NICHE‑2 phase 2 follow‑up: short‑course neoadjuvant immunotherapy linked to 100% 3‑year disease‑free survival in dMMR colon cancer

A Dutch phase 2 trial in locally advanced mismatch repair-deficient, or dMMR, colon cancer has reported a 3-year disease-free survival rate of 100% after a very short course of immunotherapy before surgery, with no recurrences seen among 111 evaluable patients. The result from the NICHE-2 study is striking because it suggests some patients with potentially curable colon cancer may do extremely well with brief neoadjuvant treatment, though the evidence comes from a single-arm trial without a randomized comparison group.

NICHE-2 is an investigator-initiated, multicenter phase 2 study in the Netherlands for patients with non-metastatic, locally advanced dMMR colon cancer. The trial, registered as NCT03026140, was led from the Netherlands Cancer Institute in Amsterdam, with Myriam Chalabi as first author. The question was whether giving immunotherapy before surgery could improve outcomes in a group of tumors already known to be especially sensitive to checkpoint blockade.

The regimen was short: patients received ipilimumab at 1 mg/kg on day 1 and nivolumab at 3 mg/kg on day 1 and again on day 15, with surgery planned within six weeks of treatment start. In total, 115 patients were enrolled. Of those, 113 underwent timely surgery, and 111 were included in the efficacy analysis. The trial’s co-primary endpoints were safety — defined in part by timely surgery with no more than a two-week delay — and 3-year disease-free survival.

Updated results presented in a late-breaking abstract at ESMO 2024 and published in Annals of Oncology showed a median follow-up after surgery of 36.5 months, with a range of 7.8 to 83.4 months. At that point, all evaluable patients were alive and there had been no disease recurrences, producing a 3-year disease-free survival rate of 100%. That exceeded the study’s prespecified success threshold of 93%, which had been set against a historical benchmark of about 82%.

The durability update builds on earlier clinical and pathologic findings published in The New England Journal of Medicine in June 2024. In that report, 109 of 111 patients, or 98%, had a pathologic response, meaning the tumor showed evidence of treatment effect when examined after surgery. A major pathologic response was seen in 105 of 111 patients, or 95%, and 75 of 111 patients, or 68%, had a pathologic complete response, meaning no viable tumor cells were found in the resected specimen. Grade 3 or 4 immune-related adverse events occurred in five patients, about 4%, and no patients discontinued treatment because of side effects.

The findings matter because dMMR colon cancers are a molecular subtype that has already shown strong responses to checkpoint inhibitors in metastatic disease, where the cancer has spread. NICHE-2 tested that strategy earlier, before surgery, in patients whose disease was still considered operable and potentially curable. If the approach holds up in further study, it could help move immunotherapy into an earlier stage of care for this subgroup.

Chalabi told Cancerworld in June 2024 that “Now, more than two years after treatment, none of the patients saw recurrence even though many had high risk tumours. These results are unprecedented. The efficacy as well as the side effects are much better compared to chemotherapy before surgery, a treatment that only works in one out of 20 patients.”

Still, the key limitation is the study design. NICHE-2 was funded by Bristol Myers Squibb, but it did not include a randomized control arm comparing the regimen with standard treatment. That means the results are best understood as highly encouraging single-arm evidence, not definitive proof that short-course neoadjuvant ipilimumab plus nivolumab should replace current approaches without confirmatory data.