title: Controversies in the management of advanced melanoma: "gray" areas amid the "black and blue".
abstract: OBJECTIVE
  To examine the current controversies and discuss consensus recommendations regarding treatment sequencing and the role of BRAF inhibitor at disease progression.
  
  
  METHODS
  An English-language literature search of MEDLINE/PubMed (1966-May 2014), using the keywords advanced melanoma, ipilimumab, cytotoxic T-lymphocyte antigen 4, dabrafenib, vemurafenib, BRAF inhibitor, trametinib, MEK inhibitor, and treatment sequencing was conducted. Data were also obtained from package inserts, meeting abstracts, and clinical registries.
  
  
  METHODS
  All relevant published articles and abstracts on ipilimumab, vemurafenib, dabrafenib, and trametinib were reviewed. Clinical trial registries and meeting abstracts were used for ongoing studies.
  
  
  RESULTS
  The availability of new agents has made therapy selection more complex. Immunotherapy supporters reason that immunotherapy offers the best chance for long-term benefit and does not compromise the antitumor activity of subsequent BRAF inhibitors. Targeted therapy advocates rely on the high probability and rapid onset of response to BRAF inhibitors. Currently, there is insufficient evidence regarding the role of BRAF inhibitor at disease progression.
  
  
  CONCLUSIONS
  Therapy should be individualized based on patient- and disease-specific factors. Immunotherapy represents the best option for durable remission; however, targeted therapy is more appropriate for patients who are symptomatic or have rapidly growing tumors. The novel therapies have also demonstrated meaningful intracranial activity; thus, the presence of brain metastases should be taken into consideration in selecting therapy. Limited data exist about the continuation of BRAF inhibitors after therapeutic failure. Active research is ongoing to define the best option for patients with BRAF inhibitor refractory disease.
authors: University of Rochester Medical Center, Rochester, NY, USA.
authors: Anthony
authors: A
authors: Jarkowski
authors: South Carolina College of Pharmacy, Columbia, SC, USA.
authors: LeAnn
authors: L
authors: Norris
authors: The University of Texas MD Anderson Cancer Center, Houston, TX, USA vtrinh@mdanderson.org.
authors: Van Anh
authors: VA
authors: Trinh
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D060908:CTLA-4 Antigen / Q000276:immunology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D007167:Immunotherapy; D007211:Indoles / Q000627:therapeutic use; D000074324:Ipilimumab; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D010091:Oximes / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics; D011728:Pyridones / Q000627:therapeutic use; D011744:Pyrimidinones / Q000627:therapeutic use; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D013449:Sulfonamides / Q000627:therapeutic use; D000077484:Vemurafenib
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; D007093:Imidazoles; D007211:Indoles; D000074324:Ipilimumab; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D013449:Sulfonamides; D000077484:Vemurafenib; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C561627:dabrafenib
keywords: BRAF inhibitor; MEK inhibitor; advanced melanoma; cytotoxic T-lymphocyte antigen 4; dabrafenib; ipilimumab; trametinib; treatment sequencing; vemurafenib