Hodi FS, et al. - Researchers sought to provide 4-year updated data on effectiveness and safety of nivolumab plus ipilimumab or nivolumab alone vs ipilimumab alone in patients with advanced melanoma. As per data, in patients with advanced melanoma, first-line nivolumab plus ipilimumab or nivolumab alone can provide a durable, sustained survival benefit.

Methods

• Experts conducted a phase 3 trial in which the eligible patients were aged 18 years or older with previously untreated, unresectable, stage III or stage IV melanoma, known BRAF^V600mutation status, and an Eastern Cooperative Oncology Group performance status of 0 or 1.
• They randomly assigned 1:1:1 the patients to receive intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks, or nivolumab 3 mg/kg every 2 weeks plus placebo, or ipilimumab 3 mg/kg every 3 weeks for four doses plus placebo.
• They performed randomization via an interactive voice response system with a permuted block schedule (block size of six) and stratification by PD-L1 status, BRAF mutation status, and metastasis stage.
• They masked the patients, investigators, study site staff, and study funder to the study drug administered.
• Progression-free survival and overall survival were the co-primary endpoints.
• They performed efficacy analyses on the intention-to-treat population, whereas safety was assessed in all patients who received at least one dose of study drug.
• The 4-year update of the ongoing study with a database lock date of May 10, 2018 were reflected by the results presented in this report.

Results

• As per data, 945 patients were enrolled and randomly assigned to nivolumab plus ipilimumab (n=314), nivolumab (n=316), or ipilimumab (n=315) between July 3, 2013 and March 31, 2014.
• In the nivolumab plus ipilimumab group, median follow-up was 46.9 months (IQR 10.9–51.8), in the nivolumab group it was 36.0 months (10.5–5.4), and 18.6 months (7.6–49.5) in the ipilimumab group.
• Findings suggested that at a minimum follow-up of 48 months from the date that the final patient was enrolled and randomized, median overall survival was not reached (95% CI 38.2–not reached) in the nivolumab plus ipilimumab group, 36.9 months (28.3–not reached) in the nivolumab group, and 19.9 months (16.9–24.6) in the ipilimumab group.
• They noted 0.54 (95% CI 0.44–0.67; p < 0.0001) to be the hazard ratio for death for the combination vs ipilimumab and for nivolumab vs ipilimumab was 0.65 (0.53–0.79; p < 0.0001).
• Researchers noted the median progression-free survival to be 11.5 months (95% CI 8.7–19.3) in the nivolumab plus ipilimumab group, 6.9 months (5.1–10.2) in the nivolumab group, and 2.9 months (2.8–3.2) in the ipilimumab group.
• For progression-free survival, the hazard ratio for the combination vs ipilimumab was 0.42 (95% CI 0.35–0.51; p < 0.0001) and for nivolumab vs ipilimumab was 0.53 (0.44–0.64; p < 0.0001).
• Results demonstrated that treatment-related grade 3-4 adverse events were reported in 185 (59%) of 313 patients who received nivolumab plus ipilimumab, 70 (22%) of 313 who received nivolumab, and 86 (28%) of 311 who received ipilimumab.
• In the nivolumab plus ipilimumab group (29 [9%] of 313) and in the nivolumab group (nine [3%] of 313), the most common treatment-related grade 3 adverse events were diarrhea and it was colitis in the ipilimumab group (23 [7%] of 311); the most common grade 4 adverse event in all three groups was increased lipase (15 [5%] of 313 in the combination group, ten [3%] of 313 in the nivolumab group, and four [1%] of 311 in the ipilimumab group).
• They did not analyze the serious adverse events for the 4-year follow-up.
• Over all, there were four treatment-related deaths: two in the nivolumab plus ipilimumab group (one cardiomyopathy and one liver necrosis), one in the nivolumab group (neutropenia), and one in the ipilimumab group (colon perforation).
• Since the previous (3-year) analysis, no additional treatment-related deaths have occurred.