Brief Report: Clinical Response, Toxicity, and Resistance Mechanisms to Osimertinib Plus MET Inhibitors in Patients With EGFR-Mutant MET-Amplified NSCLC

MET amplification is a known resistance mechanism to EGFR tyrosine kinase inhibitor (TKI) treatment in EGFR-mutant NSCLC. Dual EGFR-MET inhibition has been reported with success in overcoming such resistance and inducing clinical benefit. Resistance mechanisms to dual EGFR-MET inhibition require further investigation and characterization. Patients (pts) 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. Molecular profiling was completed by means of fluorescence in situ hybridization (FISH) and/or next-generation sequencing (NGS). Radiological response was assessed on the basis of Response Evaluation Criteria in Solid Tumors version 1.1. From March 2016 to March 2022, 23 treatments with dual MET inhibitor and osi were identified with a total of 20 pts included. Three pts received capmatinib plus osi after progression on crizotinib plus osi. Median age was 64 (38–89) years old and 75% were female. MET amplification was detected by FISH in 14 pts in the tissue, NGS in 10 pts, and circulating tumor DNA in three pts. Median MET gene copy number was 13.6 (6.4–20). Overall response rate was 34.8% (eight of 23). In assessable pts, tumor shrinkage was observed in 82.4% (14 of 17). Median time on treatment was 27 months. Two of three pts responded to capmatinib plus osi after progression on crizotinib plus osi. Dual EGFR-MET inhibition was overall well tolerated. Two pts on crizotinib plus osi and one pt on capmatinib plus osi discontinued therapy due to pneumonitis. One pt discontinued crizotinib plus osi due to gastrointestinal toxicity. Six pts were still on double TKI treatment. At disease progression to dual EGFR-MET inhibition, FISH and/or NGS on tumor and/or plasma were completed in six pts. Notable resistance mechanisms observed include acquired MET D1246H (n = 1), acquired EGFR C797S (n = 2), FGFR2 fusion (n = 1, concurrent with C797S), and EGFR G796S (n = 1, concurrent with C797S). Four pts lost MET amplification. 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.