On 18 March 2022, the US Food and Drug Administration (FDA) approved nivolumab and relatlimab-rmbw (Opdualag, Bristol-Myers Squibb Company) for adult and paediatric patients 12 years of age or older with unresectable or metastatic melanoma. Opdualag is a fixed-dose combination of the LAG-3-blocking antibody relatlimab and the PD1-blocking antibody nivolumab.

Efficacy was evaluated in RELATIVITY-047 (NCT03470922), a randomised (1:1), double-blind study conducted in 714 patients with previously untreated metastatic or unresectable Stage III or IV melanoma. The study 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 randomised to receive Opdualag (nivolumab 480 mg and relatlimab 160 mg) by intravenous infusion every 4 weeks or nivolumab 480 mg by intravenous infusion every 4 weeks until disease progression or unacceptable toxicity.

The major efficacy outcome measure was progression-free survival (PFS) determined by blind independent central review (BICR) using RECIST v1.1. The study demonstrated a statistically significant improvement in PFS by BICR for Opdualag compared to nivolumab (hazard ratio [HR] 0.75; 95% confidence interval [CI] 0.62, 0.92; p = 0.0055). Median PFS was 10.1 months (95% CI 6.4, 15.7) in the Opdualag arm and 4.6 months (95% CI 3.4, 5.6) in the nivolumab arm. An additional efficacy outcome measure was overall survival (OS). The final analysis of OS was not statistically significant (HR 0.80; 95% CI 0.64, 1.01) with median OS not reached (NR) in the Opdualag arm (95% CI 34.2, NR) and 34.1 months (95% CI 25.2, NR) in the nivolumab arm.

The most common adverse reactions (≥20%) of Opdualag, were musculoskeletal pain, fatigue, rash, pruritus, and diarrhoea. The most common laboratory abnormalities (≥20%) were decreased haemoglobin, decreased lymphocytes, increased AST, increased ALT, and decreased sodium.

The recommended Opdualag dose for adult and paediatric patients 12 years of age or older who weigh at least 40 kg is 480 mg nivolumab and 160 mg relatlimab administered intravenously every 4 weeks until disease progression or unacceptable toxicity occurs. The recommended dose for paediatric patients 12 years of age or older who weigh less than 40 kg has not been established.

Full prescribing information for Opdualag is available here.

This review was conducted under Project Orbis, an initiative of the FDA’s Oncology Center of Excellence (OCE). Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, 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 programme, 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.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact FDA OCE’s Project Facilitate.