PERSPECTIVE: Tepotinib plus cetuximab in patients with RAS/BRAF wild-type left-sided metastatic colorectal cancer and acquired resistance to anti-EGFR antibody therapy due to MET amplification

Background MET amplification (METamp) is a secondary, or co-driving, genetic change in patients with metastatic colorectal cancer (mCRC) and acquired resistance to anti-EGFR therapy, which can contribute to disease progression. In EGFR-resistant patients with mCRC and METamp, MET inhibition plus an anti-EGFR agent may achieve disease control by targeting emerging MET pathway activation and maintaining EGFR pathway inhibition. Tepotinib is an oral, once-daily, highly selective, potent MET tyrosine kinase inhibitor (TKI), recently approved in the US and Japan for NSCLC harboring MET exon 14 skipping. Tepotinib plus gefitinib has shown improved outcomes in patients with EGFR-mutant METamp NSCLC and acquired EGFR TKI resistance versus chemotherapy (INSIGHT: NCT01982955). In these patients, progression-free survival (PFS) was 16.6 vs 4.2 months (HR=0.13; 90% CI: 0.04, 0.43) and overall survival (OS) was 37.3 vs 13.1 months (HR=0.08; 90% CI: 0.01, 0.51). In patients with mCRC and acquired resistance to anti-EGFR antibody therapy due to METamp, tepotinib plus anti-EGFR antibody cetuximab may be active and provide an effective therapeutic option. Trial design This Phase II, multicenter, single-arm, open-label study will assess preliminary safety and tolerability, antitumor activity, and explore pharmacokinetic profiles of tepotinib plus cetuximab in patients with RAS/BRAF wild-type left-sided mCRC, and acquired resistance to anti-EGFR antibody-targeted therapy due to METamp (NCT04515394). After a safety run-in period (6–12 patients; endpoint: dose-limiting toxicities), the Safety Monitoring Committee will determine the recommended Phase II dose (RP2D) of tepotinib to be used in combination with cetuximab). Enrollment is based on a confirmed advanced left-sided CRC diagnosis (RAS/BRAF wild-type), documented previous anti-EGFR therapy and acquired resistance on the most recent anti-EGFR antibody, and METamp confirmed by liquid and/or tissue biopsy. Patients must be ≥18 years old, have an Eastern Cooperative Oncology Group performance status of 0/1 and normal organ function. The study will screen approximately 340 patients to account for METamp heterogeneity in this treatment setting. The study is being conducted at centers in Belgium, Czech Republic, France, Italy, Russia, Spain, the UK, and the US. As of March 2021, there are 15 active centers in Spain (7 centers), France (5 centers) and the US (3 centers). Approximately 42 patients are planned to receive study treatment at the RP2D: ∼22 in Cohort A (second-line, outside the US) and 20 in Cohort B (≥third-line, US only). Primary endpoint: investigator-assessed objective response (RECIST 1.1). Secondary endpoints are investigator-assessed duration of response (DoR), progression-free survival (PFS) (RECIST 1.1), overall survival, tolerability and safety (adverse event grading will be based on NCI-CTCAE v5.0), and cetuximab immunogenicity (measured by antidrug antibody assays at the start and end of treatment). Additional endpoints include assessment of tepotinib and cetuximab pharmacokinetic profiles, and expression of resistance biomarkers related to MET (from blood and/or tissue samples). Retrospective assessment of best overall response, DoR, and PFS by an independent review committee may be conducted. No formal statistical hypothesis will be tested in this exploratory study. Clinical trial identification NCT04515394. Editorial acknowledgement Medical writing assistance (funded by Merck KGaA, Darmstadt, Germany) was provided by Syneos Health, London, UK. Legal entity responsible for the study Merck KGaA, Darmstadt, Germany. Funding Merck KGaA, Darmstadt, Germany. Disclosure J. Tabernero: Honoraria (self): educational collaboration with Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER); Advisory / Consultancy: Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics and TheraMyc. R. Garcia-Carbonero: Honoraria (self): Hospital Universitario 12 de Octubre; Research grant / Funding (institution): Hospital Universitario 12 de Octubre; Travel / Accommodation / Expenses: Hospital Universitario 12 de Octubre. G. Finley: Speaker Bureau / Expert testimony: BMS, AstraZeneca. J. Strickler: Advisory / Consultancy: AbbVie, Bayer, Pfizer; Research grant / Funding (institution): Amgen, Roche/Genentech, Seagen. F. Beier: Full / Part-time employment: Merck. S. Salim: Full / Part-time employment: Merck KGaA, Darmstadt, Germany. R. Esser: Shareholder / Stockholder / Stock options: Merck KGaA, Merck, Merck; Full / Part-time employment: Merck Heathcare KGaA. S. Adrian: Full / Part-time employment: Merck KGaA. C. López-López: Advisory / Consultancy: Merck; Speaker Bureau / Expert testimony: Merck Research grant / Funding (self): Merck Research grant / Funding (institution): Merck; Travel / Accommodation / Expenses: Merck. All other authors have declared no conflicts of interest.