This trial is testing two novel combinations (temozolomide plus osimertinib OR temozolomide plus lorlatinib) which have not been evaluated in clinical trials. Thus, the exact benefits of these novel combinations are unclear. However, based on the mechanism of action of temozolomide and CNS(Central Nervous System) penetration/activity in other tumor types, it is hypothesized that adding temozolomide to osimertinib or temozolomide to lorlatinib may provide improvement in CNS disease control in patients with CNS progression on either of these latter two TKIs (Tyrosine kinase inhibitors).

NCT04541407

Conditions

1. Non Small Cell Lung Cancer
2. CNS Progression

Interventions

1. Drug: Temozolomide plus Osimertinib
2. Drug: Temozolomide plus Lorlatinib

MeSH:Disease Progression

Compound mutations are defined as 2 or more mutations in the EGFR tyrosine kinase domain with the following exceptions: 1. C797S and EGFR exon 19 deletion or EGFR exon 21 point mutation and 2. T790M mutation and EGFR exon 19 deletion or EGFR exon 21 point mutation. --- C797S ---

The investigators performed a multi-centered, randomized, double blinded, placebo-controlled, prospective clinical trial on the effect of Yiqi-yangyin-jiedu decoction (YYJD), a chinese herbal medicine (CHM) formula combined with gefitinib to prolong the progression free survival (PFS) of advanced pulmonary adenocarcinoma patients with activating EGFR mutation (exon19del or exon21L858R). The investigators plan to enroll 198 cases in 3 years (99 cases for gefitinib, 99 cases for gefitinib plus YYJD), expecting that combination therapy has a better efficacy on prolonging PFS, overall survival, improving quality of life(QOL).

NCT02929693

Conditions

1. Cancer

Interventions

1. Drug: gefitinib
2. Drug: Yiqi-yangyin-jiedu decoction
3. Drug: placebo

MeSH:Adenocarcinoma Adenocarcinoma of Lung

Although AZD9291 (AstraZeneca), a third-generation EGFR-TKI is reported with a response rate of 61% in NSCLC patients with EGFR T790M and a mPFS of 9.6 months, resistance to third-generation inhibitors mediated by EGFR C797S mutation is inevitable. --- T790M --- --- C797S ---

This is a clinical study with an orally administered drug, BDTX-189 in participants with advanced solid tumors that have select mutations or alterations in human epidermal growth factor receptor 2 (HER2/ErbB2) genes or epidermal growth factor receptor (EGFR/ErbB1). The main goals of this study are to: - Find the recommended dose of BDTX-189 that can be given safely to participants - Learn more about the side effects of BDTX-189 - Learn what the body does to BDTX-189 after it has been taken (pharmacokinetics or PK) - Determine the antitumor activity of BDTX-189 in participants with select allosteric ErbB gene mutations

NCT04209465

Conditions

1. Solid Tumor

Interventions

1. Drug: BDTX-189

Evidence of second- or third-degree atrioventricular block 2. Clinically significant arrhythmia (as determined by the Investigator) 3. QTcF interval of >470 msec - Leptomeningeal or untreated and/or symptomatic CNS malignancies (primary or metastatic) - Women who are pregnant or breast-feeding - Taking or unable to discontinue proton pump inhibitors within 1 week prior to baseline - Known concurrent KRAS mutation - Known tumor-harboring resistance mutations including EGFR T790M or C797S mutations or HER2 C805S mutation Phase 2 Only: - Prior documented treatment response to approved or investigational HER2 or EGFR tyrosine kinase inhibitor therapies Main Inclusion Criteria: - Histologically- or cytologically-confirmed locally advanced or metastatic solid tumor with documented recurrence or disease progression from standard anticancer therapy in the advanced/metastatic setting - No standard therapy available or standard therapy is considered unsuitable or intolerable according to the Investigator and consultation with the Medical Monitor Phase 1 Only: - Solid tumor patients with alterations that may be associated with antitumor activity based on preclinical data for BDTX-189 such as: 1. Allosteric HER2 or HER3 mutation(s) 2. EGFR or HER2 exon 20 insertion mutation(s) 3. HER2 amplified or overexpressing tumors 4. EGFR exon 19 deletion or L858R mutation Phase 2 Only: - Patients with a solid tumor harboring an: 1. Allosteric HER2 mutation (including but not limited to S310F/Y, R678Q, L755S/P, V777L, V842I) 2. EGFR or HER2 exon 20 insertion mutation Eligible mutations must be determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory. --- T790M --- --- C797S ---

