The FDA has approved pembrolizumab (Keytruda) for the first-line treatment of patients with unresectable or metastatic microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) colorectal cancer. Approval was based on KEYNOTE‑177, a multicentre, international, open-label, active-controlled, randomized trial that enrolled 307 patients with previously untreated, unresectable or metastatic MSI-H or dMMR colorectal cancer. Determination of MSI or MMR tumor status was made locally using polymerase chain reaction or immunohistochemistry, respectively.
Patients were randomly assigned 1:1 to receive pembrolizumab at 200 mg intravenously every three weeks or investigator’s choice of modified FOLFOX6 (fluorouracil [5-FU], leucovorin, and oxaliplatin) or FOLFIRI (5-FU, leucovorin, and irinotecan), with or without bevacizumab or cetuximab, given intravenously every two weeks. Patients randomly assigned to receive chemotherapy were offered pembrolizumab at the time of disease progression.
The main efficacy outcome measures were progression-free survival and overall survival. Median progression-free survival was 16.5 months (95% confidence interval [CI] = 5.4–32.4) in the pembrolizumab arm and 8.2 months (95% CI = 6.1–10.2) in the chemotherapy arm (hazard ratio [HR] = 0.60, 95% CI = 0.45–0.80, two-sided p=0.0004). At the time of the progression-free survival analysis, the overall survival data were not mature.
The most common adverse reactions reported in ≥ 20% of patients receiving pembrolizumab as a single agent were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhoea, nausea, rash, pyrexia, cough, dyspnoea, constipation, pain, and abdominal pain.
The recommended pembrolizumab dose for patients with MSI-H/dMMR colorectal cancer is 200mg every three weeks or 400 mg every six weeks.