title: Combined BRAF and MEK inhibition for the treatment of BRAF-mutated metastatic melanoma.
abstract: Combined BRAF and MEK inhibition out-performed BRAF inhibitor monotherapy in 3 randomized Phase 3 studies for BRAF-mutated metastatic melanoma patients and the combination of BRAF inhibitor dabrafenib with MEK inhibitor trametinib is now an FDA-approved treatment in this setting. Nevertheless, the majority of patients face progressive disease even when treated with the combination. Mechanisms of resistance to BRAF inhibition have been extensively investigated, whilst less is known about the specific mechanisms of resistance to combined therapy. The aim of this paper is to review the efficacy and safety of the combination of BRAF plus MEK inhibitors compared with BRAF inhibitor monotherapy and immunotherapy, as well as to discuss the existing evidence for the mechanisms of resistance to combined therapy and assess future treatment strategies to improve outcome based on data provided by clinical and translational research studies.
authors.affiliation: Department of Medical Oncology, IRCCS San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Queirolo
authors.affiliation: Department of Medical Oncology, IRCCS San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
authors.forename: Virginia
authors.initials: V
authors.lastname: Picasso
authors.affiliation: Department of Plastic and Reconstructive Surgery, IRCCS San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy. Electronic address: francesco.spagnolo85@gmail.com.
authors.forename: Francesco
authors.initials: F
authors.lastname: Spagnolo
mesh_terms: D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000556:secondary; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009154:Mutation; D010091:Oximes / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics*; D011728:Pyridones / Q000008:administration & dosage; D011744:Pyrimidinones / Q000008:administration & dosage
chemical_list: D007093:Imidazoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases; C561627:dabrafenib
keywords: BRAF; Dabrafenib; MEK; Melanoma; Trametinib; Vemurafenib