completely recovered from surgery at the time of randomization; the minimum time requirement between date of surgery and randomization must be at least 28 days, the maximum time requirement between surgery and randomization must be 90 days if no adjuvant chemotherapy was administered, 240 days if adjuvant chemotherapy was administered, and 300 days if adjuvant chemotherapy and radiation therapy was administered - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - No locally advanced or metastatic cancer requiring systemic therapy within 5 years prior to registration; no secondary primary lung cancer diagnosed concurrently or within 2 years prior to registration - Non-pregnant and non-lactating - No history of cornea abnormalities - Granulocytes >= 1,500/ul - Platelets >= 100,000/ul - Total bilirubin =< 1.5 x upper limit of normal (ULN) - Serum glutamic oxaloacetic transaminase (SGOT) =< 1.5 x ULN - Serum creatinine =< 1.5 x ULN Stage IB Lung Non-Small Cell Carcinoma AJCC v7 Stage II Lung Non-Small Cell Cancer AJCC v7 Stage IIA Lung Non-Small Cell Carcinoma AJCC v7 Stage IIB Lung Non-Small Cell Carcinoma AJCC v7 Stage IIIA Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To assess whether adjuvant therapy with erlotinib (erlotinib hydrochloride) will result in improved overall survival (OS) over observation for patients with completely resected stage IB (>= 4 cm)-IIIA epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) (confirmed centrally) following complete resection and standard post-operative therapy. --- L858R --- --- T790M --- --- L858R --- --- T790M ---

Primary Outcomes

Description: Estimated using the method of Kaplan-Meier survival curves and a 1-sided stratified log rank test (accounting for all the stratification factors) will be used to compare OS between the two arms. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess whether the distribution of OS times differ with respect to treatment regimen after having adjusted for the stratification factors as well as other potential prognostic and treatment covariates.

Measure: Overall survival (OS)

Time: The time from randomization until death, assessed up to 10 years

Secondary Outcomes

Description: DFS will be defined as the proportion of patients alive and disease free at 2 years from the date of randomization. Estimated using the method of Kaplan-Meier survival curves. A 1-sided stratified log rank test (accounting for all the stratification factors) will be used to compare DFS between the arms, as well as to compare DFS and OS between the arms within the stage groups. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess potential differences in time to event outcomes after adjusting for the stratification factors and other potential prognostic and treatment covariates.

Measure: Disease free survival (DFS) rate

Time: Time from randomization until documented disease-recurrence or death, whichever occurs first, assessed at 2 years

Description: Will be defined as the proportion of patients alive at 5 years from date of randomization. Estimated using the method of Kaplan-Meier survival curves. A 1-sided stratified log rank test (accounting for all the stratification factors) will be used to compare DFS between the arms, as well as to compare DFS and OS between the arms within the stage groups. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess potential differences in time to event outcomes after adjusting for the stratification factors and other potential prognostic and treatment covariates.

Measure: Overall survival (OS) rate at 5 years

Time: At 5 years

Description: Will be defined as the proportion of patients alive at 10 years from date of randomization. Estimated using the method of Kaplan-Meier survival curves. A 1-sided stratified log rank test [accounting for all the stratification factors] will be used to compare DFS and OS between the arms within the stage groups. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess potential differences in time to event outcomes after adjusting for the stratification factors and other potential prognostic and treatment covariates.

Measure: Overall survival (OS) rate at 10 years

Time: At 10 years

Description: Estimated using the method of Kaplan-Meier survival curves (21). A 1-sided stratified log rank test [accounting for all the stratification factors] will be used to compare DFS between the arms, as well as to compare DFS and OS between the arms within the stage groups. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess potential differences in time to event outcomes after adjusting for the stratification factors and other potential prognostic and treatment covariates.

Measure: Overall disease free survival (DFS) between the erlotinib hydrochloride and observation arms

Time: Time from randomization until documented disease-recurrence or death, whichever occurs first, assessed up to 10 years

Description: The maximum grade for each type of adverse event will be recorded for each patient and frequency tables will be reviewed to determine the overall patterns. The number and severity of grade 3 + adverse events will be tabulated and summarized. All adverse events analysis will entail comparisons between the arms within Arms A and B, respectively. Analysis of the overall adverse event rates, as well as specific events of interest will involve chi-square tests or Fisher's exact tests.

Measure: Incidence of adverse events associated with each treatment arm

Time: Up to 10 years

64 Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of AC0010 in Patients With Advanced Non Small Cell Lung Cancer Who Progressed on Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent

AC0010 Maleate Capsules is a new, irreversible, Epidermal Growth Factor Receptor (EGFR) mutation selective Tyrosine Kinase Inhibitor.Aim at local advanced or metastatic non-small cell lung cancer patients with EGFR mutation or T790M drug-resistant mutation. The molecular mechanism: by irreversible combining the EGFR-RTKs ATP binding site of cell, selectively suppress the activities of EGFR tyrosine kinase phosphorylation, block the sigal signal transduction system of EGFR, and close the function of ras/raf/MAPK downstream. at last block the tumor cell growth by EGFR induction, and promotes apoptosis. AC0010 Maleate Capsules has three characters: 1. Irreversible combination with EGFR; 2.Efficient suppress the EGFR mutant tumor cell and has no suppression to EGFR wild-type cell; 3. Efficient suppress the EGFR T790M drug-resistant mutation tumor cell.

NCT02274337 Non-Small Cell Lung Cancer Drug: AC0010
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of AC0010 in Advanced Non Small Cell Lung Cancer AC0010 Maleate Capsules is a new, irreversible, Epidermal Growth Factor Receptor (EGFR) mutation selective Tyrosine Kinase Inhibitor.Aim at local advanced or metastatic non-small cell lung cancer patients with EGFR mutation or T790M drug-resistant mutation. --- T790M ---

AC0010 Maleate Capsules has three characters: 1. Irreversible combination with EGFR; 2.Efficient suppress the EGFR mutant tumor cell and has no suppression to EGFR wild-type cell; 3. Efficient suppress the EGFR T790M drug-resistant mutation tumor cell. --- T790M ---

- Have undergone or are able to undergo a biopsy of either primary or metastatic tumor tissue within 28 days of dosing of Avitinib, and have tissue available to send to central lab for further genetic profiling especially the status of T790M. --- T790M ---

Primary Outcomes

Description: Assessed by number and severity of adverse events as recorded on the case report form, vital signs, laboratory variables, physical examination, electrocardiogram, ophthalmic examinations, RECIST1.1, and NCI CTCAE v4.03

Measure: Safety, tolerability and ORR of AC0010

Time: Adverse events will be collected from baseline until 28 days after the last dose

Secondary Outcomes

Description: Plasma concentrations of AC0010 and 4 metabolites and pharmacokinetic parameters following single dose with fast in D1 and fed in D4 (Cmax, tmax, AUC, terminal rate constant, clearance, half life, volume of distribution and mean resistance time)

Measure: Plasma concentrations and pharmacokinetic parameters of single dose AC0010

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1 ,4 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48hours post dose)

Description: Plasma concentrations of AC0010 and 4 metabolites and pharmacokinetic parameters following multiple doses (steady state Cmax, tmax, Cmin AUC, clearance, accumulation ratio and time dependency)

Measure: Plasma concentrations and pharmacokinetic parameters of multiple doses AC0010

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8 ,15 and 22. D28- pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 hours post dose)

Description: Evaluation of tumour response, duration of response, tumour shrinkage, progression free survival and overall survival as assessed by RECIST 1.1

Measure: Efficacy of AC0010

Time: CT or MRI at screening and every 4-8 weeks (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 months

Measure: Food effect on AC0010's bioavailibility

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 4 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48hours post dose)

65 A Prospective Study of Plasma Genotyping as a Noninvasive Biomarker for Genotype-directed Cancer Care

Tumor genotyping has become an essential biomarker for the care of advanced lung cancer and melanoma, and is currently used to identify patients for treatment with targeted kinase inhibitors like erlotinib and vemurafenib. However, tumor genotyping can be slow and cumbersome, and is limited by availability of tumor biopsy tissue for testing. The aim of this study is to prospectively evaluate a blood-based genotyping tool that can quantify the presence of oncogenic mutations (EGFR, KRAS, BRAF) in patients with lung cancer and melanoma. This assay is being studied both as a diagnostic tool for classifying patient genotype, and a serial measurement tool for quantification of response and progression on therapy.

NCT02279004 NSCLC Melanoma
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

We will determine the accuracy of plasma NGS in performing noninvasive genotyping compared to tumor NGS and paired ddPCR.. Inclusion Criteria To participate in this study a participant must meet the eligibility of one of the following cohorts: Cohort 1: Cancers beginning initial treatment - One of the following diagnoses: - Cohort 1A (CLOSED): ---Advanced non-squamous NSCLC (including adenosquamous) - Cohort 1B: - Stage II-III non-squamous NSCLC (including adenosquamous) - Stage IIIB-IV melanoma - Patient must be planned to begin initial therapy, or completely resected before or after receiving adjuvant therapy - For patients with NSCLC, EGFR and KRAS genotype may be known or unknown - For patients with melanoma, BRAF and NRAS genotype may be known or unknown - For patients without tumor genotyping, there must be a plan for genotyping including either: - Archived tumor tissue available and planned for genotyping - A biopsy at some future time is anticipated and will be available for genotyping Cohort 2: Cancers with acquired resistance to targeted therapy - One of the following diagnoses: - Cohort 2A (CLOSED): ---Advanced NSCLC harboring a known EGFR mutation - Cohort 2B: - Advanced NSCLC harboring a targetable genotype other than EGFR - Advanced melanoma harboring a known tumor genotype - Clinical determination of progression targeted therapy, as evidence by plans to start a new systemic treatment regimen, or obtain a biopsy to plan a new treatment regimen - New systemic treatment regimen planned OR - Re-biopsy for resistance genotyping planned - Note, date of targeted therapy start and clinical progression must be provided Cohort 3: Cancers with a known genotype starting palliative systemic therapy Cohort 3A (CLOSED): - Advanced NSCLC harboring one of the following mutations: - EGFR exon 19 deletion - EGFR L858R - EGFR T790M - KRAS G12X - BRAF V600E - Patients must be initiating palliative systemic therapy, either on or off a clinical trial Cohort 4: Paired plasma NGS and ddPCR - Cohort 4A (CLOSED): - Advanced NSCLC, newly diagnosed or with progression following treatment. --- L858R --- --- T790M ---

T790M, etc) Exclusion Criteria - Participants who are unable to provide informed consent - Participants who are 18 years of age or younger - Participants who are unable to comply with the study procedures Inclusion Criteria To participate in this study a participant must meet the eligibility of one of the following cohorts: Cohort 1: Cancers beginning initial treatment - One of the following diagnoses: - Cohort 1A (CLOSED): ---Advanced non-squamous NSCLC (including adenosquamous) - Cohort 1B: - Stage II-III non-squamous NSCLC (including adenosquamous) - Stage IIIB-IV melanoma - Patient must be planned to begin initial therapy, or completely resected before or after receiving adjuvant therapy - For patients with NSCLC, EGFR and KRAS genotype may be known or unknown - For patients with melanoma, BRAF and NRAS genotype may be known or unknown - For patients without tumor genotyping, there must be a plan for genotyping including either: - Archived tumor tissue available and planned for genotyping - A biopsy at some future time is anticipated and will be available for genotyping Cohort 2: Cancers with acquired resistance to targeted therapy - One of the following diagnoses: - Cohort 2A (CLOSED): ---Advanced NSCLC harboring a known EGFR mutation - Cohort 2B: - Advanced NSCLC harboring a targetable genotype other than EGFR - Advanced melanoma harboring a known tumor genotype - Clinical determination of progression targeted therapy, as evidence by plans to start a new systemic treatment regimen, or obtain a biopsy to plan a new treatment regimen - New systemic treatment regimen planned OR - Re-biopsy for resistance genotyping planned - Note, date of targeted therapy start and clinical progression must be provided Cohort 3: Cancers with a known genotype starting palliative systemic therapy Cohort 3A (CLOSED): - Advanced NSCLC harboring one of the following mutations: - EGFR exon 19 deletion - EGFR L858R - EGFR T790M - KRAS G12X - BRAF V600E - Patients must be initiating palliative systemic therapy, either on or off a clinical trial Cohort 4: Paired plasma NGS and ddPCR - Cohort 4A (CLOSED): - Advanced NSCLC, newly diagnosed or with progression following treatment. --- T790M ---

T790M, etc) Exclusion Criteria - Participants who are unable to provide informed consent - Participants who are 18 years of age or younger - Participants who are unable to comply with the study procedures Inclusion Criteria To participate in this study a participant must meet the eligibility of one of the following cohorts: Cohort 1: Cancers beginning initial treatment - One of the following diagnoses: - Cohort 1A (CLOSED): ---Advanced non-squamous NSCLC (including adenosquamous) - Cohort 1B: - Stage II-III non-squamous NSCLC (including adenosquamous) - Stage IIIB-IV melanoma - Patient must be planned to begin initial therapy, or completely resected before or after receiving adjuvant therapy - For patients with NSCLC, EGFR and KRAS genotype may be known or unknown - For patients with melanoma, BRAF and NRAS genotype may be known or unknown - For patients without tumor genotyping, there must be a plan for genotyping including either: - Archived tumor tissue available and planned for genotyping - A biopsy at some future time is anticipated and will be available for genotyping Cohort 2: Cancers with acquired resistance to targeted therapy - One of the following diagnoses: - Cohort 2A (CLOSED): ---Advanced NSCLC harboring a known EGFR mutation - Cohort 2B: - Advanced NSCLC harboring a targetable genotype other than EGFR - Advanced melanoma harboring a known tumor genotype - Clinical determination of progression targeted therapy, as evidence by plans to start a new systemic treatment regimen, or obtain a biopsy to plan a new treatment regimen - New systemic treatment regimen planned OR - Re-biopsy for resistance genotyping planned - Note, date of targeted therapy start and clinical progression must be provided Cohort 3: Cancers with a known genotype starting palliative systemic therapy Cohort 3A (CLOSED): - Advanced NSCLC harboring one of the following mutations: - EGFR exon 19 deletion - EGFR L858R - EGFR T790M - KRAS G12X - BRAF V600E - Patients must be initiating palliative systemic therapy, either on or off a clinical trial Cohort 4: Paired plasma NGS and ddPCR - Cohort 4A (CLOSED): - Advanced NSCLC, newly diagnosed or with progression following treatment. --- T790M --- --- L858R --- --- T790M ---

T790M, etc) Exclusion Criteria - Participants who are unable to provide informed consent - Participants who are 18 years of age or younger - Participants who are unable to comply with the study procedures NSCLC Melanoma Melanoma null --- T790M ---

Primary Outcomes

Description: We will determine the accuracy of a droplet digital PCR (ddPCR)-based plasma genotyping assay in performing noninvasive tumor genotyping.

Measure: Accuracy of Plasma Genotyping Assay

Time: 2 years

Secondary Outcomes

Description: The amount of time required to perform this noninvasive genotyping assay.

Measure: Turnaround Time of Plasma Genotyping Assay

Time: 2 years

Description: The ability of serial quantitative ddPCR-based plasma genotyping to predict early treatment failure in patients initiating a new line of therapy.

Measure: Early Treatment Failure

Time: 2 years

Description: We will determine the accuracy of plasma NGS in performing noninvasive genotyping compared to tumor NGS and paired ddPCR.

Measure: Accuracy of Plasma NGS

Time: 2 years

66 Blood Detection of EGFR Mutation For Iressa Treatment

This study was proposed to validate the efficacy of gefitinib as first-line therapy in advanced lung adenocarcinoma with EGFR mutation determined by plasma cf-DNA.

NCT02282267 Lung Adenocarcinoma Drug: Gefitinib
MeSH:Adenocarcinoma Adenocarcinoma of Lung

Meanwhile, this study was also proposed to explore the best intervention time of anti-resistant drugs (such as AZD 9291, a T790M inhibitor) through the quantitative and dynamic analysis of EGFR sensitive and resistant mutation in plasma cf-DNA during EGFR-TKI treatment process. --- T790M ---

Primary Outcomes

Measure: objective response rate of gefitinib

Time: up to 6 months

67 Use of a New Blood Test to Identify Response to Targeted Treatment in Patients With EGFR Mutated Lung Cancer. Evaluation in a Multicenter Study

In non-small celled lung cancer (NSCLC) 10-15% of the patients harbor a mutation in the tumor's epidermal growth factor receptor (EGFR M+). This receptor is the target for treatment with erlotinib. Identification of EGFR M+ is done on a biopsy, which can be difficult to retrieve. A new blood based test identifies EGFR M+ in plasma, which makes it possible to monitor the level of EGFR M+ in the patient's blood during treatment. This enables both a closer monitoring of the treatment with erlotinib and a closer study of the resistance mechanisms that almost inevitably develop during treatment. A pilot study demonstrated that the quantity of EGFR M+ in plasma correlates to the response to treatment and might be used to predict disease progression. Patients with EGFR M+ NSCLC referred to a participating oncology department may be enrolled in the project. The investigators expect to include 250 patients over a four-year period. Patients will receive standard treatment and follow up. Standard 1st line treatment for patients with metastatic disease is tyrosine kinase inhibitors (TKI) eg. erlotinib. A biopsy and blood sample will be retrieved before treatment with is initiated. The patient will be monitored prospectively with blood samples every 3rd-6th week both during erlotinib treatment, subsequent lines of treatment and treatment intermissions. The blood samples are analyzed for subtypes of EGFR M+ both sensitizing mutations and mutations known to drive resistance to erlotinib treatment. In the event of occurring resistance mutations or unexpected increase in quantity of sensitizing mutations clinical action will be taken; initially in the form of additional scans searching for signs of disease progression. Clinical data will be retrieved from the patient's medical journal. Patients are followed until death or at least 24 months after inclusion. Any excess biological material will be stored for up to 15 years in a bio bank for future research purposes. We expect our results to validate the use of EGFR M+ detection and quantification via blood samples in a clinically relevant setting. The investigators expect earlier identification of disease progression to allow more cases of local treatment thus - hopefully - increasing the progression free survival. Continued blood monitoring in subsequent lines of treatment and treatment intermissions will add to our knowledge of the nature of EGFR M+ NSCLC. The sampling of biological material allows us to further investigate the biology of resistance.

NCT02284633 Lung Neoplasms
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

The most common is the T790M mutation in EGFR, but other mechanisms such as increased MET and HER3 expression is also described. --- T790M ---

It is estimated that T790M mutations in EGFR accounts for 50% of the cases with TKI resistance development. --- T790M ---

Primary Outcomes

Measure: Progression Free Survival

Time: 2 years

68 Phase 1/2 Open Label Study Of Pf 06459988 (Epidermal Growth Factor Receptor T790m Inhibitor) In Patients With Advanced Epidermal Growth Factor Receptor Mutant (Del 19 Or L858r + - T790m) Non Small Cell Lung Cancer

Phase 1 - open label, multi-center, non-randomized, safety, pharmacokinetic and pharmacodynamics dose escalation study of PF-06459988 as a single agent in patients with advance EGFRm NSCLC (del 19, L858R, +/- T790M). The resulting PF-06459988 dose selected from the phase 1 portion will undergo a series of sub-studies to fully characterize the impact of food, antacid and CYP3A4 inhibitors/inducers. The PK studies are in addition to the MTD expansion and will be completed prior to the initiation of Phase 2. Phase 2 is an open label, multi-center single-arm study of PF-06459988 for the assessment of antitumor activity in patients with advanced EGFRm (del 19 or L858R) NSCLC with T790M.

