Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609

Abstract

Purpose: Phase III adjuvant trials have reported significant benefits in both relapse-free survival (RFS) and overall survival (OS) for high-dose interferon alfa (HDI) and ipilimumab at 10 mg/kg (ipi10). E1609 evaluated the safety and efficacy of ipilimumab at 3 mg/kg (ipi3) and ipi10 versus HDI.

Patients and methods: E1609 was a phase III trial in patients with resected cutaneous melanoma (American Joint Committee on Cancer 7th edition stage IIIB, IIIC, M1a, or M1b). It had 2 coprimary end points: OS and RFS. A 2-step hierarchic approach first evaluated ipi3 versus HDI followed by ipi10 versus HDI.

Results: Between May 2011 and August 2014, 1,670 adult patients were centrally randomly assigned (1:1:1) to ipi3 (n = 523), HDI (n = 636), or ipi10 (n = 511). Treatment-related adverse events grade ≥ 3 occurred in 37% of patients receiving ipi3, 79% receiving HDI, and 58% receiving ipi10, with adverse events leading to treatment discontinuation in 35%, 20%, and 54%, respectively. Comparison of ipi3 versus HDI used an intent-to-treat analysis of concurrently randomly assigned patient cases (n = 1,051) and showed significant OS difference in favor of ipi3 (hazard ratio [HR], 0.78; 95.6% repeated CI, 0.61 to 0.99; P = .044; RFS: HR, 0.85; 99.4% CI, 0.66 to 1.09; P = .065). In the second step, for ipi10 versus HDI (n = 989), trends in favor of ipi10 did not achieve statistical significance. Salvage patterns after melanoma relapse showed significantly higher rates of ipilimumab and ipilimumab/anti-programmed death 1 use in the HDI arm versus ipi3 and ipi10 (P ≤ .001).

Conclusion: Adjuvant therapy with ipi3 benefits survival versus HDI; for the first time to our knowledge in melanoma adjuvant therapy, E1609 has demonstrated a significant improvement in OS against an active control regimen. The currently approved adjuvant ipilimumab dose (ipi10) was more toxic and not superior in efficacy to HDI.

FIG 1.

E1609 CONSORT diagram. AE, adverse event; HDI, high-dose interferon alfa-2b; ipi3, ipilimumab at 3 mg/kg; ipi10, ipilimumab at 10 mg/kg; ITT, intent to treat. ^aAdult population. E1609 included a pediatric component (age 12-17 years) consisting of 3 separate cohorts randomly assigned to the 3 treatment regimens and analyzed separately for safety per study protocol. Total pediatric accrual was 3 patients. ^bThese overlap but are not identical with treatment-related grade 5 events reported in Table 2. ^cConcurrently randomly assigned patient cases.

FIG 2.

Kaplan-Meier plots of (A) overall survival (OS; hazard ratio [HR], 0.78; 95.6% repeated CI [RCI], 0.61 to 0.99; P = .044) and (B) relapse-free survival (RFS; HR, 0.85; 99.4% CI, 0.66 to 1.09; P = .065) with 3 mg/kg of ipilimumab (ipi3) versus high-dose interferon alfa-2b (HDI). Includes intent-to-treat concurrently randomly assigned patient cases in the 2 arms being compared.

FIG 3.

Kaplan-Meier plots of (A) overall survival (OS; hazard ratio [HR], 0.88; 95.6% CI, 0.69 to 1.12) and (B) relapse-free survival (RFS; HR, 0.84; 99.4% CI, 0.65 to 1.09) with 10 mg/kg of ipilimumab (ipi10) versus high-dose interferon alfa-2b (HDI).