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Immunotherapy Editorial The Future of Melanoma Immunotherapy Nikhil I Khushalani, MD 1 and Vernon K Sondak, MD 2 1. Associate Member, Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida, US; Associate Professor, Department of Oncologic Sciences, University of South Florida Morsani College of Medicine, Tampa, Florida, US; 2. Chair, Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida, US; Professor, Departments of Oncologic Sciences and Surgery, University of South Florida Morsani College of Medicine, Tampa, Florida, US Abstract The resurgence of immunotherapy in melanoma has led to impressive gains in therapeutic outcome. Yet we remain limited in our ability to predict response, toxicity, and prognosis. In this brief review, we outline pressing questions for clinical investigation using the backbone of checkpoint inhibition in melanoma. Future trials must also evaluate strategies to improve the economics of melanoma therapy. Keywords Immunotherapy, melanoma, checkpoint inhibitors, PD-1, biomarkers, pharmacoeconomics Disclosure: Nikhil I Khushalani, MD, has received research funding (to Institute) from Merck, Amgen, Bristol-Myers Squibb, and GlaxoSmithKline, participated in Advisory Boards for Castle Bioscience, and on Data Safety Monitoring Boards for AstraZeneca. Vernon K Sondak, MD has participated in consultancy or Advisory Boards for Merck, Genentech/ Roche, Amgen, Provectus, Bristol-Myers Squibb, and Novartis, and on Data Safety Monitoring Boards for Bristol-Myers Squibb, Array, Novartis, Polynoma, and Pfizer. No funding was received in the publication of this article. This article is a short opinion piece and has not been submitted to external peer reviewers. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: April 20, 2016 Published Online: April 26, 2016 Citation: Oncology & Hematology Review, 2016;12(1):29–30 Correspondence:Nikhil I Khushalani, MD, Cutaneous Oncology, H Lee Moffitt Cancer Center, 10920 N. McKinley Drive, Tampa, FL 33612, US. E: In no other cancer in recent times has the impact of immunotherapy been so profound as melanoma. An understanding of molecular underpinnings in this disease has led to the rational development of immunotherapy, leading to unprecedented tumor response and importantly an improvement in overall survival in metastatic melanoma. The identification and development of antibodies to block the immune checkpoint proteins cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1) led to regulatory approvals of ipilimumab (anti-CTLA-4) and nivolumab and pembrolizumab (anti-PD-1), and most recently the combination of ipilimumab plus nivolumab in the US. The availability of these immunotherapies has prompted medical oncologists to become more optimistic about long term durable responses and even cure in advanced melanoma. Anti-PD-1 therapy is now the standard front-line option for most patients with unresectable metastatic melanoma. For BRAF V600 mutated melanoma, targeting the mitogen-activated protein (MAP)-kinase pathway through combined BRAF and MEK inhibition is an alternative option, especially in the face of rapidly progressive or symptomatic disease. In ipilimumab-naïve patients, the objective response rate to single agent nivolumab or pembrolizumab ranges from 33–44%, with 1-year survival exceeding 70%. 1,2 Contrast this to the chemotherapy era, where the median survival for metastatic melanoma was typically well under one year. 3 The clinical investigation into dual inhibition of the PD-1 and CTLA-4 checkpoints was the natural sequel. In a series of well-conducted clinical trials, combination nivolumab plus ipilimumab has demonstrated a high TOU CH MED ICA L MEDIA objective response rate of approximately 50–60%. 4-6 However, more than half of the patients receiving the combination experienced grade 3 or 4 toxicity, and one-third needed to discontinue therapy secondary to adverse effects. But whether the very high response rate will translate into a meaningful improvement in survival compared to the far less toxic single agent anti-PD-1 therapy is yet to be determined. Hence, the applicability of the ipilimumab/nivolumab combination to all comers of metastatic melanoma is questionable. Rather, we believe the decision between single-agent and combination immunotherapy must be determined on a case-by-case basis, taking into account the burden of disease, need for rapid response, and existence of co-morbid conditions. Investigations into altered dose schedules of checkpoint inhibitor combinations are underway (NCT02714218, NCT02089685), and may help identify a more tolerable combination regimen without compromise of efficacy. While the start of this decade could be defined as the ‘watershed’ era in melanoma therapeutics, we are far from declaring total victory over melanoma. Over 10,000 deaths are predicted to occur in the US in 2016, 7 a number that continues to rise over prior years despite our therapeutic advances. Moreover, projections estimate melanoma will double in incidence and become the fifth most common cancer in this country by 2030, certainly a sobering statistic. 8 Hence we must continue to build on recent successes in immunotherapy. We believe the following questions must form the premise of the current and next generation of clinical trials of immunotherapy in melanoma: 29