NCT02297425 Advanced EGFRm (Del 19 or L858R +/- T790M) NSCLC Drug: PF-06459988
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

A Study For Patients With EGFRm (Epidermal Growth Factor Receptor Mutant) Lung Cancer Phase 1 - open label, multi-center, non-randomized, safety, pharmacokinetic and pharmacodynamics dose escalation study of PF-06459988 as a single agent in patients with advance EGFRm NSCLC (del 19, L858R, +/- T790M). --- L858R --- --- T790M ---

The PK studies are in addition to the MTD expansion and will be completed prior to the initiation of Phase 2. Phase 2 is an open label, multi-center single-arm study of PF-06459988 for the assessment of antitumor activity in patients with advanced EGFRm (del 19 or L858R) NSCLC with T790M. --- L858R --- --- T790M ---

Advanced EGFRm (Del 19 or L858R +/- T790M) NSCLC Lung Neoplasms null --- L858R --- --- T790M ---

Primary Outcomes

Description: The target probability of DLT at MTD will be 30%

Measure: Number of participants with Dose-limiting toxicities (DLT) (phase 1)

Time: up to 21 days

Description: Number of participants with objective response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). CR are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. PR are those as noted in the RECIST Criteria: Greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions

Measure: Number of Participants With Objective Response (phase 2)

Time: Time from first dose of study drug to objective response of CR or PR up to 24 months

Secondary Outcomes

Description: Number of participants with objective response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). CR are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. PR are those PR are those as noted in the RECIST Criteria: Greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions

Measure: Number of Participants With Objective Response for those patients with measurable disease (phase 1)

Time: time from first dose of study drug until objective response of CR or PR up to 24 months

Description: The period from study entry until disease progression, death or date of last contact.

Measure: Progression-Free Survival (PFS) - Phase 2

Time: time from first dose of study drug until Disease Progression or death (whichever first) up to 24 months

69 Establishment of Personalized Cancer Medicine Using Samsung Cancer Sequencing Platform in Lung Cancer/Mediastinal Tumor/ Head & Neck/Esophageal Cancer/Rare Cancer (PerSeq: Personalized Sequence)

The next generation of personalized medical treatment according to the type of personal genetic information are evolving rapidly. The genome analysis needs systematic infra and database based on personal genetic information Therefore, a big data of genome-clinical information is important.

NCT02299622 Lung Cancer Genetic: Genetic test
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

the spectrum of targetable genetic mutation in evaluated cancer specimens (for example, % of EGFR T790M mutation, BRAF mutation, or ALK mutation). --- T790M ---

Primary Outcomes

Description: The pattern of the tumor's molecular profiling in advanced thoracic (lung, esophagus, or tthymic) cancer

Measure: the spectrum of targetable genetic mutation in evaluated cancer specimens (for example, % of EGFR T790M mutation, BRAF mutation, or ALK mutation)

Time: 3 years

70 An epidemiOlogy Study to deteRmine the Prevalence of EGFR muTations in RUSsian Patients With Advanced NSCLC (ORTUS)

This is a multicentre, non-interventional, prospective study to be carried out in representative oncology departments / institutions in order to determine the prevalence of EGFR mutations in treatment-naive Russian patients with cytologically verified advanced NSCLC in Russia.

NCT02321046 Non-Small Cell Lung Cancer
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

EGFR mutations (EGFR del746-750, EGFR L858R, EGFR T790M) rate in cytology and plasma samples prior to treatment. --- L858R --- --- T790M ---

Primary Outcomes

Measure: EGFR mutations (EGFR del746-750, EGFR L858R, EGFR T790M) rate in cytology and plasma samples prior to treatment

Time: up to 18 months

Secondary Outcomes

Measure: Patient characteristics: Gender. Age. Race, ethnicity. Smoking habits. Family history of NSCLC.

Time: up to 18 months

Description: Date of the cytological verification of the NSCLC diagnosis. Disease stage and TNM classification. Morphological classification. Extent of the disease. Performance Status ECOG, including at diagnosis

Measure: Disease information/diagnostic procedures

Time: up to 18 months

Measure: EGFR mutations profile in cytology and/or histology (depending on the availablility of samples) and plasma samples at the time of every progression or in 1.5 year follow up in case of no progression

Time: up to 18 months

Description: 1st line and subsequent lines of therapy treatment, therapy regimen, medicines used for therapy (drugs by INN), for EGFRm+ patients - number of cycles of antitumor therapy, onset date, end date of each line

Measure: Characteristics of the 1st line and subsequent lines of antitumor therapy

Time: up to 18 months

Description: Treatment response/ progression of disease on every line of antitumor therapy: progressive disease, partial response, stable disease and complete response according to RECIST 1.1 evaluation and/or any other clinical assessment. Death: Disease-related or for other reasons

Measure: Clinical outcome/Patient response (for EGFRm+ patients who entered observation phase)

Time: up to 18 months

71 A Phase II, Multicenter, Open-label Study of EGF816 in Combination With Nivolumab in Adult Patients With EGFR Mutated Non-small Cell Lung Cancer and of INC280 in Combination With Nivolumab in Adult Patients With cMet Positive Non-small Cell Lung Cancer

To determine the efficacy and safety of Nivolumab in combination with EGF816 and of Nivolumab in combination with INC280 in previously treated NSCLC patients

NCT02323126 Non Small Cell Lung Cancer Drug: EGF816 Drug: INC280 Drug: Nivolumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

EGFR T790M positivity post progression on EGFR TKI for Group 1; cMet status for Group 2) must be provided for analysis Group 1 patients: - Patients with EGFR T790M NSCLC (adenocarcinoma) - Documented progression of disease according to RECIST v1.1 following primary standard of care (e.g. --- T790M ---

EGFR T790M positivity post progression on EGFR TKI for Group 1; cMet status for Group 2) must be provided for analysis Group 1 patients: - Patients with EGFR T790M NSCLC (adenocarcinoma) - Documented progression of disease according to RECIST v1.1 following primary standard of care (e.g. --- T790M --- --- T790M ---

Inhaled or topical steroids, and adrenal replacement steroid doses> 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease - Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) - Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection - Patients with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity - Patients with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity Prior therapy: - Patients who have been treated with prior PD-1 and PD-L1 agents - Patients who previously received agents targeting c-MET and/or EGFR T790M Note: Previous treatment with afatinib may be allowable after discussions between Novartis and Investigator. --- T790M ---

Primary Outcomes

Measure: Progression Free Survival (PFS) rate using RECIST version1.1

Time: 6 month

Secondary Outcomes

Description: Safety of EGF816 and Nivolumab and INC280 and Nivolumab by looking at hematology and chemistry laboratory parameters, vital signs, and electrocardiograms (ECGs)

Measure: Number of participants with Adverse Events (AEs)

Time: Continuously during study until 100 days after post study treatment

Measure: Objective response rate (ORR)

Time: baseline, every 8 weeks up to cycle 12, then every 12 weeks from cycle 13 until disease progression, consent withdrawal or death up to 1 year

Measure: Disease control rate

Time: baseline, every 8 weeks upto cycle 12, then every 12 weeks from cycle 13 until disease progression, consent withdrawal or death up to 1 year

Measure: Progression free survival

Time: baseline, every 8 weeks upto cycle 12, then every 12 weeks from cycle 13 until disease progression, consent withdrawal or death up to 1 year

Measure: Overall Survival

Time: Start of treatment until death, average 1 year

Measure: Plasma pharmacokinetic parameters (AUClast, AUC0-t,AUCtau,Cmax, Tmax)

Time: Cycle 1: Day1, Day 8, Day 15 and Cycle 2: Day 1, Cycle 4: Day 1 Cycle 6: Day 1 and Cycle 8: Day 1 Subsequent cycles (nivolumab only): every 8th cycle until discontinuation of study treatment

72 Induction Therapy With Gefitinib Followed by Taxane Platinum Chemotherapy and Intercalated Gefitinib in NSCLC Stages II-IIIB With Activating EGFR Mutation - A Single Arm Phase II Trial.

This study is designed as a single arm, un-controlled, open-label, multi-center hypothesis generating two-stage phase II trial. It is based on the assumption that the proposed treatment scheme doubles the rate of pathologic complete remission in Mutated epidermal growth factor receptor (EGFRmt) + NSCLC patients compared to historical control data from standard treatments. Patients with NSCLC and activating EGFR mutation in stages II, IIIA and IIIB eligible for induction therapy with docetaxel and cisplatin and gefitinib Patients will be treated for 12 days with gefitinib 250 mg/day p.o. (d -12 to -1) and induced with chemotherapy docetaxel 75 mg/m2 and cisplatin 50 mg/m2 d1+2 and intercalated gefitinib 250 mg/day d4-20 (cycle 1 and 2) and d4-17 (for cycle3). Surgery is planned in the 4th week after d1 of the last cycle.

NCT02326285 Non-squamous Non-small Cell Lung Cancer Stage II Non-squamous Non-small Cell Lung Cancer Stage IIIA Non-squamous Non-small Cell Lung Cancer Stage IIIB Activating EGFR Mutation NSCLC Drug: Gefitinib Drug: docetaxel Drug: cisplatin Procedure: Surgery
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

analysis of EGFR ctDNA in patient plasma; screening for EGFR mutation status (activating and resistance mutations especially T790M), monitoring of EGFR mutation status by means of Circulating tumor DNA (ctDNA) detection in patient plasma. --- T790M ---

T790M); 3. Significant cardiovascular disease, such as uncontrolled hypertension, myocardial infarction within the last 6 months, unstable angina pectoris, CHF ≥ NYHA 2, serious arrhythmia, significant peripheral vascular disease; 4. Pre-existing neuropathic ≥ grade 2; 5. Patients with confirmed HIV infection. --- T790M ---

Primary Outcomes

Description: The primary objective of the study is to assess the pathologic complete remission rate after induction therapy with gefitinib d -12 to d-1 followed by docetaxel 75 mg/m2 and cisplatin 50 mg/m2 d1+2 q21 and intercalated gefitinib 250 mg d4 to d20 (cycle 1 and 2) and d4-17 (for cycle3), in order to demonstrate feasibility and efficacy of this treatment scheme. It is expected to achieve a pCR ≥30% regression grade IIB and III (Junker criteria) compared to historical controls in the mediastinal lymph nodes.

Measure: pathologic complete remission rate (pCR rate)

Time: 12 weeks (after 3 cycles and surgery) after enrollment

Secondary Outcomes

Description: AEs/SAEs from 21 patients during induction CTx with docetaxel and cisplatin in combination with intercalated gefitinib

Measure: Adverse Events (AEs) / Serious adverse events (SAEs)

Time: 30 months

Description: R0 resection rate as assessed according to the German S3 guidelines

Measure: Surgical R0 resection rate

Time: 30 month

Measure: Response: radiologic response based on CT

Time: 30 month

Description: Progression-free survival (PFS) will be defined as the time from enrollment to the time of disease progression or relapse or death, or to the date of last assessment without any such event (censored observation).

Measure: progression free survival (PFS)

Time: 30 month

Description: The duration of overall survival (OS) will be determined by measuring the time interval from enrollment to the date of death or last observation (censored).

Measure: Overall survival (OS)

Time: 30 month

Description: After the end of treatment will be performed every 3 month (+/- 14 days) for minimum 12 months in order to collect information on relapse and site of relapse

Measure: relapse pattern

Time: 30 month

Description: Explorative analysis of health related quality of life, QoL at various time points throughout the study, to assess the QoL during and after induction therapy with gefitinib, after three cycles of chemotherapy with intercalated gefitinib including pre- and post surgery

Measure: quality of life

Time: 30 month

Description: To collect and store tumor tissue as well as plasma and serum samples for exploratory analyses of potential predictive markers, monitoring of biomarkers during and after treatment

Measure: translational research

Time: 30 month

Description: analysis of EGFR ctDNA in patient plasma; screening for EGFR mutation status (activating and resistance mutations especially T790M), monitoring of EGFR mutation status by means of Circulating tumor DNA (ctDNA) detection in patient plasma

Measure: monitoring of epidermal growth factor receptor (EGFR) mutation status

Time: 30 month

73 Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of AC0010 in Patients With EGFR T790M Positive Advanced Non Small Cell Lung Cancer Who Progressed on Prior Therapy With EGFR TKIs

AC0010 is a novel, potent, small molecule irreversible tyrosine kinase inhibitor (TKI) that selectively targets mutant forms of the epidermal growth factor receptor (EGFR) while sparing wild-type (WT) EGFR. The purpose of the study is to evaluate the pharmacokinetic (PK) and safety profile of oral AC0010; to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of oral AC0010; to assess the safety and efficacy of AC0010 in previously treated mutant EGFR in NSCLC patients with EGFR T790M mutation.

NCT02330367 Metastatic Non-small Cell Lung Cancer Drug: AC0010
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of AC0010 in Patients With EGFR T790M Positive Advanced Non Small Cell Lung Cancer Who Progressed on Prior Therapy With EGFR TKIs. --- T790M ---

Safety, Pharmacokinetic and Preliminary Efficacy Study of AC0010 in Patients With EGFR T790M Positive NSCLC AC0010 is a novel, potent, small molecule irreversible tyrosine kinase inhibitor (TKI) that selectively targets mutant forms of the epidermal growth factor receptor (EGFR) while sparing wild-type (WT) EGFR. --- T790M ---

The purpose of the study is to evaluate the pharmacokinetic (PK) and safety profile of oral AC0010; to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of oral AC0010; to assess the safety and efficacy of AC0010 in previously treated mutant EGFR in NSCLC patients with EGFR T790M mutation. --- T790M ---

To assess the overall objective response rate (ORR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).. DoR (Duration of Response). --- T790M ---

To assess the duration of response (DOR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).. PFS (Progression-free survival). --- T790M ---

To assess the progression-free survival (PFS) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).. DCR (Disease control rate). --- T790M ---

To assess the disease control rate (DCR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).. OS (Overall survival). --- T790M ---

To assess the overall survival (OS) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).. EORTC QLQ-C30 and LC-13 questionnaire. --- T790M ---

To assess the safety of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).. Adverse events. --- T790M ---

To assess the safety of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).. Inclusion Criteria - Stage 1: 1. Patients of either gender, aged from 18 years older to 75. 2. Histologically or cytologically confirmed metastatic, or unresectable locally advanced, recurrent NSCLC. --- T790M ---

4. Failed to the treatment of EGFRTKI with definite state of T790M, or harbored T790M mutation without the treatment of EGFRTKI. 5. Offer biopsy sample to central lab if failed or without the treatment of EGFRTKI. --- T790M ---

4. Failed to the treatment of EGFRTKI with definite state of T790M, or harbored T790M mutation without the treatment of EGFRTKI. 5. Offer biopsy sample to central lab if failed or without the treatment of EGFRTKI. --- T790M --- --- T790M ---

4. Failed to the treatment of EGFR-TKI and harbored T790M mutation. --- T790M ---

Patients with arbored T790M mutation should be treated with only one kind of medicine or never be treated. --- T790M ---

However, patients on TKIs eventually progress, and in approximately 50% of cases, progression is due to development of an additional mutation called T790M. --- T790M ---

Pre-clinical data demonstrated that AC0010 inhibits T790M. --- T790M ---

It is anticipated that AC0010 may promote cell death in tumor cells with the T790M mutation, thus providing possible therapeutic benefit in patients who have developed T790M-mediated resistance to previous TKIs. --- T790M ---

It is anticipated that AC0010 may promote cell death in tumor cells with the T790M mutation, thus providing possible therapeutic benefit in patients who have developed T790M-mediated resistance to previous TKIs. --- T790M --- --- T790M ---

This study will include 2 parts: Stage 1 : Dose-escalation Period with 28-day cycles; Optional Treatment Extension Period starting on Day 29 Stage 2 : Evaluation of activity and safety in patients with the EGFR T790M mutation --- T790M ---

Primary Outcomes

Description: To assess the overall objective response rate (ORR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: ORR(Objective Response Rate)

Time: Every 6 weeks from time of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 11 months

Secondary Outcomes

Description: To assess the duration of response (DOR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: DoR (Duration of Response)

Time: Every 6 weeks from time of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 11 months

Description: To assess the progression-free survival (PFS) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: PFS (Progression-free survival)

Time: Every 6 weeks from time of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 11 months

Description: To assess the disease control rate (DCR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: DCR (Disease control rate)

Time: Every 6 weeks from time of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 11 months

Description: To assess the overall survival (OS) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: OS (Overall survival)

Time: Every 6 weeks from time of first dose until objective disease progression, then every 3 months until death of lost of follow-up, up to approximately 18 months

Description: To assess the safety of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: EORTC QLQ-C30 and LC-13 questionnaire

Time: From screening to the end of survival follow-up, which is assessed though study completion

Description: To assess the safety of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: Adverse events

Time: From screening to 30days after end of treatment, which is assessed through study completion

74 A Phase Ib/II, Multicenter, Open-label Study of EGF816 in Combination With INC280 in Adult Patients With EGFR Mutated Non-small Cell Lung Cancer.

The study is designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of EGF816 in combination with INC280 and to estimate the preliminary anti-tumor activity of EGF816 in combination with INC280 in patients with advanced non-small cell lung cancer (NSCLC) with documented EGFR mutation.

