Approximately 10–15% of non-metastatic colon cancers are dMMR, of which about one third are associated with Lynch syndrome1. Patients with stage III dMMR tumours have recurrence rates of 20–40%, despite standard-of-care chemotherapy2. 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 5–7%3. On the other hand, neoadjuvant immunotherapy leads to high pathological responses in many tumour types, e.g. melanoma, that are associated with excellent survival outcomes4.
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)5. Based on these results, the investigator-initiated NICHE-2 study (EudraCT 2016-002940-17) was performed, in which 112 patients (83 high-risk, stage III) with previously untreated, non-metastatic dMMR colon cancer were treated with one cycle nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) followed by a second cycle 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 specimen. Dr Miriam Chalabi (Netherlands Cancer Institute, the Netherlands) presented the first results6.
Adverse (immune-related) events grade ≥3 were observed in 4 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 tumour or pCR with residual viable tumour in lymph nodes) was achieved in 95% of patients, 65% of patients achieved pCR. There 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.”