Evidence of second- or third-degree atrioventricular block 2. Clinically significant arrhythmia (as determined by the Investigator) 3. QTcF interval of >470 msec - Leptomeningeal or untreated and/or symptomatic CNS malignancies (primary or metastatic) - Women who are pregnant or breast-feeding - Taking or unable to discontinue proton pump inhibitors within 1 week prior to baseline - Known concurrent KRAS mutation - Known tumor-harboring resistance mutations including EGFR T790M or C797S mutations or HER2 C805S mutation Phase 2 Only: - Prior documented treatment response to approved or investigational HER2 or EGFR tyrosine kinase inhibitor therapies Solid Tumor BDTX-189 is an irreversible, small molecular inhibitor that is highly selective versus wild-type EGFR and potent for cancer driver mutations of the ErbB family, including extracellular, transmembrane, and kinase domain allosteric mutations of HER2, as well as EGFR and HER2 exon 20 insertion mutations. --- T790M --- --- C797S ---

The third generation epidermal growth gactor receptor-tyrosine Kinase Inhibitor（EGFR-TKI） osimertinib has obvious curative effect for EGFR sensitive mutation and T790M mutation(PMID 27959700), but acquired drug resistance will occur. Previous studies show that apoptosis escape can lead to EGFR-TKI resistance.Osimertinib resistant cells show abnormal activation of PI3K/AKT/BIM activation(PMID 28765329). The classical drug aspirin can effectively decrease AKT phosphorylation and activate of BIM(PMID 28881293).So Investigators speculate that aspirin may decrease the PI3K/AKT/BIM signaling pathways, then promote osimertinib resistant cells apoptosis. The current study aims to evaluate the combination of aspirin and osimertinib in patients with EGFR/T790M mutations.

NCT03532698

Conditions

1. Non-Small Cell Lung Cancer Stage IIIB
2. Non-small Cell Lung Cancer Stage IV
3. EGFR T790M

Interventions

1. Drug: Aspirin
2. Drug: Osimertinib

MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung

HPO:Neoplasm of the lung Non-small cell lung carcinoma

Previous study showed that one principal mechanism accounting for majority of acquired resistance to Osimertinib in lung cancer is mediated by an exon 20 C797S mutation etc(PMID 29596911). --- C797S ---

This phase I trial studies the side effects and best dose of WSD0922-FU for the treatment of glioblastoma, anaplastic astrocytoma, or non-small cell lung cancer that has spread to the central nervous system (central nervous system metastases). WSD0922-FU is a targeted treatment which blocks the EGFR protein - a strategy that has led to a lot of benefit in patients with many different cancers. WSD0922-FU may also be able to get into cancers in the brain and spinal cord and help patients with brain and spinal cord cancers.

NCT04197934

Conditions

1. Anaplastic Astrocytoma, IDH-Wildtype
2. Glioblastoma, IDH-Wildtype
3. Lung Non-Small Cell Carcinoma
4. Metastatic Malignant Neoplasm in the Central Nervous System
5. Metastatic Malignant Neoplasm in the Leptomeninges

Interventions

1. Drug: EGFR/EGFRvIII Inhibitor WSD0922-FU
2. Procedure: Therapeutic Conventional Surgery

MeSH:Neoplasms Glioblastoma Astrocytoma Neoplasms, Second Primary Carcinoma, Non-Small-Cell Lung

