On March 18, the U.S. Food and Drug Administration (FDA) approved nivolumab and relatlimab-rmbw (Opdualag) for adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma. The approved treatment is a fixed-dose combination of the LAG-3–blocking antibody relatlimab and the PD-1–blocking antibody nivolumab.
Efficacy was evaluated in RELATIVITY-047 (ClinicalTrials.gov identifier NCT03470922), a randomized, double-blinded trial in 714 patients with previously untreated metastatic or unresectable stage III or IV melanoma. The trial excluded patients with active autoimmune disease; medical conditions requiring systemic treatment with moderate or high-dose corticosteroids or immunosuppressive medications; uveal melanoma; and active or untreated brain or leptomeningeal metastases. Patients were randomly assigned to receive nivolumab at 480 mg and relatlimab at 160 mg by intravenous infusion every 4 weeks or nivolumab at 480 mg by intravenous infusion every 4 weeks until disease progression or unacceptable toxicity.
The major efficacy outcome measure was progression-free survival determined by blinded independent central review using Response Evaluation Criteria in Solid Tumors version 1.1. The trial demonstrated a statistically significant improvement in progression-free survival by blinded independent central review for relatlimab/nivolumab compared to nivolumab alone (hazard ratio [HR] = 0.75, 95% confidence interval [CI] = 0.62–0.92, P = .0055). Median progression-free survival was 10.1 months (95% CI = 6.4–5.7) in the relatlimab/nivolumab arm and 4.6 months (95% CI = 3.4–5.6) in the nivolumab arm. An additional efficacy outcome measure was overall survival; the final analysis of overall survival was not statistically significant (HR = 0.80, 95% CI = 0.64–1.01), with median overall survival not reached in the doublet arm (95% CI = 34.2–not reached) and 34.1 months (95% CI = 25.2–not reached) in the nivolumab arm.
The most common adverse reactions (≥ 20%) with relatlimab/nivolumab were musculoskeletal pain, fatigue, rash, pruritus, and diarrhea. The most common laboratory abnormalities (≥ 20%) were decreased hemoglobin, decreased lymphocytes, increased aspartate aminotransferase, increased alanine transaminase, and decreased sodium.
The recommended relatlimab/nivolumab dose for adult and pediatric patients 12 years of age or older who weigh at least 40 kg is 480 mg of nivolumab and 160 mg of relatlimab administered intravenously every 4 weeks until disease progression or unacceptable toxicity occurs. The recommended dose for pediatric patients 12 years of age or older who weigh less than 40 kg has not been established.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence, which provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with the Australian Therapeutic Goods Administration and Switzerland’s Swissmedic. The application reviews may be ongoing at the other regulatory agencies.
This review used the Real-Time Oncology Review pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. This application was granted Priority Review, Fast Track designation, and Orphan Drug designation.