MET amplification + EGFR mutation

Patients with NSCLC with both MET amplification and EGFR mutation who have received crizotinib, capmatinib, savolitinib, or tepotinib plus osimertinib (OSI) after progression on OSI at MD Anderson Cancer Center were included in this study. Dual EGFR and MET inhibition yielded high clinical response rate after progression on OSI. Resistance mechanisms to EGFR-MET double TKI inhibition include MET secondary mutation, EGFR secondary mutation, or loss of MET amplification.

HS-10241 in combination with almonertinib was well tolerated, and showed encouraging antitumor activity in treatment of advanced NSCLC with EGFR mutation and MET amplification following prior EGFR-TKI, whether MET GCN ≥10 or MET GCN ≥5 but < 10. Clinical trial information: NCT05430386.

Methods The signal transduction inhibition and cytotoxic response of ABN401 in combination with Lazertinib were tested in vitro against Osimertinib-resistance NSCLC cell lines (HCC827-AR) and patient-derived organoid (YUO-010), analyzed by western blot and Cell Titer-Glo assay. Notably, in MET gene amplification (PDX model YHIM-1035, gefitinib/Osimertinib resistant), ABN401 alone showed a potent therapeutic effect. Conclusions Our findings suggest that the clinical application of ABN401 in combination with a third-generation EGFR-TKI to NSCLC patients with MET gene amplification can provide a promising therapeutic strategy for overcoming acquired resistance to EGFR-TKIs.

Dose-response curves showed inhibitory effects on cell viability of several HER2 tyrosine kinase inhibitors including neratinib, lapatinib, poziotinib and afatinib . Our study revealed a novel class of HER2 KD indels in exon 18/19 that may act as driver mutations in several cancer types . The drug response observed in vitro indicated the potential to use anti-HER2 targeted therapies for HER2 exon 18/19 indels . Further studies on this rare type of HER2 mutation are warranted.

No abstract available

This case highlights the efficacy of concomitant treatment in a patient with two oncogenic drivers.

Savolitinib 600 mg plus gefitinib 250 mg once daily had an acceptable safety profile and demonstrated promising antitumor activity in EGFRm, MET-amplified advanced NSCLC patients who had disease progression on EGFR-TKIs. NCT02374645, Date of registration: March 2nd 2015.

Ramucirumab plus osimertinib demonstrated encouraging safety and antitumor activity in T790M-positive EGFR-mutant NSCLC.

P2 | "Background: In the ongoing, single-arm, Phase II VISION study (NCT02864992), tepotinib (a highly selective MET inhibitor) showed durable clinical activity in NSCLC patients with MET exon 14 skipping... MET exon 14 skipping can be successfully detected through non-invasive liquid biopsy analysis using next-generation sequencing. The rate of MET exon 14 skipping and the genomic profile and demographics of patients were similar to previously reported data. This abstract and presentation was previously presented at AACR 2020."

Tepotinib + gefitinib is associated with improved outcomes in pts with EGFR-mutant METamp NSCLC and EGFR TKI resistance compared to chemotherapy (INSIGHT: NCT01982955); progression-free survival (PFS) was 16.6 vs 4.2 months (HR=0.13; 90% CI: 0.04, 0.43) and overall survival (OS) was 37.3 vs 13.1 months (HR=0.08; 90% CI: 0.01, 0.51). Funding: Merck KGaA, Darmstadt, Germany. Clinical trial identification: NCT03940703.

One patient had EGFR L858R and T790M mutations and progressed very quickly on erlotinib. While detection of T790M mutation decreased upon osimertinib administration, L858R level stayed the same...Legal entity responsible for the study: Roche Sequencing Solutions, Inc. Funding: Roche Sequencing Solutions, Inc.