Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2024 Jun;23(2):183-193.
doi: 10.1016/j.clcc.2024.03.002. Epub 2024 Apr 1.

Pembrolizumab Plus Binimetinib With or Without Chemotherapy for MSS/pMMR Metastatic Colorectal Cancer: Outcomes From KEYNOTE-651 Cohorts A, C, and E

Eric X Chen  1 , Petr Kavan  2 , Mustapha Tehfe  3 , Jeremy S Kortmansky  4 , Michael B Sawyer  5 , E Gabriela Chiorean  6 , Christopher H Lieu  7 , Blase Polite  8 , Lucas Wong  9 , Marwan Fakih  10 , Kristen Spencer  11 , Jorge Chaves  12 , Chenxiang Li  13 , Pierre Leconte  14 , David Adelberg  13 , Richard Kim  15
Affiliations
Clinical Trial

Pembrolizumab Plus Binimetinib With or Without Chemotherapy for MSS/pMMR Metastatic Colorectal Cancer: Outcomes From KEYNOTE-651 Cohorts A, C, and E

Eric X Chen et al. Clin Colorectal Cancer. 2024 Jun.

Abstract

Background: Cohorts A, C, and E of the phase Ib KEYNOTE-651 study evaluated pembrolizumab + binimetinib ± chemotherapy in microsatellite stable/mismatch repair-proficient metastatic colorectal cancer.

Patients and methods: Patients received pembrolizumab 200 mg every 3 weeks plus binimetinib 30 mg twice daily alone (cohort A; previously treated with any chemotherapy) or with 5-fluorouracil, leucovorin, oxaliplatin (cohort C; previously untreated) or 5-fluorouracil, leucovorin, irinotecan (cohort E; previously treated with 1 line of therapy including fluoropyrimidine + oxaliplatin-based regimen) every 2 weeks. Binimetinib dose-escalation to 45 mg twice daily was planned in all cohorts using a modified toxicity probability interval design (target dose-limiting toxicity [DLT], 30%). The primary endpoint was safety; investigator-assessed objective response rate was secondary.

Results: In cohort A, 1/6 patients (17%) had DLTs with binimetinib 30 mg; none occurred in 14 patients with 45 mg. In cohort C, 3/9 patients (33%) had DLTs with binimetinib 30 mg; dose was not escalated to 45 mg. In cohort E, 1/5 patients (20%) had DLTs with binimetinib 30 mg; 5/10 patients (50%) had DLTs with 45 mg. Enrollment was stopped in cohort E binimetinib 45 mg and deescalated to 30 mg; 2/4 additional patients (50%) had DLTs with binimetinib 30 mg (total 3/9 [33%] had DLTs with binimetinib 30 mg). Objective response rate was 0% in cohort A, 9% in cohort C, and 15% in cohort E.

Conclusion: Per DLT criteria, binimetinib + pembrolizumab (cohort A) was tolerable, binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, oxaliplatin (cohort C) did not qualify for binimetinib dose escalation to 45 mg, and binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, irinotecan (cohort E) required binimetinib dose reduction from 45 to 30 mg. No new safety findings were observed across cohorts. There was no apparent additive efficacy when binimetinib + pembrolizumab was added to chemotherapy. Data did not support continued enrollment in cohorts C and E.

Keywords: Binimetinib; Colorectal cancer; Microsatellite stable; Mismatch repair-proficient; Pembrolizumab.

PubMed Disclaimer

Conflict of interest statement

Disclosure E. X. Chen reports advisory/consultancy roles from AstraZeneca, Eisai, and GSK; research funding to their institution from AstraZeneca, Merck & Co., Inc., Rahway, NJ, USA, BMS, Novartis, Roche, Zymeworks, and 1Globe. P. Kavan reports advisory/consultancy role with Merck; Expert Testimony for Merck & Co., Inc., Rahway, NJ, USA; and an institutional educational grant to their institution. M. Tehfe reports advisory/consultancy roles with Merck & Co., Inc., Rahway, NJ, USA, BMS, Taiho, and Pfizer; and speaker bureau for BMS and Taiho. J. S. Kortmansky reports research funding to their institution from Merck & Co., Inc., Rahway, NJ, USA and Genentech. M. B. Sawyer reports honoraria from Ipsen, BMS, Mylan, Amgen, AstraZeneca, Eisai, Sandoz, Celgene, Servier, Novartis, Leo, Taiho, and Shire; advisory/consultancy roles with AstraZeneca, Leo, and Immuneering; expert testimony for AstraZeneca; research funding to their institution from AstraZeneca and BMS; and travel/accommodation expenses from Ipsen. E. G. Chiorean reports advisory/consultancy roles with Astellas, Bayer, Cardiff, Foundation, G1 Therapeutics, Ipsen, Noxxon, Novartis, Merck & Co., Inc., Rahway, NJ, USA, Pfizer, and Stemline; research funding to their institution from Aadi, Biosplice, BioMed Valley, Boehringer-Ingelheim, Clovis, Corcept, Erasca, Fibrogen, Lona, Merck & Co., Inc., Rahway, NJ, USA, Novartis, Rafael, and Stemline; and travel/accommodation from G1 Therapeutics. C. H. Lieu reports research funding to their institution from Merck & Co., Inc., Rahway, NJ, USA. M. Fakih reports advisory/consultancy roles with AstraZeneca, Bayer, Bristol Myers Squibb, GlaxoSmithKline, Incyte, Mirati, Nouscom, PsiOxus, Roche/Genentech, and Taiho. K. Spencer reports advisory/consultancy roles from QED Therapeutics, Helsinn, Lynx Group, and Caris. C. Li, P. Leconte, and D. Adelberg report employment with Merck & Co., Inc., Rahway, NJ, USA; P. Leconte and D. Adelberg report stock ownership at Merck & Co., Inc., Rahway, NJ, USA. R. Kim reports honoraria from Taiho; advisory/consultancy roles with Bayer Servier, Ipsen and Roche; and speaker bureau for Eisai, Pfizer, and Incyte. B. Polite, L. Wong, and J. Chaves report no conflicts of interest.

Publication types

MeSH terms