The following is a message from the Director of the FDA Oncology Center of Excellence, Dr. Richard Pazdur
On March 18, 2022, the Food and Drug Administration approved nivolumab and relatlimab-rmbw (Opdualag, Bristol-Myers Squibb Company) for adult and pediatric 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 programmed death receptor-1 blocking antibody nivolumab.
Efficacy was evaluated in RELATIVITY-047 (NCT03470922), a randomized (1:1), 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 randomized 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 Blinded Independent Central Review (BICR) using RECIST v1.1. The trial demonstrated a statistically significant improvement in PFS by BICR for Opdualag compared to nivolumab (HR=0.75; 95% confidence interval [CI]: 0.62, 0.92; p-value=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 diarrhea. The most common laboratory abnormalities (≥20%) were decreased hemoglobin, decreased lymphocytes, increased AST, increased ALT, and decreased sodium.
The recommended Opdualag dose for adult and pediatric 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 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. 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 (TGA), and Switzerland’s Swissmedic. The application reviews may be ongoing at the other regulatory agencies.
This review used the Real-Time Oncology Review (RTOR) 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. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.
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 or by calling 1-800-FDA-1088.
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Please visit the FDA Hematology/Oncology (Cancer) Approvals & Safety Notifications webpage for a list of current and past approvals.