The successes achieved with immune-checkpoint inhibition (ICI) in patients with advanced-stage mismatch repair deficient (dMMR) colorectal cancers (CRCs) have largely not been replicated in those with mismatch repair proficient (pMMR) forms of CRC. Now data from the phase II NICHE study provide early evidence of safety and efficacy of neoadjuvant ICI in these subtypes.
After a preliminary safety run-in, in which three patients received the anti-PD-1 antibody nivolumab as monotherapy, a total of 37 patients (17 with pMMR CRC and 20 with dMMR CRC) received neoadjuvant therapy with one dose of the anti-CTLA4 antibody ipilimumab (1 mg/kg on day 1) plus two doses of nivolumab (3 mg/kg on days 1 and 14), with a predefined 6-week maximum time between consent and surgery. Safety and feasibility were the primary end points.
Four patients (10%) had grade ≥3 adverse events, including grade 3 rash or pruritus in two. All patients underwent radical resections as planned. Grade ≥3 surgery-related adverse events occurred in eight patients (20%), including wound and/or abdominal infections and anastomotic leaks (both in four patients (10%)).
Among 35 patients who received both agents and were eligible for efficacy evaluations (two patients with pMMR CRCs were deemed ineligible post-surgery), 100% of those with dMMR CRC and 27% with pMMR CRC had pathological responses. The majority of responders (19/20 with dMMR CRC and 3/15 with pMMR CRC) had major pathological responses, including 12 complete responses. Subsequent organoid-based investigations suggest that the lower response rates of patients with pMMR CRCs reflect a lack of highly immunogenic T cell antigens, as opposed to other tumour-intrinsic factors.
These data highlight the safety and preliminary efficacy of neoadjuvant ICI in patients with dMMR CRCs and potentially in a subset with pMMR CRCs. Data from larger cohorts of patients are eagerly awaited.
Chalabi, M. et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat. Med. 26, 566–576 (2020)
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Sidaway, P. Neoadjuvant immunotherapy shows promise. Nat Rev Clin Oncol 17, 391 (2020). https://doi.org/10.1038/s41571-020-0372-4