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

Eric Christenson, MD, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, discusses results from a phase 2 clinical trial highlighting 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.

Transcript: 

I'm Eric Christensen, I'm an assistant professor of oncology at Johns Hopkins, and today I'm going to be talking about our clinical trial, the use of nivolumab and relatlimab for the treatment of patients with unresectable or metastatic mismatch repair proficient colorectal cancer. 

The background on this is that unfortunately, colorectal cancer represents the second leading cause of cancer related death in the United States. And while immune checkpoint inhibitors have certainly shown significant success in those with mismatch repair deficient disease, few patients with mismatch repair proficient cancer ultimately have benefited from immunotherapy. It was also found via prior correlative studies that LAG-3 levels are elevated [in] both the tumor microenvironments surrounding those tumor cells as well as in draining lymph nodes in patients that had poor overall survival, so LAG-3 levels being higher was bad in patients with colorectal cancer. Prior studies have also established that the use of LAG-3 inhibition in combination with PD-1 leads to better outcomes in those with melanoma. So the hope is that the use of this LAG-3inhibitor, relatlimab, in combination with anti PD-1 might start to show activity in patients with colorectal cancer that’s mismatch repair proficient.

This study enrolled patients into 1 of 3 different cohorts and this was based on prior data from our group that suggested that higher levels of mucin, or kind of mucus in the tumor, as well as higher levels of PD-L1, which is one of the immune checkpoints targeted by anti–PD-1 therapy, were associated with better responses to immunotherapy. We enrolled patients into a cohort of patients that had higher levels of PD-L1 and mucin, a group that had lower levels of these, as well as a group that was enrolled agnostic of these features with a higher dose of relatlimab, the anti-LAG-3 that we used along with nivolumab. We enrolled a total of 59 patients in this study. None of these 3 cohorts seemed to do differentially better than the others. Overall, 3 patients were able to achieve a partial response with this approach, 6 patients had stable disease, and the other 50 patients unfortunately had progressive disease as the best treatment response. 

Looking at the correlative analysis of this study, we found a couple different features that seemed to suggest a better response or better outcomes with this treatment approach. This included patients that had lung-only metastases, so their cancer had spread to their lungs, but no other sites within their body such as the liver or the line in the abdomen, and patients that had lower levels of regulatory t-cells and immunosuppressive population and lower levels of ADAM10, which is associated with LAG-3 turnover. 

We're hopeful that in the future, this knowledge may allow us to design better studies going forward, which can target these types of approaches into populations that they're more apt to help. Thank you so much for listening and reach out with any questions.

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