title: Novel targets in the treatment of advanced melanoma: new first-line treatment options.
abstract: OBJECTIVE
  To discuss the clinical efficacy and safety of ipilimumab, vemurafenib, and investigational agents for the treatment of unresectable stage III and stage IV melanoma and define current strategies of first-line treatment selection.
  
  
  METHODS
  Literature was accessed through MEDLINE and International Pharmaceutical Abstracts (1970-November 2012) using the terms melanoma, metastatic melanoma, ipilimumab, vemurafenib, dabrafenib, and trametinib. In addition, reference citations from publications identified were reviewed.
  
  
  METHODS
  All articles published in English identified from the data sources were evaluated. Studies and abstracts including more than 10 adult patients were included in the review.
  
  
  RESULTS
  Treatment options for unresectable stage III and IV melanoma are poor and have remained largely unchanged for the past 40 years. Two randomized Phase 3 clinical trials have demonstrated a significant survival benefit with the use of ipilimumab compared to a melanoma vaccine (10.1 vs 6.4 months; p = 0.003) and compared to dacarbazine (11.2 months, 95% CI 9.4-13.6 vs 9.1 months, 95% CI 7.8-10.5). Additionally, long-term follow-up has revealed cases of durable responses of greater than 3 years. Response rates of 50% and greater have been described in vemurafenib-treated patients (1 Phase 1, 1 Phase 2, and 1 Phase 3 randomized trial), although duration of response has not been fully determined. Both new agents possess unique toxicity profiles including immune-related adverse events with ipilimumab and secondary cutaneous cancers reported with vemurafenib use.
  
  
  CONCLUSIONS
  Treatment strategies have changed for patients with advanced melanoma with the use of ipilimumab and vemurafenib as first-line agents. Increased clinical experience and further published data with these and investigational agents will guide the development of treatment algorithms outlining optimal drug selection and sequencing as well as improve management of their novel adverse events.
authors.affiliation: Department of Pharmacy Practice, University of Illinois at Chicago, Chicago IL, USA. kclenn2@uic.edu
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Culos
authors.forename: Sandra
authors.initials: S
authors.lastname: Cuellar
mesh_terms: D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000009:adverse effects; D002986:Clinical Trials as Topic; D003606:Dacarbazine / Q000009:adverse effects / Q000627:therapeutic use; D015507:Drugs, Investigational / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use; D000074324:Ipilimumab; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D016032:Randomized Controlled Trials as Topic; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use; D000077484:Vemurafenib
chemical_list: D000911:Antibodies, Monoclonal; D019496:Cancer Vaccines; D015507:Drugs, Investigational; D007211:Indoles; D000074324:Ipilimumab; D013449:Sulfonamides; D000077484:Vemurafenib; D003606:Dacarbazine