Nivolumab Plus Relatlimab Shows Activity For Unresectable or Metastatic Mismatch Repair-Proficient Colorectal Cancer

Results from a phase 2 clinical trial highlight the impact of combining nivolumab, a PD-1 inhibitor, with relatlimab, a LAG-3 inhibitor, on the tumor microenvironment among previously treated patients with unresectable or metastatic mismatch repair-proficient (pMMR) colorectal cancer.

“Higher mucin and PD-L1 expression in the [pMMR] colorectal cancer tumor microenvironment was associated with increased LAG-3 and retrospectively with prolonged progression-free survival upon PD-1 blockade,” stated Eric Christenson, MD, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, and coauthors. “This led to the hypothesis that LAG-3/PD-1 inhibition would improve clinical outcomes in this pMMR colorectal cancer subset.”

In this study, researchers enrolled 59 previously treated patients with metastatic pMMR colorectal cancer to receive nivolumab plus relatlimab. Patients were divided into 3 cohorts based on mucin and PD-L1 status (mucin/PD-L1–high, mucin/PD-L1–low, or mucin/PD-L1 unselected). The primary end point for each cohort was objective response rate (ORR). 

At analysis, there were 3 partial responses, 6 incidences of stable disease, and 50 incidences of progressive disease. The ORR did not significantly differ between treatment cohorts. Subgroup analysis results revealed that 2 patients with lung-only metastases experienced a partial response. Patients with lung metastases had higher baseline dendritic cell density in lung lesions compared to patients with liver metastases. Treatment with nivolumab and relatlimab increased intratumoral cytotoxic T cells. Lower baseline intratumoral regulatory T cells and ADAM10⁺ cells were correlated with clinical response.

“This investigation did not reach its primary end point 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,” concluded Dr Christenson et al. 

Source:

Christenson ES, Ho WJ, Shu D, et al. Nivolumab and relatlimab for the treatment of patients with unresectable or metastatic mismatch repair–proficient colorectal cancer. Clin Cancer Res. Published online: June 17, 2025. doi: 10.1158/1078-0432.CCR-25-0002