EGFR G796S

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.

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

This signal seeking biomarker study using cfDNA to better understand the association of mutational status and the treatment efficacy of the combined treatment was feasible and informative despite the small-scale study, supporting the advantage of further implementation.

The sequential use of 1-/2-generation to 3-generation epidermal growth factor (EGFR) tyrosine kinase inhibitors (TKIs) has led to the emergence of triple EGFR mutations generally consisting of the founder mutation (del 19 or L858R), gatekeeper mutation (T790M) and mutation (C797S) that abolishes the covalent binding of osimertinib to the EGFR protein (i.e., del 19 or L858R/T790M/C797S). Amivantamab, a bi-specific EGFR/MET monoclonal antibody that can affect Fc mediated trogocytosis of the EGFR protein has been approved for the treatment of EGFR exon20 insertion mutations and has demonstrated activity against a myriad of compound EGFR mutations. Here we report amivantamab monotherapy induced symptomatic, biochemical, molecular, and radiographic responses in a NSCLC patient with triple EGFR mutations in cis in the background of EGFR amplification.

"A repeated tissue biopsy and a ccfDNA analysis were useful in analyzing the mechanisms underlying acquired resistance. A long treatment history of EGFR TKIs may result in a high percentage of EGFR structural change."

Funding: Foundation Medicine Background: The emergence of osimertinib (osi) as standard of care therapy for EGFR-mutant NSCLC has led to investigations into understanding and overcoming drug resistance... Osi resistance in EGFR-mutant NSCLC is a poor prognosis condition . EGFR C797S is a recurring resistance mut which, in a minority of cases, can co-occur with alternate on and off target resistance muts detected with tissue and liquid biopsy.

In addition, EGFR G796S was predicted to be susceptible to gefitinib. This study represented the largest real-world data so far investigating Osimertinib resistance in EGFR-mutated lung cancer. We identified a collection of coexistent EGFR rare mutations and provided possible guidance for those patients who progressed on the first-line treatment of Osimertinib.

The study revealed heterogeneous mechanisms of resistance to osimertinib in advanced NSCLC patients and their association with clinical outcomes. Patients who maintained T790M mutation or with EGFR-dependent resistance mechanism had longer clinical outcome benefits.