Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial

Abstract

BACKGROUND: Any benefit of adjuvant interferon alfa-2b for melanoma could depend on dose and duration of treatment. Our aim was to determine whether pegylated interferon alfa-2b can facilitate prolonged exposure while maintaining tolerability. METHODS: 1256 patients with resected stage III melanoma were randomly assigned to observation (n=629) or pegylated interferon alfa-2b (n=627) 6 mug/kg per week for 8 weeks (induction) then 3 mug/kg per week (maintenance) for an intended duration of 5 years. Randomisation was stratified for microscopic (N1) versus macroscopic (N2) nodal involvement, number of positive nodes, ulceration and tumour thickness, sex, and centre. Randomisation was done with a minimisation technique. The primary endpoint was recurrence-free survival. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00006249. FINDINGS: All randomised patients were included in the primary efficacy analysis. 608 patients in the interferon group and 613 patients in the observation group were included in safety analyses. The median length of treatment with pegylated interferon alfa-2b was 12 (IQR 3.8-33.4) months. At 3.8 (3.2-4.2) years median follow-up, 328 recurrence events had occurred in the interferon group compared with 368 in the observation group (hazard ratio 0.82, 95% CI 0.71-0.96; p=0.01); the 4-year rate of recurrence-free survival was 45.6% (SE 2.2) in the interferon group and 38.9% (2.2) in the observation group. There was no difference in overall survival between the groups. Grade 3 adverse events occurred in 246 (40%) patients in the interferon group and 60 (10%) in the observation group; grade 4 adverse events occurred in 32 (5%) patients in the interferon group and 14 (2%) in the observation group. In the interferon group, the most common grade 3 or 4 adverse events were fatigue (97 patients, 16%), hepatotoxicity (66, 11%), and depression (39, 6%). Treatment with pegylated interferon alfa-2b was discontinued because of toxicity in 191 (31%) patients. INTERPRETATION: Adjuvant pegylated interferon alfa-2b for stage III melanoma has a significant, sustained effect on recurrence-free survival.

Role of the pro-survival molecule Bfl-1 in melanoma

“…as an adjuvant therapy based on a phase III trial which indicated improvement in relapsefree survival rates 91 . The PEG protects the interferon protein from proteolysis, thereby increasing its half-life which acts as an immunoregulatory cytokine and induces apoptosis in malignant cells 92 .…”

The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma

“…Pegylated-interferon-α2b was approved by the FDA based on improvement in relapsefree survival in patients with microscopic nodal disease. 4 A post-hoc analysis also suggested that primary tumours harbouring ulceration were more likely to benefit from pegylated-interferon-α2b. 28 The panel considered this to be level B data in support of pegylated-interferon-α2b.…”

“…The consensus panel identified two immunotherapy agents with potential clinical benefit in the adjuvant therapy of patients with stage III melanoma: interferon-α2b and pegylated-interferon-α2b. 4,[24][25][26][27] Consensus management of microscopic nodal disease The panel recognized that patients with microscopically involved lymph nodes (N1a disease) might represent a different population than those with macroscopic nodal disease (N1b and N2-N3 disease). A majority (52.2%) of the panel recommends a standard 1-year course of interferon-α2b for the adjuvant therapy of microscopic nodal disease.…”

“…There is one prospective randomized clinical trial demon strating a benefit in relapse-free survival for patients with microscopic nodal disease treated with pegylated-interferon-α2b. 4 A post-hoc analysis of that trial also suggested patients with ulcerated primary tumours might derive more clinical benefit from pegylated-interferon-α2b. 28 In this analysis, patients with ulceration of their primary melanoma (n = 849) were compared to patients without ulceration of their primary melanoma (n = 1,336), and patients with ulceration demonstrated a significant improvement in relapse-free survival (P = 0.02), distant metastasis-free survival (P <0.001) and overall survival (P <0.001).…”

“…Since 2011, three new agents have been approved for the treatment of patients with melanoma: pegylated-interferon-α2b in the adjuvant setting, the anti-CTLA4 monoclonal antibody ipilimumab for metastatic disease and an oral BRAF inhibitor vemurafenib in patients with metastatic melanoma harbouring BRAF V600 mutations. [4][5][6] Tumour immunotherapy is the clinical application of pharmacological agents that directly induce or substitute for host antitumour immunity. Melanoma can be highly sensitive to immunotherapy and of the six approved drugs highlighted above only dacarbazine and vemurafenib are not immunotherapies.…”