Nivolumab and Relatlimab for the treatment of patients with unresectable or metastatic mismatch repair proficient colorectal cancer

Purpose: Combined inhibition of lymphocyte-activation gene 3 (LAG-3) and programmed cell death protein 1 (PD-1) improves outcomes in patients with melanoma. Increased LAG-3 expression in colorectal cancer (CRC) correlates with reduced survival. Higher mucin and PD-L1 expression in the mismatch repair proficient (pMMR) CRC tumor microenvironment (TME) 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 CRC subset. Patients and Methods: NCT03642067 was a phase 2 study evaluating combining relatlimab (LAG-3 inhibitor) and nivolumab (PD-1 inhibitor) in patients with previously treated metastatic pMMR CRC. Patients were enrolled onto 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 overall response rate. Results: We enrolled 59 evaluable patients; best treatment responses were partial response: 3, stable disease: 6, progressive disease: 50. Response rates did not differ significantly between cohorts. Subgroup analyses demonstrated 2 of 5 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 Tregs 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 CRC TME and identifies subgroups that may derive greater benefit from this combination.