The FDA has granted a priority review to a supplemental biologics license application (sBLA) for nivolumab (Opdivo) to treat patients with melanoma who are at high risk of disease recurrence following complete surgical resection, according to Bristol-Myers Squibb (BMS), the manufacturer of the PD-1 inhibitor.
Previously, the FDA granted a breakthrough designation for nivolumab in this setting. The priority review is based on results from the CheckMate-238 trial, in which nivolumab significantly improved relapse-free survival (RFS) versus standard ipilimumab (Yervoy) in patients with resected stage IIIB/C and IV melanoma.
“Priority review of our sBLA and the granting of breakthrough designation are positive steps forward in our goal to address the high unmet need that exists among patients with resected advanced melanoma, many of whom experience disease recurrence,” Murdo Gordon, BMS executive vice president and chief commercial officer, said in a press release.
From March 2015 to November 2015, CheckMate-238 randomized patients aged 15 years or older with stage IIIB, IIIC, or IV melanoma to either 3 mg/kg of nivolumab every 2 weeks (n = 453) or 10 mg/kg of ipilimumab every 3 weeks for 4 doses, then every 12 weeks (n = 453) for 1 year or until documented disease progression or unacceptable toxicity. The primary endpoint was RFS, defined as the time between randomization and the date of first recurrence or death.
Randomization was stratified according to disease stage (IIIB or IIIC, stage IV M1a or M1b, or stage IV M1c) and PD-L1 status (negative or intermediate vs positive) on the basis of a 5% cutoff.
At a minimum follow-up of 18 months, the 12-month RFS rate was 70.5% (95% CI, 66.1-74.5) in the nivolumab group versus 60.8% (95% CI, 56.0-65.2) in the ipilimumab group (hazard ratio [HR] for disease recurrence or death, 0.65; 97.56% CI, 0.51-0.83; P
Among the patients with PD-L1 expression <5%, the 12-month RFS rate was 64.3% (95% CI, 58.3-69.7) in the nivolumab group and 53.7% (95% CI, 47.6-59.4) in the ipilimumab group. Among those with PD-L1 expression ≥5%, the 12-month RFS rate was 81.9% (95% CI, 74.7-87.2) in the nivolumab arm and 73.8% (95% CI, 65.9-80.1) in the ipilimumab arm.
Median RFS had not been reached in patients with stage III or stage IV disease in the nivolumab group. Among the patients with stage IIIB or IIIC disease, the 12-month RFS rate was 72.3% (95% CI, 67.4-76.7) for those assigned to nivolumab and 61.6% (95% CI, 56.3-66.5) in the ipilimumab group. The twelve-month RFS rate also favored nivolumab among those with stage IV disease, at 63.0% (95% CI, 51.6-72.5) versus 57.5% (95% CI, 46.0-67.4).
Nivolumab was associated with significantly longer RFS, with recurrence or death reported in 32.7% of the nivolumab group compared with 44.5% in the ipilimumab group among those with stage IIIB or IIIC disease (HR, 0.65; 95% CI, 0.51-0.82). Among those with stage IV disease, 33 of 82 patients (40.2%) in the nivolumab group experienced recurrence or death versus 43 of 87 patients (49.4%) in the ipilimumab group (HR, 0.70; 95% CI, 0.45-1.10).
“In addition, a benefit for nivolumab was observed with respect to recurrence-free survival in nearly every subgroup tested, including those defined according to age, sex, disease stage, microscopic versus macroscopic nodal disease, ulceration status of the primary tumor, and BRAF status,” lead CheckMate-238 author Jeffrey Weber, MD, deputy director, Perlmutter Cancer Center, New York University Langone Medical Center, and coinvestigators wrote in the publication of the findings in the New England Journal of Medicine.
The median distant metastasis–free survival was not reached in either treatment group. However, distant metastasis–free survival was superior in patients assigned to nivolumab, with events reported in 93 of 369 patients (25.2%) versus 115 of 366 patients (31.4%) in the ipilimumab group (HR for distant metastasis or death, 0.73; 95% CI, 0.55-0.95).
Nearly 97% of the nivolumab group and 98.5% of the ipilimumab group reported adverse events (AEs) of any cause. Patients in the ipilimumab were more likely to experience grade 3/4 treatment-related AEs, at 45.9% vs 14.4%. The rate of serious AEs of any grade was 17.5% in the nivolumab group and 40.4% in the ipilimumab group.
Fewer than 10% of patients assigned to nivolumab (9.7%) discontinued the trial due to AEs compared with 42.6% of those in the ipilimumab group. Grade 3/4 AEs led to such discontinuations in 4.6% of nivolumab patients and 30.9% ipilimumab patients. Investigators determined that AEs related to a trial drug that led to discontinuation were less frequent in the nivolumab group than in the ipilimumab group (7.7% vs 41.7%).
There were 2 deaths (0.4%) in the ipilimumab group of marrow aplasia and colitis, both of which occurred more than 100 days after the last dose, and no treatment-related deaths in the nivolumab group.