NICHE-2 is a large phase II study involving patients with locally advanced mismatch repair–deficient (dMMR) colon cancers with foreseen pathological assessment of both the complete tumour bed and lymph nodes. Treatment with neoadjuvant PD1 plus CTLA4 blockade had acceptable safety profile and resulted in pathological responses in 98% of patients after only 4 weeks of treatment, with a major pathological response (MPR) observed in 95% of patients and a pathological complete response (pCR) observed in 68%. 

Findings may provide sufficient justification to provide immunotherapy to patients with radiographically assessed high-risk disease, especially if 3-year disease-free survival data from this study are positive according to Dr. Myriam Chalabi of the Department of Gastrointestinal Oncology, Netherlands Cancer Institute in Amsterdam, Netherlands, and colleagues who published the findings on 5 June 2024 in The New England Journal of Medicine.

Immune checkpoint blockade is highly effective in patients with dMMR metastatic colorectal cancers, significantly improving progression-free survival. In addition, recent data strongly support the use of neoadjuvant immunotherapy in non-metastatic dMMR tumours, with clinical and pathological responses observed in high proportions of patients.  

dMMR tumours can be found in 10-15% of patients with non-metastatic colon cancer. In these patients, the efficacy of chemotherapy is limited. With the high incidence of disease recurrence in patients with dMMR tumours that are stage T4, have spread to the lymph nodes, or both, despite adjuvant chemotherapy, improved systemic treatment is needed. The use of neoadjuvant immunotherapy has shown promising results, but data from studies of this approach are limited.

The NICHE study evaluated neoadjuvant immunotherapy in a small cohort of patients with dMMR colon cancer. Based on the data from that study, Dutch investigators hypothesised that a single dose of the CTLA4 inhibitor ipilimumab and two doses of the PD1 inhibitor nivolumab would be safe and beneficial in a larger cohort of patients with locally advanced dMMR colon cancer. To test this hypothesis, they initiated the phase II NICHE-2 study to assess the safety and efficacy of neoadjuvant nivolumab plus ipilimumab in patients with locally advanced dMMR colon cancer.

The study was conducted in patients with locally advanced, previously untreated dMMR colon cancer. The two primary endpoints were safety, defined by timely surgery (i.e. ≤2-week delay of planned surgery owing to treatment-related toxic events), and 3-year disease-free survival. Secondary endpoints included pathological response and results of genomic analyses.

Of 115 enrolled patients, 113 (98%; 97.5% confidence interval [CI] 93 to 100) underwent timely surgery; 2 patients had surgery delayed by more than 2 weeks. Grade 3 or 4 immune-related adverse events occurred in 5 patients (4%), and none of the patients discontinued treatment because of adverse events.

Among the 111 patients included in the efficacy analysis, a pathological response was observed in 109 (98%; 95% CI 94 to 100), including 105 (95%) with MPR defined as ≤10% of residual viable tumour and 75 (68%) with pCR defined as 0% of residual viable tumour. With a median follow-up of 26 months (range, 9 to 65), no patients have had recurrence of disease.

In an accompanied editorial, Dr. Andrea Cercek of the Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center in New York, NY, USA wrote that although it is exciting to see such marked responses, these results alone do not support the adoption of this approach as the standard of care for patients with early-stage dMMR colon cancer. Surgical resection alone is curative in the majority of stage II dMMR colon cancers.

Staging of dMMR colon cancer is especially challenging, given that tumours with microsatellite instability are often associated with falsely positive enlarged lymph nodes owing to immune infiltration. Furthermore, although the incidence of grade 3 or 4 adverse events due to immune checkpoint blockade in this study was 4%, long-term endocrine dysfunction that resulted in treatment developed in 11% of the patients.

A randomised study of neoadjuvant immune checkpoint blockade followed by surgery, as compared with surgery alone or with adjuvant immune checkpoint blockade, in node-positive disease would address the question of risk versus benefit. At the present time, there are two options for trials, to pursue organ preservation or to better determine which patients benefit from neoadjuvant immune checkpoint blockade and surgery according to the editorialist.

The study was supported by Bristol Myers Squibb.

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