On December 22, 2014, the U. S. Food and Drug Administration granted accelerated approval to nivolumab (OPDIVO, Bristol-Myers Squibb Company) for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.
Nivolumab is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby releasing PD-1 pathway-mediated inhibition of the immune response, including anti-tumor immune response.
Approval was based on objective response rate (ORR) and durability of response in the first 120 patients who were treated with nivolumab and had a minimum 6 months follow- up from an on-going, randomized, open-label trial in which 370 patients with unresectable or metastatic melanoma received nivolumab 3 mg/kg intravenously every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102). Chemotherapy included either dacarbazine or the combination of carboplatin plus paclitaxel. Patients were treated until disease progression or unacceptable toxicity. Patients with unresectable or metastatic melanoma were required to have disease progression following ipilimumab, and a BRAF inhibitor if BRAF V600 mutation positive. Patients were excluded from the trial if they had an autoimmune disease, a medical condition that required corticosteroids or immunosuppression, or a history of severe ipilimumab-related adverse reactions.
Among these 120 patients, 65% were male, the median age was 58 years (68% less than age 65), 98% were White, and 58% and 42% had a baseline ECOG performance status of 0 or 1, respectively. Disease characteristics included BRAF V600 mutation -positive melanoma (22%), elevated lactate dehydrogenase (56%), M1c disease (76%), history of brain metastases (18%), and two or more prior therapies for advanced or metastatic disease (68%).
The major efficacy endpoints were confirmed ORR according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and response duration. ORR was assessed by a blinded independent review committee. The ORR was 32% (95% CI: 23, 41) with four complete responses and 34 partial responses. Five responding patients have progressed, while the remaining 33 patients (87%) have ongoing responses (range 2.6+ to 10+ months). Thirteen patients have ongoing responses of 6 months or longer.
The most common (greater than or equal to 20%) adverse reaction among the 268 patients receiving nivolumab was rash. The most frequent Grade 3 and 4 adverse drug reactions observed in 2% to less than 5% with nivolumab were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. Clinically significant immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, nephritis/renal dysfunction, hypothyroidism, and hyperthyroidism.
As a condition of this accelerated approval, Bristol-Myers Squibb is required to conduct a multicenter, randomized trial(s) establishing the superiority of nivolumab over standard therapy in adult patients with unresectable or metastatic melanoma to verify and describe the clinical benefit of nivolumab.
FDA granted nivolumab breakthrough therapy designation in September 2014 based on preliminary evidence of clinical activity in this patient population.
The recommended dose of nivolumab is 3 mg/kg, administered as an intravenous infusion over 60 minutes, every 2 weeks.
Full prescribing information is available at:
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 by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).