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Melanoma Metastatic Melanoma Combination and Sequencing of Therapies for the Treatment of Metastatic Melanoma Richard W Joseph, 1 Ryan J Sullivan, 2 Ahmad A Tarhini 3 and Richard M Sherry 4 1. Department of Hematology and Oncology, Mayo Clinic, Jacksonville, Florida, US; 2. Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, US; 3. Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh; 4. Tumor Immunology Section, Surgery Branch, National Cancer Institute, Bethesda, Maryland, US Abstract Advances in molecular biology have lead to the development and approval of new treatments that improve survival for patients with metastatic melanoma. The limited duration of clinical response for targeted agents and the low overall response rate for immunotherapies illustrate that more work needs to be carried out. There are four Food and Drug Administration (FDA)-approved therapies for the treatment of metastatic melanoma. The optimal sequence of these therapies remains unclear with no prospective data to guide clinicians. It is also uncertain whether combining agents with different cell signaling properties or different immune mechanisms will provide therapeutic benefit to patients. Defining appropriate therapeutic sequences and or combinations may lead to improved treatment efficacy and is currently an area of active research. In this article we discuss recent advances in the treatment of metastatic melanoma and current treatment limitations. We summarize the limited clinical data on the sequencing and combination of therapies and discuss future therapeutic strategies. Keywords Combination therapy, metastatic melanoma, sequential therapy, targeted therapies Disclosure: The authors have no conflicts of interest to declare. Received: February 11, 2013 Accepted: April 8, 2013 Citation: Oncology & Hematology Review 2013;9(1):36–40. Correspondence: Richard W Joseph, 4500 San Pablo Road, Jacksonville, FL 32224, US. E: Joseph.Richard@mayo.edu Support: The publication of this article was sponsored by Prometheus. The views and opinions expressed are not necessarily those of Prometheus. Melanoma is the fifth leading cancer in men and the seventh in women. The incidence is increasing and it is estimated that in 2012 76,250 people in the US were diagnosed with melanoma of the skin and 9,180 died of the disease. 1 The majority of patients are cured following primary resection of the tumor; however, in approximately 16  % of cases, the disease will ultimately metastasize. 2 Melanoma has a propensity for hematogenous and lymphatic dissemination to regional and distant sites and has a low response rate (RR) to most systemic therapies. 3 The five-year survival rate for metastatic melanoma is poor, ranging from 5 % to 10 % 4 with a median survival of 8 to 9  months. 5 However, recent advances in immunotherapy and targeted therapy have translated into improved survival rates up to a median of 10–13 months. 6,7 response duration of 4–8 months, 8 a progression-free survival (PFS) of 1.5–3 months and limited overall survival (OS). To date, no clinical trials with DTIC or other chemotherapies have been reported to improve the OS of patients with metastatic melanoma. Although not approved for use in melanoma by the FDA, the oral prodrug temozolomide yields the same active intermediate (3-methyl-[triazen-1-yl]imidazole-4-carboxamide) as DTIC, is able to cross the blood–brain barrier, and has similar activity to DTIC. It is often used as an alternative to DTIC. A randomized phase III study of temozolomide versus DTIC for patients with advanced melanoma demonstrated that these agents have equal efficacy. The median OS was 7.7  months for patients treated with temozolomide and 6.4  months for those treated with DTIC. 9 Approved Therapies Immunotherapy with HD IL-2, a type 1 cytokine, at a dose of 600,000– 720,000 IU given to tolerance every 8 hours for up to 5 days is associated with an overall RR of approximately 16  %, with around 6  % of patients achieving durable complete responses (CRs) 10 Although this therapy can be associated with significant toxicities including hypotension, pulmonary edema, renal failure, and mental status changes, these side effects are transient and can be safely managed by experienced clinicians. A recent retrospective study suggested that patients with an elevated lactate dehydrogenase (LDH) may be less likely to derive benefit from HD IL-2 There are currently four US Food and Drug Administration (FDA)-approved treatments for metastatic melanoma: intravenous bolus high-dose interleukin-2 (HD IL-2), dacarbazine (DTIC), ipilimumab, and vemurafenib. DTIC was the first FDA-approved treatment and was considered the standard first-line therapy for patients with metastatic disease treatment prior to the emergence of ipilimumab and vemurafenib. DTIC is a cytotoxic alkylating agent and is associated with RRs of 5–15  %, with median 36 © Touc h ME dical ME dia 2013