The human programmed death receptor-1 (PD-1) blocking antibody nivolumab (Opdivo, Bristol-Myers Squibb Company) injection gained accelerated marketing approval for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab (Yervoy) and, if BRAF V600 mutation positive, a BRAF inhibitor. Nivolumab is approved for use in patients previously treated with Yervoy. Although both treatments are immunotherapies, PD-1 and CTLA-4 are distinct pathways.
This indication is approved under accelerated approval based on tumor response rate and durability of response. The company notes that continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
Nivolumab is associated with immune-mediated: pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, hypothyroidism and hyperthyroidism, and embryofetal toxicity.
The drug has demonstrated efficacy in a Phase 3, pivotal clinical trial with advanced melanoma in patients who had been previously treated and progressed with ipilimumab and, if BRAF mutation positive, a BRAF inhibitor. The efficacy of nivolumab was evaluated based on a single-arm, non-comparative planned interim analysis of the first 120 patients who received nivolumab with a minimum of 6 months follow-up in the Phase 3 CheckMate -037 trial.
Nivolumab achieved a 32% (95% CI: 23, 41) response rate (38/120) with a dosing strength and frequency of 3 mg/kg intravenously over 60 minutes every 2 weeks. Three percent of patients (4/120) achieved a complete response, and 28% (34/120) achieved a partial response. Of 38 patients with responses, 33 patients (87%) had ongoing responses with durability of response ranging from 2.6+ to 10+ months, which included 13 patients with ongoing responses of 6 months or longer. Responses to nivolumab were demonstrated in both patients with and without BRAF mutation.
In the Phase 3 CheckMate-037 trial, serious adverse reactions occurred in 41% of patients receiving nivolumab. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving nivolumab. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving nivolumab were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. The most common adverse reaction (≥20%) reported with nivolumab was rash (21%).
The approval of nivolumab gives patients and physicians an important new treatment option for a population where they were once very limited, according to Jeffrey S. Weber, MD, PhD, director of the Donald A. Adam Comprehensive Melanoma Research Center at Moffitt Cancer Center. “For the first time, a PD-1 blocking antibody has shown a response rate of 32% in a Phase 3 randomized clinical trial of patients with unresectable or metastatic melanoma, who have progressed following first line therapy,” he says, Efficacy was evaluated in a single-arm, non-comparative, planned interim analysis of the first 120 patients who received nivolumab in the CheckMate -037 trial in whom the minimum duration of follow up was 6 months.
“The emergence of effective immuno-oncology therapies that are capable of successfully treating metastatic melanoma has reinvigorated the field of cancer immunology with an optimism that immune based treatments will play a central role in therapeutic strategies for cancer patients,” says Jill O’Donnell-Tormey, Ph.D., CEO and director of Scientific Affairs at the Cancer Research Institute, a nonprofit organization dedicated to advancing the science of cancer immunology.
CheckMate -037 was a randomized, Phase 3 trial evaluating nivolumab 3 mg/kg (n=268), administered every 2 weeks, or chemotherapy (n=102) (investigator's choice of either single-agent dacarbazine 1000 mg/m2 every 3 weeks or the combination of carboplatin AUC 6 every 3 weeks plus paclitaxel 175 mg/m2 every 3 weeks) in patients with advanced melanoma who had been previously treated and progressed with ipilimumab and, if BRAF mutation positive, a BRAF inhibitor. No premedication is required with nivolumab.
