FDA Approves Relatlimab Plus Nivolumab Combo for Unresectable or Metastatic Melanoma

The FDA has granted approval to a fixed-dose combination of relatlimab plus nivolumab (Opdualag) for the treatment of adult and pediatric patients 12 years of age and older with unresectable or metastatic melanoma.¹

The approval was based on data from the phase 2/3 RELATIVITY-047 trial, which found combination (n = 355) produced a median progression-free survival (PFS) of 10.1 months (95% CI, 6.4-15.7) compared with 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, said in a press release. “Today’s approval is particularly significant, as it introduces an entirely new combination of 2 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 with an ECOG performance status of 0 or 1. The investigators randomized 714 patients 1:1 for the fixed-dose combination of relatlimab at 160 mg and nivolumab at 480 mg administered every 4 weeks versus single-agent nivolumab at the same dose and schedule.

The trial’s primary end point was PFS per blinded independent central review (BICR), with secondary end points that included overall survival (OS) and ORR per BICR. Patients enrolled had a median age of 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 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. Further, 38.5% of patients had BRAF-mutated disease and 61.5% had BRAF wild-type disease, 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, median OS with the combination therapy 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 The benefit was not deemed to be statistically significant, however, it was considered clinically meaningful.

At 12 months, PFS was 48.0% (95% CI, 42.5%-53.4%) in the combination cohort compared with 36.9% (95% CI, 31.7%-42.1%) in the control group. At 24 months, PFS rates were 38.5% (95% CI, 32.7%-44.2%) and 29.0% (95% CI, 23.8%-34.4%), respectively.

In the combination cohort, the complete response rate was 16.3%, the partial response rate was 26.8%, and 17.2% of patients experienced stable disease. Further, 29.6% of patients in the combination cohort experienced disease progression. The median duration of response was not reached in both the combination cohort (95% CI, 29.57-NR) and the control cohort (95% CI, 29.93-NR).

The combination therapy is associated with severe and fatal immune-mediated adverse events (AEs), such as pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions, myocarditis, and other immune-mediated AEs. The combination is also associated 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, said 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.”

References

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