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All 12 patients with locally advanced dMMR rectal cancer had a complete clinical response to a PD-1 antibody alone, avoiding chemotherapy, radiotherapy and surgery.
This single-centre phase 2 study at Memorial Sloan Kettering treated patients with stage II or III mismatch-repair-deficient rectal adenocarcinoma with dostarlimab 500 mg every three weeks for six months, with the plan to proceed to chemoradiotherapy and surgery only if disease persisted. In the first 12 patients who completed treatment and had at least six months of follow-up, all had a clinical complete response on MRI, endoscopy, digital examination and biopsy, and none required chemoradiotherapy or surgery; no grade 3 or higher adverse events occurred. The follow-up report (NEJM 2025) extended the approach to more than 100 patients with dMMR cancers of several organs, with rectal cancer patients continuing to show near-universal complete responses and most avoiding surgery at two years.
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.
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.
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 origin of organ preservation in rectal cancer. Twenty years later OPRA made it a planned strategy and the dostarlimab series made it the expected outcome in mismatch repair-deficient disease.
Shares Luis A. Diaz Jr., NICHE-2: a month of nivolumab and ipilimumab before surgery clears mismatch-repair-deficient colon cancer in most patients, MSI and mismatch-repair testing, Le 2015: PD-1 blockade works in tumours with mismatch-repair deficiency, whatever the organ.
Shares Luis A. Diaz Jr., MSI and mismatch-repair testing, Le 2015: PD-1 blockade works in tumours with mismatch-repair deficiency, whatever the organ, dMMR (mismatch repair deficiency by IHC).
Shares Andrea Cercek, A funded programme of organ-preservation trials to avoid radical surgery, Nonoperative management of mismatch repair-deficient tumors, Dostarlimab.
Shares Julio Garcia-Aguilar, Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results, Andrea Cercek, Nonoperative management of mismatch repair-deficient tumors.
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 Julio Garcia-Aguilar, Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results, Andrea Cercek, Nonoperative management of mismatch repair-deficient tumors.
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 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).