NCT02335944 Non Small Cell Lung Cancer Drug: INC280 Drug: EGF816
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion criteria: - Histologically documented, locally advanced or recurrent (stage IIIB who are not eligible for combined modality treatment) or metastatic (Stage IV) NSCLC - Locally documented EGFR mutation L858R and/or ex19del, or a characterized de novo EGFR T790M mutation (or other rare activating mutations that confer sensitivity to 1st and 2nd generation EGFR inhibitors (e.g. --- L858R --- --- T790M ---

- Phase II Group 1 (EGFRmut, any T790M, any c-MET, 2/4L antineoplastic, EGFR TKI resistant) only: Patients demonstrated a documented clinical benefit (CR (any duration), PR (any duration), or SD for at least 6 months) on prior EGFR TKI (e.g. --- T790M ---

- Phase II Group 2 (EGFRmut, de novo T790M, any c-MET, 1/3L antineoplastic, EGFR TKI naïve) only: Advanced NSCLC patients who have not been previously treated with any therapy known to inhibit EGFR and harbor de novo T790M mutation . --- T790M ---

- Phase II Group 2 (EGFRmut, de novo T790M, any c-MET, 1/3L antineoplastic, EGFR TKI naïve) only: Advanced NSCLC patients who have not been previously treated with any therapy known to inhibit EGFR and harbor de novo T790M mutation . --- T790M --- --- T790M ---

- Phase II Group 3 (EGFRmut, T790M negative, any c-MET, 1L antineoplastic) only: patients must harbor an EGFR activating mutation and must be naïve from any line of systemic antineoplastic therapy in the advanced setting. --- T790M ---

- Phase II Group 4 (EGFRmut, any T790M, any c-MET, 1L (treatment-naïve), 2//3L antineoplastic): All patients must harbor an EGFR activating mutation and 2/3L patients must have failed (defined as intolerance to treatment or documented disease progression) a maximum of 2 prior lines of antineoplastic therapy in the advanced setting Exclusion Criteria: - Phase Ib: - More than one previous treatment line with erlotinib, gefitinib or afatinib - Previous treatment with any investigational agent known to inhibit EGFR (mutant or wild-type) - Patients who have received more than three prior lines of antineoplastic therapies (including EGFR TKI) in advanced setting. --- T790M ---

- Phase II Group 1 (EGFRmut, any T790M, any c-MET, 2/4L antineoplastic, EGFR TKI resistant): - More than 3 prior lines of systemic antineoplastic therapies (including EGFR TKI) in the advanced setting - More than 1 previous treatment line with 1st or 2nd generation EGFR TKI (e.g. --- T790M ---

- Phase II Group 2 (EGFRmut, de novo T790M, any c-MET, 1/3L antineoplastic, EGFR TKI naïve): - More than two previous treatment lines of systemic antineoplastic therapies in the advanced setting - Previous treatment with an investigational or marketed agent that inhibits EGFR. --- T790M ---

- Phase II Group 3 (EGFRmut, T790M negative, any c-MET, 1L antineoplastic): - De novo EGFR T790M mutation identified by central assessment - Previous treatment with any systemic antineoplastic therapy in the advanced setting (NSCLC stage IIIB or IV. --- T790M ---

- Phase II Group 3 (EGFRmut, T790M negative, any c-MET, 1L antineoplastic): - De novo EGFR T790M mutation identified by central assessment - Previous treatment with any systemic antineoplastic therapy in the advanced setting (NSCLC stage IIIB or IV. --- T790M --- --- T790M ---

- Phase II Group 4 (EGFRmut, any T790M, any c-MET, 1/3L antineoplastic): - More than 2 prior lines of systemic antineoplastic therapies in the advanced setting - Previous treatment with an investigational or marketed 3rd generation EGFR TKI (e.g. --- T790M ---

Primary Outcomes

Measure: Phase Ib: Incidence of dose limiting toxicities (DLTs) and Estimation of the Maximum tolerated dose (MTD) or Recommended Phase II dose (RP2D)

Time: First 28 days of treatment

Description: ORR is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) determined by Blinded Independent Review Committee (BIRC) assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Measure: Phase II Groups 1, 2 and 3: Overall Response Rate per RECIST 1.1

Time: At least 24 weeks

Description: Frequency of treatment-emergent adverse events

Measure: Phase II Group 4 Incidence and severity of AEs/SAEs, dose interruptions, reductions and dose intensity

Time: At least 24 weeks

Secondary Outcomes

Description: Assessment of the safety of EGF816 in combination with INC280 will be performed continuously during the treatment phase and 30 days after discontinuation of the study treatment

Measure: Safety of INC280 and EGF816: Incidence and severity of AEs and SAEs, including changes in hematology and chemistry values, vital signs and ECGs (Phase I/II)

Time: At least 24 weeks

Description: Assessment of the tolerability of EGF816 in combination with INC280 will be performed continuously during the treatment phase and 30 days after discontinuation of the study treatment

Measure: Frequency of dose interruption, frequency of reduction and dose intensity (Phase I/II)

Time: At least 24 weeks

Description: ORR is defined as proportion of patients with best overall response of (PR+CR) determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Measure: Overall Response Rate (Phase Ib and Phase II Group 4)

Time: At least 24 weeks

Description: DCR is defined as the proportion of patients with best overall response of CR, PR, or SD determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Measure: Disease Control Rate (Phase I/II)

Time: At least 24 weeks

Description: Progression-free survival (PFS). PFS is defined as time from date of first dose of study treatment to date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1

Measure: Progression Free Survival (Phase I/II)

Time: At least 24 weeks

Description: DOR is defined as the time from first documented response (PR or CR) to the date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1

Measure: Duration of Response (Phase I/II)

Time: At least 24 weeks

Description: OS is defined as the time from first dose of the study treatment to the date of death due to any cause.

Measure: Overall Survival (Phase I/II)

Time: At least 24 weeks

Measure: Plasma concentration versus time profiles

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Area under the plasma concentration versus time curve (AUC) of EGF816

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Area under the plasma concentration versus time curve (AUC) of INC280

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Peak plasma concentration (Cmax) of INC280

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Peak plasma concentration (Cmax) of EGF816

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Elimination half life (t1/2) of INC280

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Elimination half life (t1/2) of EGF816

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Description: TTR is defined as the time from the date of the first dose to the date of first documented response (CR or PR) determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Measure: Time to Response (Phase I/II)

Time: At least 24 weeks

75 A Phase I/II Study of Pacritinib in Patients With EGFR Mutant NSCLC After EGFR TKI

The goal of the study is to find the best dose of pacritinib when given in combination with erlotinib.

NCT02342353 Non-Small Cell Lung Cancer Nonsmall Cell Lung Cancer Carcinoma, Non-Small-Cell Lung Drug: Pacritinib Drug: Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Patients with mutations in T790M are eligible if they have progressed after treatment with a third generation EGFR tyrosine kinase inhibitor (osimertinib), but otherwise patients must have EGFR T790M negative or unknown status. --- T790M ---

Patients with mutations in T790M are eligible if they have progressed after treatment with a third generation EGFR tyrosine kinase inhibitor (osimertinib), but otherwise patients must have EGFR T790M negative or unknown status. --- T790M --- --- T790M ---

Primary Outcomes

Description: The maximum tolerated dose (MTD) is defined as the dose level immediately below the dose level at which 2 patients of a cohort (of 2 to 6 patients) experience dose-limiting toxicity during the first cycle. Dose escalations will proceed until the MTD has been reached. A patient is evaluable for DLT assessment only during Cycle 1 of treatment. If the patient is not able to be treated on Day 1 of Cycle 2, then s/he is still considered in Cycle 1 active treatment and can experience a DLT. Once the patient has been treated in Cycle 2, s/he will no longer be evaluated for DLTs in all subsequent cycles.

Measure: Dose-limiting toxicities and maximum tolerated dose (MTD) - Phase I only

Time: Completion of cycle 1 of all Phase I patients (estimated to be 1 year)

Description: Partial response + complete response per RECIST 1.1 criteria Study terminated prior to enrolling any phase II participants Complete response (CR) = disappearance of all target lesions, non-target lesions, and normalization of tumor marker level Partial response (PR) = at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline of sum diameters

Measure: Response rate - Phase II only

Time: Up to 5 years

Secondary Outcomes

Description: The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.

Measure: Adverse events (toxicities)

Time: 30 days post completion of treatment (estimated to be 9 months)

Description: Percentage of patients who achieve complete response, partial response, or stable disease per RECIST 1.1 criteria. Complete response (CR) = disappearance of all target lesions, non-target lesions, and normalization of tumor marker level Partial response (PR) = at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline of sum diameters Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Measure: Disease control rate (DCR)

Time: Up to 5 years

Description: PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progressive disease (PD) = at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study, appearance of one or more non-target lesion(s) and/or unequivocal progression of existing non-target lesions

Measure: Progression-free survival (PFS)

Time: Up to 5 years

Description: Overall survival is defined as the time interval from date of diagnosis to date of death from any cause.

Measure: Overall survival (OS)

Time: Up to 5 years

76 PHASE 1/2 OPEN-LABEL STUDY OF PF-06747775 (EPIDERMAL GROWTH FACTOR RECEPTOR T790M INHIBITOR) IN PATIENTS WITH ADVANCED EPIDERMAL GROWTH FACTOR RECEPTOR MUTANT (DEL 19 OR L858R ± T790M) NON-SMALL CELL LUNG CANCER

This is a Phase 1/2 study of PF-06747775 as a single agent and in combination with other cancer treatments in patients with advanced EGFRm NSCLC. The overall clinical study consists of a Phase 1 single agent dose-escalation and expansion part to determine the RP2D of PF-06747775 single agent in patients with previously-treated EGFRm NSCLC followed by sequential evaluations of PF-06747775 at the RP2D in 3 different clinical scenarios as detailed below: - Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously untreated patients with advanced EGFRm NSCLC, - Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of PF 06747775 in combination with palbociclib vs PF-06747775 single agent (Cohort 2B) in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M), and - Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M).

NCT02349633 Non-Small Cell Lung Cancer Drug: PF-06747775 Drug: Palbociclib Drug: Avelumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

PHASE 1/2 OPEN-LABEL STUDY OF PF-06747775 (EPIDERMAL GROWTH FACTOR RECEPTOR T790M INHIBITOR) IN PATIENTS WITH ADVANCED EPIDERMAL GROWTH FACTOR RECEPTOR MUTANT (DEL 19 OR L858R ± T790M) NON-SMALL CELL LUNG CANCER. --- T790M ---

PHASE 1/2 OPEN-LABEL STUDY OF PF-06747775 (EPIDERMAL GROWTH FACTOR RECEPTOR T790M INHIBITOR) IN PATIENTS WITH ADVANCED EPIDERMAL GROWTH FACTOR RECEPTOR MUTANT (DEL 19 OR L858R ± T790M) NON-SMALL CELL LUNG CANCER. --- T790M --- --- L858R --- --- T790M ---

Study For Patients With NSCLC EGFR Mutations (Del 19 or L858R +/- T790M) This is a Phase 1/2 study of PF-06747775 as a single agent and in combination with other cancer treatments in patients with advanced EGFRm NSCLC. --- L858R --- --- T790M ---

The overall clinical study consists of a Phase 1 single agent dose-escalation and expansion part to determine the RP2D of PF-06747775 single agent in patients with previously-treated EGFRm NSCLC followed by sequential evaluations of PF-06747775 at the RP2D in 3 different clinical scenarios as detailed below: - Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously untreated patients with advanced EGFRm NSCLC, - Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of PF 06747775 in combination with palbociclib vs PF-06747775 single agent (Cohort 2B) in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M), and - Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M). --- T790M ---

The overall clinical study consists of a Phase 1 single agent dose-escalation and expansion part to determine the RP2D of PF-06747775 single agent in patients with previously-treated EGFRm NSCLC followed by sequential evaluations of PF-06747775 at the RP2D in 3 different clinical scenarios as detailed below: - Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously untreated patients with advanced EGFRm NSCLC, - Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of PF 06747775 in combination with palbociclib vs PF-06747775 single agent (Cohort 2B) in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M), and - Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M). --- T790M --- --- T790M ---

The overall clinical study consists of a Phase 1 single agent dose-escalation and expansion part to determine the RP2D of PF-06747775 single agent in patients with previously-treated EGFRm NSCLC followed by sequential evaluations of PF-06747775 at the RP2D in 3 different clinical scenarios as detailed below: - Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously untreated patients with advanced EGFRm NSCLC, - Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of PF 06747775 in combination with palbociclib vs PF-06747775 single agent (Cohort 2B) in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M), and - Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M). --- T790M --- --- T790M --- --- L858R --- --- T790M ---

The overall clinical study consists of a Phase 1 single agent dose-escalation and expansion part to determine the RP2D of PF-06747775 single agent in patients with previously-treated EGFRm NSCLC followed by sequential evaluations of PF-06747775 at the RP2D in 3 different clinical scenarios as detailed below: - Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously untreated patients with advanced EGFRm NSCLC, - Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of PF 06747775 in combination with palbociclib vs PF-06747775 single agent (Cohort 2B) in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M), and - Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M). --- T790M --- --- T790M --- --- L858R --- --- T790M --- --- T790M ---

The overall clinical study consists of a Phase 1 single agent dose-escalation and expansion part to determine the RP2D of PF-06747775 single agent in patients with previously-treated EGFRm NSCLC followed by sequential evaluations of PF-06747775 at the RP2D in 3 different clinical scenarios as detailed below: - Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously untreated patients with advanced EGFRm NSCLC, - Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of PF 06747775 in combination with palbociclib vs PF-06747775 single agent (Cohort 2B) in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M), and - Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M). --- T790M --- --- T790M --- --- L858R --- --- T790M --- --- T790M --- --- T790M ---

The overall clinical study consists of a Phase 1 single agent dose-escalation and expansion part to determine the RP2D of PF-06747775 single agent in patients with previously-treated EGFRm NSCLC followed by sequential evaluations of PF-06747775 at the RP2D in 3 different clinical scenarios as detailed below: - Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously untreated patients with advanced EGFRm NSCLC, - Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of PF 06747775 in combination with palbociclib vs PF-06747775 single agent (Cohort 2B) in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M), and - Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M). --- T790M --- --- T790M --- --- L858R --- --- T790M --- --- T790M --- --- T790M --- --- L858R --- --- T790M ---

2. T790M disease as follows: Phase 1 If a repeat biopsy was performed on the tumor following prior EGFR TKI therapy, then T790M positive disease must be present. --- T790M ---

2. T790M disease as follows: Phase 1 If a repeat biopsy was performed on the tumor following prior EGFR TKI therapy, then T790M positive disease must be present. --- T790M --- --- T790M ---

Patients of unknown T790M status following EGFR TKI progression (ie, no post EGFR TKI progression biopsy was performed) are eligible. --- T790M ---

In the PK sub-studies involving food/antacid and CYP3A4 effects, patients with EGFRm (del 19 or L858R) with any T790M status are eligible to enroll. --- L858R --- --- T790M ---

Studies at RP2D Cohort 1: Patients may have de novo T790M mutation, but it is not required. --- T790M ---

Cohort 2 and Cohort 3: Patients must have EGRFm (del 19 AND T790M or L858R AND T790M) NSCLC tumors as detected by local EGFR mutation test that includes QIAGEN Therascreen EGFR RGQ PCR kit, Roche cobas® EGFR Mutation Test or a sponsor-approved laboratory developed test that is validated in a CLIA laboratory, which will then be retrospectively confirmed by the central validated Thermo Fisher Scientific Oncomine Next Generation Sequencing (NGS) cancer panel test. --- T790M ---

Cohort 2 and Cohort 3: Patients must have EGRFm (del 19 AND T790M or L858R AND T790M) NSCLC tumors as detected by local EGFR mutation test that includes QIAGEN Therascreen EGFR RGQ PCR kit, Roche cobas® EGFR Mutation Test or a sponsor-approved laboratory developed test that is validated in a CLIA laboratory, which will then be retrospectively confirmed by the central validated Thermo Fisher Scientific Oncomine Next Generation Sequencing (NGS) cancer panel test. --- T790M --- --- L858R --- --- T790M ---

Patients will also be enrolled if they solely test positive for EGFR (del 19 AND T790M or L858R AND T790M) NSCLC in plasma detected by local EGFR mutation test that includes QIAGEN Therascreen EGFR Plasma RGQ kit, Roche cobas® EGFR mutation test v2 (US-IVD) or Sysmex Inostic's OncoBEAMTM EGFR test or a sponsor-approved laboratory developed test that is validated in a CLIA laboratory, which will then be retrospectively confirmed by a validated cfDNA test as determined by the Sponsor. --- T790M ---

Patients will also be enrolled if they solely test positive for EGFR (del 19 AND T790M or L858R AND T790M) NSCLC in plasma detected by local EGFR mutation test that includes QIAGEN Therascreen EGFR Plasma RGQ kit, Roche cobas® EGFR mutation test v2 (US-IVD) or Sysmex Inostic's OncoBEAMTM EGFR test or a sponsor-approved laboratory developed test that is validated in a CLIA laboratory, which will then be retrospectively confirmed by a validated cfDNA test as determined by the Sponsor. --- T790M --- --- L858R --- --- T790M ---

An archival specimen is acceptable for Phase 1; a de novo specimen is required for Cohorts 2, and 3 if the T790M status was confirmed by tissue biopsy. --- T790M ---

Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible Use of immunosuppressive medication at time of randomization Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung There remains an unmet medical need to develop EGFR TKI agents that effectively target both the single activating mutations of del 19 and L858R, and the secondary resistance mutation T790M, while sparing WT EGFR. --- L858R --- --- T790M ---

Primary Outcomes

Description: The target probability of DLT at MTD will be 30%

Measure: Phase 1 Primary Endpoint - Number of patients with dose limiting toxicities during Phase 1

Time: 21 days

Description: Cohort 1 is an evaluation of PF 06747775 single agent at RP2D Cohorts 2A and 3 will determine the RP2D of PF-06747775 in combination with either palbociclib or avelumab, respectively, based on safety and tolerability. Determination of the RP2D will be performed using the mTPI design. For Cohort 2A, after determination of the RP2D for the PF-06747775 and palbociclib combination, a randomized evaluation of the combination vs PF-06747775 single agent (2:1 ratio) will be initiated (Cohort 2B). For Cohort 3, after determination of the RP2D for the PF-06747775 and avelumab combination, the dose level will be expanded to enroll an overall total of approximately 20 patients to further explore the safety, PK, and antitumor activity of the combination.

Measure: Phase 1b/2 - Cohort 1 = confirmed OR per RECIST; Cohort 2A = Cycle 2 DLT; Cohort 2B = PFS and Cohort 3 = Cycle 1 DLT

Time: Cohorts 1, 2A and 2B = 21 day cycles and Cohort 3 = 28 day cycles

Secondary Outcomes

Description: Number of patients with OR based assessment of confirmed CR or PR according to RECIST. CR are those that persist on repeat imaging at least 4 weeks after the initial documentation of response. PR are those that are greater or equal to a 30% decrease ( per RECIST) under the baseline of the sum of diameters of all target measurable disease

Measure: Phase 1: Secondary Endpoint - Number of patients with Objective Response (OR)

Time: Time from first dose of study drug until OR of CR or PR up to 24 months

Description: PFS (cohort 1, 2A and 3) ORR (cohort 2A, 2B and 3) DOR (All cohorts)

Measure: Phase 1b/2

Time: Time from first dose of study drug until Disease Progression or death (whichever first) up to 24 months

77 A Randomized, Double-blind Phase 2 Study of Itacitinib in Combination With Erlotinib Versus Erlotinib Alone in Subjects With Stage IIIB/ IV or Recurrent Non-Small Cell Lung Cancer (NSCLC) Whose Tumors Have Epidermal Growth Factor Receptor (EGFR) Activating Mutations

The purpose of this study is to determine if Itacitinib in combination with erlotinib is safe and effective in the treatment of nonsquamous non-small cell lung cancer (NSCLC) that is Stage IIIB/Stage IV or recurrent whose tumors have EGFR activating mutations.

