NICHE-2: a single dose of ipilimumab and two of nivolumab before surgery clears dMMR colon cancer in most patients
In NICHE-2, four weeks of checkpoint blockade before surgery eliminated nearly all tumour in 95% of patients with mismatch-repair-deficient colon cancer, and none had relapsed at three years.
NICHE-2 was a single-arm phase 2 trial at the Netherlands Cancer Institute in 115 patients with non-metastatic, mismatch-repair-deficient colon cancer, most with locally advanced (cT3-4 and/or node-positive) disease. Patients received one dose of ipilimumab (1 mg/kg) and two doses of nivolumab (3 mg/kg) and underwent surgery within six weeks. The co-primary endpoints were safety (timely surgery) and three-year disease-free survival. Among 111 evaluable patients, 98% had a pathological response, 95% a major pathological response (10% or less residual tumour) and 68% a pathological complete response; 98% had surgery on time, and grade 3-4 immune-related adverse events occurred in 4%. Three-year disease-free survival was 100%. The earlier NICHE study (Chalabi et al., Nature Medicine 2020) had shown pathological responses in 20 of 20 dMMR tumours and, unexpectedly, in 4 of 15 MMR-proficient tumours.
- 115 patients with non-metastatic dMMR colon cancer (74% high-risk stage III); ipilimumab x1 + nivolumab x2, surgery within 6 weeks.
- Pathological response 98%; major pathological response 95%; pathological complete response 68%.
- Three-year disease-free survival 100% (co-primary endpoint met).
- Grade 3-4 immune-related adverse events 4%; 98% had surgery within the planned window.
- NICHE (2020): pathological response in 20 of 20 dMMR and 4 of 15 MMR-proficient tumours after the same short course.
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.
- Single-arm, single-country study; no randomised comparison with upfront surgery plus adjuvant chemotherapy.
- Pathological response is a surrogate; longer follow-up will confirm survival.
- Patients still had surgery; organ preservation was not the design.
- Only 4% grade 3-4 toxicity with one ipilimumab dose, but late endocrine effects are possible.
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.
This paper established a new regulatory paradigm: a drug approved for a molecular feature regardless of organ. It made MSI/MMR testing standard across advanced cancers and remains the clearest example of a biomarker that works across histologies. It also anchored the idea that mutation load, via neoantigens, is what makes tumours visible to T cells.