Nivolumab and Relatlimab for the Treatment of Patients with Unresectable or Metastatic Mismatch Repair–Proficient Colorectal Cancer

Abstract Purpose: Combined inhibition of lymphocyte-activation gene 3 (LAG-3) and PD-1 improves outcomes in patients with melanoma. Increased LAG-3 expression in colorectal cancer correlates with reduced survival. Higher mucin and PD-L1 expression in the mismatch repair–proficient (pMMR) colorectal cancer tumor microenvironment was associated with increased LAG-3 and retrospectively with prolonged progression-free survival upon PD-1 blockade. This led to the hypothesis that LAG-3/PD-1 inhibition would improve clinical outcomes in this pMMR colorectal cancer subset. Patients and Methods: NCT03642067 was a phase II study evaluating the combination of relatlimab (LAG-3 inhibitor) and nivolumab (PD-1 inhibitor) in patients with previously treated metastatic pMMR colorectal cancer. Patients were enrolled into one of three cohorts: A, mucin/PD-L1–high; B, mucin/PD-L1–low; or C, mucin/PD-L1 unselected. The primary endpoint for each cohort was the objective response rate. Results: We enrolled 59 evaluable patients; best treatment responses were partial response (3), stable disease (6), and progressive disease (50). Response rates did not differ significantly between cohorts. Subgroup analyses demonstrated that two of five patients with lung-only metastases had a partial response. Comparison of liver and lung metastases identified higher baseline dendritic cell densities in lung lesions. Nivolumab/relatlimab resulted in increased intratumoral cytotoxic T cells. Lower baseline intratumoral regulatory T cells and ADAM10+ cancer cells correlated with clinical response. Conclusions: This investigation did not reach its primary endpoint for any of the three treatment cohorts but does provide critical insight into the effects of combining nivolumab/relatlimab on the colorectal cancer tumor microenvironment and identifies subgroups that may derive greater benefit from this combination.