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

Presented by
Dr Miriam Chalabi, Netherlands Cancer Institute, the Netherlands
ESMO 2022
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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