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Forty-one patients settled a decade of argument: colorectal cancers with a broken DNA spell-checker responded to immunotherapy in 40 percent of cases, and those without responded in none.
Le, Uram, Wang and colleagues conducted a phase 2 study of pembrolizumab at 10 mg per kilogram every 14 days in 41 patients with progressive metastatic carcinoma, in three cohorts: mismatch repair-deficient colorectal cancers, mismatch repair-proficient colorectal cancers, and mismatch repair-deficient cancers that were not colorectal. The co-primary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate.
Whole-exome sequencing showed a mean of 1,782 somatic mutations per tumour in mismatch repair-deficient tumours against 73 in proficient ones (p=0.007), and high somatic mutation loads were associated with prolonged progression-free survival (p=0.02).
The paper that split colorectal cancer into two diseases for immunotherapy purposes, and the direct ancestor of the first tumour-agnostic drug approval two years later.
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.
First-line chemotherapy-free treatment for mismatch repair-deficient metastatic colorectal cancer, approved in June 2020; the five-year follow-up published in 2024 reported median overall survival of 77.5 months despite 62 percent crossover.
The first tumour-agnostic approval, and the reason every patient with metastatic colorectal cancer has mismatch repair status tested regardless of where the tumour started.
Shares Pembrolizumab in microsatellite-instability-high advanced colorectal cancer (KEYNOTE-177), Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Mismatch-repair deficient (MSI-high) colorectal cancer and the tag colorectal-evidence.
Shares Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Mismatch-repair deficient (MSI-high) colorectal cancer, 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 Kenneth W. Kinzler, Bert Vogelstein, Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center, 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 Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Whole-exome & whole-genome sequencing, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Mismatch-repair deficient (MSI-high) colorectal cancer and the tag colorectal-evidence.
Shares Kenneth W. Kinzler, Bert Vogelstein, Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center, 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 Kenneth W. Kinzler, Bert Vogelstein, 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 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, Colorectal cancer and the tag colorectal-evidence.
Shares 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.