title: Combination dabrafenib and trametinib in the management of advanced melanoma with BRAFV600 mutations.
abstract: BACKGROUND
  In the 40-50% of advanced melanoma patients with tumors harboring BRAF V600E and V600 K mutations, BRAF inhibitors such as dabrafenib are a highly effective treatment. However, most patients develop resistance after several months on treatment. The addition of a MEK inhibitor, such as trametinib, to BRAF inhibition mitigates one key pathway of resistance, further increasing response rates and improving survival.
  
  
  METHODS
  This article summarizes the mechanism of action of the combination of dabrafenib and trametinib, its evolution through Phase I, II and III clinical trials and discusses its current use in the management of patients with advanced melanoma.
  
  
  CONCLUSIONS
  Combination therapy with dabrafenib and trametinib improves response rate, progression-free survival and overall survival when compared to dabrafenib or vemurafenib alone. The addition of trametinib to dabrafenib changes the adverse event profile, making hyperkeratosis and cutaneous squamous cell carcinomas less common but side effects such as fever and nausea more common. How dabrafenib/trametinib is best sequenced with other effective treatments such as immune checkpoint blockade remains uncertain.
authors.affiliation: a Melanoma Unit, Royal Marsden Foundation NHS Trust , London , UK.
authors.forename: Lavinia
authors.initials: L
authors.lastname: Spain
authors.affiliation: a Melanoma Unit, Royal Marsden Foundation NHS Trust , London , UK.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Julve
authors.affiliation: a Melanoma Unit, Royal Marsden Foundation NHS Trust , London , UK.
authors.forename: James
authors.initials: J
authors.lastname: Larkin
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005334:Fever / Q000139:chemically induced; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics; D009154:Mutation; D009325:Nausea / Q000139:chemically induced; D010091:Oximes / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D011728:Pyridones / Q000008:administration & dosage; D011744:Pyrimidinones / Q000008:administration & dosage; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics
chemical_list: D007093:Imidazoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib
keywords: BRAF mutation; Dabrafenib; MAPK pathway; advanced melanoma; toxicity; trametinib