Pegylated interferon for the adjuvant treatment of melanoma: FDA approved, but what is its role?

In 2011, the U.S. Food and Drug Administration (FDA) approved peginterferon-alfa-2b (Sylatron ; Merck/ScheringPlough, Kenilworth, NJ) for the adjuvant treatment of patients with resected node-positive melanoma based on the results of a single, large European Organization for Research and Treatment of Cancer (EORTC) trial showing a statistically significant improvement in the relapse-free survival (RFS) interval without an accompanying overall survival (OS) advantage [1]. The article by Herndon et al. [2] in this issue of The Oncologist helps to answer some of the questions that have surrounded this approval and provides important context to physicians counseling melanoma patients. This is particularly important because melanoma oncologists in the U.S. and worldwide had very limited experience using pegylated interferon for the adjuvant therapy of melanoma prior to the FDA approval [3]. Among the questions Herndon et al. [2] address are: Why approve this therapy based only on an RFS improvement? Why approve it for all patients with node-positive melanoma and not a subset, such as those with microscopic nodal involvement detected by sentinel node biopsy? Why approve a 5-year treatment regimen? Regarding the RFS interval, the FDA concluded that “the clinically meaningful prolongation in time without disease ..., which is evidence of direct clinical benefit given its magnitude” [2], outweighed the risk for toxicity, particularly in view of the lack of alternatives and salvage therapies. Their analysis of the EORTC data also indicated that the RFS benefit was “internally consistent across relevant subsets defined by... prognostic variables” [2], an important observation that differs from the conclusion of the EORTC investigators themselves [4]. By contrast, however, post hoc analyses were unable to discern the optimal dose or duration of peginterferon, and so they chose to approve the therapy for all node-positive patients in the dose and schedule used in the EORTC trial. They recognize the significance of the questions about dose and duration, which they believe is an issue for postmarketing trials to further explore. Despite the insights Herndon et al. [2] provide, many questions remain about the role of pegylated interferon—or any formulation, dose, and schedule of interferon for that matter—in the adjuvant therapy of patients with melanoma. Thousands of patients have been treated in adjuvant interferon trials evaluating dosing, schedule, toxicity, and quality of life, yet controversies persist regarding the OS benefit and the appropriateness of the RFS time as an endpoint justifying substantial toxicity. More importantly, many have asked whether or not advances in treating metastatic disease (salvage treatment) make adjuvant interferon regimens irrelevant. We agree with the FDA that the available evidence supporting the RFS benefit with adjuvant interferon and peginterferon is compelling, and note that current and future adjuvant trials (such as two large multicenter trials evaluating ipilimumab compared with either placebo or high-dose interferonalfa-2b) employ the RFS duration as a primary endpoint, in part because of concerns about the confounding effects of postrelapse therapy on the survival time. But from the patient’s perspective, delaying relapse is potentially more important than ever: we have more effective drugs for treating metastatic melanoma than ever, but their use has not been optimized and improvements are coming at a dramatic rate. Two to 3 years from now, treatments for stage IV melanoma will likely be substantively more effective and probably less toxic than they are now. A few extra months could afford patients access to options that would otherwise not be available in time. By contrast, evidence supporting a specific interferon dose, duration, or formulation—or identifying subsets of patients most likely to benefit from therapy—is currently uncon-