Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study

Abstract

Background: Pembrolizumab has demonstrated superior progression-free survival (PFS) versus chemotherapy in newly-diagnosed MSI-H/dMMR metastatic colorectal cancer (mCRC). However, its impact on overall survival (OS) in this cohort of patients was unknown. Here we present the final OS analysis of KEYNOTE-177. Methods: The phase 3, open-label study involved 193 sites in 23 countries. Patients aged at least 18 years, with Eastern Cooperative Oncology Group performance status of 0 or 1, and who had newly-diagnosed MSI-H/dMMR mCRC were randomized 1:1 in blocks of four per stratum using an interactive voice response system /integrated web response system to intravenous pembrolizumab 200 mg every 3 weeks or to investigator’s choice of intravenous mFOLFOX6 or FOLFIRI every 2 weeks with or without intravenous bevacizumab 5 mg/kg every 2 weeks or intravenous cetuximab (first dose 400 mg/m2, then 250 mg/m2 for every subsequent dose) weekly. Patients receiving chemotherapy could cross over to pembrolizumab for 35 treatments after progression. Dual-primary endpoints were OS and PFS in the intention-to-treat population. KEYNOTE-177 is registered at ClinicalTrials.gov NCT02563002 and is no longer enrolling patients. Findings: Between February 11, 2016 and February 19, 2018, 307 patients were randomized to pembrolizumab (n = 153) or chemotherapy (n = 154). Sixty percent of patients crossed over from chemotherapy to anti-PD-1/anti-PD-L1 therapy (56 patients to on-study pembrolizumab, 37 patients to off-study therapy). At final analysis (median follow-up of 44.5 months [IQR, 39.7–49.8]), the hazard ratio [HR] for OS was 0.74 (95% confidence interval [CI] 0.53–1.03; P=0.0359; median not reached [95% CI 49.2-not reached] versus 36.7 months [95% CI, 27.6-not reached]) with pembrolizumab versus chemotherapy. Superiority of pembrolizumab versus chemotherapy for OS was not demonstrated as the prespecified α of 0.0246 needed for statistical significance was not achieved. The updated HR for PFS was 0.59 (95% CI 0.45–0.79; median 16.5 [95% CI 5.4–38.1] versus 8.2 months [95% CI 6.1–10.2]). Serious adverse events occurred in 62 of 153 (41%) patients who received pembrolizumab and 75 of 143 (52%) patients who received chemotherapy. Grade ≥3 treatment-related adverse events occurred in 33 of 153 (22%) versus 95 of 143 (66%) patients, respectively. Common grade ≥3 adverse events attributed to pembrolizumab were increased alanine aminotransferase, colitis, diarrhea, and fatigue in 3 of 153 (2%) patients each, and to chemotherapy were decreased neutrophil count (24 of 143 [17%] patients), neutropenia (22 of 143 [15%]), diarrhea (14 of 143 [10%]), and fatigue (13 of 143 [9%]). No deaths attributed to pembrolizumab occurred; one death due to intestinal perforation was attributed to chemotherapy. Interpretation: Pembrolizumab versus chemotherapy continued to provide durable antitumor activity, with no significant difference in OS, and fewer treatment-related events. These findings support pembrolizumab as effective first-line therapy in patients with MSI-H/dMMR mCRC.