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

Background Cohorts A, C, and E of the phase Ib KEYNOTE-651 study evaluated pembrolizumab+binimetinib±chemotherapy in MSS/pMMR mCRC. Patients and Methods Patients received pembrolizumab 200mg Q3W plus binimetinib 30mg BID alone (cohort A; previously treated with any chemotherapy) or with mFOLFOX7 (cohort C; previously untreated) or FOLFIRI (cohort E; previously treated with one line of therapy including fluoropyrimidine+oxaliplatin-based regimen) Q2W. Binimetinib dose-escalation to 45mg BID was planned in all cohorts using an mTPI design (target dose-limiting toxicity [DLT], 30%). The primary endpoint was safety; investigator-assessed ORR was secondary. Results In cohort A, 1/6 patients (17%) had DLTs with binimetinib 30mg; none occurred in 14 patients with 45mg. In cohort C, 3/9 patients (33%) had DLTs with binimetinib 30mg; dose was not escalated to 45mg. In cohort E, 1/5 patients (20%) had DLTs with binimetinib 30mg; 5/10 patients (50%) had DLTs with 45mg. Enrollment was stopped in cohort E binimetinib 45mg and deescalated to 30mg; 2/4 additional patients (50%) had DLTs with binimetinib 30mg (total 3/9 [33%] had DLTs with binimetinib 30mg). ORR was 0% in cohort A, 9% in cohort C, and 15% in cohort E. Conclusions Per DLT criteria, binimetinib+pembrolizumab (cohort A) was tolerable, binimetinib+pembrolizumab+mFOLFOX7 (cohort C) did not qualify for binimetinib dose escalation to 45mg, and binimetinib+pembrolizumab+FOLFIRI (cohort E) required binimetinib dose reduction from 45mg to 30mg. 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. MicroAbstract: Most patients with mCRC have MSS/pMMR tumors and have limited immunotherapy options. This study assessed immunotherapy-based combination therapy across different lines of therapy in MSS/pMMR mCRC. Addition of the MEK inhibitor binimetinib and the PD-1 inhibitor pembrolizumab to chemotherapy did not add to the efficacy of chemotherapy. These results do not support the use of binimetinib in this patient population. ClinicalTrials.gov Identifier: NCT03374254