Abstract 1012P
Background
MET amplification is a known resistance mechanism to EGFR-mutant NSCLC with EGFR TKI treatment. Dual EGFR-MET inhibition has been reported with success in overcoming such resistance and inducing clinical benefit. There are currently clinical trials ongoing to evaluate such benefit formally. However, resistance mechanisms to dual MET-EGFR inhibition require further investigation and characterization.
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. Molecular profiling was completed via FISH and/or NGS. Response was defined as treating physicians’ judgment of clinical benefit.
Results
From 3/2016 to 3/2022, 20 patients (pts) received dual MET inhibitor and osi. Median age was 64 (38 – 89) and 75% were female. Three pts received capmatinib plus osi after progression on crizotinib plus osi. MET amplification was detected via FISH in 14 pts and median MET GCN was 13.6 (6.4 – 20). Clinical response rate was 65% (15/23, 3 pts had sequential MET TKIs). Median duration on treatment was 105 days (35 – 1035). Two of three pts responded to capmatinib plus osi after progression on crizotinib plus osi. 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 GI toxicity. Six pts are still on double TKI treatment. FISH and/or NGS on tumor and/or plasma were completed in 6 pts at progression. Resistance mechanism observed including loss of MET amplification (N=3), 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).
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.
Clinical trial identification
Editorial acknowledgement
No writing assistance was provided.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
Y.Y. Elamin: Financial Interests, Personal, Advisory Role: Eli Lilly, AstraZeneca, Turning Point Therapeutics; Financial Interests, Personal, Funding: Spectrum Pharmaceuticals, AstraZeneca, Takeda, Xcovery, Eli Lilly, Elevation Oncology, Turning Point Therapeutics. F. Skoulidis: Financial Interests, Advisory Board: Amgen. G. Blumenschein: Financial Interests, Personal, Advisory Role: AbbVie, Adicet, Amgen, Ariad, Bayer, Clovis Oncology, AstraZeneca, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Instil Bio, Genentech, Gilead, Eli Lilly, Janssen, MedImmune, Merck, Novartis, Roche, Tyme Oncology, Xcovery, Virogin Biotech, Maverick Therapeutics; Financial Interests, Personal, Funding: Amgen, Bayer, Adaptimmune, Elelixis, Daiichi Sankyo, GlaxoSmithKline, Immatics, Immunocore, Incyte, Kite Pharma, Macrogenics, Torque, AstraZeneca, Bristol-Myers Squibb, Celgene, Genentech, MedImmune, Merck, Novartis, Roche, Xcovery, Tmunity Therapeutics, Regeneron, BeiGene, Repertoire Immune Medicines, Verastem. A. Tsao: Financial Interests, Advisory Board: Novartis, Genentech. J. Zhang: Financial Interests, Personal, Other, Honoraria: Roche, Sino-USA Biomedical Platform, Geneplus, Origimed, Innovent Biologics, CancerNet, Zhejiang Cancer Hospital; Financial Interests, Personal, Advisory Role: AstraZeneca, Geneplus, Capital Medical University, Johnson & Johnson/Janssen, Novartis; Financial Interests, Personal, Funding: Merck, Novartis, Innovent Biologics, Zhejiang Cancer Hospital. J. Heymach: Financial Interests, Personal, Stocks/Shares: Cardinal Spine, Bio-Tree; Financial Interests, Personal, Advisory Role: AstraZeneca, Bristol Myers Squibb, Spectrum Pharmaceuticals, Guardant Health, Hengrui Pharmaceutical, GlaxoSmithKline, EMD Serono, Eli Lilly, Takeda, Sanofi/Aventis, Genentech/Roche, Boehringer Ingelheim, Catalyst Biotech, Foundation Medicine, Novartis, Mirati Therapeutics, BrightPath Biotheraputics, Janssen, Nexus Health Systems, Pneuma Respiratory, Kairos Ventures, Roche, Leads Biolabs; Financial Interests, Personal, Funding: AstraZeneca (Inst), Spectrum Pharmaceuticals, GlaxoSmithKline; Financial Interests, Personal and Institutional, Other, Licensing agreement between Spectrum and MD Anderson (including myself) regarding intellectual property for treatment of EGFR and HER2 exon 20 mutations: Spectrum Pharmaceuticals. X. Le: Financial Interests, Personal, Advisory Role: EMD Serono (Merck KGaA), AstraZeneca, Spectrum Pharmaceutics, Novartis, Eli Lilly, Boehringer Ingelheim, Hengrui Therapeutics, Daiichi Sankyo, AbbVie; Financial Interests, Personal, Funding: Eli Lilly, Boehringer Ingelheim. All other authors have declared no conflicts of interest.