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Pembrolizumab shrank tumours in 40% of colorectal and 71% of other cancers with faulty DNA mismatch repair, but in none with intact repair, tying immunotherapy response to mutation burden.
This investigator-initiated phase 2 study tested the hypothesis that tumours with defective DNA mismatch repair (dMMR), which accumulate thousands of mutations and neoantigens, would respond to PD-1 blockade. Forty-one patients with treatment-refractory metastatic cancer were enrolled in three cohorts: dMMR colorectal cancer, MMR-proficient colorectal cancer, and dMMR non-colorectal cancers, all treated with pembrolizumab 10 mg/kg every two weeks. Immune-related objective response rates were 40% (4 of 10) in dMMR colorectal cancer, 0% (0 of 18) in MMR-proficient colorectal cancer and 71% (5 of 7) in dMMR non-colorectal cancers; 20-week PFS was 78% versus 11% in the two colorectal cohorts. Whole-exome sequencing showed a mean of 1782 somatic mutations in dMMR versus 73 in proficient tumours, and higher mutation load correlated with longer PFS.
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.
The first credible response signal in microsatellite stable colorectal cancer, and the reason the field's attention has moved to Fc engineering and to excluding patients with active liver metastases, in whom responses are rare.
Cercek's dostarlimab study is the clearest demonstration that immunotherapy can replace surgery in a solid tumour: patients with dMMR rectal cancer can keep their rectum and avoid the permanent effects of pelvic radiotherapy and surgery. Non-operative management after PD-1 blockade is now in guidelines for this group, and MMR testing before treatment of rectal cancer is essential. The approach applies only to the 5-10% of rectal cancers that are dMMR.
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%).
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.
Shares NICHE-2, Cercek 2022: six months of dostarlimab alone made rectal cancer disappear in every patient with mismatch-repair deficiency, Le 2017: mismatch-repair deficiency predicts response to PD-1 blockade across twelve tumour types, leading to the first tissue-agnostic drug approval, MSI and mismatch-repair testing.
Shares 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, KEYNOTE-177, Microsatellite-stable (MSS) / mismatch-repair proficient (pMMR), Le 2017: mismatch-repair deficiency predicts response to PD-1 blockade across twelve tumour types, leading to the first tissue-agnostic drug approval.
Shares Dung T. Le, Le 2017: mismatch-repair deficiency predicts response to PD-1 blockade across twelve tumour types, leading to the first tissue-agnostic drug approval, dMMR (mismatch repair deficiency by IHC), MSI-high (microsatellite instability by PCR or sequencing).
Shares Kenneth W. Kinzler, MSI and mismatch-repair testing, Bert Vogelstein, dMMR (mismatch repair deficiency by IHC).
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 Microsatellite-stable (MSS) / mismatch-repair proficient (pMMR), TMB-high (tumour mutational burden >= 10 mutations per megabase), Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Neoantigen.
Shares KEYNOTE-177, Microsatellite-stable (MSS) / mismatch-repair proficient (pMMR), MSI and mismatch-repair testing, MSI-high (microsatellite instability by PCR or sequencing).