HPO:Astrocytoma Glioblastoma multiforme Neoplasm Non-small cell lung carcinoma Subependymal giant-cell astrocytoma

Patients are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for more than three years prior to registration - Any of the following cardiac criteria: - A marked baseline prolongation of QT/corrected QT (QTc) interval - (e.g., repeated demonstration of a QTc interval > 480 milliseconds (ms) (Common Terminology Criteria for Adverse Events [CTCAE] grade 1) using Fridericia's QT correction formula - A history of additional risk factors for torsade de pointes (TdP) (e.g., heart failure, hypokalemia, family history of long QT syndrome) - The use of concomitant medications that prolong the QT/QTc interval - Patients confirmed to have a cis double mutation (Del19/T790M or L858R/T790M) or cis triple mutation (Del19/T790m/C797S or L858R/T790M/C797S) - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease. --- T790M --- --- L858R --- --- C797S ---

The third generation epidermal growth factor receptor-tyrosine Kinase Inhibitor（EGFR-TKI） osimertinib has obvious curative effect for EGFR sensitive mutation and T790M mutation(PMID 27959700), but acquired drug resistance will occur. Previous studies show that apoptosis escape can lead to EGFR-TKI resistance.Osimertinib resistant cells show abnormal activation of PI3K/AKT/BIM activation(PMID 28765329). The classical drug aspirin can effectively decrease AKT phosphorylation and activate of BIM(PMID 28881293).So Investigators speculate that aspirin may decrease the PI3K/AKT/BIM signaling pathways, then promote osimertinib resistant cells apoptosis. The current study aims to evaluate the combination of aspirin and osimertinib in patients with EGFR/T790M mutations.

NCT04184921

Conditions

1. Lung Cancer Non-small Cell Stage IV

Interventions

1. Drug: Aspirin 100mg
2. Drug: Osimertinib 80 MG

MeSH:Carcinoma, Non-Small-Cell Lung

HPO:Non-small cell lung carcinoma

Previous study showed that one principal mechanism accounting for majority of acquired resistance to Osimertinib in lung cancer is mediated by an exon 20 C797S mutation etc(PMID 29596911). --- C797S ---

The third generation epidermal growth gactor receptor-tyrosine Kinase Inhibitor（EGFR-TKI） osimertinib has obvious curative effect for EGFR sensitive mutation and T790M mutation(PMID 27959700), but acquired drug resistance will occur. Previous studies show that apoptosis escape can lead to EGFR-TKI resistance.Osimertinib resistant cells show abnormal activation of PI3K/AKT/BIM activation(PMID 28765329). The classical drug aspirin can effectively decrease AKT phosphorylation and activate of BIM(PMID 28881293).So Investigators speculate that aspirin may decrease the PI3K/AKT/BIM signaling pathways, then promote osimertinib resistant cells apoptosis. The current study aims to evaluate the combination of aspirin and osimertinib in patients with EGFR/T790M mutations.

NCT03543683

Conditions

1. Non-Small Cell Lung Cancer Stage IIIB
2. Non-small Cell Lung Cancer Stage IV
3. EGFR T790M

Interventions

1. Drug: Osimertinib
2. Drug: Aspirin

MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung

HPO:Neoplasm of the lung Non-small cell lung carcinoma

Previous study showed that one principal mechanism accounting for majority of acquired resistance to Osimertinib in lung cancer is mediated by an exon 20 C797S mutation etc(PMID 29596911). --- C797S ---

This is a phase 2 single-arm, non-randomized multicentre and tissue acquisition study to evaluate acquired resistance mechanisms, efficacy, and safety in advanced, EGFR tyrosine kinase inhibitor-naïve NSCLC patients with EGFR-activating mutations who receive a first-line osimertinib orally at a dose of 80mg once daily.

