Five Years Without Recurrence: Short-Course Immunotherapy Reshapes dMMR Colon Cancer Care

A short course of immunotherapy given before surgery has kept every patient in a landmark trial free of disease recurrence for five years, according to long-term results from the NICHE-2 study published in The Lancet. Among the 111 patients in the primary efficacy population, all of whom had non-metastatic mismatch repair-deficient (dMMR) colon cancer, not a single recurrence was observed, and all patients were alive at their most recent follow-up. NICHE-2 is a multicenter, single-arm phase 2 study led by the Netherlands Cancer Institute in collaboration with five other Dutch hospitals.

A total of 115 patients received treatment, of whom 111 were included in the primary efficacy population. Earlier analyses of NICHE-2 demonstrated pathological responses in 98 percent of patients, meaning that the tumor tissue removed at surgery showed major destruction of cancer cells. Strikingly, 68 percent achieved a pathological complete response, with no viable tumor cells remaining in the surgical specimen.

The three-year follow-up had already reported no recurrences in the primary efficacy population. The new publication extends these observations with a median postoperative follow-up of 58.7 months, reporting a three-year disease-free survival rate of 100 percent and an estimated five-year overall survival rate that also stands at 100 percent. These numbers carry particular weight because many participants had locally advanced tumors, a stage associated with a heightened risk of recurrence after standard treatment.

"These long-term data are particularly important because the ultimate goal is not just to induce a strong pathological response, but to achieve durable disease control," said Myriam Chalabi, medical oncologist at the Netherlands Cancer Institute. "The absence of recurrences after this extended follow-up is exceptional, particularly given the short duration of treatment." Alongside the survival data, the researchers investigated circulating tumor DNA, or ctDNA, as a potential biomarker of treatment response.

In the study, tumor-derived DNA was detectable in blood samples from most patients before treatment. Among patients with detectable ctDNA at baseline and available follow-up samples, clearance was observed in 45 percent after the first treatment cycle and 82 percent after the second cycle, before surgery. However, the researchers caution that preoperative ctDNA testing is not yet accurate enough to replace surgery.

The sensitivity of preoperative ctDNA testing for residual disease remains insufficient to reliably identify all patients who have achieved a pathological complete response. The team emphasizes that ctDNA will need further refinement and combination with other diagnostic approaches before it can safely support treatment de-escalation. That question—whether surgery itself can be spared—is the central challenge emerging from NICHE-2.

Because pathological complete response could only be confirmed after the tumor was removed, the 68 percent of patients whose specimens contained no viable cancer cells underwent an operation that may ultimately have been avoidable. "Our next challenge is to determine which patients have achieved a complete response without relying on surgical pathology," said Lauren van den Dungen, PhD researcher involved in the study. "We are investigating how approaches such as ctDNA analysis, endoscopy and imaging can be combined to assess response more accurately.

Ultimately, this could help identify patients who may safely avoid surgery." Further studies are also investigating whether a single immunotherapy agent could achieve comparable outcomes and whether longer treatment could increase pathological complete response rates. The long-term outcomes have already influenced clinical practice beyond the trial itself: results from NICHE-2 have contributed to international treatment guidelines, and the neoadjuvant immunotherapy approach has been adopted in several countries, including Norway, Scotland and Uruguay, with efforts ongoing to make the treatment available to eligible patients in the Netherlands.

As follow-up continues and de-escalation studies mature, the trial stands as a proof of principle that approximately four weeks of immunotherapy can produce durable disease control in dMMR colon cancer, with no sign of recurrence so far in the patients treated.

Subject of Research: Long-term outcomes of short-course neoadjuvant nivolumab and ipilimumab in mismatch repair-deficient colon cancer

Article Title: NICHE-2: No disease recurrences after five years of follow-up

Article References: NICHE-2: No disease recurrences after five years of follow-up. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: NICHE-2 trial, colon cancer, dMMR, neoadjuvant immunotherapy, nivolumab, ipilimumab, disease-free survival, circulating tumor DNA, pathological complete response, Netherlands Cancer Institute, checkpoint inhibitors, organ preservation