As reported in the Journal of Clinical Oncology by Tarhini et al, the phase III Intergroup E1609 trial has shown an overall survival advantage with adjuvant ipilimumab at 3 mg/kg—but not at 10 mg/kg—vs high-dose interferon alfa-2b in patients with resected high-risk cutaneous melanoma. The investigators noted that this outcome marks the first time a survival benefit of adjuvant treatment has been observed against an active comparator in this setting.

Study Details

In the open-label trial, 1,670 adult patients with resected melanoma (stage IIIB, IIIC, M1a, or M1b) were randomly assigned 1:1:1 between May 2011 and August 2014 to receive ipilimumab at 3 mg/kg (n = 523), high-dose interferon (n = 636), or ipilimumab at 10 mg/kg (n = 511). Ipilimumab at both 3 mg/kg and 10 mg/kg was given every 3 weeks for four doses as induction therapy, followed by the same dose every 12 weeks for up to four additional doses as maintenance. High-dose interferon was given intravenously at 20 million units/m² per day 5 days per week for 4 weeks as induction therapy and was followed by 10 million units/m² per day subcutaneously every other day 3 days per week for 48 weeks as maintenance.

The co-primary endpoints were overall survival and relapse-free survival. Comparisons were made in a hierarchic approach that first evaluated 3 mg/kg of ipilimumab vs high-dose interferon, and then 10 mg/kg of ipilimumab vs high-dose interferon.

Overall and Relapse-Free Survival

The median follow-up was 57.4 months. The comparison of ipilimumab at 3 mg/kg vs high-dose interferon used an intent-to-treat analysis of 1,051 concurrently randomly assigned patients. The analysis (adjusted for previous interim analyses) showed hazard ratios of 0.78 (P = .044) for overall survival and 0.85 (P = .065) for relapse-free survival. Overall survival at 5 years was 72% vs 67%. Median relapse-free survival was 4.5 vs 2.5 years.

The comparison of ipilimumab at 10 mg/kg vs high-dose interferon used intent-to-treat analysis of 989 concurrently randomly assigned patients. The analysis showed hazard ratios of 0.88 (95.6% confidence interval [CI] = 0.69–1.12) for overall survival and 0.84 (99.4% CI = 0.65–1.09) for relapse-free survival. Overall survival at 5 years was 70% vs 65%. Median relapse-free survival was 3.9 years vs 2.4 years.

Adverse Events

Treatment-related grade ≥ 3 adverse events occurred in 37% of patients receiving 3 mg/kg of ipilimumab, 79% of those receiving high-dose interferon, and 58% of those receiving 10 mg/kg of ipilimumab. Adverse events led to treatment discontinuation in 35%, 20%, and 54% of patients, respectively.

Salvage Therapy

Salvage treatment after relapse showed higher rates of ipilimumab use after high-dose interferon vs after 3 mg/kg of ipilimumab or 10 mg/kg of ipilimumab (22.8% vs 7.6% and 4.8%), and higher rates of ipilimumab plus a programmed cell death protein 1 (PD-1) inhibitor (12.7% vs 6.6% and 3.9%); use of PD-1 inhibitor treatment alone was similar among groups (22% vs 25% and 19%).

The investigators concluded, “Adjuvant therapy with 3 mg/kg of ipilimumab benefits survival vs high-dose interferon; for the first time to our knowledge in melanoma adjuvant therapy, E1609 has demonstrated a significant improvement in overall survival against an active control regimen. The currently approved adjuvant ipilimumab dose (10 mg/kg of ipilimumab) was more toxic and not superior in efficacy to high-dose interferon.”

Ahmad A. Tarhini, MD, PhD, of the Department of Cutaneous Oncology, H. Lee Moffitt Comprehensive Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the National Cancer Institute and by Bristol-Myers Squibb. For full disclosures of the study authors, visit ascopubs.org.