Regulatory Decision Summary for Opdivo

Market authorization was primarily based on results of a single pivotal phase III, randomized, double-blind clinical trial in the adjuvant setting in patients with completely resected melanoma with regional lymph node involvement, in transit metastases/satellites without metastatic nodes, or distant metastases. Patients (n = 906) were randomized and received either nivolumab monotherapy (n = 453) as an intravenous infusion at 3 mg/kg every 2 weeks for up to 1 year or ipilimumab monotherapy (n = 453) as an intravenous infusion at 10 mg/kg every 3 weeks for 4 doses then every 12 weeks for up to 1 year. The primary efficacy outcome was recurrence-free survival (RFS). At the pre-planned interim analysis with a median follow-up of 19.5 months, nivolumab monotherapy demonstrated a statistically significant improvement in RFS [hazard ratio 0.65, 97.56% confidence interval: 0.51, 0.83; p<0.0001], corresponds to a 35% risk reduction of disease recurrence. As melanoma recurrence is often associated with distant metastases which lead to mortality and deterioration of quality of life, this magnitude of risk reduction of disease recurrence is considered clinically meaningful.

The safety profile of nivolumab in the adjuvant setting was generally consistent with the known safety profile of Opdivo. The most frequently reported adverse reactions (ARs, in ≥10%) in the nivolumab arm were fatigue, rash, diarrhea, pruritus, nausea, arthralgia, musculoskeletal pain and hyperthyroidism. Clinically significant ARs were less frequent in the nivolumab arm than the ipilimumab arm. Grade 3-4 ARs were reported in 14% and 46% in the nivolumab and ipilimumab arms, respectively. Eight percent of patients discontinued nivolumab treatment due to an AR compared to 42% of patients treated with ipilimumab. Serious ARs occurred in 5% of patients in the nivolumab arm versus 31% in the ipilimumab arm. No deaths due to study drug toxicity were reported in the nivolumab arm, compared with 2 (0.4%) in the ipilimumab arm. One case of fulminant type I diabetes was reported in the nivolumab arm and considered related to nivolumab. Fulminant type I diabetes is unique, serious variant of type I diabetes and considered a new identified risk of nivolumab.

Key safety and efficacy findings were adequately labeled in Opdivo Product Monograph.

Overall, adjuvant treatment option for resected melanoma at high risk of recurrence is limited in Canada. Based on the efficacy and safety results in the submission, the benefit/risk profile of nivolumab monotherapy administered as an intravenous infusion at 3 mg/kg every 2 weeks for up to 1 year is considered positive.