NCT02355431 Solid Tumors and Hematologic Malignancy NSCLC (Non-small Cell Lung Carcinoma) Drug: Itacitinib Drug: erlotinib Drug: placebo
MeSH:Carcinoma, Non-Small-Cell Lung Hematologic Neoplasms
HPO:Hematological neoplasm Leukemia Non-small cell lung carcinoma

Exclusion Criteria: - Known presence of the T790M mutation in EGFR in tumor samples - Candidates for curative radiation therapy or surgery. --- T790M ---

Primary Outcomes

Description: Subjects will take erlotinib daily and begin dosing with itacitinib once daily (QD) on Cycle 1, Day 1. The safety and tolerability of the regimen will be assessed during the first 21 days of therapy

Measure: Part 1: Determination of the dose of itacitinib that is safe and tolerable in combination with erlotinib as measured by the number of dose-limiting toxicities (DLTs) observed in the evaluation cohort.

Time: Baseline through Day 21

Measure: Part 2: Overall Survival (OS)

Time: Randomization until death. Approximately 31 months.

Description: PFS is defined as the time from randomization until the earliest date of disease progression determined by investigator assessment of objective radiographic disease assessments per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or death due to any cause if sooner.

Measure: Part 2: Progression-free survival (PFS)

Time: Randomization to disease progression, or death due to any cause if sooner. Approximately 23 months.

Secondary Outcomes

Description: Objective response determined by radiographic disease assessments per RECIST (v1.1), by investigator assessment

Measure: Part 2: Objective Response

Time: Baseline through end of study. Approximately 31 months.

Description: Duration of response determined by radiographic disease assessments per RECIST (v1.1), by investigator assessment Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

Measure: Part 2: Duration of Response

Time: Baseline through end of study. Approximately 31 months.

Measure: Part 2: Safety and tolerability of the treatment regimens assessed by a summary of adverse events and clinical laboratory assessments.

Time: Baseline through approximately 30 days post treatment discontinuation. Assessed after approximately 31 months.

78 T-STAR - T790M Mutation Positive 2nd Line STandard of cAre Registry

The aim of the study is to collect real world information on patients with locally advanced or metastatic non small cell lung cancer (NSCLC) who progressed after first line treatment with an approved Tyrosine-Kinase Inhibitor (TKI), who are known to be T790M positive and have been prescribed second line platinum-based chemotherapy (Pemetrexed + Cisplatin /Carboplatin).

NCT02368990 Non Small Cell Lung Cancer
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

T-STAR - T790M Mutation Positive 2nd Line STandard of cAre Registry. --- T790M ---

T790M Mutation Positive 2nd Line STandard of cAre Registry The aim of the study is to collect real world information on patients with locally advanced or metastatic non small cell lung cancer (NSCLC) who progressed after first line treatment with an approved Tyrosine-Kinase Inhibitor (TKI), who are known to be T790M positive and have been prescribed second line platinum-based chemotherapy (Pemetrexed + Cisplatin /Carboplatin). --- T790M ---

T790M Mutation Positive 2nd Line STandard of cAre Registry The aim of the study is to collect real world information on patients with locally advanced or metastatic non small cell lung cancer (NSCLC) who progressed after first line treatment with an approved Tyrosine-Kinase Inhibitor (TKI), who are known to be T790M positive and have been prescribed second line platinum-based chemotherapy (Pemetrexed + Cisplatin /Carboplatin). --- T790M --- --- T790M ---

- Patients must have had confirmation that tumour is T790M mutation positive from a biopsy or cytology sample taken after confirmed disease progression on 1st line treatment with an approved EGFR-targeted TKI. - WHO performance status 0-1 with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks. --- T790M ---

Further tests on biopsied tissue or cytology at progression after treatment with an approved EGFR targeted TKI are used to determine positivity to T790M mutation. --- T790M ---

Primary Outcomes

Description: This will be assessed as the time from the start date of 2nd line chemotherapy until death due to any cause or censoring (at end of 24 months).To assess efficacy of permetrexed + cisplatinum/carboplatin as the 2nd line of treatment of NSCLC.

Measure: Overall Survival

Time: 24 months from last subject in

Secondary Outcomes

Description: This will be assessed as the time from start of 2nd line therapy until the date of disease progression or death (by any cause in the absence of progression). To assess efficacy of 2nd line treatment and beyond.

Measure: Response to Therapy as assessed by the physician

Time: 24 months from last subject in

Description: This will be assessed as the time from start date of line of therapy to end date of line of therapy or death date. To describe treatment patterns for 2nd line and beyond.

Measure: Time on treatment by line of therapy and between therapies

Time: 24 months from last subject in

Description: This will be assessed as the number and Time from the dates of admission and exit of attendance. To describe Healthcare resource utilization for 2nd line treatment and beyond.

Measure: Admission of planned/unplanned hospitalizations, emergency department visits and outpatient/physician visits

Time: 24 months from last subject in

Description: For each of the symptoms in EORTC QLQ-LC13 and EORTC QLQ-C30, Time from inclusion until the date of first clinically meaningful symptom deterioration or death by any cause in the absence of a clinically meaningful symptom deterioration. To assess the impact of 2nd and subsequent lines of therapy on patients' disease-related symptoms and health related quality of life.

Measure: Time to symptom deterioration

Time: 24 months from last subject in

Description: This will be assessed as the number of patients with two consecutive assessments, which showed a clinically meaningful improvement in that symptom from baseline. To assess the impact of 2nd and subsequent lines of therapies on patients' disease-related symptoms and health related quality of life.

Measure: Symptom Improvement Rate

Time: 24 months from last subject in

Description: This will be assessed as the time from the date of complete or partial response until the first date of recurrence or progression. To assess the efficacy of 2nd line treatment and beyond.

Measure: Duration of Response as defined by the physician

Time: 24 months from last subject in

Description: This will be assessed as the time from start of 2nd line therapy until the date of disease progression or death by any cause. This will be done to assess efficacy of pemetrexed + cisplatin/carboplatin as the 2nd line treatment of NSCLC.

Measure: Progression Free Survival

Time: 24 months from last subject in

79 TAURAS - T790 AURA ScreenFailure SOC Registry Study

The aim of this study is to evaluate clinical outcomes of 2nd line therapy in NSCLC patients without the T790M mutation, both independently and when compared indirectly with NSCLC patients with the T790M mutation in the T STAR non interventional study (D5160R00001). The patient population in the TAURAS study will consist of patients who fail screening for AURA3 (D5160C00003) due to a T790M mutation not detected using the central cobas® EGFR Mutation Test (Roche Molecular Systems).

NCT02405247 Non Small Cell Lung Cancer Other: Patient Reported Outcome (PRO)
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

TAURAS - T790 AURA ScreenFailure SOC Registry Study The aim of this study is to evaluate clinical outcomes of 2nd line therapy in NSCLC patients without the T790M mutation, both independently and when compared indirectly with NSCLC patients with the T790M mutation in the T STAR non interventional study (D5160R00001). --- T790M ---

TAURAS - T790 AURA ScreenFailure SOC Registry Study The aim of this study is to evaluate clinical outcomes of 2nd line therapy in NSCLC patients without the T790M mutation, both independently and when compared indirectly with NSCLC patients with the T790M mutation in the T STAR non interventional study (D5160R00001). --- T790M --- --- T790M ---

The patient population in the TAURAS study will consist of patients who fail screening for AURA3 (D5160C00003) due to a T790M mutation not detected using the central cobas® EGFR Mutation Test (Roche Molecular Systems). --- T790M ---

Patients from Japan aged at least 20 years 3. Patients who have been considered ineligible for entry into the AZD9291 AURA3 registration trial as a result of their tumour not harbouring the T790M mutation, according to the cobas EGFR test of a biopsy taken following the latest line of therapy, at a central testing lab participating in the D5160C00003 (AURA3) study. --- T790M ---

6. Patients with an invalid or unsuccessful T790M mutation test result during screening for AURA3. --- T790M ---

Biopsy tissue is collected to assess T790M mutation status. --- T790M ---

The primary objectives of the NIS study in NSCLC patients who have progressed on a previous EGFR-TKI (with no intervening chemotherapy) and who do not harbour the T790M mutation (according to central analysis using the Roche cobas® EGFR Mutation Test), are: - To estimate overall survival - To estimate disease progression (as assessed and defined by physician) - To estimate partial, complete, and overall response rates by line of therapy (as assessed and defined by physician) - To describe treatment patterns for 2nd line and beyond, including time on treatment by line of therapy and time to subsequent therapies (or death) - To describe health resource utilization patterns (e.g., hospitalizations, emergency room visits) - To capture patient reported symptoms, functioning and health-related quality of life (HRQoL) data using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 items (EORTC QLQ-C30), and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 items (EORTC QLQ-LC13) - To capture health state utilities using the EQ-5D-5L questionnaire --- T790M ---

Primary Outcomes

Description: This will be assessed as the time from start of 2nd line therapy until the date of disease progression or death by any cause.

Measure: Progression Free Survival

Time: 24 months from last subject in

Description: This will be assessed as the time from start of 2nd line therapy until the date of disease progression or death (by any cause in the absence of progression). To assess efficacy of 2nd line treatment and beyond.

Measure: Response to Therapy as assessed by the physician

Time: 24 months from last subject in

Description: This will be assessed as the time from start date of line of therapy to end date of line of therapy or death date. To describe treatment patterns for 2nd line and beyond.

Measure: Time on treatment by line of therapy and between therapies

Time: 24 months from last subject in

Description: This will be assessed as the number and Time from the dates of admission and exit of attendance. To describe Healthcare resource utilization for 2nd line treatment and beyond.

Measure: Admission of planned/unplanned hospitalizations, emergency department visits and outpatient/physician visit

Time: 24 months from last subject in

Description: For each of the symptoms in EORTC QLQ-LC13 and EORTC QLQ-C30, Time from inclusion until the date of first clinically meaningful symptom deterioration or death by any cause in the absence of a clinically meaningful symptom deterioration. To assess the impact of 2nd and subsequent lines of therapy on patients' disease-related symptoms and health related quality of life.

Measure: Time to symptom deterioration

Time: 24 months from last subject in

Description: This will be assessed as the number of patients with two consecutive assessments, which showed a clinically meaningful improvement in that symptom from baseline. To assess the impact of 2nd and subsequent lines of therapies on patients' disease-related symptoms and health related quality of life.

Measure: Symptom Improvement Rate

Time: 24 months from last subject in

Description: This will be assessed as the time from the start date of 2nd line chemotherapy until death due to any cause.

Measure: Overall Survival

Time: 24 months from last subject in

80 A Multicenter, Randomized, Double-Blind Study of Erlotinib in Combination With Ramucirumab or Placebo in Previously Untreated Patients With EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer

The main purpose of this study is to evaluate the efficacy and safety of ramucirumab in combination with erlotinib as compared to placebo in combination with erlotinib in previously untreated participants with stage IV non-small cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation (Exon 19-Del and Exon 21 L858R). Safety and tolerability of ramucirumab in combination with erlotinib will be assessed in Part A before proceeding to Part B. The purpose of Part C is to determine the efficacy and safety of ramucirumab in combination with gefitinib in previously untreated East Asian participants with EGFR mutation-positive metastatic NSCLC and of ramucirumab in combination with osimertinib in those participants whose disease progressed on ramucirumab and gefitinib and that have T790M - positive metastatic NSCLC.

NCT02411448 Metastatic Non-Small Cell Lung Cancer Drug: Ramucirumab Drug: Placebo Drug: Erlotinib Drug: Gefitinib Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Safety and tolerability of ramucirumab in combination with erlotinib will be assessed in Part A before proceeding to Part B. The purpose of Part C is to determine the efficacy and safety of ramucirumab in combination with gefitinib in previously untreated East Asian participants with EGFR mutation-positive metastatic NSCLC and of ramucirumab in combination with osimertinib in those participants whose disease progressed on ramucirumab and gefitinib and that have T790M - positive metastatic NSCLC. --- T790M ---

Exclusion Criteria: - Known T790M EGFR mutation (not applicable for Part C Period 2). --- T790M ---

Primary Outcomes

Description: PFS is defined as the time from the date of randomization to the date of radiographically documented progressive disease (PD) based on investigator assessment, or the date of death due to any cause, whichever is first assessed via Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1 or more new lesions is also considered progression.

Measure: Part B: Progression Free Survival (PFS)

Time: Randomization to Measured Progressive Disease or Death from Any Cause (Up To 37 Months)

Description: A summary of other non-serious adverse events and all serious adverse events, regardless of causality, is located in the Reported Adverse Events Section.

Measure: Number of Participants With Treatment-Emergent Adverse Events

Time: Cycle 1 Day 1 through End of Study (Up To 3 Years)

Secondary Outcomes

Description: OS was defined as the time from the date of randomization to the date of death from any cause. For each participant who was not known to have died as of the data-inclusion cutoff date for a particular analysis,OS was censored for that analysis at the date of last contact prior to the data-inclusion cutoff date (contacts considered in the determination of last contact date include adverse event (AE) date, lesion assessment date, visit date, and last known alive date).

Measure: Part B: Overall Survival (OS)

Time: Randomization to Date of Death from Any Cause (Up To 37 Months)

Description: ORR was defined as the percentage of randomized participants achieving a best overall response of partial response (PR) or complete response (CR) assessed via Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR was defined as the disappearance of all lesions, pathological lymph node reduction in short axis to <10 mm, and normalization of tumor marker levels of non-target lesions. PR was at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1 or more new lesions is also considered progression.

Measure: Part B: Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR])

Time: Randomization to Progressive Disease (Up To 37 Months)

Description: DCR was defined as the percentage of randomized participants achieving a best overall response of CR,PR, or stable disease(SD) assessed via Response Evaluation Criteria in Solid Tumors(RECIST) version 1.1. CR was defined as the disappearance of all lesions,pathological lymph node reduction in short axis to <10 mm, and normalization of tumor marker levels of non-target lesions.PR was at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters.SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease(PD) was at least a 20% increase in the sum of the diameters of target lesions,taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.The appearance of 1 or more new lesions is also considered progression.

Measure: Part B: Percentage of Participants With CR, PR, or Stable Disease (SD) (Disease Control Rate [DCR])

Time: Randomization to Progressive Disease (Up To 37 Months)

Description: DoR was defined as the date of first documented CR or PR (responder) to the date of progressive disease or the date of death due to any cause, whichever was earlier. If a responder was not known to have died or have progressive disease, then the participant was censored at the date of last evaluable tumor assessment.CR was defined as the disappearance of all lesions, pathological lymph node reduction in short axis to <10 mm, and normalization of tumor marker levels of non-target lesions. PR was at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1 or more new lesions is also considered progression.

Measure: Part B: Duration of Response (DoR)

Time: Date of Complete Response (CR) or Partial Response (PR) to Date of Objective Disease Progression or Death Due to Any Cause (Up To 37 Months)

Description: Part B: Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab

Measure: Part B: Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab

Time: Cycle 2 Day 1: Predose; Cycle 4 Day 1: Predose; Cycle 7 Day 1: Predose; Cycle 14 Day 1

Description: Part B: Number of Participants With Anti-Ramucirumab Antibodies.

Measure: Part B: Number of Participants With Anti-Ramucirumab Antibodies

Time: Cycle 1 Predose through Follow-up (Up To 37 Months)

Description: The LCSS consisted of 9 items: 6 items focused on lung cancer symptoms [loss of appetite, fatigue, cough, dyspnea (shortness of breath), hemoptysis (blood in sputum), and pain] and 3 global items (symptom distress, interference with activity level, and global quality of life). Participant responses to each item were measured using visual analogue scales (VAS) with 100-millimeter (mm) lines. A higher score for any item represented a higher level of symptoms/problems. The LCSS total score was defined as the mean of all 9 items. Average symptom burden index (ASBI) was calculated as the mean of the six symptom-specific questions from the LCSS. Potential scores range from 0 (for best outcome) to 100 (for worst outcome).

Measure: Part B: Best Change From Baseline on the Lung Cancer Symptom Scale (LCSS)

Time: Baseline, End of Study (Up To 37 Months)

Description: The EQ-5D-5L is a standardized instrument used to measure self-reported health status of the participants. It consists of 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). There are 5 response levels (no problems, slight problems, moderate problems, severe problems, and extreme problems/unable to), ranging from 1 to 5 (good to bad). Dimension responses were converted to an index score using UK weights. The index scores were anchored on full health (1.0) to dead (0) with negative values assigned to health states considered worse than death.

Measure: Part B: Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score

Time: Baseline, Cycle 10 (each cycle is 2 weeks)

Description: The EQ-5D-5L is a standardized instrument used to measure self-reported health status of the participants. It consists of 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). There are 5 response levels (no problems, slight problems, moderate problems, severe problems, and extreme problems/unable to), ranging from 1 to 5 (good to bad). Dimension responses were converted to an index score using UK weights. The index scores were anchored on full health (1.0) to dead (0) with negative values assigned to health states considered worse than death.

Measure: Part B: Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score

Time: Baseline, Cycle 28 (each cycle is 2 weeks)

Description: The EQ-5D-5L is a standardized instrument used to measure self-reported health status of the participants. It consists of 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). There are 5 response levels (no problems, slight problems, moderate problems, severe problems, and extreme problems/unable to), ranging from 1 to 5 (good to bad). Dimension responses were converted to an index score using UK weights. The index scores were anchored on full health (1.0) to dead (0) with negative values assigned to health states considered worse than death.

Measure: Part B: Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score

Time: Baseline, Cycle 40 (each cycle is 2 weeks)

81 Frequency and Abundance of T790M Mutation on Circulating Tumor DNA in Patients With Non-small Cell Lung Cancer After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Treatment Failure: a Perspective Observational Study

The purpose of this study is to compare the frequency and abundance of T790M mutation among the different Clinical modes of EGFR-TKI failure.

