High dose Interferon-α2b (HDI): Toxicity, response, and predictive markers in a neoadjuvant trial for regional lymph node metastatic melanoma

Abstract

7517 Background: High-dose interferon-α2b (HDI) is the only adjuvant therapy to show consistently significant clinical benefit in resected high-risk melanoma, as tested in randomized multicenter cooperative group trials. However, the mechanism of HDI action remains uncertain, and definition of its mechanism and response markers would allow improvement upon this therapy. Neoadjuvant application of interferon may improve surgical resectability, treatment responsiveness, and enable identification of surrogate endpoints for therapy. We investigated neoadjuvant HDI in patients (pts) with palpable regional lymph node positive melanoma (AJCC Stage IIIB and IIIC) to assess the feasibility, efficacy, and molecular-histological predictors of clinical outcome. Methods: Consenting pts with palpable biopsy-proven regional lymph node metastasis received one month of daily intravenous HDI followed by lymphadenectomy and standard maintenance HDI for one year. Responses were assessed clinically, pathologically, and radiographically at day 29. Proteomic and immunohistochemical (IHC) analysis of the pre- and post-treatment biopsies was performed. Results: 17 pts (age: median 57, range 41–76) were enrolled; 11 had regional lymph node recurrence and 6 initial node + presentation. 13 completed 4 weeks of intravenous HDI, and 4 required dose reduction. Response at day 29 was complete in 1, partial in 8, and pathology established complete response in 3, with microscopic residual disease in 4. At median follow up of 14 months (range 2–38 months) there were 4 deaths from metastatic disease, 4 alive with metastatic disease, and 9 have no evidence of disease. Grade 3 and 4 toxicities occurred in 4/17 pts requiring dose reduction in 3 pts and discontinuation of HDI in 1 pt. HDI significantly increased CD4+ cell infiltration of the tumor (p=0.03). Conclusions: Neoadjuvant HDI is well-tolerated and active in stage IIIB-IIIC disease, inducing clinical response in 53% of pts prior to definitive surgery in this study. In pts with clinical response to HDI an increase in CD4+ cell infiltration of tumor by IHC suggests an indirect immunomodulatory mechanism that is currently under intense study. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering-Plough Schering-Plough