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Two immunotherapy drugs together kept 72 percent of patients progression-free at two years against 14 percent on chemotherapy, the largest effect size of any first-line trial in colorectal cancer.
André, Elez, Van Cutsem and colleagues randomly assigned patients with unresectable or metastatic colorectal cancer and locally determined microsatellite-instability-high or mismatch repair-deficient status 2:2:1 to nivolumab plus ipilimumab, nivolumab alone, or chemotherapy with or without targeted therapies. The dual primary end points, assessed in patients with centrally confirmed status, were progression-free survival with the combination against chemotherapy in the first line and against nivolumab alone regardless of previous treatment; this prespecified interim analysis reports the first.
A total of 303 previously untreated patients were randomised to the combination or chemotherapy, and 255 had centrally confirmed microsatellite-instability-high or mismatch repair-deficient tumours.
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.
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.
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%).
Shares Heinz-Josef Lenz, Takayuki Yoshino, Eric Van Cutsem, Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation and the tag colorectal-evidence.
Shares 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, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR) and the tag colorectal-evidence.
Shares Heinz-Josef Lenz, Takayuki Yoshino, Eric Van Cutsem, Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation and the tag colorectal-evidence.
Shares Heinz-Josef Lenz, CTLA-4, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation and the tag colorectal-evidence.
Shares Thierry André, Takayuki Yoshino, Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation, New England Journal of Medicine and the tag colorectal-evidence.
Shares CTLA-4, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Ipilimumab, Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation and the tag colorectal-evidence.
Shares NICHE-2: a month of nivolumab and ipilimumab before surgery clears mismatch-repair-deficient colon cancer in most patients, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation, Colorectal cancer and the tag colorectal-evidence.
Shares Takayuki Yoshino, Eric Van Cutsem, Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation, New England Journal of Medicine and the tag colorectal-evidence.