NCT03969823

Conditions

1. Locally Advanced or Metastatic NSCLC

Interventions

1. Drug: Tagrisso

MeSH:Carcinoma, Non-Small-Cell Lung

HPO:Non-small cell lung carcinoma

Acquired resistance to first-line osimertinib is mediated by heterogeneous mechanisms including MET amplification (15%), secondary EGFR mutation including C797S or S768I (7%), PIK3CA mutation (7%), CDK4/6 amplification (5%), KRAS mutation (3%), BRAF mutation (3%), CCND1-3 amplification (3%), CCNE1 amplification (2%), HER2 amplification (2%), and SPTBN1-ALK fusion (1%) using plasma genotyping of FLAURA study (N=91). --- C797S ---

Evaluate the efficacy and safety of Anlotinib combined with Icotinib as the second-line treatment in stage IIIb-IV NSCLC patients with sensitive EGFR and T790M mutations.

NCT04029350

Conditions

1. Non Small Cell Lung Cancer

Interventions

1. Drug: Anlotinib Combined With Osimertinib

MeSH:Carcinoma, Non-Small-Cell Lung

HPO:Non-small cell lung carcinoma

Exclusion Criteria: 1. Squamous cell carcinoma (including adenosquamous carcinoma); Small Cell Lung Cancer (including small cell cancer and other kinds of cancer mixed with non-small cell cancer) 2. Non-small cell lung cancer (NSCLC) with an EGFR C797S mutation. --- C797S ---

The study primary objective is to assess the concordance of T790M resistance mutation testing from hospital-based laboratories with T790M resistance mutation testing from a central laboratory.

NCT02991274

Conditions

1. Locally Advanced or Metastatic EGFR(+) NSCLC Patients

Interventions

1. Procedure: genomic testing of T790M mutation

The prevalence of C797S (An amino acid substitution at position 797 in EGFR, from a Cysteine (C) to a Serine (S) ) resistance mutation based on the local lab testing. --- C797S ---

Prevalence (%) = (number of patients with C797S mutation positive)/(total number of patients with evaluable C797S testing)×100%. --- C797S ---

Prevalence (%) = (number of patients with C797S mutation positive)/(total number of patients with evaluable C797S testing)×100%. --- C797S --- --- C797S ---

The aim of this study is to evaluate concordance of T790M mutation plasma testing between the Cobas test and each of other platforms: Super-ARMS, digital PCR or NGS. And to assess the efficacy of AZD9291 monotherapy by assessment of PFS in adult patients with advanced or metastatic NSCLC, who have received prior EGFR-tyrosine kinase inhibitor (TKI) therapy and are T790M mutation positive detected by any one of the four plasma testing platforms: Cobas/Super-ARMS/ digital PCR/NGS.

NCT02997501

Conditions

1. Lung Cancer

Interventions

1. Procedure: T790M+ Testing
2. Procedure: Baseline Visit Blood & Urine Testing
3. Procedure: Baseline ECG
4. Procedure: Visual Slit-Lamp Testing
5. Drug: AZD9291 Dosing
6. Procedure: Plasma AZD9291 testing

To evaluate the NPV of Super-ARMS/digital PCR/NGS by using Cobas as the reference.. Proportion of patients with each EGFR mutation (C797S and T790M etc.) at different time point.. --- C797S ---

Background: Some non-small-cell lung cancers (NSCLC) have a mutation in a gene that makes a protein called EGFR. This particular cancer can be treated with certain drugs such as Erlotinib (Tarceva), Gefitinib (Iressa) and Osimertinib (Tagrisso). But many tumors become resistant to these drugs because of a second mutation. Researchers want to test if adding local ablative therapy (LAT) extends the benefits of the drug, Osimertinib. LAT can include techniques such as surgery, radiofrequency ablation, cryotherapy or radiation therapy. Objective: To test if re-taking osimertinib after LAT is safe, tolerable, and effective for people whose NSCLC has progressed after initial treatment with osimertinib. Eligibility: Adults ages 18 and older with certain types of NSCLC. Participants will be divided into various groups as described below. Design: Participants will be screened with: Medical history Physical exam Blood, urine, and heart tests Tumor scans Eye exam Review of tumor sample. Participants will take the study drug by mouth once a day. They will continue until they can no longer tolerate it or their disease worsens. They will keep a dosage diary. All participants will start each 21-day course with physical exam; blood, urine, and saliva tests; and electrocardiogram. They will have scans every 6 weeks and echocardiogram every 3 months. Groups 1 and 2 will: Start osimertinib right away. Have LAT if their disease gets worse and is suitable for LAT. If LAT cannot be performed or LAT consists of a procedure other than surgery, a tumor biopsy will be performed. Re-start osimertinib after LAT, or other treatments if not suitable for LAT. Group 3 will: Have LAT. If LAT consists of a procedure other than surgery, a tumor biopsy will be performed. Start osimertinib after LAT. After participants stop taking the drugs, they will have a final visit. This will include: Medical history Physical exam Heart and blood tests Participants will be called every year for follow-up.

