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

Background The phase 1b KEYNOTE-651 study evaluated pembrolizumab plus chemotherapy in microsatellite stable or mismatch repair-proficient (MSS/pMMR) metastatic colorectal cancer (mCRC). Patients and Methods Patients with MSS/pMMR mCRC received pembrolizumab 200 mg every 3 weeks plus mFOLFOX7 (previously untreated; cohort B) or FOLFIRI (previously treated with fluoropyrimidine plus oxaliplatin; cohort D) every 2 weeks. Primary end point was safety; investigator-assessed objective response rate (ORR) 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 3/4 treatment-related adverse events (AEs) occurred in 18 patients (58%), most commonly neutropenia and decreased neutrophil count (n = 5 each). In cohort D, grade 3/4 treatment-related AEs occurred in 17 patients (53%), most commonly neutropenia (n = 7). No grade 5 treatment-related AEs occurred. ORR 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 non-responders. No association between tumor mutational burden and response was observed. Conclusions Pembrolizumab plus mFOLFOX7/FOLFIRI 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. ClinicalTrials.gov Identifier ClinicalTrials.gov; NCT03374254