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Across 86 patients with 12 different dMMR cancers, pembrolizumab produced responses in 53% and complete responses in 21%, prompting the first approval of a cancer drug based on a genetic marker rather than tumour site.
Extending the 2015 study, this report treated 86 patients with treatment-refractory, mismatch-repair-deficient cancers of 12 types (colorectal, endometrial, gastric, biliary, pancreatic, small bowel and others) with pembrolizumab. The objective response rate was 53% (46 of 86) with complete responses in 21% (18); disease control was 77%, and neither median PFS nor OS had been reached at a median follow-up of 12.5 months. Responses were seen in every tumour type. Functional analysis showed rapid in vivo expansion of neoantigen-specific T-cell clones. The FDA approved pembrolizumab for any unresectable or metastatic MSI-H/dMMR solid tumour in May 2017, the first tissue-agnostic cancer drug approval, and the randomised KEYNOTE-177 trial later confirmed first-line benefit in dMMR colorectal cancer (median PFS 16.5 versus 8.2 months).
This paper established a new regulatory paradigm: a drug approved for a molecular feature regardless of organ. It made MSI/MMR testing standard across advanced cancers and remains the clearest example of a biomarker that works across histologies. It also anchored the idea that mutation load, via neoantigens, is what makes tumours visible to T cells.
For colon cancer that is mismatch-repair deficient (about 10-15% of colon cancers, more in older patients), a single short course of immunotherapy before surgery is now a reasonable standard and is far more effective than chemotherapy, which has little effect in this subtype. It requires testing every colon cancer for mismatch repair at diagnosis, before surgery. Whether some patients can safely skip surgery, as in dMMR rectal cancer, is the next question.
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., NICHE-2: a month of nivolumab and ipilimumab before surgery clears mismatch-repair-deficient colon cancer in most patients, MSI and mismatch-repair testing, Le 2015: PD-1 blockade works in tumours with mismatch-repair deficiency, whatever the organ.
Shares CheckMate 8HW, MSI and mismatch-repair testing, dMMR (mismatch repair deficiency by IHC), MSI-high (microsatellite instability by PCR or sequencing).
Shares MSI and mismatch-repair testing, dMMR (mismatch repair deficiency by IHC), MSI-high (microsatellite instability by PCR or sequencing), Mismatch repair deficient (MSI-high) pancreatic ductal adenocarcinoma.
Shares CheckMate 8HW, NICHE-2: a month of nivolumab and ipilimumab before surgery clears mismatch-repair-deficient colon cancer in most patients, Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Mismatch-repair deficient (MSI-high) colorectal cancer.
Shares MSI and mismatch-repair testing, dMMR (mismatch repair deficiency by IHC), MSI-high (microsatellite instability by PCR or sequencing), Mismatch repair deficient (MSI-high) pancreatic ductal adenocarcinoma.
Shares CheckMate 8HW, MSI and mismatch-repair testing, Le 2015: PD-1 blockade works in tumours with mismatch-repair deficiency, whatever the organ, MSI-high (microsatellite instability by PCR or sequencing).
Shares CheckMate 8HW, KEYNOTE-177, Mismatch-repair deficient (MSI-high) colorectal cancer, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR).