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For the roughly 5% of metastatic bowel cancers with defective DNA mismatch repair, pembrolizumab alone lengthened the time without progression compared with chemotherapy, with far fewer severe side effects, and 83% of responses lasted two years or more. It made first-line pembrolizumab the standard for this group.
Open-label phase 3 trial of 307 patients with untreated microsatellite-instability-high or mismatch-repair-deficient metastatic colorectal cancer randomised to pembrolizumab or investigator's choice chemotherapy (FOLFOX or FOLFIRI with or without bevacizumab or cetuximab). Primary endpoints were PFS and OS.
Median PFS was 16.5 vs 8.2 months (HR 0.60), with 43.8% vs 33.1% responding and 83% vs 35% of responses lasting two years or more. Overall survival was not significantly different (HR 0.74) because 60% of chemotherapy patients crossed over to immunotherapy. It made first-line pembrolizumab the standard for dMMR metastatic colorectal cancer and cemented mismatch repair testing for every colorectal cancer.
Every colorectal cancer should be tested for mismatch repair deficiency, because patients whose metastatic tumour is dMMR should receive pembrolizumab rather than chemotherapy as first treatment, gaining a much better chance of durable remission with fewer side effects. About a third of dMMR tumours do not respond initially, so early scans are essential and chemotherapy remains available. The trial does not apply to the 95% of metastatic colorectal cancers that are mismatch-repair proficient (the deficient share is higher in localised disease, about 15%).
Combination checkpoint blockade became a first-line standard for mismatch repair-deficient metastatic colorectal cancer in 2025; the later all-lines comparison against nivolumab alone showed the CTLA-4 antibody adds to the PD-1 antibody, the first phase 3 to prove that in this disease.
This small trial explained why colorectal cancer had seemed immune-resistant (most is MMR-proficient) and established the principle that a genomic feature, not the tissue of origin, can predict immunotherapy response. It led directly to the 2017 tissue-agnostic approval of pembrolizumab and to routine MMR/MSI testing of many cancers. Every patient with advanced dMMR cancer should now be considered for checkpoint blockade.
Shares Dung T. Le, Luis A. Diaz Jr., KEYNOTE-177, MSI and mismatch-repair testing.
Shares Luis A. Diaz Jr., MSI and mismatch-repair testing, Le 2015: PD-1 blockade works in tumours with mismatch-repair deficiency, whatever the organ, dMMR (mismatch repair deficiency by IHC).
Shares Thierry André, MSI and mismatch-repair testing, dMMR (mismatch repair deficiency by IHC), MSI-high (microsatellite instability by PCR or sequencing).
Shares Nivolumab plus ipilimumab in microsatellite-instability-high metastatic colorectal cancer (CheckMate 8HW), MSI and mismatch-repair testing, dMMR (mismatch repair deficiency by IHC), MSI-high (microsatellite instability by PCR or sequencing).
Shares Dung T. Le, dMMR (mismatch repair deficiency by IHC), MSI-high (microsatellite instability by PCR or sequencing), Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2).
Shares Lines of therapy, Progression-free survival (PFS), Overall survival (OS), No one can predict who responds to immunotherapy.
Shares dMMR (mismatch repair deficiency by IHC), MSI-high (microsatellite instability by PCR or sequencing), Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Mismatch repair & microsatellite instability.
Shares Tae Won Kim, Elena Élez, Takayuki Yoshino, Lines of therapy.