Cercek 2022: six months of dostarlimab alone made rectal cancer disappear in every patient with mismatch-repair deficiency
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.
- 12 patients with stage II-III dMMR rectal adenocarcinoma; dostarlimab 500 mg every 3 weeks for 6 months.
- Clinical complete response in 12 of 12 (100%) at 6 months or more of follow-up.
- No patient needed chemoradiotherapy or surgery; no recurrence at 6-25 months follow-up in the initial report.
- No grade 3 or higher adverse events.
- Larger follow-up (2025): sustained complete responses in the great majority of dMMR rectal cancer patients, and high rates of organ preservation across other dMMR tumour types.
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.
- Small, single-centre, single-arm study; the 2022 report had only 12 patients and short follow-up.
- Clinical complete response requires expert surveillance with MRI and endoscopy; salvage surgery must remain available.
- Applies only to dMMR disease, a minority of rectal cancers.
- Long-term durability beyond five years and late relapse risk are not yet known.
NICHE-2 shows that a month of immunotherapy before surgery can effectively cure locally advanced dMMR colon cancer, where chemotherapy after surgery has limited benefit. It is changing guidelines towards neoadjuvant checkpoint blockade for this group and raises the question of whether surgery can be omitted altogether, as in dMMR rectal cancer. Whether the same applies to MMR-proficient tumours is being tested but is not established.
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.