Melanoma cancer cells of human under microscope
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The U.S. Food and Drug Administration has approved the use of the anti-lymphocyte-activation gene (LAG)-3 agent relatlimab in combination with the anti-programmed death (PD)-1 drug nivolumab for patients with treatment-naïve advanced melanoma.

The approval is based on the results of the Phase II/III RELATIVITY-047 trial published in the New England Journal of Medicine in January.

Study co-author Evan Lipson, associate professor of oncology at the Johns Hopkins Kimmel Cancer Center and Bloomberg–Kimmel Institute for Cancer Immunotherapy, told Inside Precision Medicine that this is an exciting development “not just because it expands the list of therapies in melanoma, but because it validated the third checkpoint pathway in history, after PD-1 and CTLA-4, to demonstrate anti-cancer activity in a Phase III trial.”

This this third pathway involves LAG-3, an immune checkpoint receptor that regulates immune cell activity contributing to T cell exhaustion and has a similar mode of action to PD1.

“Preclinical studies demonstrated anti-tumor synergy with simultaneous blockade of PD-1 and LAG-3 [and] provided a scientific rationale for the clinical development of nivolumab and relatlimab in combination,” Lipson explained.

The two drugs were evaluated in the international RELATIVITY-047 trial, which included 714 patients with previously untreated metastatic or unresectable melanoma who were randomly assigned to receive either relatlimab plus nivolumab or nivolumab monotherapy.

The results showed that individuals given relatlimab plus nivolumab had a 25% lower risk for disease progression or death than those who received nivolumab monotherapy.

Median progression-free survival (PFS) was 10.1 months with the immune checkpoint inhibitor combination versus 4.6 months with nivolumab monotherapy, while PFS at 12 months was 47.7% and 36.0%, respectively.

Individuals who received relatlimab plus nivolumab experienced more grade 3 or 4 treatment-related adverse events than those given nivolumab alone, at 18.9% versus 9.7% but Lipton noted that the rate seen with relatlimab plus nivolumab “was lower than we typically associate with simultaneous blockade of CTLA-4 and PD-1,” which is currently a standard-of-care option (ipilimumab plus nivolumab or pembrolizumab) in these patients.

He added: “We make every effort to optimize the risk-benefit ratio of any cancer therapy, and partner with patients and their caregivers to address potential side effects as early as possible.”

Relatlimab and other LAG-3-targeted agents are now being evaluated in other settings such as adjuvant use, in different patient populations including those with brain metastases, and in different tumor types.

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