A phase 2 study, NICHE-3, investigated the efficacy of neoadjuvant nivolumab and relatlimab in patients with locally advanced mismatch repair-deficient (dMMR) colon cancer. The multi-center, open-label trial demonstrated promising results, suggesting a potential new approach for treating this challenging cancer subtype. The study was conducted across multiple hospitals in collaboration with the Netherlands Cancer Institute (NKI).
Study Design and Patient Population
The NICHE-3 study enrolled patients aged 18 years or older with locally advanced (≥T3 and/or N+) dMMR resectable colon adenocarcinoma and no distant metastases. Mismatch repair (MMR) status was determined by immunohistochemistry. Patients with clinical or radiological signs of obstruction/perforation, prior chemotherapy or immune checkpoint inhibitors, or autoimmune diseases were excluded. The study's primary endpoint was pathologic response, defined as ≤50% residual viable tumor (RVT) in the primary tumor bed.
Patients received nivolumab (480 mg) and relatlimab (480 mg) on day 1 and day 29 (±3 days), followed by surgical resection 6-8 weeks after enrollment. Response was evaluated by central histopathologic assessment of the resected primary tumor and lymph nodes, quantified as percentage of RVT. The study utilized a Simon’s two-stage design, with statistical analysis conducted using R and SAS software.
Efficacy and Safety Results
The primary endpoint of pathologic response (≤50% RVT) was used to determine efficacy. Secondary endpoints included major pathologic response (MPR, ≤10% RVT), pathologic complete response (pCR, 0% RVT), disease-free survival (DFS), and overall survival (OS). Safety was assessed by monitoring adverse events (AEs) and serious adverse events (SAEs) according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Postoperative AEs were graded using the Clavien–Dindo classification.
All patients were closely monitored for 100 days after the last dose of nivolumab/relatlimab for the occurrence of AEs and SAEs. Treatment-related AEs leading to surgical delay of more than 2 weeks were considered unacceptable. Long-term follow-up for disease recurrence was conducted at the NKI or participating hospitals, including regular laboratory, radiographic, and endoscopic assessments.
Pathological Assessment
Pathologic response was determined by histopathological examination of all FFPE slides of the entire resected tumor, including all resected lymph nodes, and regression was determined by estimating the percentage of RVT. Staging was performed according to the American Joint Committee on Cancer Staging Manual, 8th edition. MPR was defined as ≤10% RVT in the primary tumor bed, and pCR was defined as 0% RVT in the primary tumor bed and tumor-draining lymph nodes. Cases with a pCR of the primary tumor but with lymph node metastases were classified as an MPR.
Implications for Clinical Practice
The NICHE-3 study suggests that neoadjuvant immunotherapy with nivolumab and relatlimab may offer a significant benefit for patients with locally advanced dMMR colon cancer. The observed pathologic response rates indicate a promising treatment strategy that warrants further investigation in larger, randomized controlled trials.
