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Two doses of immunotherapy over four weeks before surgery left little or no living tumour in 95% of patients with mismatch-repair-deficient colon cancer, and none had relapsed at three years.
Single-arm phase 2 trial of 115 patients with non-metastatic, mismatch-repair-deficient colon cancer (mostly stage III, including bulky T4 and node-positive tumours) treated with one dose of ipilimumab (1 mg/kg) and two doses of nivolumab (3 mg/kg) over four weeks, followed by surgery within six weeks. Primary endpoints were safety and three-year disease-free survival.
Of 111 patients evaluable, 109 (98%) had a pathological response, 105 (95%) a major pathological response (10% or less residual tumour), and 75 (68%) a complete response. At three years no patient had relapsed. The result challenges the need for adjuvant chemotherapy in dMMR colon cancer and raises the possibility of avoiding surgery altogether in some patients.
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.
For mismatch repair-deficient rectal cancer, six months of a single antibody now replaces chemotherapy, radiotherapy and an operation, and the same appears to be true for early-stage mismatch repair-deficient cancers of other organs.
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.
A UK-led trial that moved part of colon cancer chemotherapy in front of the operation, and showed that tumour regression grade after six weeks predicts recurrence, which is the basis for using the response itself to choose what follows.
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.
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 John Haanen, Netherlands Cancer Institute (NKI-AvL), Immune-related adverse events (irAEs), CTLA-4.
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 MSI and mismatch-repair testing, dMMR (mismatch repair deficiency by IHC), MSI-high (microsatellite instability by PCR or sequencing), Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2).
Shares Nivolumab plus ipilimumab in microsatellite-instability-high metastatic colorectal cancer (CheckMate 8HW), Le 2017: mismatch-repair deficiency predicts response to PD-1 blockade across twelve tumour types, leading to the first tissue-agnostic drug approval, CTLA-4, Mismatch-repair deficient (MSI-high) colorectal cancer.
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 CTLA-4, Mismatch-repair deficient (MSI-high) colorectal cancer, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Ipilimumab.
Shares NICHE-2, MSI and mismatch-repair testing, dMMR (mismatch repair deficiency by IHC), MSI-high (microsatellite instability by PCR or sequencing).