As reported in The Lancet by Livingstone et al, the final analysis of the German phase II IMMUNED trial showed significantly improved recurrence-free survival with adjuvant nivolumab/ipilimumab and nivolumab alone vs placebo in patients with resected stage IV melanoma who had no evidence of disease after undergoing resection or radiotherapy. Nivolumab/ipilimumab—but not nivolumab alone—was associated with significantly improved overall survival, although findings may have been confounded by the common use of subsequent anti–PD-1 therapy in the placebo group.
The initial report from the trial showed a significant recurrence-free survival benefit with nivolumab/ipilimumab and nivolumab alone vs placebo.
Study Details
In the double-blind multicenter trial, 167 patients were randomly assigned 1:1:1 between September 2015 and November 2018 to receive nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks for four doses, followed by nivolumab at 3 mg/kg every 2 weeks (n = 56), nivolumab at 3 mg/kg every 2 weeks (n = 59), or matching placebo (n = 52) for up to 1 year. Crossover to nivolumab from the placebo group was permitted at disease recurrence; a total of 19 patients crossed over to receive nivolumab.
Key Findings
The median follow-up at final analysis was 49.2 months (interquartile range = 34.9–58.1 months). Median recurrence-free survival was not reached (95% confidence interval [CI] = 25.0 months–not reached) in the nivolumab/ipilimumab group (hazard ratio [HR] vs placebo = 0.25, 97.5% CI = 0.13–0.48, P < .0001), 12.3 months (95% CI = 5.3–23.9 months) in the nivolumab group (HR vs placebo = 0.60, 97.5% CI = 0.36–1.00, P = .024), and 6.3 months (95% CI = 3.3–9.6 months) in the placebo group. Rates at 4 years were 64.2%, 31.4%, and 15.0%, respectively.
In addition to the 19 patients in the placebo group who crossed over to nivolumab, 14 (61%) of 23 patients with recurrence and available data in the placebo group also received anti–PD-1 therapy alone or in combination with other immunotherapy as their first subsequent systemic treatment.
Median overall survival was not reached in any study group. The 25th percentile was not reached (95% CI = 34.1 months–not reached) in the nivolumab/ipilimumab group, 43.2 months (95% CI = 20.4 months–not reached) in the nivolumab group, and 31.9 months (95% CI = 21.8 months–not reached) in the placebo group. Hazard ratios were 0.41 (95% CI = 0.17–0.99, P = .040) for nivolumab/ipilimumab vs placebo and 0.75 (95% CI = 0.36–1.56, P = .44) for nivolumab vs placebo. Rates at 4 years were 93.9%, 87.3%, and 63.1%, respectively.
Rates of grade 3 or 4 treatment-related adverse events were largely unchanged from the prior study report, observed in 71% of patients in the nivolumab/ipilimumab group and 29% of patients in the nivolumab group. No treatment-related deaths were observed.
The investigators concluded, “Both active regimens continued to show significantly improved recurrence-free survival compared with placebo in patients with stage IV melanoma with no evidence of disease who were at high risk of recurrence. Overall survival was significantly improved for patients receiving nivolumab plus ipilimumab compared with placebo. Use of subsequent anti–PD-1–based therapy was high in patients in the placebo group after recurrence and most likely impacted the overall survival comparison of nivolumab alone vs placebo. The recurrence-free and overall survival benefit of nivolumab plus ipilimumab over placebo reinforces the change of practice already initiated for the treatment of patients with stage IV melanoma with no evidence of disease.”
Dirk Schadendorf, MD, of the Department of Dermatology, University Hospital Essen, is the corresponding author for The Lancet article.
Disclosure: The study was funded by Bristol Myers Squibb. For full disclosures of the study authors, visit thelancet.com.