NCT02418234 Non-small Cell Lung Cancer Stage III Non-Small-Cell Lung Cancer Metastatic Other: mutation detection Other: ARMS and ddPCR Genetic: ctDNA analysis
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Frequency and Abundance of T790M Mutation on Circulating Tumor DNA in Patients With Non-small Cell Lung Cancer After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Treatment Failure: a Perspective Observational Study. --- T790M ---

T790M Mutation on ctDNA in Patients With NSCLC After EGFR-TKI Failure The purpose of this study is to compare the frequency and abundance of T790M mutation among the different Clinical modes of EGFR-TKI failure. --- T790M ---

T790M Mutation on ctDNA in Patients With NSCLC After EGFR-TKI Failure The purpose of this study is to compare the frequency and abundance of T790M mutation among the different Clinical modes of EGFR-TKI failure. --- T790M --- --- T790M ---

Number of Patients With T790M Mutation Detected by Amplification Refractory Mutation System (ARMS) Assay. --- T790M ---

The investigators will describe the number of T790M mutation on ctDNA detected by ARMS assay in patients with non-small cell lung cancer (NSCLC) resistant to tyrosine kinase inhibitors (TKIs).. Abundance of T790M Mutation Detected by Digital Droplet PCR (ddPCR) Assay in Each Individual Patient. --- T790M ---

The investigators will describe the number of T790M mutation on ctDNA detected by ARMS assay in patients with non-small cell lung cancer (NSCLC) resistant to tyrosine kinase inhibitors (TKIs).. Abundance of T790M Mutation Detected by Digital Droplet PCR (ddPCR) Assay in Each Individual Patient. --- T790M --- --- T790M ---

The investigators will describe the abundance of T790M mutation on ctDNA detected by ddPCR assay in patients with NSCLC resistant to TKIs.. Number of T790M Mutation by ARMS and ddPCR Assays in Each Different Clinical Modes of TKI Failure. --- T790M ---

The investigators will describe the abundance of T790M mutation on ctDNA detected by ddPCR assay in patients with NSCLC resistant to TKIs.. Number of T790M Mutation by ARMS and ddPCR Assays in Each Different Clinical Modes of TKI Failure. --- T790M --- --- T790M ---

The investigators will describe the number of participants with T790M mutation in each different clinical mode of TKI failure by ARMS and ddPCR, and employ chi-square test to analyze the distribution of T790M mutation by ARMS and ddPCR in patients among the different Clinical modes of TKI failure.. Differences of T790M Mutation by ddPCR Among the Different Clinical Modes of TKI Failure. --- T790M ---

The investigators will describe the number of participants with T790M mutation in each different clinical mode of TKI failure by ARMS and ddPCR, and employ chi-square test to analyze the distribution of T790M mutation by ARMS and ddPCR in patients among the different Clinical modes of TKI failure.. Differences of T790M Mutation by ddPCR Among the Different Clinical Modes of TKI Failure. --- T790M --- --- T790M ---

The investigators will describe the number of participants with T790M mutation in each different clinical mode of TKI failure by ARMS and ddPCR, and employ chi-square test to analyze the distribution of T790M mutation by ARMS and ddPCR in patients among the different Clinical modes of TKI failure.. Differences of T790M Mutation by ddPCR Among the Different Clinical Modes of TKI Failure. --- T790M --- --- T790M --- --- T790M ---

The investigators will employ Analysis of Variance (ANOVA) method to analyze the differences of T790M mutation by ddPCR in patients among the different Clinical modes of TKI failure.. Inclusion Criteria: - Histologically confirmed stage IIIB/IV NSCLC. --- T790M ---

Non-small Cell Lung Cancer Stage III Non-Small-Cell Lung Cancer Metastatic Lung Neoplasms Carcinoma, Non-Small-Cell Lung An observational, non-interventional, multi-central study of comparison of the frequency and abundance of T790M mutation using both amplification refractory mutation system (ARMS) and digital droplet PCR (ddPCR) methods among the different Clinical modes of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) failure --- T790M ---

Primary Outcomes

Description: The investigators will describe the number of T790M mutation on ctDNA detected by ARMS assay in patients with non-small cell lung cancer (NSCLC) resistant to tyrosine kinase inhibitors (TKIs).

Measure: Number of Patients With T790M Mutation Detected by Amplification Refractory Mutation System (ARMS) Assay

Time: up to 2 years

Description: The investigators will describe the abundance of T790M mutation on ctDNA detected by ddPCR assay in patients with NSCLC resistant to TKIs.

Measure: Abundance of T790M Mutation Detected by Digital Droplet PCR (ddPCR) Assay in Each Individual Patient

Time: up to 2 years

Secondary Outcomes

Description: The investigators will describe the number of participants with T790M mutation in each different clinical mode of TKI failure by ARMS and ddPCR, and employ chi-square test to analyze the distribution of T790M mutation by ARMS and ddPCR in patients among the different Clinical modes of TKI failure.

Measure: Number of T790M Mutation by ARMS and ddPCR Assays in Each Different Clinical Modes of TKI Failure

Time: up to 2 years

Description: The investigators will employ Analysis of Variance (ANOVA) method to analyze the differences of T790M mutation by ddPCR in patients among the different Clinical modes of TKI failure.

Measure: Differences of T790M Mutation by ddPCR Among the Different Clinical Modes of TKI Failure

Time: up to 2 years

82 Correlation Between Epithelial Growth Factor Receptor(EGFR) Mutation Using cfDNA and CTCs in Patients With Non-Small Cell Lung Cancer

Correlation of epithelial growth factor receptor mutation in blood of lung cancer patient and clinical outcome.

NCT02422628 Lung Cancer
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

3. Tumor harboring EGFR mutation including activating mutation L858R, Del19 or/and resistant mutation T790M, or/and rare mutation G719, S768, L861 4. Treatment naive 5. Patients will receive EGFR-TKI as first line treatment. --- L858R --- --- T790M ---

3. Tumor with no EGFR mutation detected (mutation L858R, Del19 or/and resistant mutation T790M, or/and rare mutation G719, S768, L861) 4. EGFR TKI treatment naïve and without any EGFR TKI treatment in the following process ------- Exclusion criteria For exclusion in the study of NSCLC patients and control subjects should fulfill the following criteria: 1. Subjects should not enter the study if any of the following exclusion criteria are fulfilled: Involvement in the planning and/or conduct of the study (applies to staff at the study site) 2. Previous enrolment in the present study 3. --- L858R --- --- T790M ---

More than half of patients acquired resistant by new EGFR T790M resistance mutation. --- T790M ---

Primary Outcomes

Measure: Progressive disease measured by RECIST criteria after receiving 1st line EGFR-TKI

Time: 3 years

83 Phase I Study to Evaluate the Safety and Tolerability of ASLAN001 in Combination With Oxaliplatin and Capecitabine or Oxaliplatin and 5-FU With Leucovorin

This is a Phase I, open-label, dose escalation study of ASLAN001 given in combination with CAPOX or mFolfox6, in patients with metastatic solid tumours, whom are suitable to receive CAPOX or mFolfox6, or with tumours that have dysregulated EGFR or HER2 signaling.

NCT02435927 Solid Tumors Drug: ASLAN001+ CAPOX (Oxaliplatin, capecitabine) Drug: ASLAN001 + mFolfox6 (5-FU, leucovorin)

5. Patients undergoing mandatory biopsy in dose expansion of a non-DLT cohort should have any of the following: - known HER2 or EGFR dysregulation - Patients with T790M mutation will be excluded. --- T790M ---

Primary Outcomes

Measure: Maximum tolerated dose (MTD) of ASLAN001 when used in combination with Oxaliplatin and Capecitabine (CAPOX) or Oxaliplatin and 5-FU with leucovorin (mFolfox6)

Time: one year

Secondary Outcomes

Measure: Pharmacokinetic parameter Area under the plasma concentration time curve (AUC)

Time: Day 1 and Day 15 of Cycle 1 and Day 1 of Cycle 3

Measure: Pharmacokinetic parameter Maximum plasma concentration (Cmax)

Time: Day 1 and Day 15 of Cycle 1 and Day 1 of Cycle 3

Measure: Pharmacokinetic parameter Minimum (trough) plasma concentration (Cmin)

Time: Day 1 and Day 15 of Cycle 1 and Day 1 of Cycle 3

Measure: Efficacy of ASLAN001 when given in combination in CAPOX or mFolfox6 as measured by the objective response rate (ORR)

Time: one year

84 A Randomized Phase II/III Trial of Afatinib Plus Cetuximab Versus Afatinib Alone in Treatment-Naive Patients With Advanced, EGFR Mutation Positive Non-small Cell Lung Cancer (NSCLC)

This randomized phase II/III trial studies how well afatinib dimaleate with cetuximab works and compares it with afatinib dimaleate alone in treating patients with newly diagnosed stage IV or recurrent (has come back), epidermal growth factor receptor (EGFR) mutation positive non-small cell lung cancer. Afatinib dimaleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab, may block tumor growth in different ways by targeting certain cells. It is not yet known whether afatinib dimaleate is more effective when given alone or with cetuximab in treating patients with non-small cell lung cancer.

NCT02438722 Recurrent Non-Small Cell Lung Carcinoma Stage IV Non-Small Cell Lung Cancer Drug: Afatinib Dimaleate Biological: Cetuximab Other: Laboratory Biomarker Analysis
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

To evaluate if EGFRs/EGFR T790M is lower at progression than in pre-treatment specimens among patients with results available for pre-treatment and progression, a one-sample t-test (or Wilcoxon signed-rank test) will be used to test the null hypothesis that the difference between the progression ratio and the pre-treatment ratio (or an appropriate transformation of the difference, determined after exploratory data analysis) is greater than zero in favor of the alternative that the difference is less than zero.. EGFR immunohistochemistry H-score. --- T790M ---

A landmark analysis will be used to evaluate the correlation between post-randomization biomarker values and PFS and OS (from the landmark timepoint) using a Cox proportional hazards model.. Presence of de novo EGFR T790M mutation or other molecular alterations. --- T790M ---

To evaluate if the presence of de novo T790M mutation is associated with primary resistance to afatinib dimaleate, PFS and OS will be compared between T790M mutation positive and negative patients randomized to the afatinib dimaleate monotherapy arm using a log-rank test... Ratio of sensitizing EGFR mutation to EGFR T790 mutation. --- T790M ---

To evaluate if the presence of de novo T790M mutation is associated with primary resistance to afatinib dimaleate, PFS and OS will be compared between T790M mutation positive and negative patients randomized to the afatinib dimaleate monotherapy arm using a log-rank test... Ratio of sensitizing EGFR mutation to EGFR T790 mutation. --- T790M --- --- T790M ---

To evaluate if the ratio of EGFR sensitizing mutation to EGFR T790M mutation (EGFRs/EGFR T790M) among patients with T790M is predictive for afatinib dimaleate monotherapy, analyses will be performed in a similar fashion to the evaluation of T790M among patients with measurable T790M (which defines T790M). --- T790M ---

To evaluate if the ratio of EGFR sensitizing mutation to EGFR T790M mutation (EGFRs/EGFR T790M) among patients with T790M is predictive for afatinib dimaleate monotherapy, analyses will be performed in a similar fashion to the evaluation of T790M among patients with measurable T790M (which defines T790M). --- T790M --- --- T790M ---

To evaluate if the ratio of EGFR sensitizing mutation to EGFR T790M mutation (EGFRs/EGFR T790M) among patients with T790M is predictive for afatinib dimaleate monotherapy, analyses will be performed in a similar fashion to the evaluation of T790M among patients with measurable T790M (which defines T790M). --- T790M --- --- T790M --- --- T790M ---

To evaluate if the ratio of EGFR sensitizing mutation to EGFR T790M mutation (EGFRs/EGFR T790M) among patients with T790M is predictive for afatinib dimaleate monotherapy, analyses will be performed in a similar fashion to the evaluation of T790M among patients with measurable T790M (which defines T790M). --- T790M --- --- T790M --- --- T790M --- --- T790M ---

To evaluate if the ratio of EGFR sensitizing mutation to EGFR T790M mutation (EGFRs/EGFR T790M) among patients with T790M is predictive for afatinib dimaleate monotherapy, analyses will be performed in a similar fashion to the evaluation of T790M among patients with measurable T790M (which defines T790M). --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

To evaluate if the ratio of EGFR sensitizing mutation to EGFR T790M mutation (EGFRs/EGFR T790M) among patients with T790M is predictive for afatinib dimaleate monotherapy, analyses will be performed in a similar fashion to the evaluation of T790M among patients with measurable T790M (which defines T790M). --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV (American Joint Committee on Cancer [AJCC] 7th Edition) or recurrent non-small cell lung cancer (NSCLC) - Patients must have documented presence of an EGFR exon 19 deltion or exon 21 (L858R) substitution mutation; T790M mutation or other molecular abnormality will be allowed as long as it accompanies one of the mutations listed above; EGFR testing must be performed using a Food and Drug Administration (FDA)-approved test or in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. --- L858R --- --- T790M ---

Crohn's disease, malabsorption, etc) - Patients must be able to swallow medication by oral route - Patients must not have a history of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia or myocardial infarction within 6 months prior to registration; if clinically indicated, echocardiogram or multigated acquisition (MUGA) must be performed and cardiac ejection fraction must be >= 50% - Patients must not have had major surgery within 28 days prior to registration or be scheduled for surgery during the projected course of protocol treatment; tumor biopsy is allowed - Patients must not have a known history of active hepatitis B infection (defined as presence of hepatitis B surface antigen [Hep B sAg] and/ or Hep B deoxyribonucleic acid [DNA]), active hepatitis C infection (defined as presence of hepatitis C [Hep C] ribonucleic acid [RNA]) and/or known human immunodeficiency virus (HIV) seropositive - Patients must not have any other concomitant serious illness or organ system dysfunction which in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety of the study drug - Patients must not be planning to receive any other investigational agents during the course of protocol treatment - Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to afatinib and/or cetuximab - Prestudy history and physical must be obtained with 28 days prior to registration - Patients must have Zubrod performance status of 0 - 2 - No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years - Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures - Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV (American Joint Committee on Cancer [AJCC] 7th Edition) or recurrent non-small cell lung cancer (NSCLC) - Patients must have documented presence of an EGFR exon 19 deltion or exon 21 (L858R) substitution mutation; T790M mutation or other molecular abnormality will be allowed as long as it accompanies one of the mutations listed above; EGFR testing must be performed using a Food and Drug Administration (FDA)-approved test or in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. --- L858R --- --- T790M ---

TERTIARY OBJECTIVES: I. To investigate the molecular mechanisms that confer benefit from afatinib and afatinib plus cetuximab by evaluating whether the presence of de novo EGFR T790M mutation or other molecular alterations in the pre-treatment tumor influence the clinical outcomes. --- T790M ---

To quantitatively assess whether the ratio of sensitizing EGFR (EGFRs) mutation to EGFR T790M influences outcome and is altered during treatment. --- T790M ---

Primary Outcomes

Measure: OS (phase III)

Time: From date of registration to date of death due to any cause, assessed up to 3 years

Measure: PFS (phase II)

Time: From date of registration to date of first documentation of progression or symptomatic deterioration or death due to any cause, assessed up to 3 years

Secondary Outcomes

Measure: PFS

Time: From date of registration to date of first documentation of progression or symptomatic deterioration or death due to any cause, assessed up to 3 years

Description: Compared between arms using a chi-squared test of independence at the 1-sided 5% level.

Measure: Response rates

Time: Up to 3 years

Measure: Time to treatment discontinuation

Time: From date of registration to date of discontinuation of treatment or death due to any cause, assessed up to 3 years

Measure: Time to treatment failure

Time: From date of registration to date of first documentation of progression or symptomatic deterioration, early discontinuation of treatment, or death due to any cause, assessed up to 3 years

Description: Assessed using a chi-squared or Fisher's exact test (as appropriate) at the 1-sided 5% level.

Measure: Toxicity rates assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0

Time: Up to 3 years

Other Outcomes

Description: For each of these markers, a one-sample t-test (or Wilcoxon signed-rank test) will be used to test the null hypothesis that the absolute difference between the copy number after progression and the copy number in the pre-treatment specimen (or an appropriate transformation of the difference, determined after exploratory data analysis) is not equal to zero.

Measure: Change in copy number alterations in MET, EGFR, and HER2, analyzed using fluorescence in situ hybridization

Time: Baseline up to 3 years (after disease progression)

Description: To evaluate if EGFRs/EGFR T790M is lower at progression than in pre-treatment specimens among patients with results available for pre-treatment and progression, a one-sample t-test (or Wilcoxon signed-rank test) will be used to test the null hypothesis that the difference between the progression ratio and the pre-treatment ratio (or an appropriate transformation of the difference, determined after exploratory data analysis) is greater than zero in favor of the alternative that the difference is less than zero.

Measure: Change in the ratio of sensitizing EGFR mutation to EGFR T790 mutation

Time: Baseline up to 3 years (at progression)

Description: To evaluate the hypothesis that H-score positive status at baseline is associated with absolute difference in PFS (and OS) among patients randomized to receive afatinib dimaleate monotherapy a test of interaction will be performed at the 1-sided 20% level.

Measure: EGFR immunohistochemistry H-score

Time: Baseline

Description: Tumor marker levels over time will be evaluated using a linear mixed model for continuous markers and using generalized estimating equations for binary markers. A landmark analysis will be used to evaluate the correlation between post-randomization biomarker values and PFS and OS (from the landmark timepoint) using a Cox proportional hazards model.

Measure: Levels of circulating tumor markers

Time: Up to 3 years

Description: To evaluate if the presence of de novo T790M mutation is associated with primary resistance to afatinib dimaleate, PFS and OS will be compared between T790M mutation positive and negative patients randomized to the afatinib dimaleate monotherapy arm using a log-rank test..

Measure: Presence of de novo EGFR T790M mutation or other molecular alterations

Time: Baseline

Description: To evaluate if the ratio of EGFR sensitizing mutation to EGFR T790M mutation (EGFRs/EGFR T790M) among patients with T790M is predictive for afatinib dimaleate monotherapy, analyses will be performed in a similar fashion to the evaluation of T790M among patients with measurable T790M (which defines T790M). Cox regression will be used to assess the predictive association of the ratio in the afatinib dimaleate monotherapy arm with both OS and PFS

Measure: Ratio of sensitizing EGFR mutation to EGFR T790 mutation

Time: Up to 3 years

85 A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Asia Pacific Patients With Locally Advanced/Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed With Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Whose Tumours Harbour a T790M Mutation Within the Epidermal Growth Factor Receptor Gene

A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Asia Pacific Patients with Locally Advanced/Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours harbour a T790M mutation within the Epidermal Growth Factor Receptor Gene

NCT02442349 Non-Small Cell Lung Cancer Drug: AZD9291
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Asia Pacific Patients With Locally Advanced/Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed With Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Whose Tumours Harbour a T790M Mutation Within the Epidermal Growth Factor Receptor Gene. --- T790M ---

Phase II Single Arm Study of AZD9291 to Treat NSCLC Patients in Asia Pacific A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Asia Pacific Patients with Locally Advanced/Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours harbour a T790M mutation within the Epidermal Growth Factor Receptor Gene Objective Response Rate (ORR) According to RECIST 1.1. --- T790M ---

- Patients must have central confirmation of tumour T790M mutation positive status from a biopsy sample taken after confirmation of disease progression on the most recent treatment regimen. --- T790M ---

Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a phase II, open label, single arm study assessing the safety and efficacy of AZD9291 (80 mg, orally, once daily) in Asia Pacific patients with a confirmed diagnosis of Epidermal Growth Factor Receptor (EGFR) sensitising mutation positive (ie, G719X, exon 19 deletion, L858R, L861Q) and T790M mutation positive (hereafter referred to as EGFRm+ and T790M+) un-resectable, locally advanced or metastatic NSCLC (Stage IIIB-IV), who have progressed on an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor(EGFR-TKI), either as first line treatment or following one line of EGFR-TKI and one line of platinum containing doublet chemotherapy. --- L858R --- --- L861Q --- --- T790M ---

Patients must agree to provide a biopsy for central confirmation of T790M mutation status following confirmed disease progression on the most recent treatment regimen. --- T790M ---

Primary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR) According to RECIST 1.1

Time: RECIST tumour assessments every 6 weeks from time of first dose until objective disease progression, for an average of approximately 12 months. Results are based on the data cut off of 04 March 2016 (about 18 weeks after LSFD).

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. DCR is the percentage of patients with best response of CR, PR or SD (according to independent review), prior to progression (PD) or further anti-cancer therapy.

