61 (PB051) - Capmatinib response in patients with advanced non–small cell lung cancer (NSCLC) harboring focal MET amplifications: Analysis from the phase 2, multicohort GEOMETRY mono-1 study

Abstract

Background: MET amplifications (METamp) occur in 1–6% of patients (pts) with NSCLC and are associated with a poor prognosis. Capmatinib is a highly selective and potent MET inhibitor (METi) with antitumor activity in pretreated and treatment-naive pts with MET-amplified (gene copy number [GCN] 310) NSCLC. Focal METamp are associated with a relatively high MET GCN and may be a predictor of benefit from METi. In this retrospective analysis from GEOMETRY mono-1 (NCT02414139), we aimed to determine the response to capmatinib according to focality of METamp detected in cell-free DNA (cfDNA) using a blood-based assay. Materials and Methods: Pretreated (1 or 2 prior lines) pts with EGFR wild-type, ALK-negative, MET exon 14 skipping–negative, stage IIIB/IV NSCLC were grouped into cohorts C1a, C1b, C2, and C3 based on different levels of MET GCN amp by FISH on tumor tissue. Pts received capmatinib 400 mg twice daily. cfDNA isolated from blood plasma samples collected at baseline was enriched using RNA-bait–based hybrid capture and analyzed using next-generation sequencing (PanCancer assay 1.0, NGDx, Novartis). Focal METamp were defined using the PureCN pipeline that estimates a gene-level log-ratio relative to normal samples, adjusting for gene probe signal variation. MET was called focally amplified if gene-level P value was <0.001 and gene-level log-ratio reached 90th percentile of all genes. The overall response rate (ORR) by Blinded Independent Review Committee was descriptively compared between pts with focal vs nonfocal METamp (data cutoff, August 2021). Results: 195 pts across the 4 cohorts had METamp by FISH. Of these, baseline cfDNA samples from 113 pts were successfully analyzed (C1a [n = 29], C1b [n = 32], C2 [n = 31], C3 [n = 21]). Baseline characteristics were comparable between pts who were analyzed by cfDNA (n = 113) vs not analyzed (n = 82) and between pts with focal (n = 18) vs nonfocal (n = 95) METamp. Of all pts with focal METamp, most were in high MET-amplified C1a (14 of 18 pts [78%]). In C1a, the distribution of GCN by FISH was similar in pts with focal vs nonfocal METamp but more responders were found in pts with focal vs nonfocal METamp (ORR, 57% vs 13%). In C1b, 3 of 32 pts (9%) had focal METamp; 2 were responders (Table).Tabled 1CohortMET GCN by FISHParameterFocal METampNonfocal METampPts analyzedAll pts in cohortC1a≥10N14152969ORR, n (%)8 (57)2 (13)10 (34)20 (29)C1b≥6 and <10N3293242ORR, n (%)2 (67)1 (3)3 (9)5 (12)C2≥4 and <6N0313154ORR, n (%)-2 (6)2 (6)5 (9)C3<4N1202130ORR, n (%)0 (0)1 (5)1 (5)2 (7) Open table in a new tab Conclusions: METamp status, including focal METamp, was successfully determined using cfDNA isolated from blood. For pts with high MET- amplified NSCLC by FISH, a numerically higher proportion of responders to capmatinib was observed in pts with focal vs nonfocal METamp. Given the small sample size, a larger study is needed to verify this result. Conflict of interest: Ownership: Juergen Wolf: None Markus Riester, Lexiang Ji, Anna Robeva, Aislyn Boran: Novartis stock Advisory Board: Juergen Wolf: Consulting or advisory role for Abbvie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Chugai Pharma, Ignyta, Lilly, MSD Oncology, Novartis, Pfizer, Roche, Janssen, Loxo/Lilly, Blueprint Medicines, Amgen, Takeda, Bayer, Daiichi Sankyo Europe GmbH, Seattle Genetics Edward B. Garon: Consultant and/or advisor for Abbvie, ABL-Bio, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Dracen Pharmaceuticals, EMD Serono, Eisai, Eli Lilly, Gilead, GlaxoSmithKline, Merck, Natera, Novartis, Personalis, Regeneron, Sanofi, Shionogi, and Xilio. Daniel S. W. Tan: Consulting/advisory role for Pfizer, Novartis, Takeda, Boehringer Ingelheim, Merck, Amgen, AstraZeneca, DKSH, Roche, C4 Therapeutics, GSK Board of Directors: Juergen Wolf: None Corporate-sponsored Research: Juergen Wolf: Research funding from Bristol-Myers Squibb, Novartis, Pfizer, Janssen Edward B. Garon: Grant/research support from ABL-Bio, AstraZeneca, Bristol Myers Squibb, Dynavax Technologies, Eli Lilly, EMD Serono, Genentech, Iovance Biotherapeutics, Merck, Mirati Therapeutics, Neon, and Novartis Daniel S. W. Tan: Research funding (payments to institution) from AstraZeneca, Pfizer, ACM Biolabs, Amgen Rebecca S. Heist: To institution (not to self) from Agios, Abbvie, Lilly, Novartis, Turning Point, Daichii Sankyo, Mirati, Corvus, Exelixis, Erasca Other Substantive Relationships: Juergen Wolf: Honoraria from Abbvie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, MSD, Novartis, Roche, Amgen, Bayer, Blueprint Medicines, Chugai Pharma Europe, Daiichi Sankyo Europe GmbH, Ignyta, Janssen, Lilly, Loxo, Loxo/Lilly, Pfizer, Seattle Genetics, Takeda Sylvie Le Mouhaer, Markus Riester, Lexiang Ji, Anna Robeva, Lauren Fairchild, Aislyn Boran: Employment at Novartis Rebecca S. Heist: Consulting for Novartis, Daichii Sankyo, EMD Serono