Treatment with the anti–PD-1 therapy nivolumab plus the LAG-3–blocking antibody relatlimab extended time to disease progression for patients with previously untreated, unresectable, or metastatic melanoma. Findings from the RELATIVITY-047 trial were presented by Evan J. Lipson, MD, and colleagues at a presscast in advance of the 2021 ASCO Annual Meeting (Abstract 9503).

This is the first phase III study to validate inhibition of the LAG-3 immune checkpoint as a therapeutic strategy for patients with cancer. Our findings establish the LAG-3 pathway as the third immune checkpoint pathway in history, after CTLA-4 and PD-1, for which blockade has clinical benefit.

— Evan J. Lipson, MD

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About the Study

Until now, phase III studies evaluating combinations of immune checkpoint inhibitors have only demonstrated clinical benefit by blocking the PD-1 and CTLA-4 pathways. Nivolumab acts on the PD-1 protein and is approved by the U.S. Food and Drug Administration for the treatment of patients with melanoma and several other cancers. Relatlimab is the first to bind to LAG-3 on T cells, reinvigorating their activity and potentially unleashing enhanced antitumor responses.

The RELATIVITY-047 study is the first randomized phase III trial to evaluate the immunotherapy agents nivolumab and relatlimab, administered as a fixed-dose combination, to patients with previously untreated, unresectable, or metastatic melanoma.

In all, 714 patients with previously untreated, unresectable, or metastatic melanoma were randomly assigned 1:1 to receive either a fixed-dose combination of nivolumab and relatlimab or nivolumab alone.

The primary endpoint was progression-free survival for all study participants and for subgroups; secondary endpoints were overall survival and objective response rate.

Progression-Free Survival Extended

The researchers found that the median progression-free survival was significantly longer with nivolumab and relatlimab compared with nivolumab alone: 10.1 vs 4.6 months, respectively. At 1 year, progression-free survival rates were 47.7% for patients receiving the combination and 36.0% for those receiving nivolumab alone.

Treatment-related adverse events associated with nivolumab and relatlimab were generally manageable and reflected the typical safety profile seen with immune checkpoint inhibitors. Grade 3/4 adverse events were more common among patients receiving nivolumab and relatlimab (18.9%) vs nivolumab alone (9.7%). There were three treatment-related deaths among patients receiving the dual immunotherapy regimen and two in the nivolumab monotherapy group. Adverse events led to therapy discontinuation in 14.6% and 6.7% of patients, respectively.

The researchers are awaiting objective response and overall survival outcomes.

“Our results demonstrate that combination therapy with nivolumab and relatlimab is a potential novel treatment option for patients with previously untreated, unresectable, or metastatic melanoma. This is the first phase III study to validate inhibition of the LAG-3 immune checkpoint as a therapeutic strategy for patients with cancer. Our findings establish the LAG-3 pathway as the third immune checkpoint pathway in history, after CTLA-4 and PD-1, for which blockade has clinical benefit,” said lead author Dr. Lipson, Associate Professor of Oncology at the Johns Hopkins Kimmel Cancer Center and Bloomberg~Kimmel Institute for Cancer Immunotherapy.

Commentary

“Immunotherapy has transformed the outlook for patients with advanced melanoma. The success seen in this study by combining two immunotherapy drugs that act on different checkpoints, in this case PD-1 and LAG-3, adds support for additional investigation of this approach with other drugs that target other checkpoints,” said ASCO Chief Medical Officer and Executive Vice President Julie R. Gralow, MD, FACP, FASCO.

Disclosure: For full disclosures of the study authors, visit coi.asco.org.