A phase II, multicenter, four-cohort study of oral cMET inhibitor capmatinib (INC280) in patients with EGFR wild-type, advanced NSCLC who have received one or two prior lines of systemic therapy for advanced/metastatic disease

Background

Amplification of cMET leading to oncogenic signaling occurs in ≈4% of non-small cell lung cancer (NSCLC) cases. Mutations in cMET leading to exon 14 deletion (cMETΔ^ex14) are also an actionable target in NSCLC. Capmatinib (INC280) is a potent and selective cMET inhibitor that has shown strong evidence of antitumor activity in an ongoing Phase I study in patients (pts) with EGFR wild-type (WT) advanced NSCLC harboring cMET dysregulation, including high-level cMET amplification (fluorescence in situ hybridization [FISH] gene copy number [GCN] ≥5), and cMETΔ^ex14.

Trial design

This multicenter Phase II four-cohort study (ClinicalTrials.gov identifier NCT02414139) was designed to confirm the clinical activity of capmatinib in pretreated pts with advanced NSCLC according to cMET amplification and cMETΔ^ex14. Eligible pts (≥18 years of age, Eastern Cooperative Oncology Group Performance Status 0–1) must have ALK-negative, EGFR-WT (for activating mutations including exon 19 deletion, and L858R mutation) stage IIIB/IV NSCLC (any histology), and have received 1–2 prior lines of therapy for advanced disease (no prior cMET inhibitor). Centrally assessed cMET amplification and mutation status will be used to assign pts to one of four cohorts (≈69 pts each; N ≈ 276): 1: cMET GCN ≥6 2: cMET GCN ≥4 and <6 3: cMET GCN <4 4: cMETΔ^ex14 mutation regardless of GCN Capmatinib 400 mg tablets will be administered twice daily on a continuous dosing schedule 12 hours apart. Primary and key secondary objectives are to evaluate overall response rate (ORR) and duration of response (DOR), respectively (assessed by blinded independent review). Other secondary objectives include investigator-assessed ORR, DOR, time to response, disease control rate, progression-free survival, safety, and pharmacokinetics. Enrollment is ongoing.

Clinical trial identification

EUDRACT 2014-003850-15

Disclosure

J. Wolf: Advisory boards (compensated) and lecture fees: AstraZeneca, BMS, Boehringer-Ingelheim, MSD, Clovis, Novartis, Pfizer, Roche. E.B. Garon: funds to institution for research sponsored by AstraZeneca, Bristol Myers Squibb, Eli Lilly, Heat, Genentech, Merck, Novartis, Pfizer. H.J.M. Groen: Advisory Board: Pfizer, MSD, Eli Lilly. R. Heist: consulting: Boehringer Ingelheim; research funding (to institution, not to myself): Genentech, Millenium, Debiopharm, Novartis, GSK, Celgene, Abbvie, Sanofi, Incyte, Mirati, Peregrine, Exelixis. E. Felip: Advisory Board: Eli Lilly, Pfizer, Roche, Boehringer Ingelheim, BMS, AstraZeneca and Novartis. N. Reguart: Advisory boards: Pfizer, Boehringuer, Roche, Lilly; research sponsored: Boehringuer, Pfizer. R. Soo: Advisory board: Astra-Zeneca, Boehringer Ingelheim, Merck, Novartis, Pfizer, Roche. L. Paz-Ares: Advisory board: Lilly, Pfizer, Novartis, Boehringer, Roche, Astra, Clovis, BMS. E.F. Smit: Advisory boards: Novartis dealing with ceretinib. M. Giovannini: NVS associate and own NVS stocks. M. Squires, Y. Zhang: employee of Novartis. X. Cui: employee of Novartis; stock ownership. D. Tan: Advisory Board: Novartis, Pfizer; research sponsored: Novartis. All other authors have declared no conflicts of interest.