On October 13, 2023, the U.S. Food and Drug Administration (FDA) approved nivolumab (Opdivo®) for the adjuvant treatment of completely resected stage IIB/C melanoma in patients aged 12 years and older.
Efficacy was evaluated in CHECKMATE-76K (NCT04099251), a randomized, double-blind trial enrolling 790 patients with stage IIB/C melanoma. Patients were randomized 2:1 to receive nivolumab 480 mg or placebo by IV infusion every four weeks for up to one year or until they experienced 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 randomization and ECOG 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, as well as those with prior melanoma therapy other than surgery. Randomization was stratified by the American Joint Committee on Cancer’s Eighth Edition Cancer Staging Manual (T3b versus T4a versus T4b).
The major efficacy outcome measure was recurrence-free survival (RFS) defined as the investigator-assessed time between randomization 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 for the first three years and every 52 weeks thereafter for five years. Median RFS was not reached in either the nivolumab arm (95% CI = 28.5, not reached) or in the placebo arm (95% CI = 21.6, not reached) (HR = 0.42 [95% CI = 0.30, 0.59]; p < 0.0001).
The most common adverse reactions reported in at least 20% of patients were fatigue, musculoskeletal pain, rash, diarrhea, and pruritis.
The recommended nivolumab dose for patients weighing 40 kg or greater is 240 mg every two weeks or 480 mg every four weeks for up to one year or until they experience disease progression or unacceptable toxicity. The recommended dose for pediatric patients weighing less than 40 kg is 3 mg/kg every two weeks or 6 mg/kg every four weeks for up to one year or until they experience disease progression or unacceptable toxicity.
The review was conducted under Project Orbis, an FDA Oncology Center of Excellence initiative that provides a framework for concurrent submission and review of oncology drugs among international partners. For the review, 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.
The review used the Real-Time Oncology Review pilot program, which streamlined data submission prior to completing the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate FDA’s assessment. The application was granted orphan drug designation. FDA expedited programs are described 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 800-FDA-1088.
For assistance with single-patient applications for investigational oncology products, healthcare professionals may contact the Office of Oncology Excellence’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.