PMID- 37649681 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230901 IS - 2666-3643 (Electronic) IS - 2666-3643 (Linking) VI - 4 IP - 8 DP - 2023 Aug TI - Brief Report: Clinical Response, Toxicity, and Resistance Mechanisms to Osimertinib Plus MET Inhibitors in Patients With EGFR-Mutant MET-Amplified NSCLC. PG - 100533 LID - 10.1016/j.jtocrr.2023.100533 [doi] LID - 100533 AB - INTRODUCTION: 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. METHODS: 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. Molecular profiling was completed by means of fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS). Radiological response was assessed on the basis of Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: From March 2016 to March 2022, 23 treatments with dual MET inhibitor and osi were identified with a total of 20 patients included. Three patients 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 patients in the tissue, NGS in 10 patients, and circulating tumor DNA in three patients. Median MET gene copy number was 13.6 (6.4-20). Overall response rate was 34.8% (eight of 23). In assessable patients, tumor shrinkage was observed in 82.4% (14 of 17). Median time on treatment was 27 months. Two of three patients responded to capmatinib plus OSI after progression on crizotinib plus OSI. Dual EGFR-MET inhibition was overall well tolerated. Two patients 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 patients were still on double TKI treatment. At disease progression to dual EGFR-MET inhibition, FISH and NGS on tumor and plasma were completed in six patients. 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 patients lost MET amplification. CONCLUSIONS: 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. CI - (c) 2023 The Authors. FAU - Wang, Kaiwen AU - Wang K AD - Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Du, Robyn AU - Du R AD - Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Roy-Chowdhuri, Sinchita AU - Roy-Chowdhuri S AD - Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Li, Ziping T AU - Li ZT AD - Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Hong, Lingzhi AU - Hong L AD - Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Vokes, Natalie AU - Vokes N AD - Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Elamin, Yasir Y AU - Elamin YY AD - Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Hume, Celyne Bueno AU - Hume CB AD - Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Skoulidis, Ferdinandos AU - Skoulidis F AD - Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Gay, Carl M AU - Gay CM AD - Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Blumenschein, George AU - Blumenschein G AD - Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Fossella, Frank V AU - Fossella FV AD - Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Tsao, Anne AU - Tsao A AD - Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Zhang, Jianjun AU - Zhang J AD - Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Karachaliou, Niki AU - Karachaliou N AD - The Healthcare Business of Merck KGaA, Darmstadt, Germany. FAU - O'Brate, Aurora AU - O'Brate A AD - The Healthcare Business of Merck KGaA, Darmstadt, Germany. FAU - Gann, Claudia-Nanette AU - Gann CN AD - The Healthcare Business of Merck KGaA, Darmstadt, Germany. FAU - Lewis, Jeff AU - Lewis J AD - Department of Quantitative Research Computing, The University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Rinsurongkawong, Waree AU - Rinsurongkawong W AD - Department of Quantitative Research Computing, The University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Lee, J Jack AU - Lee JJ AD - Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Gibbons, Don Lynn AU - Gibbons DL AD - Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Vaporciyan, Ara A AU - Vaporciyan AA AD - Department of Thoracic & Cardiovasc Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Heymach, John V AU - Heymach JV AD - Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Altan, Mehmet AU - Altan M AD - Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. FAU - Le, Xiuning AU - Le X AD - Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. LA - eng PT - Journal Article DEP - 20230601 PL - United States TA - JTO Clin Res Rep JT - JTO clinical and research reports JID - 101769967 PMC - PMC10462815 OTO - NOTNLM OT - EGFR OT - MET OT - NSCLC OT - Resistance mechanisms EDAT- 2023/08/31 06:41 MHDA- 2023/08/31 06:42 PMCR- 2023/06/01 CRDT- 2023/08/31 04:02 PHST- 2023/01/26 00:00 [received] PHST- 2023/05/17 00:00 [revised] PHST- 2023/05/25 00:00 [accepted] PHST- 2023/08/31 06:42 [medline] PHST- 2023/08/31 06:41 [pubmed] PHST- 2023/08/31 04:02 [entrez] PHST- 2023/06/01 00:00 [pmc-release] AID - S2666-3643(23)00072-3 [pii] AID - 100533 [pii] AID - 10.1016/j.jtocrr.2023.100533 [doi] PST - epublish SO - JTO Clin Res Rep. 2023 Jun 1;4(8):100533. doi: 10.1016/j.jtocrr.2023.100533. eCollection 2023 Aug.