FDA Approves Relatlimab Plus Nivolumab for Unresectable or Metastatic Melanoma


The FDA has approved the fixed-dose combination of relatlimab plus nivolumab for the treatment of adult and pediatric patients who are 12 years of age or older and who have unresectable or metastatic melanoma.



The FDA has approved the fixed-dose combination of relatlimab plus nivolumab (Opdualag) for the treatment of adult and pediatric patients who are 12 years of age or older and who have unresectable or metastatic melanoma.1

The regulatory decision is based on data from the phase 2/3 RELATIVITY-047 trial (NCT03470922), which showed that the doublet (n = 355) resulted in a median progression-free survival (PFS) of 10.1 months (95% CI, 6.4-15.7) vs 4.6 months (95% CI, 3.4-5.6) with single-agent nivolumab (n = 359; HR, 0.75; 95% CI, 0.62-0.92; P = .0055).

“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,” F. Stephen Hodi, MD, director of the Melanoma Center and the Center for Immuno-Oncology at Dana-Farber Cancer Institute, stated in a press release. “Today’s approval is particularly significant, as it introduces an entirely new combination of two immunotherapies that may act together to help improve anti-tumor response by targeting two different immune checkpoints — LAG-3 and PD-1.”

To be eligible for enrollment to RELATIVITY-047, patients had to have previously untreated, unresectable, or metastatic melanoma and an ECOG performance status of 0 or 1.

A total of 714 patients were randomized 1:1 to receive the fixed-dose combination of relatlimab at 160 mg and nivolumab at 480 mg administered every 4 weeks vs single-agent nivolumab at the same dose and schedule.

Patients were stratified by LAG-3 expression on immune cells in the tumor microenvironment, PD-L1 expression on tumor cells, BRAF mutational status, and AJCC v8 M stage.

The primary end point of the trial was PFS per blinded independent central review (BICR). Secondary end points included overall survival (OS) and ORR per BICR. End points were tested in hierarchy, with PFS evaluated first, followed by OS, and then objective response rate (ORR).

Baseline characteristics were well balanced between the arms. The median age of participants was 63 years, 41.7% were female, and 66.9% had an ECOG performance status of 0. The serum lactate dehydrogenase level was above the upper limit of normal in 36.1% of patients.

LAG-3 expression was 1% or higher in 75.2% of patients, and it was lower than 1% in 24.8% of patients. PD-L1 expression was at least 1% in 41.0% of patients, and lower than 1% in 59.0% of patients. Moreover, 38.5% of patients had BRAF-mutated disease, and 61.5% had BRAF wild-type disease. Lastly, 65.7% of patients had AJCC M stage of M0/M1any[0], and 34.3% had M1any[1].

Data presented during the March 2022 ASCO Plenary Series showed that at a median follow-up of 19.3 months, the median OS with the doublet had not yet been reached (NR; 95% CI, 43.20-NR) vs 34.10 months (95% CI, 25.32-NR) with nivolumab monotherapy (HR, 0.80; 95% CI, 0.64-1.01; P = .0593).2 Although this benefit was not found to be statistically significant, it was considered to be clinically meaningful.

Additional data showed that PFS rates continued to be higher in the doublet arm vs the monotherapy arm. At 12 months, these rates were 48.0% (95% CI, 42.5%-53.4%) and 36.9% (95% CI, 31.7%-42.1%), respectively; at 24 months, these rates were 38.5% (95% CI, 32.7%-44.2%) and 29.0% (95% CI, 23.8%-34.4%), respectively.

Notably, PFS and OS benefit favored the doublet over the monotherapy across all stratification factors that were assessed.

In the investigative arm, the complete response rate achieved was 16.3%, the partial response rate was 26.8%, and 17.2% of patients experienced stable disease. Additionally, 29.6% of patients in this arm had disease progression.

The median duration of response had not yet been reached in both the relatlimab/nivolumab arm (95% CI, 29.57-NR) and the control arm (95% CI, 29.93-NR). Moreover, the disease control rate achieved with the doublet was 62.8% (95% CI, 57.6%-67.9%) vs 50.7% (95% CI, 45.4%-56.0%) with the monotherapy.

Notably, fewer patients who received the doublet went on to receive subsequent therapy vs those who received single-agent nivolumab, at 40.8% and 42.6%, respectively. Specifically, fewer patients in the investigative arm received systemic therapy vs those in the control arm, at 32.7% vs 34.5%, respectively. Additionally, 11.8% of patients who received relatlimab/nivolumab went on to receive PD-L1 and/or CTLA-4 inhibitors vs 15.9% of those who received nivolumab monotherapy.

Specifically, 4.2% of patients on the relatlimab/nivolumab arm went on to recive nivolumab and ipilimumab (Yervoy), 4.2% received nivolumab monotherapy, 3.7% received ipilimumab, 1.7% received pembrolizumab (Keytruda) monotherapy, and no patients received single-agent avelumab (Bavencio); these rates were 6.7%, 5.6%, 5.3%, 2.8%, and 0.3%, respectively.

Additionally, 12.4% of patients on the investigative arm went on to receive BRAF and/or MEK inhibitors vs 14.8% of those on the control arm. Other subsequent treatment was received by 13.8% of those who received the doublet vs 12.3% of those who were given the monotherapy. Slightly more patients on the investigative arm received radiotherapy at 14.6% vs 12.3% on the control arm; however, more patients on the control arm underwent surgery, at 8.1% vs 7.0%, respectively.

The fixed-dose combination is associated with severe and fatal immune-mediated adverse reactions such as pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions, myocarditis, and other immune-mediated adverse reactions; infusion-related reactions. The doublet is also linked with complications of allogeneic hematopoietic stem cell transplantation and embryo-fetal toxicity.

“While we have made great progress in the treatment of advanced melanoma over the past decade, we are committed to expanding dual immunotherapy treatment options for these patients,” Samit Hirawat, chief medical officer of global drug development at Bristol Myers Squibb, added in the press release. “Inhibiting LAG-3 with relatlimab, in a fixed-dose combination with nivolumab, represents a new treatment approach that builds on our legacy of bringing innovative immunotherapy options to patients. The approval of a new medicine that includes our third distinct checkpoint inhibitor marks an important step forward in giving patients more options beyond monotherapy treatment.”


  1. US Food and Drug Administration approves first LAG-3-blocking antibody combination, Opdualag (nivolumab and relatlimab-rmbw), as treatment for patients with unresectable or metastatic melanoma. News release. Bristol Myers Squibb; March 18, 2022. Accessed March 18, 2022. https://bit.ly/3wk6PDx
  2. Long GV, Hodi FS, Lipson EJ, et al. Relatlimab and nivolumab vs nivolumab in previously untreated metastatic or unresectable melanoma: overall survival and response rates from RELATIVITY-047 (CA224-047). J Clin Oncol. 2022;40(suppl 36):360385. doi:10.1200/JCO.2022.40.36_suppl.360385
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