Research in context
Evidence before the study
We searched PubMed for studies published from inception to Dec 9, 2021, using the terms (“PD-1” OR “PD-L1” OR “pembrolizumab” OR “Keytruda” OR “nivolumab” OR “Opdivo” OR “atezolizumab” OR “Tecentriq” OR “durvalumab” OR “Imfinzi” OR “avelumab” OR “Bavencio” AND “MSI-H/dMMR metastatic colorectal cancer”). No exclusion criteria were applied to the search. We also searched the 2020 and 2021 abstract records of the American Society of Clinical Oncology, American Society of Clinical Oncology Gastrointestinal Cancers Symposium, the World Congress on Gastrointestinal Cancer, and the European Society for Medical Oncology Congress using the same search terms to identify results of clinical studies that were not yet published in the peer-reviewed literature. We identified three published clinical studies of anti-PD-1 or anti-PD-L1 therapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer: the phase 3, open-label KEYNOTE-177 interim analysis of first-line pembrolizumab versus chemotherapy; the phase 2, open-label KEYNOTE-164 study of pembrolizumab as second-line or later therapy; and the phase 2, open-label CheckMate 142 study of nivolumab as second-line or later therapy in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer.
Added value of this study
Data from the final analysis of KEYNOTE-177 support the results observed in the previously published interim analysis, which were the first from a phase 3 randomised study of an anti-PD-1 inhibitor as a first-line treatment for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer versus an active comparator. These data show that progression-free survival improved with pembrolizumab versus chemotherapy. However, we found no significant difference in overall survival. The overall survival analysis might have been affected by the high proportion of patients who crossed over from chemotherapy to second-line anti-PD-1 or anti-PD-L1 therapy. Responses were durable and continued to improve with pembrolizumab versus chemotherapy. The safety profile was favourable at final analysis, with fewer high-grade treatment-related adverse events observed with pembrolizumab than with chemotherapy.
Implications of the available evidence
These data show that pembrolizumab results in a durable antitumour response and fewer treatment-related adverse events in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer in the first-line setting compared with chemotherapy, and support pembrolizumab as a standard first-line treatment in this population.