High pathological responses to neoadjuvant immune checkpoint inhibition in locally advanced dMMR colon cancer

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

Approximately 10–15% of non-metastatic colon cancers demonstrate dMMR [1]. Patients with stage III dMMR tumours have recurrence rates of 20–40%, despite standard-of-care chemotherapy [2] and high-risk disease (T4- and/or N2-status) is associated with poor survival. Neoadjuvant chemotherapy in patients with dMMR colon cancer leads to a slim pathological response of 5–7% [3]. More promisingly, 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% pathological responses and 60% pathological complete responses (pCR) [4].

Dr Miriam Chalabi (Netherlands Cancer Institute, the Netherlands) presented the first results of the subsequent (investigator-initiated) NICHE-2 study (EudraCT 2016-002940-17). The study included 112 patients (83 high-risk, stage III) with previously untreated, non-metastatic dMMR colon cancer, who 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 (<2 weeks delay in surgery for 95% of patients) and 3-year disease-free survival. Secondary objectives were response rates assessed in post-treatment specimens. [5].

Grade ≥3 immune-related adverse events were observed in 4 participants and were manageable. All participants underwent surgery, resulting in 100% R0 resection. The median time from the first dose of immunotherapy to surgery was 5.4 weeks and 98% of participants underwent timely surgery. Based on these results, the primary safety endpoint was met.

Major pathological responses (≤10% residual viable tumour or pCR with a residual viable tumour in lymph nodes) were achieved in 95% of participants and 65% of participants achieved pCR. These results agree with the outcomes of the NICHE-1 study (see Figure). At the median follow-up of 13.1 months, none of the participants had disease recurrence.

Dr Chalabi concluded that “with only 4 weeks of neoadjuvant immunotherapy, an unprecedented major pathological response rate was achieved and the treatment was well tolerated. While we are currently acquiring the 3-year disease-free survival data, these data already show that neoadjuvant immunotherapy may have the potential to become standard-of-care for patients with dMMR colon cancer.”

1. Eikenboom EL, et al. Clin Gastroenterol Hepatol. 2022;20(3):e496–e507.
2. André T, et al. J Clin Oncol. 2015;33(35):4176–4187.
3. Seligmann JF, FOxTROT Collaborative Group. J Clin Oncol. 2020;38:15_Suppl, 4013–4013.
4. Chalabi M, et al. Nat Med. 2020;26(4):566–576.
5. Chalabi M, et al. Neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer: The NICHE-2 study. Abstract LBA7, ESMO Congress 2022, 09–13 September, Paris, France.

Figure: Pathological tumour regression upon neoadjuvant immune checkpoint inhibition in locally advanced dMMR colon cancer: comparison of NICHE-1 and NICHE-2 [5].



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Posted on 16 November, 202228 March, 2024