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

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%. In colon cancer, 3-year disease free survival, one of the two primary endpoints of the trial, is consider a surrogate for overall survival in colorectal cancer. In the paper now published, the disease-free survival rate was 100% after a median postoperative follow-up of 58.7 months, meaning no recurrences were observed among the 111 patients in the efficacy population. All patients were alive at their most recent follow-up, corresponding to an estimated 5-year overall survival of 100%.

Implications for clinical practice

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

The long-term outcomes strengthen the evidence supporting neoadjuvant immunotherapy as an effective treatment strategy for dMMR colon cancer. These findings are also in line with previous data in melanoma, where pathologic response to neoadjuvant immunotherapy is also strongly associated with improved outcomes. 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.

CtDNA 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, prior to surgery. After surgery, none of the patients had detectable ctDNA, in line with the absence of recurrences. 

These findings demonstrate the rapid molecular response to immunotherapy in dMMR colon cancer. Patients who remained ctDNA positive before surgery were likely to have residual disease, suggesting that ctDNA could eventually help identify limited responders in whom treatment might be escalated. Conversely, the sensitivity of preoperative ctDNA testing for residual disease is insufficient on its own to reliably identify all patients with a pathological complete response. Further refinement and combination with other diagnostic approaches will be important going forward.

The next challenge: identifying patients who may safely avoid surgery

One of the questions arising from NICHE-2 is whether surgery could eventually be omitted in selected patients with a complete response to immunotherapy. In 68% of patients, no viable tumor was found in the resection specimen, yet at present, this can only be confirmed by pathological examination after surgery. Reliably identifying these patients beforehand remains a major challenge.

Ongoing cohorts within the NICHE platform are also investigating whether a single immunotherapy agent can achieve comparable outcomes and whether longer treatment could increase pathological complete response rates.

Overall, the long-term NICHE-2 results show that short-course neoadjuvant immunotherapy leads to durable responses in locally advanced dMMR colon cancer, with no recurrences after a median follow-up of nearly five years. Based on these findings, the investigators believe neoadjuvant immunotherapy should become the new standard of care for these patients, while ongoing research focuses on identifying patients in whom surgery can safely be omitted.

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.