Pembrolizumab Does Not Improve OS Over Chemotherapy in Patients With Colorectal Cancer: KEYNOTE-177

Superior overall survival (OS) for pembrolizumab over chemotherapy was not established among patients with previously untreated microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer in the phase 3 KEYNOTE-177 study.

“In this updated analysis, although pembrolizumab continued to show durable antitumour activity and fewer treatment-related adverse events compared with chemotherapy, there was no significant difference in [OS] between the [2] treatment groups,” wrote lead author Luis Diaz, Jr, MD, Memorial Sloan Kettering Cancer Center, New York City, and coauthors.

The open-label study enrolled 307 patients from 193 academic medical centers and hospitals in 23 countries. Eligible patients had an Eastern Cooperative Oncology Group performance status of 0 or 1.

Patients were randomized to intravenous (IV) pembrolizumab 200 mg every 3 weeks or investigator's choice of IV mFOLFOX6 (oxaliplatin 85 mg/m² on day 1, leucovorin 400 mg/m² on day 1, and fluorouracil 400 mg/m² bolus on day 1 followed by a continuous infusion of 1200 mg/m² per day for 2 days on days 1–2) or IV FOLFIRI (irinotecan 180 mg/m² on day 1, leucovorin 400 mg/m² on day 1, and fluorouracil 400 mg/m² bolus on day 1 followed by a continuous infusion of 1200 mg/m² per day for 2 days on days 1–2), every 2 weeks with or without IV bevacizumab 5 mg/kg every 2 weeks or IV weekly cetuximab (first dose 400 mg/m², then 250 mg/m² for every subsequent dose).

After disease progression, 60% of patients crossed over from chemotherapy to anti-PD-1 or anti-PD-L1 therapy.

The median OS was not reached (NR; 95% CI 49.2 to NR) with pembrolizumab vs 36.7 months (27.6 to NR) with chemotherapy (hazard ratio [HR] 0.74; 95% CI 0.53 to 1.03; P = .036), but the threshold for statistical significance had been prespecified as .025.

In the pembrolizumab arm, median progression-free survival was almost twice as long, 16.5 months (95% CI 5.4 to 38.1), compared with 8.2 months (6.1 to 10.2) in those who received chemotherapy (HR 0.59, 95% CI 0.45 to 0.79).

Grade 3 or higher treatment-related adverse events occurred in less than a quarter (22%) of the pembrolizumab group versus 66% of the chemotherapy group. No deaths attributed to pembrolizumab occurred, but 1 death due to intestinal perforation was attributed to chemotherapy.

Source:
Diaz L, Shiu K, Kim T, et al. 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. Lancet Oncology. Published online April 12, 2022. doi:10.1016/S1470-2045(22)00197-8.