Measure: Disease Control Rate (DCR) According to RECIST 1.1

Time: RECIST tumour assessments every 6 weeks from time first dose until date of progression, for an average of approximately 12 months. Results are based on the data cut off of 04 March 2016 (about 18 weeks after LSFD).

86 A Phase I, Multicenter, Open-Label Safety, Pharmacokinetic and Preliminary Efficacy Study of Wild-type Sparing EGFR Inhibitor, AC0010MA, in Adult Patients With Previously Treated EGFRmut and Acquired T790M Mutation Non-Small Cell Lung Cancer (NSCLC)

AC0010MA is a new, irreversible, Epidermal Growth Factor Receptor (EGFR) mutation selective Tyrosine Kinase Inhibitor. Aim at local advanced or metastatic non-small cell lung cancer patients with EGFR mutation or T790M drug-resistant mutation. The molecular mechanism: by irreversible combining the EGFR-RTKs ATP binding site of cell, selectively suppress the activities of EGFR tyrosine kinase phosphorylation, block the signal transduction pathway of EGFR and inhibit the function of ras/raf/MAPK downstream, thus block the tumor cell growth by EGFR induction, and promotes apoptosis. AC0010MA Maleate Capsules has three characters: 1. Irreversible binding to EGFR; 2. Effectively suppresses the tumor cell with EGFR mutant while has no suppression to EGFR wild-type cell; 3. Efficient suppress the tumor cell with EGFR T790M drug-resistant mutation.

NCT02448251 Non Small Cell Lung Cancer Drug: AC0010MA
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

A Phase I, Multicenter, Open-Label Safety, Pharmacokinetic and Preliminary Efficacy Study of Wild-type Sparing EGFR Inhibitor, AC0010MA, in Adult Patients With Previously Treated EGFRmut and Acquired T790M Mutation Non-Small Cell Lung Cancer (NSCLC). --- T790M ---

Aim at local advanced or metastatic non-small cell lung cancer patients with EGFR mutation or T790M drug-resistant mutation. --- T790M ---

AC0010MA Maleate Capsules has three characters: 1. Irreversible binding to EGFR; 2. Effectively suppresses the tumor cell with EGFR mutant while has no suppression to EGFR wild-type cell; 3. Efficient suppress the tumor cell with EGFR T790M drug-resistant mutation. --- T790M ---

4. Has documented evidence of an activating EGFR mutation in the tumor tissue determined by either sequencing or PCR-based technique (Part 1). 5. For Part 1 only: subjects with a positive T790M mutation are preferred, but not required. --- T790M ---

Confirmation of T790M mutation status will be determined from an archived tumor tissue sample or fresh tumor tissue sample obtained via biopsy if archived tissue is not available. --- T790M ---

In Part 2, subjects must have a confirmed, positive T790M EGFR mutation (acquired T790M EGFR mutation or "de novo" T790M EGFR mutation). --- T790M ---

In Part 2, subjects must have a confirmed, positive T790M EGFR mutation (acquired T790M EGFR mutation or "de novo" T790M EGFR mutation). --- T790M --- --- T790M ---

In Part 2, subjects must have a confirmed, positive T790M EGFR mutation (acquired T790M EGFR mutation or "de novo" T790M EGFR mutation). --- T790M --- --- T790M --- --- T790M ---

9. Has documented disease progression while receiving at least 30 days of treatment with a currently approved EGFR tyrosine kinase inhibitor (TKI) (e.g., erlotinib, gefitinib or afatinib) with intervening treatment after most recent EGFR TKI therapy (not required for "de novo" T790M EGFR mutation). --- T790M ---

Primary Outcomes

Description: To determine the safety and tolerability and to establish the maximum tolerated dose (MTD) of AC0010MA by incidence of dose limiting toxicity (DLT), defined as Grade 3 or 4 adverse events (AEs) and clinical lab abnormalities occurring within the first 28 days of treatment.

Measure: Safety and tolerability, and the maximum tolerated dose (MTD) of AC0010MA determined by incidence of dose limiting toxicity (DLT)

Time: Within the first 28 days of treatment.

Secondary Outcomes

Description: To characterize tumor response (objective response rate, ORR) and duration of response of AC0010MA as a criterion for further development of AC0010MA in this patient population.

Measure: Evaluation of tumor response and duration of response of AC0010MA ((objective response rate, ORR)

Time: within the time frame of every 8 weeks (2 cycles) for up to 3 years

Description: To evaluate pharmacokinetic parameter of AC0010MA

Measure: Maximum plasma concentration (Cmax) of AC0010MA

Time: Blood samples will be collected at pre-treatment, and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24h post-treatment on Days 1, 8, and 28 in the first treatment cycle (QD and BID) in Phase I

Description: To evaluate pharmacokinetic parameter of AC0010MA

Measure: Time to Cmax

Time: Blood samples will be collected at pre-treatment, and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24h post-treatment on Days 1, 8, and 28 in the first treatment cycle (QD and BID) in Phase I

Description: To evaluate pharmacokinetic parameter of AC0010MA

Measure: Terminal half-life (t1/2)

Time: Blood samples will be collected at pre-treatment, and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24h post-treatment on Days 1, 8, and 28 in the first treatment cycle (QD and BID) in Phase I

Description: To evaluate pharmacokinetic parameter of AC0010MA

Measure: Area under the plasma concentration-time curve

Time: Blood samples will be collected at pre-treatment, and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24h post-treatment on Days 1, 8, and 28 in the first treatment cycle (QD and BID) in Phase I

Description: To evaluate pharmacokinetic parameter of AC0010MA

Measure: Volume of distribution (V/F)

Time: Blood samples will be collected at pre-treatment, and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24h post-treatment on Days 1, 8, and 28 in the first treatment cycle (QD and BID) in Phase I

Description: To evaluate pharmacokinetic parameter of AC0010MA

Measure: Plasma Concentration (CL/F)

Time: Blood samples will be collected at pre-treatment, and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24h post-treatment on Days 1, 8, and 28 in the first treatment cycle (QD and BID) in Phase I

87 Pilot Study of Local Therapies for Oligometastatic Non-Small Cell Lung Cancer Harboring Sensitizing EGFR Mutations

This study will test if local therapies in addition to erlotinib can improve responses and delay the time until new treatment is required. This study will also collect blood samples for research blood tests.

NCT02450591 Oligometastatic Lung Adenocarcinoma Drug: Erlotinib Other: Local Therapies
MeSH:Adenocarcinoma Adenocarcinoma of Lung

- For women of child-bearing potential, negative pregnancy test within 14 days prior to starting treatment - Men and women of childbearing age must be willing to use effective contraception while on treatment and for at least 3 months thereafter Exclusion Criteria: - Treatment with erlotinib prior to developing metastatic disease - Patients with activating but not sensitizing mutations (exon 20 insertions, EGFR T790M) - Malignant pleural effusion or pleural disease - Leptomeningeal disease - Any site of disease that is not amenable to definitively local therapy including surgery or radiation therapy - Women who are breastfeeding or pregnant - Concurrent malignancies other than non-melanoma skin cancer that require active ongoing treatment. --- T790M ---

Primary Outcomes

Description: At least five patients will need to complete local therapy within 2 years of the study being open to accrual for the primary endpoint to be met.

Measure: Feasibility as Measured by at Least Five Patients Will Need to Complete Local Therapy.

Time: 2 years

88 A Multi-center, AZD9291 Expanded Access Program for the Treatment of Patients With Advanced/Metastatic EGFR T790M Mutation-positive Non-small Cell Lung Cancer (NSCLC) Who Have Received Prior EGFR TKI Therapy

To provide access to AZD9291 for adult patients with advanced/metastatic, epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer.

NCT02451852 EGFR T790M Mutation Positive NSCLC Drug: AZD9291

A Multi-center, AZD9291 Expanded Access Program for the Treatment of Patients With Advanced/Metastatic EGFR T790M Mutation-positive Non-small Cell Lung Cancer (NSCLC) Who Have Received Prior EGFR TKI Therapy. --- T790M ---

AZD9291 US Expanded Access Program To provide access to AZD9291 for adult patients with advanced/metastatic, epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer. --- T790M ---

Inclusion Criteria: - Provision of signed and dated, written informed consent prior to any treatment protocol-specific procedures - Patients aged at least 18 years - Locally advanced or metastatic EGFRm NSCLC, not amenable to curative surgery or radiotherapy with confirmation of the presence of the T790M mutation - Two lines of prior therapy including at least one EGFR TKI - World Health Organization (WHO) performance status 0-2. --- T790M ---

- Patients with symptomatic CNS metastases who are neurologically unstable - Past medical history of ILD, drug-induced ILD, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active ILD - Any of the following cardiac criteria: 1. Mean resting corrected QT interval (QTc using Fredericia's formula) > 470 msec 2. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block) 3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval - Any unresolved toxicity from prior therapy Common Terminology Criteria for Adverse Events (CTCAE) > grade 3 at the time of starting treatment in the access program - History of hypersensitivity to AZD9291 (or drugs with a similar chemical structure or class to AZD9291) or any excipients of these agents - Males and females of reproductive potential who are not using an effective method of birth control and females who are pregnant or breastfeeding or have a positive (urine or serum) pregnancy test prior to access program entry Inclusion Criteria: - Provision of signed and dated, written informed consent prior to any treatment protocol-specific procedures - Patients aged at least 18 years - Locally advanced or metastatic EGFRm NSCLC, not amenable to curative surgery or radiotherapy with confirmation of the presence of the T790M mutation - Two lines of prior therapy including at least one EGFR TKI - World Health Organization (WHO) performance status 0-2. --- T790M ---

- Patients with symptomatic CNS metastases who are neurologically unstable - Past medical history of ILD, drug-induced ILD, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active ILD - Any of the following cardiac criteria: 1. Mean resting corrected QT interval (QTc using Fredericia's formula) > 470 msec 2. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block) 3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval - Any unresolved toxicity from prior therapy Common Terminology Criteria for Adverse Events (CTCAE) > grade 3 at the time of starting treatment in the access program - History of hypersensitivity to AZD9291 (or drugs with a similar chemical structure or class to AZD9291) or any excipients of these agents - Males and females of reproductive potential who are not using an effective method of birth control and females who are pregnant or breastfeeding or have a positive (urine or serum) pregnancy test prior to access program entry EGFR T790M Mutation Positive NSCLC - This is a multi-center, AZD9291 expanded access protocol for the treatment of adult patients with advanced/metastatic EGFR T790M mutation-positive non-small cell lung cancer (NSCLC) who have received prior EGFR TKI therapy and at least one additional line of therapy (≥ 3rd line). --- T790M ---

- Patients with symptomatic CNS metastases who are neurologically unstable - Past medical history of ILD, drug-induced ILD, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active ILD - Any of the following cardiac criteria: 1. Mean resting corrected QT interval (QTc using Fredericia's formula) > 470 msec 2. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block) 3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval - Any unresolved toxicity from prior therapy Common Terminology Criteria for Adverse Events (CTCAE) > grade 3 at the time of starting treatment in the access program - History of hypersensitivity to AZD9291 (or drugs with a similar chemical structure or class to AZD9291) or any excipients of these agents - Males and females of reproductive potential who are not using an effective method of birth control and females who are pregnant or breastfeeding or have a positive (urine or serum) pregnancy test prior to access program entry EGFR T790M Mutation Positive NSCLC - This is a multi-center, AZD9291 expanded access protocol for the treatment of adult patients with advanced/metastatic EGFR T790M mutation-positive non-small cell lung cancer (NSCLC) who have received prior EGFR TKI therapy and at least one additional line of therapy (≥ 3rd line). --- T790M --- --- T790M ---


89 A Phase 2 Study of TH-4000 (Tarloxotinib) in Patients With EGFR-Mutant, T790M-Negative, Advanced Non-Small Cell Lung Cancer Progressing on an EGFR Tyrosine Kinase Inhibitor

This phase 2 study is designed to evaluate the safety and activity of TH-4000 (Tarloxotinib), a hypoxia-activated prodrug, in patients with EGFR-Mutant, T790M-Negative, Advanced non-small cell lung cancer (NSCLC).

NCT02454842 Non-small Cell Lung Cancer NSCLC Non-squamous NSCLC Drug: TH-4000 (Tarloxotinib)
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

A Phase 2 Study of TH-4000 (Tarloxotinib) in Patients With EGFR-Mutant, T790M-Negative, Advanced Non-Small Cell Lung Cancer Progressing on an EGFR Tyrosine Kinase Inhibitor. --- T790M ---

Study for Treatment of Patients With EGFR Mutant, T790M-negative NSCLC This phase 2 study is designed to evaluate the safety and activity of TH-4000 (Tarloxotinib), a hypoxia-activated prodrug, in patients with EGFR-Mutant, T790M-Negative, Advanced non-small cell lung cancer (NSCLC). --- T790M ---

Study for Treatment of Patients With EGFR Mutant, T790M-negative NSCLC This phase 2 study is designed to evaluate the safety and activity of TH-4000 (Tarloxotinib), a hypoxia-activated prodrug, in patients with EGFR-Mutant, T790M-Negative, Advanced non-small cell lung cancer (NSCLC). --- T790M --- --- T790M ---

Key Eligibility Criteria: - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Confirmed recurrent Stage IV NSCLC which progressed while on treatment with EGFR TKI - Measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) - Documented evidence of an EGFR mutation known to be associated with an EGFR TKI sensitivity - No T790M mutation or small cell transformation including an assessment from tumor biopsy obtained while on or subsequent to the most recent EGFR TKI therapy - Acceptable laboratory results as indicated by protocol - Acceptable cardiac function as indicated by protocol Key Exclusion Criteria: - Receiving medication that prolongs QT interval, with a risk of causing Torsades de Pointes (TdP) unless ECG meets inclusion criteria while on a stable dose of the medication - Family history of long QTc syndrome - Symptomatic central nervous system (CNS) lesions - Radiation therapy within 2 weeks prior to the first dose of study medication - Major surgery within 4 weeks or minor surgery within 2 weeks prior to the first dose of study medication - Concurrent active malignancy requiring systemic treatment - Any other serious uncontrolled medical disorders or psychological conditions that may interfere with study conduct including but not limited to: clinically significant active infection (e.g., tuberculosis, viral hepatitis, human immunodeficiency virus [HIV]), recent (within 6 months) myocardial infarction or unstable angina, congestive heart failure, poorly-controlled hypertension or diabetes, concurrent active malignancy, or psychiatric condition that may interfere with the patient's ability to follow study procedures - Pregnant or breast-feeding Key Eligibility Criteria: - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Confirmed recurrent Stage IV NSCLC which progressed while on treatment with EGFR TKI - Measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) - Documented evidence of an EGFR mutation known to be associated with an EGFR TKI sensitivity - No T790M mutation or small cell transformation including an assessment from tumor biopsy obtained while on or subsequent to the most recent EGFR TKI therapy - Acceptable laboratory results as indicated by protocol - Acceptable cardiac function as indicated by protocol Key Exclusion Criteria: - Receiving medication that prolongs QT interval, with a risk of causing Torsades de Pointes (TdP) unless ECG meets inclusion criteria while on a stable dose of the medication - Family history of long QTc syndrome - Symptomatic central nervous system (CNS) lesions - Radiation therapy within 2 weeks prior to the first dose of study medication - Major surgery within 4 weeks or minor surgery within 2 weeks prior to the first dose of study medication - Concurrent active malignancy requiring systemic treatment - Any other serious uncontrolled medical disorders or psychological conditions that may interfere with study conduct including but not limited to: clinically significant active infection (e.g., tuberculosis, viral hepatitis, human immunodeficiency virus [HIV]), recent (within 6 months) myocardial infarction or unstable angina, congestive heart failure, poorly-controlled hypertension or diabetes, concurrent active malignancy, or psychiatric condition that may interfere with the patient's ability to follow study procedures - Pregnant or breast-feeding Non-small Cell Lung Cancer NSCLC Non-squamous NSCLC Lung Neoplasms Carcinoma, Non-Small-Cell Lung A single arm open label multi-center Phase 2 study in which the pharmacokinetics, safety, tolerability and efficacy of TH-4000 (Tarloxotinib) will be assessed in patients with EGFR mutant, T790M negative advanced NSCLC. --- T790M ---

Key Eligibility Criteria: - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Confirmed recurrent Stage IV NSCLC which progressed while on treatment with EGFR TKI - Measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) - Documented evidence of an EGFR mutation known to be associated with an EGFR TKI sensitivity - No T790M mutation or small cell transformation including an assessment from tumor biopsy obtained while on or subsequent to the most recent EGFR TKI therapy - Acceptable laboratory results as indicated by protocol - Acceptable cardiac function as indicated by protocol Key Exclusion Criteria: - Receiving medication that prolongs QT interval, with a risk of causing Torsades de Pointes (TdP) unless ECG meets inclusion criteria while on a stable dose of the medication - Family history of long QTc syndrome - Symptomatic central nervous system (CNS) lesions - Radiation therapy within 2 weeks prior to the first dose of study medication - Major surgery within 4 weeks or minor surgery within 2 weeks prior to the first dose of study medication - Concurrent active malignancy requiring systemic treatment - Any other serious uncontrolled medical disorders or psychological conditions that may interfere with study conduct including but not limited to: clinically significant active infection (e.g., tuberculosis, viral hepatitis, human immunodeficiency virus [HIV]), recent (within 6 months) myocardial infarction or unstable angina, congestive heart failure, poorly-controlled hypertension or diabetes, concurrent active malignancy, or psychiatric condition that may interfere with the patient's ability to follow study procedures - Pregnant or breast-feeding Key Eligibility Criteria: - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Confirmed recurrent Stage IV NSCLC which progressed while on treatment with EGFR TKI - Measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) - Documented evidence of an EGFR mutation known to be associated with an EGFR TKI sensitivity - No T790M mutation or small cell transformation including an assessment from tumor biopsy obtained while on or subsequent to the most recent EGFR TKI therapy - Acceptable laboratory results as indicated by protocol - Acceptable cardiac function as indicated by protocol Key Exclusion Criteria: - Receiving medication that prolongs QT interval, with a risk of causing Torsades de Pointes (TdP) unless ECG meets inclusion criteria while on a stable dose of the medication - Family history of long QTc syndrome - Symptomatic central nervous system (CNS) lesions - Radiation therapy within 2 weeks prior to the first dose of study medication - Major surgery within 4 weeks or minor surgery within 2 weeks prior to the first dose of study medication - Concurrent active malignancy requiring systemic treatment - Any other serious uncontrolled medical disorders or psychological conditions that may interfere with study conduct including but not limited to: clinically significant active infection (e.g., tuberculosis, viral hepatitis, human immunodeficiency virus [HIV]), recent (within 6 months) myocardial infarction or unstable angina, congestive heart failure, poorly-controlled hypertension or diabetes, concurrent active malignancy, or psychiatric condition that may interfere with the patient's ability to follow study procedures - Pregnant or breast-feeding Non-small Cell Lung Cancer NSCLC Non-squamous NSCLC Lung Neoplasms Carcinoma, Non-Small-Cell Lung A single arm open label multi-center Phase 2 study in which the pharmacokinetics, safety, tolerability and efficacy of TH-4000 (Tarloxotinib) will be assessed in patients with EGFR mutant, T790M negative advanced NSCLC. --- T790M --- --- T790M ---

