BACKGROUND: Chemotherapy is currently the standard of care for patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) colorectal cancer (CRC); however, some patients have disease that is refractory to chemotherapy. Programmed-cell death (PD)-1 inhibitors have emerged as a highly effective therapy in this setting.
METHODS: KEYNOTE-177 was a multicenter, international, open-label, phase 3 study that enrolled 307 treatment-naïve patients with metastatic MSI-H or dMMR CRC. Patients were randomized in a 1:1 ratio to pembrolizumab 200 mg every 3 weeks or to chemotherapy with 5-fluorouracil–based therapy (with or without bevacizumab or cetuximab) every 2 weeks. Crossover from chemotherapy to pembrolizumab was allowed after disease progression. The median duration of patients’ exposure to treatment was 11.1 months in the pembrolizumab group and 5.7 months in the chemotherapy group. Pembrolizumab therapy was continued for a maximum of 35 treatments or until disease progression, unacceptable side effects, illness, or withdrawal. The primary end points were progression-free survival (PFS) and overall survival.
RESULTS: After a median follow-up of 32.4 months, PFS was doubled in the pembrolizumab group compared with the chemotherapy group, for a median of 16.5 months versus 8.2 months, respectively (hazard ratio, 0.60; P = .0002). More patients were alive and progression-free at 12 months and at 24 months in the pembrolizumab group (55.3% and 48.3%, respectively) compared with the chemotherapy group (37.3% and 18.6%, respectively). “After an initial crossing of the progression-free survival Kaplan–Meier curves, a pronounced separation of the curves for pembrolizumab and chemotherapy was observed, which indicated a meaningful long-term benefit with pembrolizumab,” the researchers noted. As of the data cutoff date, 56 patients in the pembrolizumab group and 69 patients in the chemotherapy group had died. Data on overall survival were still evolving and remain blinded until the final analysis. The overall (partial or complete) response was 43.8% in the pembrolizumab group versus 33.1% in the chemotherapy group. The overall ongoing response rate at 24 months was also greater in the pembrolizumab group (83%) compared with the chemotherapy group (35%). The incidence of grade 3 or 4 adverse events was lower with pembrolizumab (56%) versus chemotherapy (78%). In addition, patients in the PD-1 inhibitor group had fewer treatment-related adverse events (22%) than in the chemotherapy group (66%), and 1 death was reported in the chemotherapy group. “These data represent another step forward for biomarker-driven studies targeting MSI-H–dMMR colorectal cancers….Pembrolizumab should be considered an option for initial therapy for patients with MSI-H–dMMR metastatic colorectal cancer,” the authors noted.
Source: André T, Shiu KK, Kim TW, et al; for the KEYNOTE-177 investigators. Pembrolizumab in microsatellite-instability–high advanced colorectal cancer. N Engl J Med. 2020;383:2207-2218.