Abstract
METHODS
In this single-arm, multicentre, phase 2, NICHE-2 trial, patients with previously untreated, clinical stage 2 or 3, resectable dMMR colon cancer received a single dose of intravenous ipilimumab (1 mg per kg) on day 1, and two doses of intravenous nivolumab (3 mg per kg) on days 1 and 15, followed by surgery in one of the six participating hospitals in the Netherlands. Here, we report the independent primary efficacy endpoint of 3-year disease-free survival (time from surgery until disease recurrence or death from any cause) and the secondary endpoint of circulating tumour DNA (ctDNA) analysis. Overall survival (time from study enrolment until death from any cause) is reported as an exploratory post-hoc analysis. All endpoints were assessed in the per-protocol population (patients who met the eligibility criteria and received at least one cycle of therapy). The study is registered with ClinicalTrials.gov, NCT03026140, and has completed accrual.
BACKGROUND
Neoadjuvant immune checkpoint blockade induces high pathological response rates in patients with locally advanced mismatch repair-deficient (dMMR) colon cancer, yet long-term survival outcomes have not been established. Previously, we reported safety (a primary endpoint) and pathological response (a secondary endpoint) data from the NICHE-2 trial. Here, we report the primary efficacy endpoint of 3-year disease-free survival and the exploratory endpoint of 5-year overall survival.
FINDINGS
From July 4, 2017, to July 18, 2022, 123 patients were screened, of whom 115 were treated and 111 were included in the per-protocol population. At the data cutoff (June 19, 2026), the postoperative median follow-up was 58·7 months (IQR 49·0-72·9). The 3-year disease-free survival was 100% (97·5% CI 100-100). After a median follow-up of 60·4 months (IQR 50·6-74·1), calculated from time of study enrolment, the 5-year overall survival was 100% (95% CI 100-100). In patients with available plasma samples, ctDNA was detected in 99 (92%) of 108 patients at baseline, and ctDNA clearance was observed in 44 (45%) of 98 patients after the first cycle in week 2 and in 80 (82%) of 97 patients after the second cycle before surgery. In patients with a pathological near-complete response and complete response, presurgery ctDNA clearance was observed in 19 (70%) of 27 patients and 60 (92%) of 65 patients, respectively. Assessment for minimal residual disease after surgery revealed that all patients were ctDNA negative.
INTERPRETATION
In patients with locally advanced dMMR colon cancer, treatment with ipilimumab and nivolumab before surgery resulted in a 3-year disease-free survival and 5-year overall survival of 100%. These findings support neoadjuvant nivolumab plus ipilimumab as a potential standard of care for patients with locally advanced dMMR colon cancer.
FUNDING
Bristol Myers Squibb.