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
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.
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.The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.