NCT02759835

Conditions

1. Lung Adenocarcinoma
2. Lung Neoplasms

Interventions

1. Drug: osimertinib
2. Other: LAT

MeSH:Lung Neoplasms Adenocarcinoma of Lung

HPO:Neoplasm of the lung

In fact, a newly identified EGFR mutation (C797S) that results in acquired resistance to osimertinib has been reported recently. --- C797S ---

The purpose of study is to evaluate the safety, pharmacokinetics, and preliminary efficacy of Amivantamab as a monotherapy and in combination with lazertinib, and to determine the recommended Phase 2 dose (RP2D) (monotherapy), recommended Phase 2 combination dose (RP2CD) (combination therapy), and to determine recommended Phase 2 Dose (RP2q3W) with combination chemotherapy (Amivantamab in combination with standard of care carboplatin and pemetrexed) in 21 day treatment cycle for participants with advanced non-small cell lung cancer (NSCLC).

NCT02609776

Conditions

1. Non-Small-Cell Lung Cancer

Interventions

1. Drug: Amivantamab
2. Drug: Amivantamab
3. Drug: Lazertinib
4. Drug: Carboplatin
5. Drug: Pemetrexed

MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung

HPO:Neoplasm of the lung Non-small cell lung carcinoma

Cohort C: Participants with primary EGFR mutated disease, with a documented EGFR alteration (example, C797S) mediating resistance to previous treatment with a third generation EGFR TKI (for example, osimertinib), in participants with primary Exon 20ins disease, the documented EGFR alteration may arise following treatment with a TKI with known activity against Exon 20ins disease (for example, poziotinib). --- C797S ---

Based on the possibilities that both plasma and circulating tumor cells (CTCs) (the "liquid biopsy") may offer, we consider that it could be feasible to longitudinally monitor the genetic evolution and the biologic characteristics of CTCs, by using Circulating tumor DNA (ctDNA) and CTCs as a source of biologic material. This approach could provide information regarding the genetic/molecular changes associated with primary and acquired resistance to AZD9291 and, thus, to facilitate to more appropriately adapt the tailored treatment in this particular group of NSCLC patients. It has been recently reported that the detection of resistant clones, based on the tumor-associated genetic aberrations in the blood, can identify treatment resistance up to 10 months earlier than the radiological methods providing, thus, the potential for an early switch to a non cross-resistant therapy in order to improve patients' outcome.

NCT02771314

Conditions

1. Non Small Cell Lung Cancer

Interventions

1. Drug: AZD9291

MeSH:Carcinoma, Non-Small-Cell Lung

HPO:Non-small cell lung carcinoma

The patients will be followed every 3 months for the detection of mutations (T790M), (C797S), (L858R), del 19 EGFR mutations as well as the mutations [(KRAS)/(NRAS), (BRAF), (PI3K)] in the serum/plasma, the determination of the serum levels of Hepatocyte Growth Factor (HGF), the presence of T790M (+) and C797S(+) CTCs as well as the molecular (c-MET) and (HER2 amplification) and phenotypic characterization of CTCs using the filtration platform (ISET). --- T790M --- --- C797S ---