Nivolumab Plus Relatlimab for Patients With Unresectable or Metastatic Mismatch Repair Proficient Colorectal Cancer

Results from a phase 2 study identified the impact of treatment with nivolumab, a PD-L1 inhibitor, and relatlimab, a LAG-3 inhibitor, on the tumor microenvironment among previously treated patients with unresectable or metastatic mismatch repair proficient (pMMR) colorectal cancer (CRC). 

“Increased LAG-3 expression in colorectal cancer correlates with reduced survival,” stated Eric Christenson, MD, Johns Hopkins University, Baltimore, Maryland, and coauthors. “Higher mucin and PD-L1 expression in the pMMR CRC tumor microenvironment was associated with increased LAG-3 and retrospectively with prolonged progression-free survival upon PD-1 blockade… [which] led to the hypothesis that LAG-3/PD-1 inhibition would improve clinical outcomes in this pMMR CRC subset.”

In this study, researchers enrolled 59 previously treated patients with high mucin or PD-L1 (cohort 1), low mucin or PD-L1 (cohort 2), and unselected mucin or PD-L1 (cohort 3) to receive nivolumab plus relatlimab. The primary end point was objective response rate (ORR). 

At analysis, 3 patients achieved partial responses, 6 experienced stable disease, and 50 experienced progressive disease. There was no significant difference in response rates observed between patient cohorts. Subgroup analysis results revealed that 40% of patients with lung-only metastases (n = 5) experienced partial response. Patients with lung metastases had higher baseline dendritic cell density in lesions compared to patients with liver metastases. Treatment was correlated with increased intratumoral cytotoxic T cells and lower baseline intratumoral Tregs and ADAM10⁺ cells was correlated with clinical response.

“This investigation did not reach its primary end point for any of the 3 treatment cohorts, but does provide critical insight into the effects of combining nivolumab/relatlimab on the CRC [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: May 19, 2025. doi: 10.1158/1078-0432.CCR-25-0002