Pembrolizumab Plus mFOLFOX7 or FOLFIRI for Microsatellite Stable/Mismatch Repair-Proficient Metastatic Colorectal Cancer: KEYNOTE-651 Cohorts B and D

Richard Kim; Mustapha Tehfe; Petr Kavan; Jorge Chaves; Jeremy S Kortmansky; Eric X Chen; Christopher H Lieu; Lucas Wong; Marwan Fakih; Kristen Spencer; Qing Zhao; Raluca Predoiu; Chenxiang Li; Pierre Leconte; David Adelberg; E Gabriela Chiorean

doi:10.1016/j.clcc.2024.03.001

Pembrolizumab Plus mFOLFOX7 or FOLFIRI for Microsatellite Stable/Mismatch Repair-Proficient Metastatic Colorectal Cancer: KEYNOTE-651 Cohorts B and D

Clin Colorectal Cancer. 2024 Apr 1:S1533-0028(24)00023-9. doi: 10.1016/j.clcc.2024.03.001. Online ahead of print.

Authors

Richard Kim¹, Mustapha Tehfe², Petr Kavan³, Jorge Chaves⁴, Jeremy S Kortmansky⁵, Eric X Chen⁶, Christopher H Lieu⁷, Lucas Wong⁸, Marwan Fakih⁹, Kristen Spencer¹⁰, Qing Zhao¹¹, Raluca Predoiu¹¹, Chenxiang Li¹¹, Pierre Leconte¹², David Adelberg¹³, E Gabriela Chiorean¹⁴

Affiliations

¹ Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL. Electronic address: richard.kim@moffitt.org.
² Hematology and Medical Oncology Division, Centre Hospitalier de l'Université de Montréal, Montréal, Canada.
³ Department of Medicine and Oncology, Sir Mortimer B. Davis Jewish General Hospital, Segal Cancer Centre, McGill University, Montreal, Canada.
⁴ Medical Oncology, Northwest Medical Specialties, Tacoma, WA.
⁵ Section of Medical Oncology, Yale Cancer Center, New Haven, CT.
⁶ Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada.
⁷ Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO.
⁸ Division of Hematology and Oncology, Baylor Scott and White, Temple, TX.
⁹ Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA.
¹⁰ Department of Medicine, Perlmutter Cancer Center of NYU Langone Health and Department of Internal Medicine NYU Grossman School of Medicine, New York, NY.
¹¹ Department of Medical Oncology, BARDS, Merck & Co., Inc., Rahway, NJ.
¹² Department of Medical Oncology, MSD France, Puteaux, France.
¹³ Department of Medical Oncology, Merck & Co., Inc., Rahway, NJ.
¹⁴ Division of Medical Oncology, Department of Medicine, University of Washington and Fred Hutchinson Cancer Center, Clinical Research Division, Seattle, WA.

PMID: 38762348
DOI: 10.1016/j.clcc.2024.03.001

Abstract

Background: The phase 1b KEYNOTE-651 study evaluated pembrolizumab plus chemotherapy in microsatellite stable or mismatch repair-proficient metastatic colorectal cancer.

Patients and methods: Patients with microsatellite stable or mismatch repair-proficient metastatic colorectal cancer received pembrolizumab 200 mg every 3 weeks plus 5-fluorouracil, leucovorin, oxaliplatin (previously untreated; cohort B) or 5-fluorouracil, leucovorin, irinotecan (previously treated with fluoropyrimidine plus oxaliplatin; cohort D) every 2 weeks. Primary end point was safety; investigator-assessed objective response rate per RECIST v1.1 was secondary and biomarker analysis was exploratory.

Results: Thirty-one patients were enrolled in cohort B and 32 in cohort D; median follow-up was 30.2 and 33.5 months, respectively. One dose-limiting toxicity (grade 3 small intestine obstruction) occurred in cohort D. In cohort B, grade 3 or 4 treatment-related adverse events (AEs) occurred in 18 patients (58%), most commonly neutropenia and decreased neutrophil count (n = 5 each). In cohort D, grade 3 or 4 treatment-related AEs occurred in 17 patients (53%), most commonly neutropenia (n = 7). No grade 5 treatment-related AEs occurred. Objective response rate was 61% in cohort B (KRAS wildtype: 71%; KRAS mutant: 53%) and 25% in cohort D (KRAS wildtype: 47%; KRAS mutant: 6%). In both cohorts, PD-L1 combined positive score and T-cell-inflamed gene expression profiles were higher and HER2 expression was lower in responders than nonresponders. No association between tumor mutational burden and response was observed.

Conclusion: Pembrolizumab plus 5-fluorouracil, leucovorin, oxaliplatin/5-fluorouracil, leucovorin, irinotecan demonstrated an acceptable AE profile. Efficacy data appeared comparable with current standard of care (including by KRAS mutation status). Biomarker analyses were hypothesis-generating, warranting further exploration.

Gov identifier: ClinicalTrials.gov; NCT03374254.

Keywords: CRC; Chemotherapy; Microsatellite stable; Mismatch repair-proficient; Pembrolizumab.

Associated data

ClinicalTrials.gov/NCT03374254