Combination of Nivolumab and Relatlimab Approved for Unresectable or Metastatic Melanoma

Melanoma cells.

The FDA has approved the combination of nivolumab and relatlimab-rmbw (Opdualag™, Bristol-Myers Squibb) for patients with unresectable or metastatic melanoma. OpdualagTM is a fixed-dose dual immunotherapy combination of nivolumab, a programmed cell death protein 1 (PD-1)–blocking antibody, and relatlimab, a first-in-class human lymphocyte–activation gene 3 (LAG-3)–blocking antibody, and is administered as a single intravenous (IV) infusion.

“LAG-3 and PD-1 are distinct inhibitory immune checkpoints that contribute to T-cell exhaustion,” wrote Hussein A. Tawbi, MD, PhD, Professor of Melanoma Medical Oncology at the University of Texas MD Anderson Cancer Center, and colleagues, in their published results of the RELATIVITY-047 clinical trial (NCT03470922), on which the approval was based. “The combination of relatlimab, a LAG-3–blocking antibody, and nivolumab, a PD-1–blocking antibody, has been shown to be safe and to have antitumor activity in patients with previously treated melanoma, but the safety and activity in patients with previously untreated melanoma need investigation.”

The phase 2/3, global, double-blind trial enrolled 714 patients with previously untreated metastatic or unresectable stage III or IV melanoma. Patients were randomized in a 1:1 ratio to receive a combination of 480 mg of nivolumab and 160 mg of relatlimab via IV every four weeks, or 480 mg of nivolumab alone via IV every four weeks. The primary end point was progression-free survival to be gauged by blind independent central review. A secondary end point of overall survival was also analyzed.

At a median follow-up of 13.2 months, nivolumab/relatlimab produced a statistically significant improvement in progression-free survival as determined by blinded independent central review, with a median survival rate of 10.1 months in comparison with nivolumab alone, which saw a median survival rate of 4.6 months. At 12 months, the rate of progression-free survival was 47.7% in those who received nivolumab/relatlimab and 36% in those who received nivolumab. The analysis of overall survival was not statistically significant, with the median overall survival being not reached in the nivolumab/relatlimab arm compared with 34.1 months in the nivolumab arm.

Adverse reactions experienced by ≥20% of patients receiving nivolumab/relatlimab were musculoskeletal pain, fatigue, rash, pruritus, and diarrhea. The most common laboratory abnormalities in ≥20% of patients receiving nivolumab/relatlimab were decreased hemoglobin, decreased lymphocytes, increased aspartate aminotransferase (AST), increased alanine transaminase (ALT), and decreased sodium.

“These results validate blocking LAG-3 in combination with PD-1 as a therapeutic strategy for patients with melanoma and establish LAG-3 as the third immune checkpoint pathway, the inhibition of which shows clinical benefit,” concluded Dr. Tawbi and colleagues in their publication in the New England Journal of Medicine. “These data further support the added benefit of dual checkpoint inhibition over monotherapy, add another immune checkpoint combination to the therapeutic armamentarium, and establish relatlimab/nivolumab as a potential new treatment option for patients with previously untreated metastatic or unresectable melanoma.”

The recommended dose is 480 mg of nivolumab and 160 mg of relatlimab given intravenously every four weeks until disease progression or unacceptable toxicity occurs. It is noted that this dosage is for adults and pediatric patients 12 years and older who weigh at least 40 kg; the recommended dosage for those under 40 kg has not yet been established.

For More Information

Tawbi HA, Schadendorf D, Lipson EJ, et al (2022). Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med, 384:2394-2405. DOI:10.1056/NEJMoa2109970. (2021). A study of relatlimab plus nivolumab versus nivolumab alone in participants with advanced melanoma (RELATIVITY-047). NLM identifier: NCT03470922.

Opdualag™ (nivolumab and relatlimab-rmbw) prescribing information (2022). Bristol-Myers Squibb. Available at:

US Food and Drug Administration (2022). FDA approves Opdualag for unresectable or metastatic melanoma. Available at:

Image credit: Jenflorian. Licensed under CC BY-SA 3.0

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