Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer

Thierry André , Kai-Keen Shiu, Tae Won Kim, Benny Vittrup Jensen, Lars Henrik Jensen, Cornelis Punt, Denis Smith, Rocio Garcia-Carbonero, Manuel Benavides, Peter Gibbs, Christelle de la Fouchardiere, Fernando Rivera, Elena Elez, Johanna Bendell, Dung T Le , Takayuki Yoshino, Eric Van Cutsem, Ping Yang, Mohammed Z H Farooqui, Patricia Marinello Luis A Diaz Jr , KEYNOTE-177 Investigators

Research output: Contribution to journalArticlepeer-review


Background: Programmed death 1 (PD-1) blockade has clinical benefit in microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) tumors after previous therapy. The efficacy of PD-1 blockade as compared with chemotherapy as first-line therapy for MSI-H-dMMR advanced or metastatic colorectal cancer is unknown.
Methods: In this phase 3, open-label trial, 307 patients with metastatic MSI-H-dMMR colorectal cancer who had not previously received treatment were randomly assigned, in a 1:1 ratio, to receive pembrolizumab at a dose of 200 mg every 3 weeks or chemotherapy (5-fluorouracil-based therapy with or without bevacizumab or cetuximab) every 2 weeks. Patients receiving chemotherapy could cross over to pembrolizumab therapy after disease progression. The two primary end points were progression-free survival and overall survival.
Results: At the second interim analysis, after a median follow-up (from randomization to data cutoff) of 32.4 months (range, 24.0 to 48.3), pembrolizumab was superior to chemotherapy with respect to progression-free survival (median, 16.5 vs. 8.2 months; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.80; P = 0.0002). The estimated restricted mean survival after 24 months of follow-up was 13.7 months (range, 12.0 to 15.4) as compared with 10.8 months (range, 9.4 to 12.2). As of the data cutoff date, 56 patients in the pembrolizumab group and 69 in the chemotherapy group had died. Data on overall survival were still evolving (66% of required events had occurred) and remain blinded until the final analysis. An overall response (complete or partial response), as evaluated with Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was observed in 43.8% of the patients in the pembrolizumab group and 33.1% in the chemotherapy group. Among patients with an overall response, 83% in the pembrolizumab group, as compared with 35% of patients in the chemotherapy group, had ongoing responses at 24 months. Treatment-related adverse events of grade 3 or higher occurred in 22% of the patients in the pembrolizumab group, as compared with 66% (including one patient who died) in the chemotherapy group.
Conclusions: 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. (Funded by Merck Sharp and Dohme and by Stand Up to Cancer; KEYNOTE-177 number, NCT02563002.).
Original languageEnglish
Pages (from-to)2207-2218
Number of pages12
JournalThe New England Journal of Medicine
Issue number23
Publication statusPublished - 3 Dec 2020

Bibliographical note

We thank the patients and their families and caregivers for participating in the trial; all site personnel; Conrad Messam, Aleksandra Eyring, Laura O’Grady, Jennifer Davis — all of Merck Sharp and Dohme — and Toya Lennon (ExecuPharm, on assignment to Merck Sharp and Dohme) for critical clinical trial support; Ruixue Wang for assistance with statistical analyses; Jonathan Cheng (Merck Sharp and Dohme) for critical review of the manuscript; and Luana Atherly-Henderson (Merck Sharp and Dohme) for medical writing assistance.

Data Availability Statement


Dive into the research topics of 'Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer'. Together they form a unique fingerprint.

Cite this