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; Petr Kavan; Mustapha Tehfe; Jeremy S Kortmansky; Michael B Sawyer; E Gabriela Chiorean; Christopher H Lieu; Blase Polite; Lucas Wong; Marwan Fakih; Kristen Spencer; Jorge Chaves; Chenxiang Li; Pierre Leconte; David Adelberg; Richard Kim

doi:10.1016/j.clcc.2024.03.002

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

Clin Colorectal Cancer. 2024 Apr 1:S1533-0028(24)00024-0. doi: 10.1016/j.clcc.2024.03.002. Online ahead of print.

Authors

Eric X Chen¹, Petr Kavan², Mustapha Tehfe³, Jeremy S Kortmansky⁴, Michael B Sawyer⁵, E Gabriela Chiorean⁶, Christopher H Lieu⁷, Blase Polite⁸, Lucas Wong⁹, Marwan Fakih¹⁰, Kristen Spencer¹¹, Jorge Chaves¹², Chenxiang Li¹³, Pierre Leconte¹⁴, David Adelberg¹³, Richard Kim¹⁵

Affiliations

¹ Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON M5G 2C1, Canada. Electronic address: eric.chen@uhn.ca.
² Department of Medicine and Oncology, Sir Mortimer B. Davis Jewish General Hospital, Segal Cancer Centre, McGill University, Montreal, QC H3T 1E2, Canada.
³ Hematology and Medical Oncology Division, Centre Hospitalier Universitaire de Montreal, University of Montreal, Montreal, QC H2X 0C1, Canada.
⁴ Section of Medical Oncology, Yale Cancer Center, New Haven, CT.
⁵ Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, Canada.
⁶ Division of Medical Oncology, Department of Medicine, University of Washington and Fred Hutchinson Cancer Center, Clinical Research Division, Seattle, WA.
⁷ Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO.
⁸ Department of Hematology and Oncology, University of Chicago, Chicago, IL.
⁹ Division of Hematology and Oncology, Baylor Scott and White, Temple, TX.
¹⁰ Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA.
¹¹ Department of Medicine, Perlmutter Cancer Center of NYU Langone Health and Department of Internal Medicine NYU Grossman School of Medicine, New York, NY.
¹² Medical Oncology, Northwest Medical Specialties, PLLC, Tacoma, WA.
¹³ Merck & Co., Inc., Rahway, NJ.
¹⁴ MSD France, Puteaux 92800, France.
¹⁵ Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL.

PMID: 38653648
DOI: 10.1016/j.clcc.2024.03.002

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.