Molecular correlates of response to capmatinib in advanced non-small-cell lung cancer: clinical and biomarker results from a phase I trial.

BACKGROUND

Dysregulation of receptor tyrosine kinase MET by various mechanisms occurs in 3%-4% of non-small-cell lung cancer (NSCLC) and is associated with unfavorable prognosis. While MET is a validated drug target in lung cancer, the best biomarker strategy for the enrichment of a susceptible patient population still remains to be defined. Towards this end we analyze here primary data from a phase I dose expansion study of the MET inhibitor capmatinib in patients with advanced MET-dysregulated NSCLC.

PATIENTS AND METHODS

Eligible patients [≥18 years; Eastern Cooperative Oncology Group (ECOG) performance status ≤2] with MET-dysregulated advanced NSCLC, defined as either (i) MET status by immunohistochemistry (MET IHC) 2+ or 3+ or H-score ≥150, or MET/centromere ratio ≥2.0 or gene copy number (GCN) ≥5, or (ii) epidermal growth factor receptor wild-type (EGFRwt) and centrally assessed MET IHC 3+, received capmatinib at the recommended dose of 400 mg (tablets) or 600 mg (capsules) b.i.d. The primary objective was to determine safety and tolerability; the key secondary objective was to explore antitumor activity. The exploratory end point was the correlation of clinical activity with different biomarker formats.

RESULTS

Of 55 patients with advanced MET-dysregulated NSCLC, 40/55 (73%) had received two or more prior systemic therapies. All patients discontinued treatment, primarily due to disease progression (69.1%). The median treatment duration was 10.4 weeks. The overall response rate per RECIST was 20% (95% confidence interval, 10.4-33.0). In patients with MET GCN ≥6 (n = 15), the overall response rate by both the investigator and central assessments was 47%. The median progression-free survival per investigator for patients with MET GCN ≥6 was 9.3 months (95% confidence interval, 3.8-11.9). Tumor responses were observed in all four patients with METex14. The most common toxicities were nausea (42%), peripheral edema (33%), and vomiting (31%).

CONCLUSIONS

MET GCN ≥6 and/or METex14 are suited to predict clinical activity of capmatinib in patients with NSCLC (NCT01324479).

Informations de copyright

Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

Disclosure MS reports grants and personal fees from AstraZeneca (AZ), Boehringer Ingelheim (BI), Bristol-Myers Squibb (BMS), Novartis; and personal fees from Celgene, Lilly, Merck Sharp & Dohme GmbH (MSD), Pierre Fabre, Roche, AbbVie, Alexion, outside the submitted work. RB reports personal fees from Otsuka, outside the submitted work. W-TL reports personal fees (advisory role) from Novartis. TMB reports personal fees (consulting or advisory role) from Ignyta, Guardant Health, Loxo, Pfizer, Moderna Therapeutics; personal fees (speakers' bureau) from Bayer; and research funding: Daiichi Sankyo, MedPacto, Inc., Incyte, Mirati Therapeutics, MedImmune, AbbVie, AZ, Leap Therapeutics, MabVax, Stemline Therapeutics, Merck, Lilly, GSK, Novartis, Pfizer, Genentech/Roche, Deciphera, Merrimack, ImmunoGen, Millennium, Ignyta, Calithera Biosciences, Kolltan Pharmaceuticals, Principia Biopharma, Peloton, Immunocore, Roche, Aileron Therapeutics, BMS, Amgen, Moderna Therapeutics, Sanofi, BI, Astellas Pharma, Five Prime Therapeutics, Jacobio, Top Alliance BioSciences, Loxo, Janssen, Clovis Oncology, Takeda, Karyopharm Therapeutics, Onyx, Phosplatin Therapeutics, and Foundation Medicine. DHL reports personal fees from AZ, BI, BMS, CJ Healthcare, Eli Lilly, ChongKeunDang, Janssen, Merck, MSD, Mundipharma, Novartis, Ono, Pfizer, Roche, Samyang Biopharm, ST Cube, AbbVie, and Takeda, outside the submitted work. MW reports personal fees from MSD, BMS, BI, Hoffmann-La Roche, Pfizer, Takeda, and Novartis, outside the submitted work. DSH reports research grants from Novartis during the conduct of the study; research grants from AbbVie, Amgen, AZ, BMS, Daiichi Sankyo, Eisai, Fate Therapeutics, Genmab, Ignyta, Kite, Kyowa, Lilly, Merck, MedImmune, Mirati Therapeutics, Molecular Templates, Mologen, NCI-CTEP, Pfizer; research grants and personal fees (advisory role) from Adaptimmune, Bayer, Genentech, Infinity, Seattle Genetics, Takeda; grants and non-financial support (travel) from Loxo, MiRNA; and personal fees (advisory role) from Alpha Insights, Axiom, Baxter, GLG, groupH, Guidepoint Global, Janssen, Merrimack, Medscape, Numab, Trieza Therapeutics, Molecular Match, Presagia Inc., OncoResponse, outside the submitted work. MA, SG, XC, MGi, and NN are employees of Novartis; MA, SG, XC, and NN also own stock in Novartis. TMK reports research grant from AZ, outside the submitted work. All remaining authors have declared no conflicts of interest.