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The FDA approved a first-in-class, fixed-dose for advanced melanoma.

Known as Opdualag, the combination includes the PD-1 inhibitor nivolumab (Opdivo) and the novel lymphocyte-activation gene 3 (LAG-3) inhibitor relatlimab. Nivolumab-relatlimab is indicated for patients ages 12 and older with unresectable or metastatic melanoma. Support for the approval came from the phase II/III RELATIVITY-047 trial that showed improved progression-free survival (PFS) with the fixed-dose combination as compared with nivolumab alone.

"Since the approval of the first immune checkpoint inhibitor more than 10 years ago, we've seen immunotherapy, alone and in combination, revolutionize the treatment of patients with advanced melanoma," said F. Stephen Hodi, MD, of Dana-Farber Cancer Institute in Boston, in a statement from Bristol Myers Squibb. "Today's approval is particularly significant, as it introduces an entirely new combination of two immunotherapies that may act together to help improve antitumor response by targeting two different immune checkpoints -- LAG-3 and PD-1."

RELATIVITY-047 involved 714 patients with previously untreated unresectable or metastatic melanoma. They were randomized to the immunotherapy combination or to nivolumab alone, with a primary endpoint of PFS.

As reported at the 2021 American Society of Clinical Oncology (ASCO) virtual meeting, the combination therapy doubled the median PFS versus nivolumab alone (10.1 vs 4.6 months). The difference translated into a 25% reduction in the hazard for disease progression or death (95% CI 0.62-0.92, P=0.0055). An updated presentation at an showed a numerical, clinically meaningful improvement in overall survival (HR 0.80, 95% CI 0.64-1.01), as well as persistence of the PFS advantage.

Overall, the fixed-dose combination had a safety profile similar to that of single-agent nivolumab, although grade 3/4 adverse events (AEs) occurred more often with the combination (18.9% vs 9.7%), as did drug-related AEs leading to discontinuation (14.6% vs 6.7%).

The rationale behind the fixed-dose combination came from observations that LAG-3 and PD-1 are that are often co-expressed by tumor-infiltrating lymphocytes and contribute to tumor-mediated T-cell exhaustion. The combination of nivolumab and relatlimab increases T-cell activation as compared with either agent alone.

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