As reported in The New England Journal of Medicine, the second interim analysis of the phase III KEYNOTE-177 trial has shown significantly prolonged progression-free survival with pembrolizumab vs fluorouracil (5-FU)-based chemotherapy as first-line treatment of patients with advanced microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) colorectal cancer. The study was reported by Thierry André, MD, and colleagues. The trial supported the June 2020 approval of pembrolizumab for first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer.

Thierry André, MD

Study Details

In the open-label trial, 307 patients with measurable disease from 192 sites in 23 countries were randomly assigned between February 2016 and February 2018 to receive pembrolizumab at 200 mg every 3 weeks (n = 153) or investigator’s choice of chemotherapy selected prior to random assignment (n = 154). Chemotherapy options consisted of mFOLFOX6 (oxaliplatin, leucovorin, 5-FU) alone (n = 11) or combined with bevacizumab (n = 64) or cetuximab (n = 5) and FOLFIRI (leucovorin, 5-FU, irinotecan) alone (n =16) or combined with bevacizumab (n = 36) or cetuximab (n = 11). Chemotherapy regimens were repeated every 2 weeks. Treatment was continued for a maximum of 35 doses of pembrolizumab or until disease progression, unacceptable toxicity, illness, or physician or patient decision to withdraw from the trial. A total of 153 patients in the pembrolizumab group and 143 in the chemotherapy group received at least one dose of trial treatment (as-treated population). The primary endpoints were disease progression on Response Evaluation Criteria in Solid Tumors version 1.1 confirmed by blinded independent central review and overall survival in the intention-to-treat population. Patients receiving chemotherapy could cross over to pembrolizumab after disease progression.

Progression-Free and Overall Survival

At data cutoff in February 2020, the median follow-up was 32.4 months (range = 24.0–48.3 months).

Median progression-free survival was 16.5 months (95% confidence interval [CI] = 5.4–32.4 months) in the pembrolizumab group vs 8.2 months (95% CI = 6.1–10.2 months) in the chemotherapy group (hazard ratio [HR] = 0.60, 95% CI = 0.45–0.80, P = .0002). Progression-free survival rates at 12 and 24 months were 55.3% vs 37.3% and 48.3% vs 18.6%. Estimated restricted mean survival time for progression-free survival after 24 months of follow-up (analyzed due to violation of proportional hazards assumption) was 13.7 months (range = 12.0­–15.4 months) vs 10.8 months (range = 9.4–12.2 months). Hazard ratios favored pembrolizumab in virtually all subgroups evaluated.

At the time of data cutoff, 56 patients in the chemotherapy group (36%) had crossed over to receive pembrolizumab. An additional 35 patients received anti–PD-1 or anti­–PD-L1 therapy outside of the trial, yielding an overall crossover rate to anti–PD-1 or anti–PD-L1 therapy of 59% in the intention-to-treat population. Overall survival data at data cutoff were not mature, with 66% of events required for analysis having occurred; death had occurred in 56 patients in the pembrolizumab group and 69 in the chemotherapy group.

An objective response was observed in 43.8% vs 33.1% of patients, with a complete response in 11.1% vs 3.9%. The median duration of response was not reached (range = 2.3+ to 41.4+ months) vs 10.6 months (range = 2.8–37.5+ months), with a response persisting for at least 24 months in 82.6% vs 35.3% of responders.

Adverse Events

Grade ≥ 3 adverse events occurred in 56% of patients in the pembrolizumab group vs 78% in the chemotherapy group. The most common adverse events in the pembrolizumab group were hypertension (7% vs 5% in chemotherapy group), diarrhea (6% vs 11%), abdominal pain (5% vs 6%), and anemia (5% vs 10%). The most common adverse events in the chemotherapy group were decreased neutrophil count (17% vs 0% in the pembrolizumab group), neutropenia (15% vs 0%), diarrhea, and anemia. Adverse events led to discontinuation of treatment in 14% vs 12% of patients. Adverse events led to death in six patients (4%) vs seven patients (5%), with one death in the chemotherapy group considered related to treatment. Treatment-related adverse events of any grade occurred in 80% vs 99% of patients and were of grade ≥ 3 in 22% vs 66%.

Immune-mediated adverse events or infusion reactions occurred in 47 patients (31%) in the pembrolizumab group vs 18 (13%) in the chemotherapy group and were of grade 3 or 4 in 14 (9%) vs 3 (2%).

The investigators concluded: “Pembrolizumab led to significantly longer progression-free survival than chemotherapy when received as first-line therapy for MSI-H/dMMR metastatic colorectal cancer, with fewer treatment-related adverse events.”

Disclosure: The study was funded by Merck Sharp and Dohme and Stand Up to Cancer. For full disclosures of the study authors, visit nejm.org.