On October 13, the U.S. Food and Drug Administration (FDA) approved nivolumab (Opdivo) for the adjuvant treatment of completely resected stage IIB or IIC melanoma in patients aged 12 years and older.
CheckMate 76K
Efficacy was evaluated in CheckMate 76K (ClinicalTrials.gov identifier NCT04099251), a randomized, double-blind trial enrolling 790 patients with stage IIB/IIC melanoma. Patients were randomly assigned 2:1 to receive either nivolumab at 480 mg or placebo by intravenous infusion every 4 weeks for up to 1 year or until disease recurrence or unacceptable toxicity.
Enrollment required complete resection of the primary melanoma with negative margins and a negative sentinel lymph node within 12 weeks prior to random assignment, and an Eastern Cooperative Oncology Group performance status of 0 or 1. The trial excluded patients with ocular/uveal or mucosal melanoma, autoimmune disease, any condition requiring systemic treatment with either corticosteroids (≥10 mg daily prednisone or equivalent) or other immunosuppressive medications, and who had received any prior melanoma therapy except surgery. Random assignment was stratified by the American Joint Committee on Cancer staging system, 8th edition (T3b vs T4a vs T4b).
The major efficacy outcome measure was recurrence-free survival, defined as the investigator-assessed time between random assignment and first recurrence (local, regional, or distant metastasis), new primary melanoma, or death from any cause—whichever occurred first. Assessments were conducted every 26 weeks during years 1 to 3 and every 52 weeks thereafter for 5 years. Median recurrence-free survival was not reached in either the nivolumab arm (95% confidence interval [CI] = 28.5 months to not reached) or in the placebo arm (95% CI = 21.6 months to not reached, hazard ratio = 0.42, 95% CI = 0.30–0.59, P = .0001).
The most common adverse reactions (reported in ≥ 20% of patients) were fatigue, musculoskeletal pain, rash, diarrhea, and pruritus.
Additional Details
The recommended nivolumab dose for patients weighing 40 kg or greater is 240 mg every 2 weeks or 480 mg every 4 weeks until disease progression or unacceptable toxicity for up to 1 year. The recommended dose for pediatric patients weighing less than 40 kg is 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks until disease progression or unacceptable toxicity for up to 1 year.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence that 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, Health Canada, Israel’s Ministry of Health, and Switzerland’s Swissmedic. The application reviews are 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. The application was granted Orphan Drug designation.
