NICHE-2: a month of nivolumab and ipilimumab before surgery clears mismatch-repair-deficient colon cancer in most patients
Two doses of immunotherapy over four weeks before surgery left little or no living tumour in 95% of patients with mismatch-repair-deficient colon cancer, and none had relapsed at three years.
Single-arm phase 2 trial of 115 patients with non-metastatic, mismatch-repair-deficient colon cancer (mostly stage III, many with bulky T4 or node-positive tumours) treated with one dose of ipilimumab (1 mg/kg) and two doses of nivolumab (3 mg/kg) over four weeks, followed by surgery within six weeks. Primary endpoints were safety and three-year disease-free survival.
Of 111 patients evaluable, 109 (98%) had a pathological response, 105 (95%) a major pathological response (10% or less residual tumour), and 75 (68%) a complete response. At three years no patient had relapsed. The result challenges the need for adjuvant chemotherapy in dMMR colon cancer and raises the possibility of avoiding surgery altogether in some patients.
- Pathological response in 109 of 111 evaluable patients (98%); major pathological response 95%; pathological complete response 68%.
- Three-year disease-free survival 100% at a median follow-up of about 26 months.
- Grade 3-4 immune-related adverse events in 4% of patients; 98% underwent surgery on time.
- Responses were independent of PD-L1, tumour mutational burden or Lynch syndrome status.
- Radiological response underestimated pathological response, as in other neoadjuvant immunotherapy studies.
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 barely works 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.
- Single-arm phase 2 without a control; the 100% disease-free survival is remarkable but from a single-centre network with limited follow-up.
- Surgery was still performed in all patients, so organ preservation is not yet demonstrated in colon cancer.
- Requires reliable pre-operative mismatch repair testing and rapid access to immunotherapy, which many systems lack.
- Two-drug regimen with ipilimumab; whether nivolumab alone would suffice is untested.