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

A short course of neoadjuvant immunotherapy continues to show remarkable long-term outcomes in patients with locally advanced mismatch repair-deficient (dMMR) colon cancer. In the NICHE-2 study, none of the 111 patients in the primary efficacy population experienced disease recurrence, and all were alive at their most recent follow-up. The findings, now published in The Lancet, provide further evidence of the durability of response to neoadjuvant immunotherapy in this patient population.

Durable outcomes after short-course immunotherapy

The phase 2 NICHE-2 study investigated neoadjuvant nivolumab and ipilimumab in patients with non-metastatic dMMR colon cancer. Patients received two cycles of immunotherapy over approximately four weeks, followed by surgery.

Earlier findings demonstrated a pathological response in 98% of patients, including a pathological complete response in 68%. Three-year follow-up results had already shown no disease recurrences in the primary efficacy population.

The latest analysis extends these observations, with a median postoperative follow-up of 58.7 months. No recurrences were observed among the 111 patients in the primary efficacy population, and all patients were alive at their most recent follow-up. The three-year disease-free survival rate was 100%, while the estimated five-year overall survival rate was also 100%.

"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," says 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."

Implications for clinical practice

The findings are especially relevant because many patients enrolled in NICHE-2 had locally advanced tumors associated with an increased risk of recurrence.

The long-term outcomes strengthen the evidence supporting neoadjuvant immunotherapy as a treatment strategy for dMMR colon cancer. Results from NICHE-2 have already contributed to international treatment guidelines and the adoption of this approach in several countries, including Norway, Scotland and Uruguay. Efforts are ongoing to make the treatment available to eligible patients in the Netherlands.

Circulating tumor DNA provides insights into treatment response

Alongside the survival analysis, the researchers investigated circulating tumor DNA (ctDNA) as a potential biomarker of response to neoadjuvant immunotherapy.

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, ctDNA clearance was observed in 45% after the first treatment cycle and 82% after the second cycle, before surgery.

These findings demonstrate the rapid molecular response to immunotherapy in dMMR colon cancer. However, the sensitivity of preoperative ctDNA testing for residual disease remains insufficient to reliably identify all patients with a pathological complete response. Further refinement and combination with other diagnostic approaches will therefore be necessary.

The next challenge: identifying patients who may safely avoid surgery

One of the most important questions arising from NICHE-2 is whether surgery could eventually be omitted in selected patients who achieve a complete response to immunotherapy.

Although 68% of patients had no viable tumor cells remaining in their surgical specimens, this could only be confirmed after surgery. Reliably identifying a complete response before surgery remains a major challenge.

"Our next challenge is to determine which patients have achieved a complete response without relying on surgical pathology," says Lauren van den Dungen, PhD researcher involved in the NICHE-2 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.

Together, the long-term NICHE-2 results provide a strong foundation for further clinical research into treatment optimization and organ-preserving strategies in dMMR colon cancer.

About the study

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, with 111 included in the primary efficacy population.

The NICHE-2 study was funded by Bristol Myers Squibb. Research at the Netherlands Cancer Institute is also supported by the Dutch Cancer Society (KWF) and the AVL Foundation.