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The extension of the rectal dostarlimab result to every organ: 49 of 49 rectal cancers and 35 of 54 other early-stage mismatch repair-deficient cancers disappeared on six months of one drug, and 82 patients avoided surgery altogether.
Cercek, Foote, Rousseau and colleagues conducted a phase 2 study in which patients with stage I, II or III mismatch repair-deficient solid tumours amenable to curative-intent surgery were treated with neoadjuvant dostarlimab, a PD-1 blocking agent, for six months. Response was assessed in two cohorts: cohort 1 had mismatch repair-deficient locally advanced rectal cancer and cohort 2 had mismatch repair-deficient non-rectal solid tumours. Patients with a clinical complete response could elect non-operative management; those with residual disease were to undergo resection. The primary end point, assessed in cohort 1, was a sustained clinical complete response at 12 months.
The option of curative resection was not compromised during or after treatment in any patient, which is the safety claim that makes the strategy defensible outside a trial.
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.
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.
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.
Shares Organ preservation in patients with rectal adenocarcinoma treated with total neoadjuvant therapy (OPRA), Clinical complete response (cCR), Complete response, Organ preservation (watch-and-wait, bladder-sparing, larynx 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 Surgery and radiotherapy cure most, get least, 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, Toxicity and quality of life are undervalued, New England Journal of Medicine 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, Surgery and radiotherapy cure most, get least, 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 Organ preservation in patients with rectal adenocarcinoma treated with total neoadjuvant therapy (OPRA), Randomise organ preservation against surgery in mismatch repair-proficient rectal cancer, with bowel function as a co-primary endpoint, Surgery and radiotherapy cure most, get least, 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 Surgery and radiotherapy cure most, get least, 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, Toxicity and quality of life are undervalued, New England Journal of Medicine and the tag colorectal-evidence.
Shares Andrea Cercek, 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, Rectal cancer, Colorectal cancer and the tag colorectal-evidence.
Shares Surgery and radiotherapy cure most, get least, 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, Rectal cancer, Colorectal cancer and the tag colorectal-evidence.