Key Eligibility Criteria: - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Confirmed recurrent Stage IV NSCLC which progressed while on treatment with EGFR TKI - Measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) - Documented evidence of an EGFR mutation known to be associated with an EGFR TKI sensitivity - No T790M mutation or small cell transformation including an assessment from tumor biopsy obtained while on or subsequent to the most recent EGFR TKI therapy - Acceptable laboratory results as indicated by protocol - Acceptable cardiac function as indicated by protocol Key Exclusion Criteria: - Receiving medication that prolongs QT interval, with a risk of causing Torsades de Pointes (TdP) unless ECG meets inclusion criteria while on a stable dose of the medication - Family history of long QTc syndrome - Symptomatic central nervous system (CNS) lesions - Radiation therapy within 2 weeks prior to the first dose of study medication - Major surgery within 4 weeks or minor surgery within 2 weeks prior to the first dose of study medication - Concurrent active malignancy requiring systemic treatment - Any other serious uncontrolled medical disorders or psychological conditions that may interfere with study conduct including but not limited to: clinically significant active infection (e.g., tuberculosis, viral hepatitis, human immunodeficiency virus [HIV]), recent (within 6 months) myocardial infarction or unstable angina, congestive heart failure, poorly-controlled hypertension or diabetes, concurrent active malignancy, or psychiatric condition that may interfere with the patient's ability to follow study procedures - Pregnant or breast-feeding Key Eligibility Criteria: - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Confirmed recurrent Stage IV NSCLC which progressed while on treatment with EGFR TKI - Measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) - Documented evidence of an EGFR mutation known to be associated with an EGFR TKI sensitivity - No T790M mutation or small cell transformation including an assessment from tumor biopsy obtained while on or subsequent to the most recent EGFR TKI therapy - Acceptable laboratory results as indicated by protocol - Acceptable cardiac function as indicated by protocol Key Exclusion Criteria: - Receiving medication that prolongs QT interval, with a risk of causing Torsades de Pointes (TdP) unless ECG meets inclusion criteria while on a stable dose of the medication - Family history of long QTc syndrome - Symptomatic central nervous system (CNS) lesions - Radiation therapy within 2 weeks prior to the first dose of study medication - Major surgery within 4 weeks or minor surgery within 2 weeks prior to the first dose of study medication - Concurrent active malignancy requiring systemic treatment - Any other serious uncontrolled medical disorders or psychological conditions that may interfere with study conduct including but not limited to: clinically significant active infection (e.g., tuberculosis, viral hepatitis, human immunodeficiency virus [HIV]), recent (within 6 months) myocardial infarction or unstable angina, congestive heart failure, poorly-controlled hypertension or diabetes, concurrent active malignancy, or psychiatric condition that may interfere with the patient's ability to follow study procedures - Pregnant or breast-feeding Non-small Cell Lung Cancer NSCLC Non-squamous NSCLC Lung Neoplasms Carcinoma, Non-Small-Cell Lung A single arm open label multi-center Phase 2 study in which the pharmacokinetics, safety, tolerability and efficacy of TH-4000 (Tarloxotinib) will be assessed in patients with EGFR mutant, T790M negative advanced NSCLC. --- T790M --- --- T790M --- --- T790M ---

Primary Outcomes

Measure: Number of participants with response rate as evaluated by RECIST criteria

Time: Approximately 12 months

Secondary Outcomes

Measure: Incidence of adverse events (AEs)

Time: Up to 30 days after last dose

Measure: Type of adverse events (AEs)

Time: Up to 30 days after last dose

Measure: Severity of adverse events (AEs)

Time: Up to 30 days after last dose

Measure: Duration of response (DOR) calculated for all patients achieving an objective response

Time: Approximately 12 months

Measure: Progression-free survival (PFS)

Time: Approximately 12 months

Measure: Overall Survival (OS)

Time: Approximately 12 months

Description: Time to peak plasma concentration (Tmax), maximum plasma concentration (Cmax), area under concentration-time curve (AUC)

Measure: Time to peak plasma concentration (Tmax)

Time: Cycle 1 Day 1 predose and up to 24 hours post dose

Measure: Maximum plasma concentration (Cmax)

Time: Cycle 1 Day 1 predose and up to 24 hours post dose

Measure: Area under concentration-time curve (AUC)

Time: Cycle 1 Day 1 predose and up to 24 hours post dose

Measure: QTc Interval

Time: Screening, Cycle 1 Day 1, 8, 15 & 22, Day 1 of subsequent cycles

Other Outcomes

Measure: Hypoxic volume as measured by Positron Emission Tomography (PET) hypoxia imaging

Time: Baseline

90 A Phase III, Multi-Centre, Open Label, Randomized Study to Assess the Efficacy and Safety of AZD9291 in Combination With MEDI4736 Versus AZD9291 Monotherapy in Patients With Locally Advanced or Metastatic Epidermal Growth Factor Receptor T790M Mutation-positive Non-Small Cell Lung Cancer Who Have Received Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy (CAURAL)

A Phase III, Multi-Centre, Open Label, Randomized Study to Assess the Efficacy and Safety of AZD9291 in Combination with MEDI4736 versus AZD9291 Monotherapy in patients with Locally Advanced or Metastatic Epidermal Growth Factor Receptor T790M mutation-positive Non-Small Cell Lung Cancer who have received Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy

NCT02454933 Locally Advanced or Metastatic EGFR T790M+ NSCLC Drug: AZD9291 Drug: MEDI4736
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

A Phase III, Multi-Centre, Open Label, Randomized Study to Assess the Efficacy and Safety of AZD9291 in Combination With MEDI4736 Versus AZD9291 Monotherapy in Patients With Locally Advanced or Metastatic Epidermal Growth Factor Receptor T790M Mutation-positive Non-Small Cell Lung Cancer Who Have Received Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy (CAURAL). --- T790M ---

Study of AZD9291 Plus MEDI4736 Versus AZD9291 Monotherapy in NSCLC After Previous EGFR TKI Therapy in T790M Mutation Positive Tumours A Phase III, Multi-Centre, Open Label, Randomized Study to Assess the Efficacy and Safety of AZD9291 in Combination with MEDI4736 versus AZD9291 Monotherapy in patients with Locally Advanced or Metastatic Epidermal Growth Factor Receptor T790M mutation-positive Non-Small Cell Lung Cancer who have received Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy Number of Subjects With Adverse Events (AEs) as a Measure of the Safety and Tolerability of Osimertinib in Combination With Durvalumab. --- T790M ---

Study of AZD9291 Plus MEDI4736 Versus AZD9291 Monotherapy in NSCLC After Previous EGFR TKI Therapy in T790M Mutation Positive Tumours A Phase III, Multi-Centre, Open Label, Randomized Study to Assess the Efficacy and Safety of AZD9291 in Combination with MEDI4736 versus AZD9291 Monotherapy in patients with Locally Advanced or Metastatic Epidermal Growth Factor Receptor T790M mutation-positive Non-Small Cell Lung Cancer who have received Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy Number of Subjects With Adverse Events (AEs) as a Measure of the Safety and Tolerability of Osimertinib in Combination With Durvalumab. --- T790M --- --- T790M ---

- Patients must have central lab confirmation of tumour T790M status from a biopsy taken after disease progression on the most recent treatment regimen. --- T790M ---

Only patients with T790M+ will be included in the study - At least one lesion, not previously irradiated and not chosen for biopsy during the study screening period, that can be accurately measured at baseline as ≥ 10mm in the longest diameter (except lymph nodes which must have short axis ≥ 15mm) with computerised tomography (CT) or magnetic resonance imaging (MRI) which is suitable for accurate repeated measurements - World Health Organisation (WHO) performance status 0-1 with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks - Females of child-bearing potential using contraception; negative pregnancy test Exclusion Criteria: - Treatment with an EGFR-TKI within 5x half-life of study entry; any cytotoxic chemotherapy, investigational agents or other anticancer drugs within 14 days of study entry; current treatment with potent inhibitors/inducers of cytochrome P450 3A4 (CYP3A4); previous treatment with AZD9291 (or other agents specifically targeted against EGFR T790M mutation positive NSCLC); Prior neo-adjuvant or adjuvant chemotherapy treatment within 6 months of starting 1st EGFR TKI treatment; prior exposure to immune-mediated therapy including, but not limited to, other anti cytotoxic T-lymphocyte-associated antigen 4 (anti CTLA-4), anti- programmed cell death 1 (anti-PD-1), anti- programmed cell death ligand 1 (anti-PD-L1), and anti-programmed cell death ligand 2 (anti-PD-L2) antibodies, excluding therapeutic anticancer vaccines; radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks; major surgery within 4 weeks; - Current or prior use of immunosuppressive medication within 14 days before the first dose of MEDI4736 (excluding intranasal, inhaled, topical steroids, or local steroid injections) - Unresolved toxicities from prior therapy - History of active primary immunodeficiency - Unstable brain metastases or spinal cord compression - Severe/uncontrolled systemic diseases, including uncontrolled hypertension, renal transplant, bleeding diatheses or infection - Cardiac disease - Ophthalmological conditions - Refractory nausea/vomiting, chronic gastrointestinal diseases or bowel resection - Past history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease. --- T790M ---

- History of another primary malignancy - Active or prior documented autoimmune or inflammatory disorders within the past 3 years prior to the start of treatment - History of organ transplant that requires use of immunosuppressive medications - Known history of tuberculosis - Receipt of live, attenuated vaccine within 30 days prior to the first dose of MEDI4736 - Inadequate bone marrow reserve or organ function Locally Advanced or Metastatic EGFR T790M+ NSCLC Carcinoma, Non-Small-Cell Lung This a phase III, Multi Centre, Open Label, Randomized, Study to Assess the Efficacy and Safety of AZD9291 (80 mg, orally, once daily) in Combination with MEDI4736 (10 mg/kg (IV) infusion q2w) versus AZD9291 Monotherapy (80 mg, orally, once daily) in patients with a confirmed diagnosis of Epidermal Growth Factor Receptor (EGFR) T790M mutation positive NSCLC, who have progressed following prior therapy with an approved Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) agent. --- T790M ---

A mandatory biopsy will be needed for central testing of T790M mutation status following confirmed disease progression on the most recent treatment regimen. --- T790M ---

Primary Outcomes

Description: As a measure of the safety and tolerability of osimertinib in combination with durvalumab the number of subjects who experienced any treatment emergent AE (TEAE), any causally related AE, any serious AE (SAE), and any causally related SAE are presented.

Measure: Number of Subjects With Adverse Events (AEs) as a Measure of the Safety and Tolerability of Osimertinib in Combination With Durvalumab

Time: From Baseline up to 3 months after the last dose (up to 24 months).

91 Open Label, Multinational, Multicenter, Real World Treatment Study of Single Agent AZD9291 for Patients With Advanced/Metastatic Epidermal Growth Factor Receptor (EGFR) T790M Mutation-Positive Non-Small Cell Lung Cancer (NSCLC) Who Have Received Prior Therapy With an EGFR Tyrosine Kinase Inhibitor (EGFR-TKI)

The aim of this study is to assess the efficacy and safety of single agent AZD9291 in a real world setting in adult patients with advanced or metastatic, epidermal growth factor receptor (EGFR) T790M mutation-positive Non-Small Cell Lung Cancer (NSCLC), who have received prior EGFR-tyrosine kinase inhibitor (TKI) therapy.

NCT02474355 Lung Cancer Procedure: T790M+ Testing Procedure: Baseline Visit Blood & Urine Testing Procedure: Baseline ECG Procedure: Visual Slit-Lamp Testing Drug: AZD9291 Dosing
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Open Label, Multinational, Multicenter, Real World Treatment Study of Single Agent AZD9291 for Patients With Advanced/Metastatic Epidermal Growth Factor Receptor (EGFR) T790M Mutation-Positive Non-Small Cell Lung Cancer (NSCLC) Who Have Received Prior Therapy With an EGFR Tyrosine Kinase Inhibitor (EGFR-TKI). --- T790M ---

Real World Treatment Study of AZD9291 for Advanced/Metastatic EGFR T790M Mutation NSCLC The aim of this study is to assess the efficacy and safety of single agent AZD9291 in a real world setting in adult patients with advanced or metastatic, epidermal growth factor receptor (EGFR) T790M mutation-positive Non-Small Cell Lung Cancer (NSCLC), who have received prior EGFR-tyrosine kinase inhibitor (TKI) therapy. --- T790M ---

Real World Treatment Study of AZD9291 for Advanced/Metastatic EGFR T790M Mutation NSCLC The aim of this study is to assess the efficacy and safety of single agent AZD9291 in a real world setting in adult patients with advanced or metastatic, epidermal growth factor receptor (EGFR) T790M mutation-positive Non-Small Cell Lung Cancer (NSCLC), who have received prior EGFR-tyrosine kinase inhibitor (TKI) therapy. --- T790M --- --- T790M ---

PFS will be summarized using Kaplan-Meier estimates of the median time to progression or death and quartiles with their 95% confidence intervals.. Inclusion Criteria: 1. Provision of signed and dated written informed consent by the patient or legally acceptable representative prior to any study-specific procedures 2. Adults (according to each country regulations for age of majority) 3. Locally advanced (stage IIIB) or metastatic (stage IV) EGFRm NSCLC, not amenable to curative surgery or radiotherapy, with confirmation of the presence of the T790M mutation 4. Prior therapy with an EGFR-TKI. --- T790M ---

Any of the following cardiac criteria: 1. Mean resting corrected QT interval (QTcF) > 470 ms using Fredericia's formula : 2. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block) 3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 7. Any unresolved toxicity from prior therapy CTCAE > grade 3 at the time of starting treatment 8. History of hypersensitivity to excipients of AZD9291 or to drugs with a similar chemical structure or class to AZD9291 Inclusion Criteria: 1. Provision of signed and dated written informed consent by the patient or legally acceptable representative prior to any study-specific procedures 2. Adults (according to each country regulations for age of majority) 3. Locally advanced (stage IIIB) or metastatic (stage IV) EGFRm NSCLC, not amenable to curative surgery or radiotherapy, with confirmation of the presence of the T790M mutation 4. Prior therapy with an EGFR-TKI. --- T790M ---

Any of the following cardiac criteria: 1. Mean resting corrected QT interval (QTcF) > 470 ms using Fredericia's formula : 2. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block) 3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 7. Any unresolved toxicity from prior therapy CTCAE > grade 3 at the time of starting treatment 8. History of hypersensitivity to excipients of AZD9291 or to drugs with a similar chemical structure or class to AZD9291 Lung Cancer Lung Neoplasms Objective: The primary objective of this study is to assess the efficacy and safety of single agent AZD9291 in a real world setting in adult patients with advanced or metastatic, epidermal growth factor receptor (EGFR) T790M mutation-positive Non-Small Cell Lung Cancer (NSCLC), who have received prior EGFR-tyrosine kinase inhibitor (TKI) therapy. --- T790M ---

Target patient population: Adult patients (fulfilling the definition of "age of majority" per local regulations) with locally advanced (stage IIIB) or metastatic (stage IV) NSCLC with confirmed T790M mutation, who have received prior EGFR-TKI therapy. --- T790M ---

Primary Outcomes

Description: Efficacy will be measured by the analysis of Overall Survival defined as the date of 1st dose until date of death.

Measure: Efficacy of AZD9291 by the analysis of overall survival.

Time: From first dose intake to end of study (Last subject last visit (LSLV)) (up to approximately 24 months)

Measure: Safety of AZD9291 by assessment of Serious Adverse Events, Adverse Events of special interest (Interstitial Lung Disease/pneumonitis-like events, Cardiac events)

Time: Patient receiving at least one dose until 30 days post last dose of AZD9291

Secondary Outcomes

Description: PFS will be summarized using Kaplan-Meier estimates of the median time to progression or death and quartiles with their 95% confidence intervals.

Measure: Efficacy of AZD9291 by the analysis of Progression Free Survival (PFS)

Time: from first dose intake to progression or death.

92 A Single Arm, Open-label, Phase 2 Study Evaluating the Efficacy, Safety and PK of HM61713 in Patients With T790M-positive NSCLC After Treatment With an Epidermal Growth Factor Receptor-tyrosine Kinase Inhibitor

The purpose of this study is to evaluate the efficacy, safety and pharmacokinetics of HM61713 in patients with T790M-positive non-small cell lung cancer (NSCLC) after treatment with an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI).

NCT02485652 Non Small Cell Lung Cancer Drug: HM61713
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

A Single Arm, Open-label, Phase 2 Study Evaluating the Efficacy, Safety and PK of HM61713 in Patients With T790M-positive NSCLC After Treatment With an Epidermal Growth Factor Receptor-tyrosine Kinase Inhibitor. --- T790M ---

Phase II Trial of HM61713 for the Treatment of ≥2nd Line T790M Mutation Positive Adenocarcinoma of the Lung The purpose of this study is to evaluate the efficacy, safety and pharmacokinetics of HM61713 in patients with T790M-positive non-small cell lung cancer (NSCLC) after treatment with an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). --- T790M ---

Phase II Trial of HM61713 for the Treatment of ≥2nd Line T790M Mutation Positive Adenocarcinoma of the Lung The purpose of this study is to evaluate the efficacy, safety and pharmacokinetics of HM61713 in patients with T790M-positive non-small cell lung cancer (NSCLC) after treatment with an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). --- T790M --- --- T790M ---

The QT interval will be rate-corrected using 3 methods: QTcF, QTcB and QTcS.. To assess the safety and tolerability of HM61713.. Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a single-arm, open-label, Phase 2 study to assess the anti-tumor efficacy of oral single agent HM61713 administered to patients with T790M-positive NSCLC after treatment with an EGFR-TKI as measured by objective response rate (ORR). --- L858R --- --- L861Q --- --- T790M ---

The QT interval will be rate-corrected using 3 methods: QTcF, QTcB and QTcS.. To assess the safety and tolerability of HM61713.. Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a single-arm, open-label, Phase 2 study to assess the anti-tumor efficacy of oral single agent HM61713 administered to patients with T790M-positive NSCLC after treatment with an EGFR-TKI as measured by objective response rate (ORR). --- L858R --- --- L861Q --- --- T790M --- --- T790M ---

The QT interval will be rate-corrected using 3 methods: QTcF, QTcB and QTcS.. To assess the safety and tolerability of HM61713.. Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a single-arm, open-label, Phase 2 study to assess the anti-tumor efficacy of oral single agent HM61713 administered to patients with T790M-positive NSCLC after treatment with an EGFR-TKI as measured by objective response rate (ORR). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- L858R --- --- L861Q --- --- T790M ---

The QT interval will be rate-corrected using 3 methods: QTcF, QTcB and QTcS.. To assess the safety and tolerability of HM61713.. Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a single-arm, open-label, Phase 2 study to assess the anti-tumor efficacy of oral single agent HM61713 administered to patients with T790M-positive NSCLC after treatment with an EGFR-TKI as measured by objective response rate (ORR). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- L858R --- --- L861Q --- --- T790M --- --- T790M ---

The QT interval will be rate-corrected using 3 methods: QTcF, QTcB and QTcS.. To assess the safety and tolerability of HM61713.. Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a single-arm, open-label, Phase 2 study to assess the anti-tumor efficacy of oral single agent HM61713 administered to patients with T790M-positive NSCLC after treatment with an EGFR-TKI as measured by objective response rate (ORR). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M ---

Primary Outcomes

Description: To assess the anti-tumor efficacy of HM61713 as measured by objective response rate (ORR).

