As reported in The New England Journal of Medicine by Thierry André, MD, of Sorbonne Université and Hôpital Saint Antoine, Paris, and colleagues, the second interim analysis of the phase III KEYNOTE-177 trial has shown significantly prolonged progression-free survival with
Thierry André, MD
pembrolizumab vs fluorouracil (5-FU)-based chemotherapy as first-line treatment of patients with advanced microsatellite instability (MSI)-high or mismatcha repair–deficient colorectal cancer.1 The trial supported the June 2020 approval of pembrolizumab for the first-line treatment of patients with unresectable or metastatic MSI-high or mismatch repair–deficient colorectal cancer.
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 randomization (n = 154). Chemotherapy options consisted of modified FOLFOX6 (5-FU, leucovorin, oxaliplatin) alone (n = 11) or combined with bevacizumab (n = 64) or cetuximab (n = 5) and FOLFIRI (5-FU, leucovorin, 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 v1.1 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, 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 at 12 and 24 months was 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 every subgroup evaluated except among the 74 patients with KRAS or NRAS mutation (HR = 1.19, 95% CI = 0.68–2.07; HR = 0.44, 95% CI = 0.29–0.67 among 151 with wild-type). Hazard ratios were 0.52 (95% CI = 0.37–0.75) among patients aged ≤ 70 years and 0.77 (95% CI = 0.46–1.27) among those aged > 70 years; 0.59 (95% CI = 0.38–0.90) among males and 0.58 (95% CI = 0.39–0.87) among females; 0.65 (95% CI = 0.30–1.41) in Asia and 0.62 (95% CI = 0.44–0.87) in North America/Western Europe; 0.53 (95% CI = 0.34–0.82) among those with recurrent metachronous disease and 0.70 (95% CI = 0.47–1.04) among those with newly diagnosed metastatic disease; 0.54 (95% CI = 0.38–0.77) for right-sided and 0.81 (95% CI = 0.46–1.43) for left-sided primary tumors; and 0.50 (95% CI = 0.31–0.80) for BRAF wild-type and 0.48 (95% CI = 0.27–0.86) for BRAF V600E–mutant disease.
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 therapies 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 patients in the chemotherapy group.
Objective response was observed in 43.8% vs 33.1% of patients, with a complete response in 11.1% vs 3.9%. Median duration of response was not reached (range = 2.3+ to 41.4+ months) vs 10.6 months (range = 2.8 to 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 the pembrolizumab group vs 78% of the chemotherapy group. The most common grade ≥ 3 adverse events in the pembrolizumab group were hypertension (7% vs 5% in the chemotherapy group), diarrhea (6% vs 11%), abdominal pain (5% vs 6%), and anemia (5% vs 10%). The most common in the chemotherapy group were decreased neutrophil count, neutropenia, diarrhea, and anemia. 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 attributed by the investigator to treatment 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 patients (13%) in the chemotherapy group. Grade 3 or 4 events occurred in 14 (9%) vs 3 (2%), with the most common in the pembrolizumab group being colitis (3%) and hepatitis (3%) and the most common in the chemotherapy group being infusion reactions (1%) and skin reactions (1%). No grade 5 immune-mediated adverse events were reported.
The investigators concluded: “Pembrolizumab led to significantly longer progression-free survival than chemotherapy when received as first-line therapy for [MSI-high or mismatch repair–deficient] metastatic colorectal cancer, with fewer treatment-related adverse events.”
DISCLOSURE: The study was funded by Merck Sharp and Dohme and Stand Up to Cancer. Dr. André has received honoraria from Amgen, Bayer, Bristol Myers Squibb, GlaxoSmithKline, Pierre Fabre, Roche/Genentech, Sanofi, Servier, and Vantana; has served as a consultant or advisor to Amgen, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, Clovis Oncology, GamaMabs Pharma SA, GIC Advice, HalioDX, MSD Oncology, Pierre Fabre, Servier, and Tesaro; and has been reimbursed for travel, accommodations, or other expenses by Amgen, Bristol Myers Squibb, MSD Oncology, Roche, Roche/Genentech, and Vantana.