Neoadjuvant nivolumab and relatlimab in locally advanced MMR-deficient colon cancer: a phase 2 trial

Abstract

Mismatch repair deficiency (dMMR) is found in approximately 15% of non-metastatic colon cancers (CCs) and is characterized by a defective DNA mismatch repair system, resulting in hypermutated and highly immunogenic tumors. Although patients with dMMR CC have limited benefit from chemotherapy, these tumors have been shown to respond exceptionally well to neoadjuvant anti-PD-1 plus anti-CTLA-4, with high rates of pathologic responses. Here, based on data from melanoma studies, we postulated a high efficacy and favorable toxicity profile of anti-PD-1 plus anti-LAG-3. In the NICHE-3 study, a total of 59 patients with locally advanced dMMR CC were treated with two 4-weekly cycles of nivolumab (480 mg) plus relatlimab (480 mg) before surgery. Pathologic response was observed in 57 of 59 (97%; 95% confidence interval (CI): 88-100%) patients, meeting the primary endpoint. Responses included 54 (92%; 95% CI: 81-97%) major pathologic responses (≤10% residual viable tumor) and 40 (68%; 95% CI: 54-79%) pathologic complete responses. With a median follow-up of 8 months (range, 2-19), one patient had recurrence of disease. The treatment displayed an acceptable safety profile, with all-grade and grade 3-4 immune-related adverse events (irAEs) occurring in 80% and 10% of patients, respectively. The most common irAEs were infusion-related reactions (29%), thyroid dysfunction (22%) and fatigue (20%). In conclusion, our results show that neoadjuvant nivolumab/relatlimab induces high rates of pathologic responses and that further investigation of this treatment in larger studies is warranted. These data add to the body of evidence in support of neoadjuvant immunotherapy regimens in dMMR CC. ClinicalTrials.gov identifier: NCT03026140 .

Fig. 1. CONSORT diagram.

CONSORT diagram with an overview of screening and enrollment of patients.

Fig. 2. Pathologic response and outcome after neoadjuvant nivolumab plus relatlimab.

a, Percentage of pathologic regression in the primary tumor bed shown per tumor. The horizontal black line depicts the threshold of 50% regression for a pathologic response, and the horizontal dashed line depicts the threshold of 90% regression for an MPR. Boxes above each bar indicate the corresponding pathologic lymph node status. b, Kaplan–Meier plot for DFS. c, Kaplan–Meier plot for overall survival.

Fig. 3. pCR according to subgroups.

The pCR rates are stratified according to baseline patient and tumor characteristics of the 59 patients included in the efficacy analysis. Each gray square with a dash inside represents the proportion of pCR for a specific subgroup. The horizontal lines extending from the square depict the 95% CI. N/A, not available.

Extended Data Fig. 1. Study design.

All patients underwent screening through CT-scan, endoscopy and blood tests. After enrollment patients were treated with 480 mg nivolumab plus 480 mg relatlimab at day 1 and day 29 followed by surgical resection at a maximum of 8 weeks after enrollment.