Treatment with neoadjuvant immunotherapy (nivolumab/ipilimumab) for 4 weeks achieved a major pathological response in 95% of patients with stage III mismatch repair-deficient colon cancer, the first results of NICHE-2 trial show.

Approximately 10% to 15% of non-metastatic colon cancers are mismatch repair-deficient (dMMR), of which about one-third are associated with Lynch syndrome. Patients with stage III dMMR tumors have recurrence rates of 20% to 40%, despite standard-of-care chemotherapy. In addition, high-risk disease (T4 or N2) is associated with poor survival. Neoadjuvant chemotherapy in patients with dMMR colon cancer leads to a pathological response of 5% to 7%. On the other hand, neoadjuvant immunotherapy leads to high pathological responses in many tumor types (eg, melanoma) that are associated with excellent survival outcomes.

Previously, results from the proof-of-concept NICHE-1 trial (N=32) showed that immune checkpoint inhibition is highly effective in non-metastatic dMMR colon cancers, with 100% pathologic responses and 60% pathologic complete responses (pCR). Based on these results, the investigator-initiated NICHE-2 study was performed, in which 112 patients (83 high-risk, stage III) with previously untreated, non-metastatic dMMR colon cancer were treated with one cycle of nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) followed by a second cycle of nivolumab (3 mg/kg) and subsequent surgery. The primary objectives were safety/feasibility (no more than 2 weeks delay in surgery for 95% of patients) and 3-year disease-free survival. Secondary objectives were response rates in post-treatment specimens. Dr. Miriam Chalabi (Netherlands Cancer Institute, the Netherlands) presented the first results at ESMO 2022.

Adverse (immune-related) events grade 3 or higher were observed in four patients and were manageable. All patients underwent surgery, resulting in 100% R0 resection. The median time from first dose immunotherapy to surgery was 5.4 weeks and 98% of patients underwent timely surgery. Based on these results, the primary safety endpoint was met.

Major pathological responses (10% or less residual viable tumor or pCR with residual viable tumor in lymph nodes) was achieved in 95% of patients; 65% of patients achieved pCR. These results are in line with the NICHE-1 outcomes. With a median follow-up of 13.1 months, no disease recurrence has been observed yet.

Dr. Chalabi concluded that “with only 4 weeks of neoadjuvant immunotherapy, an unprecedented major pathological response rate was achieved. In addition, treatment is well tolerated. Therefore, neoadjuvant immunotherapy has the potential to become standard-of-care for patients with dMMR colon cancer.”


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