Measure: Objective response rate (ORR)

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Secondary Outcomes

Description: To assess clinical efficacy of HM61713 regarding disease control rate (DCR).

Measure: Disease control rate (DCR), defined as the proportion of patients with a documented CR, PR, and SD during the treatment cycles according to the RECIST version 1.1

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Description: To assess clinical efficacy of HM61713 regarding Duration of overall tumor response (DR).

Measure: Duration of overall tumor response (DR), defined as the interval between the date of the first observation of tumor response (CR or PR) and the date of disease progression or death

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Description: To assess clinical efficacy of HM61713 regarding Progression-free survival (PFS).

Measure: Progression-free survival (PFS), defined as the time from first administration of study drug to determination of tumor progression by RECIST version 1.1 or death due to any cause, whichever occurs first

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Description: To assess clinical efficacy of HM61713 regarding Overall survival (OS).

Measure: Overall survival (OS), defined as the time from first administration of study drug until death from any cause

Time: From first dose to end of study or date of death from any cause whichever came first, assessed up to 48 months

Description: To assess clinical efficacy of HM61713 regarding Time to progression (TTP).

Measure: Time to progression (TTP), defined as the time from first administration of study drug to determination of tumor progression by RECIST version 1.1

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Description: To assess clinical efficacy of HM61713 regarding tumor shrinkage.

Measure: Tumor shrinkage calculated as absolute change and percentage change from baseline in sum of tumor size at each assessment using RECIST tumor response

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Description: To determine the pharmacokinetic (PK) profile of HM61713.

Measure: Peak concentration (Cmax) of HM61713

Time: Pre-dose (-30 to 0 mins) and 1 hour (± 5 mins), 3, 4, 6 hours (± 10 mins) on Day 1 and Day 15 of Cycle 1 and pre-dose (-30 to 0 mins) only on Day 8 of Cycle 1 and Day 1 of Cycle 2 (Day 22)

Description: To determine the pharmacokinetic (PK) profile of HM61713.

Measure: Trough plasma concentration (Ctrough) of HM61713

Time: Pre-dose (-30 to 0 mins) and 1 hour (± 5 mins), 3, 4, 6 hours (± 10 mins) on Day 1 and Day 15 of Cycle 1 and pre-dose (-30 to 0 mins) only on Day 8 of Cycle 1 and Day 1 of Cycle 2 (Day 22)

Description: To determine the pharmacokinetic (PK) profile of HM61713.

Measure: Area under the plasma concentration time curve over the 24-hour dosing interval (AUC) of HM61713

Time: Pre-dose (-30 to 0 mins) and 1 hour (± 5 mins), 3, 4, 6 hours (± 10 mins) on Day 1 and Day 15 of Cycle 1 and pre-dose (-30 to 0 mins) only on Day 8 of Cycle 1 and Day 1 of Cycle 2 (Day 22)

Description: To assess patient reported outcomes (PROs) of health-related quality of life (HRQoL), disease/treatment-related symptoms of lung cancer, and general health status.

Measure: Patient reported outcomes (PROs)

Time: At baseline and every 6 weeks from time of discontinuation, assessed up to 24 months

Description: To evaluate the effect of HM61713 on the QT interval.

Measure: ECG/QTc (absolute values and change from baseline)

Time: Adverse events will be collected from baseline until 28 days after the last dose

Description: To assess the safety and tolerability of HM61713.

Measure: Incidence of reported AEs and abnormal laboratory tests (AEs will be assessed using the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 4).

Time: Adverse events will be collected from baseline until 28 days after the last dose

Description: To assess the safety and tolerability of HM61713.

Measure: QTc interval as assessed by digital ECG with central reading. The QT interval will be rate-corrected using 3 methods: QTcF, QTcB and QTcS.

Time: Adverse events will be collected from baseline until 28 days after the last dose

93 A Randomized, Open-label, Phase II Study of Maintaining Pan-ERBB Blockade Following Platinum-based Induction Chemotherapy in Patients With EGFR Mutated, Metastatic Non-small-cell Lung Cancer Progressing After Treatment With Afatinib as First EGFR-targeting Agent

This study aims to compare the efficacy of afatinib maintenance with pemetrexed maintenance following induction therapy with platinum/ pemetrexed in patients with metastatic epidermal growth factor receptor (EGFR) mutated non-small-cell lung cancer (NSCLC) progressing after first-line treatment with afatinib with respect to progression-free survival.

NCT02488694 Non-small-cell Lung Cancer With Somatic EGFR Mutations Drug: Afatinib Drug: Pemetrexed
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Ability to comply with the protocol for the duration of the study, including hospital/office visits for treatment and scheduled follow-up visits and examinations Exclusion Criteria: 1. Systemic therapy for metastatic disease or relapse other than (a) first-line therapy with afatinib or (b) afatinib given as first EGFR-targeting agent following up to 4 courses of platinum-based chemotherapy with no disease progression between first-line chemotherapy and initiation of afatinib (prior adjuvant chemotherapy is allowed) and 3 to 4 cycles of induction chemotherapy with cisplatin or carboplatin and pemetrexed following afatinib failure 2. Prior treatment with erlotinib, gefitinib or other investigational or approved EGFR-targeting small molecules or antibodies 3. Known EGFR T790M mutation (analysis not mandatory) 4. Major surgery within 4 weeks before starting study treatment or scheduled for surgery during the projected course of the study 5. Extended radiotherapy within 4 weeks prior to randomization, except as follows: 1. Palliative, limited local radiation to non-target lesions (e.g. --- T790M ---

Primary Outcomes

Description: The primary endpoint of this study is progression-free survival (RECIST 1.1).

Measure: Progression-free survival

Time: 40 months

Secondary Outcomes

Description: Efficacy measure

Measure: Overall survival

Time: 40 months

Description: Objective response rate (ORR), clinical benefit rate (RECIST 1.1); Efficacy measure

Measure: Objective response rate

Time: 40 months

Description: Health-Related Quality of Life (HRQoL)

Measure: Quality of Life

Time: 40 month

Description: Safety, toxicity (intensity and incidence of adverse events, graded according to US NCI CTCAE Version 4.03)

Measure: Safety (intensity and incidence of adverse events, graded according to US NCI CTCAE Version 4.03)

Time: 40 month

94 A Phase II Study of RRx-001 in Platinum Refractory/Resistant Small Cell Carcinoma, EGFR TKI Resistant EGFR+ T790M Negative Non-Small Cell Lung Cancer, High Grade Neuroendocrine Tumors and Resistant/Refractory Ovarian Cancer Prior to Re-administration of Platinum Based Doublet Regimens (QUADRUPLE THREAT)

This study is designed to explore the potential of the epigenetic agent RRx-001 to sensitize patients who previously received and now have failed a platinum based doublet regimen. RRx-001 is administered with autologous blood once weekly followed by or in combination with reintroduction of platinum-based doublet therapy.

NCT02489903 Small Cell Carcinoma Carcinoma, Non-Small-Cell Lung Neuroendocrine Tumors Ovarian Epithelial Cancer Drug: RRx-001 Drug: Cisplatin Drug: Etoposide Drug: Carboplatin Drug: Irinotecan Drug: Vinorelbine Drug: Doxil Drug: Gemcitabine Drug: Taxane Drug: Paclitaxel Drug: Nab-Paclitaxel Drug: Pemetrexed
MeSH:Carcinoma Carcinoma, Ovarian Epithelial Neuroendocrine Tumors Carcinoma, Non-Small-Cell Lung Carcinoma, Small Cell Small Cell Lung Carcinoma
HPO:Carcinoma Neuroendocrine neoplasm Non-small cell lung carcinoma Small cell lung carcinoma

A Phase II Study of RRx-001 in Platinum Refractory/Resistant Small Cell Carcinoma, EGFR TKI Resistant EGFR+ T790M Negative Non-Small Cell Lung Cancer, High Grade Neuroendocrine Tumors and Resistant/Refractory Ovarian Cancer Prior to Re-administration of Platinum Based Doublet Regimens (QUADRUPLE THREAT). --- T790M ---

Primary Outcomes

Description: the time from enrollment until the time of death from any cause or last follow-up. Patients will be followed clinically as outlined in the treatment schedule and will be followed off study for death.

Measure: Overall Survival

Time: up to one year

Secondary Outcomes

Description: The proportion of patients who achieve a reduction in the sum of target lesions by 30% following the re-administration of chemotherapy. Radiographic assessment of disease burden will be evaluated by CT and disease RR will be documented using RECIST v1.1.

Measure: Overall Response Rate (ORR)

Time: 12 weeks

Description: The percentage of patients who have achieved complete response, partial response and stable disease (as per RECIST v1.1).

Measure: Disease Control Rate (DCR)

Time: 12weeks

Description: the time from enrollment to the time of the first radiographic documentation of objective progression as defined by RECIST v1.1 or death from any cause.

Measure: Progression Free Survival (PFS)

Time: 12 weeks

Measure: Number of Participants with Adverse Events as a Measure of Safety and Tolerability of platinum doublet therapy post RRx-001

Time: 12 weeks

Measure: Changes in the level of serum biomarkers will be calculated and treatment samples will be compared to baseline samples using one-sample tests (e.g., paired t test or Wilcoxon signed rank test).

Time: 12 weeks

95 Genomic Landscape of EGFR Mutant NSCLC Prior to Afatinib and at the Time of Disease Progression Following Afatinib

The investigators propose to conduct a pilot feasibility study of single agent afatinib in patients with previously untreated metastatic EGFR (epidermal growth factor receptor) mutant adenocarcinoma of the lung (NSCLC = non-small cell lung cancer) with the sole purpose of characterizing the genomic landscape before afatinib and at the time of disease progression.

NCT02491775 Carcinoma, Non-Small-Cell Lung Non-Small Cell Lung Cancer Non-small Lung Cancer
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Duration of response is the duration of overall response is measured from the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).. Inclusion Criteria/Exclusion Criteria: - Diagnosis of metastatic stage IIIB/IV lung adenocarcinoma - Presence of known sensitizing mutations in EGFR TK domain (exon 19 deletion and L858R) - Absence of known resistant mutations in the EGFR TK domain (T790M) - Consented to HRPO # 201305031 ("Tissue and Blood Acquisition for Genomic Analysis and Collection of Health Information from Patients with Thoracic Malignancies, Suspected Thoracic Malignancies, or Mesothelioma") - No prior treatment for this malignancy - No prior localized therapy to the biopsy site - Planned treatment with standard of care afatinib at 40 mg QD (daily) - Not pregnant or breastfeeding - At least 18 years of age Inclusion Criteria/Exclusion Criteria: - Diagnosis of metastatic stage IIIB/IV lung adenocarcinoma - Presence of known sensitizing mutations in EGFR TK domain (exon 19 deletion and L858R) - Absence of known resistant mutations in the EGFR TK domain (T790M) - Consented to HRPO # 201305031 ("Tissue and Blood Acquisition for Genomic Analysis and Collection of Health Information from Patients with Thoracic Malignancies, Suspected Thoracic Malignancies, or Mesothelioma") - No prior treatment for this malignancy - No prior localized therapy to the biopsy site - Planned treatment with standard of care afatinib at 40 mg QD (daily) - Not pregnant or breastfeeding - At least 18 years of age Carcinoma, Non-Small-Cell Lung Non-Small Cell Lung Cancer Non-small Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung The current proposal will include exome and transcriptome sequencing from blood collected at baseline along with tumor samples obtained prior to starting afatinib and at the time of disease progression (a total of two tissue samples and one blood sample per patient). --- L858R --- --- T790M ---

Duration of response is the duration of overall response is measured from the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).. Inclusion Criteria/Exclusion Criteria: - Diagnosis of metastatic stage IIIB/IV lung adenocarcinoma - Presence of known sensitizing mutations in EGFR TK domain (exon 19 deletion and L858R) - Absence of known resistant mutations in the EGFR TK domain (T790M) - Consented to HRPO # 201305031 ("Tissue and Blood Acquisition for Genomic Analysis and Collection of Health Information from Patients with Thoracic Malignancies, Suspected Thoracic Malignancies, or Mesothelioma") - No prior treatment for this malignancy - No prior localized therapy to the biopsy site - Planned treatment with standard of care afatinib at 40 mg QD (daily) - Not pregnant or breastfeeding - At least 18 years of age Inclusion Criteria/Exclusion Criteria: - Diagnosis of metastatic stage IIIB/IV lung adenocarcinoma - Presence of known sensitizing mutations in EGFR TK domain (exon 19 deletion and L858R) - Absence of known resistant mutations in the EGFR TK domain (T790M) - Consented to HRPO # 201305031 ("Tissue and Blood Acquisition for Genomic Analysis and Collection of Health Information from Patients with Thoracic Malignancies, Suspected Thoracic Malignancies, or Mesothelioma") - No prior treatment for this malignancy - No prior localized therapy to the biopsy site - Planned treatment with standard of care afatinib at 40 mg QD (daily) - Not pregnant or breastfeeding - At least 18 years of age Carcinoma, Non-Small-Cell Lung Non-Small Cell Lung Cancer Non-small Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung The current proposal will include exome and transcriptome sequencing from blood collected at baseline along with tumor samples obtained prior to starting afatinib and at the time of disease progression (a total of two tissue samples and one blood sample per patient). --- L858R --- --- T790M --- --- L858R --- --- T790M ---

Primary Outcomes

Description: The investigators will compare tumor sequencing prior to afatinib treatment to the time of disease progression to see if the genetic sequencing changed between pre-treatment and progression. The investigators plan to conduct exome and transcriptome sequencing of tumor before therapy with afatinib and at the time of relapse. In addition, exome sequencing of peripheral blood DNA will be done (for germline). Given the complexities of genomic analyses of paired samples in the face of limited data, the investigators will not be able to do any formal power calculations in this feasibility study. Disease progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study or appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.

Measure: Genetic changes associated with disease progression following treatment with afatinib

Time: Estimated to be 1 year

Secondary Outcomes

Description: Investigators will look at tumor tissue associated with a therapeutic response and compare with tumor tissue associated with disease progression and see if there are any mutation differences. Therapeutic Response Complete response is disappearance of all target lesions and non-target lesions. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Measure: Types of mutations in signaling kinases associated with therapeutic response

Time: Estimated to be 1 year

Description: A variant is considered to have mutant biased expression if the variant is expressed and the variant allele frequency is greater than 20% higher in the RNA-seq data compared to the exome sequencing data. A variant is considered to have wild type biased expression if the gene is expressed, the region of the variant is covered at 5X or greater depth, and the VAF is at least 20% lower in the RNA-seq data compared to the exome sequencing data. Duration of response is the duration of overall response is measured from the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).

Measure: Allelic ratio of wild type to mutant EGFR (roughly corrected for intrinsic differences in tumor cellularity) with duration of response

Time: Estimated to be 1 year

96 A Phase 1b/2 Study of ASP2215 in Combination With Erlotinib in Subjects With EGFR Activating Mutation-Positive (EGFRm+) Advanced NSCLC Who Have Acquired Resistance to an EGFR Tyrosine Kinase Inhibitor (TKI)

The purpose of the Phase 1b part of the study was to evaluate the safety and tolerability of ASP2215 in combination with erlotinib and determine the recommended phase 2 dose (RP2D) of ASP2215. The purpose of the Phase 2 part of the study was to evaluate the objective response rate (ORR) of the RP2D of ASP2215 in combination with erlotinib.

NCT02495233 Non-Small-Cell Lung Cancer Drug: Gilteritinib Drug: Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Participant's baseline tumor specimen (obtained after participant developed resistance to EGFR TKI therapy) is T790M negative. --- T790M ---

- Participant received any agent with antitumor activity (other than an EGFR inhibitor, including a T790M inhibitor) including chemotherapy, radiotherapy, immunotherapy, within 14 days prior to the first dose of study drug (palliative radiotherapy is allowed). --- T790M ---

Primary Outcomes

Measure: Number of Participants With Dose Limiting Toxicities (DLTs)

Time: Cycle 1 and Cycle ≥2 (up to 141 days)

Description: Treatment-emergent adverse events (TEAE) was defined as an adverse event (AE) that started after administration of the study drugs and occurred within 30 days of the last dose of the study drugs. If a participant experienced an event both during the preinvestigational period and during the investigational period, the event was considered a TEAE only if it worsened in severity.

Measure: Number of Participants With Adverse Events

Time: From first dose of study drug up to 30 days after the last dose of study (maximum study drug exposure 114 days)

Secondary Outcomes

Measure: Area Under the Concentration-time Curve at 24 Hours (AUC24) for Gilteritinib

Time: 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Days 1 and 28 of cycle 1

Measure: Maximum Concentration (Cmax) for Gilteritinib

Time: 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Days 1 and 28 of cycle 1

Measure: Time After Dosing When Cmax Occurs (Tmax) for Gilteritinib

Time: 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Days 1 and 28 of cycle 1

Description: All participants in Gilteritinib 120 mg + Erlotinib 150 mg group discontinued before cycle 3.

Measure: Concentration Immediately Prior to Dosing at Multiple Dosing (Ctrough) of Gilteritinib

Time: Predose on Day 1, 3, 8, 15, 22, 28 of cycle 1, Day 1 of cycle 3 and Day 1 of cycle 4

Measure: AUC24 of Erlotinib

Time: 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Day 28 of cycle 1

Measure: Cmax of Erlotinib

Time: 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Day 28 of cycle 1

Measure: Tmax of Erlotinib

Time: 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Day 28 of cycle 1

Measure: Ctrough of Erlotinib

Time: Day 8, 15, 22, 28 of cycle 1

Description: ORR was defined as Objective Response Rate (ORR) was the proportion of patients whose best overall response was complete response (CR) or partial response (PR) per RECIST version 1.1. Only patients with measurable disease at baseline were to be included in the analysis of ORR.

Measure: Objective Response Rate (ORR) in Phase 1b

Time: End of treatment (approximately 4 months)

97 A Phase I Trial of AZD9291 and Necitumumab in EGFR-Mutant Non-Small Cell Lung Cancer After Progression on a Previous EGFR Tyrosine Kinase Inhibitor

This phase I trial studies the side effects and best dose of necitumumab when given together with osimertinib in treating patients with EGFR-mutant non-small cell lung cancer that is stage IV or has come back (recurrent) and who have progressed on a previous EGFR tyrosine kinase inhibitor. Immunotherapy with monoclonal antibodies, such as necitumumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving necitumumab with osimertinib may be a better treatment for EGFR-mutant non-small cell lung cancer.

NCT02496663 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Biological: Necitumumab Drug: Osimertinib
MeSH:Carcinoma Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Non-small cell lung carcinoma

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on