title: Cutaneous Toxic Effects of BRAF Inhibitors Alone and in Combination With MEK Inhibitors for Metastatic Melanoma.
abstract: OBJECTIVE
  The cutaneous adverse effects of the BRAF inhibitors vemurafenib and dabrafenib mesylate in the treatment of metastatic melanoma have been well reported. The addition of a MEK inhibitor to a BRAF inhibitor improves the blockade of the mitogen-activated protein kinase pathway. The combination of dabrafenib with the MEK inhibitor trametinib dimethyl sulfoxide (CombiDT therapy) increases response rate and survival compared with a BRAF inhibitor alone. Clinical trials have suggested that CombiDT therapy induces fewer cutaneous toxic effects than a single-agent BRAF inhibitor. To our knowledge, a direct comparison has not been performed before.
  
  
  OBJECTIVE
  To compare the cutaneous toxic effects of BRAF inhibitor monotherapy and CombiDT therapy in a large cohort of patients.
  
  
  METHODS
  We performed a retrospective cohort study from September 1, 2009, through November 30, 2013. The study population included 185 Australian patients with unresectable stages IIIC and IV melanoma referred from Crown Princess Mary Cancer Care Centre who underwent review at the Department of Dermatology, Westmead Hospital. Of these, 119 patients received dabrafenib; 36, vemurafenib; and 30, CombiDT therapy. Data analysis were performed in December 2013.
  
  
  METHODS
  Multiple cutaneous adverse effects between BRAF inhibitor monotherapy and CombiDT therapy were identified and compared in a cohort of patients who underwent the same dermatologic assessment.
  
  
  RESULTS
  The most common cutaneous adverse effects seen in patients receiving the single-agent BRAF inhibitor dabrafenib or vemurafenib included Grover disease (51 patients [42.9%] and 14 [38.9%], respectively [P = .67]), plantar hyperkeratosis (47 [39.5%] and 14 [38.9%], respectively [P = .95]), verrucal keratosis (79 [66.4%] and 26 [72.2%], respectively [P = .51]), and cutaneous squamous cell carcinoma (31 [26.1%] and 13 [36.1%], respectively [P = .54]). Photosensitivity was more common with vemurafenib (14 patients [38.9%]) compared with dabrafenib (1 [0.8%]; P < .001). Compared with dabrafenib, CombiDT therapy showed a higher frequency of folliculitis (12 patients [40.0%] vs. 8 [6.7%]; P < .001) and a significant decrease of cutaneous squamous cell carcinoma (0 vs. 31 [26.1%]; P < .001), verrucal keratosis (0 vs. 79 [66.4%]; P < .001), and Grover disease (0 vs. 51 [42.9%]; P < .001).
  
  
  CONCLUSIONS
  This study confirms that the prevalence of cutaneous toxic effects differs among vemurafenib, dabrafenib, and CombiDT therapies. Cutaneous squamous cell carcinoma is the most concerning cutaneous toxic effect related to BRAF inhibitor monotherapy that did not appear with CombiDT therapy. Although CombiDT therapy has an improved profile of cutaneous toxic effects, continuous dermatologic assessments should be provided for all patients when receiving these treatments.
authors.affiliation: Department of Dermatology, Westmead Hospital, Sydney, Australia2University of Sydney Medical Faculty, Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Carlos
authors.affiliation: Department of Dermatology, Westmead Hospital, Sydney, Australia2University of Sydney Medical Faculty, Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: Rachael
authors.initials: R
authors.lastname: Anforth
authors.affiliation: University of Sydney Medical Faculty, Sydney Medical School, University of Sydney, Sydney, Australia3Westmead Institute for Cancer Research, Westmead Hospital, Westmead, Australia4Department of Medical Oncology, Westmead and Blacktown Hospitals, Sydney, A.
authors.forename: Arthur
authors.initials: A
authors.lastname: Clements
authors.affiliation: University of Sydney Medical Faculty, Sydney Medical School, University of Sydney, Sydney, Australia3Westmead Institute for Cancer Research, Westmead Hospital, Westmead, Australia4Department of Medical Oncology, Westmead and Blacktown Hospitals, Sydney, A.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Menzies
authors.affiliation: University of Sydney Medical Faculty, Sydney Medical School, University of Sydney, Sydney, Australia3Westmead Institute for Cancer Research, Westmead Hospital, Westmead, Australia4Department of Medical Oncology, Westmead and Blacktown Hospitals, Sydney, A.
authors.forename: Matteo S
authors.initials: MS
authors.lastname: Carlino
authors.affiliation: Department of Tissue Pathology and Diagnostic Oncology, Westmead Hospital, Westmead, Australia.
authors.forename: Shaun
authors.initials: S
authors.lastname: Chou
authors.affiliation: Department of Dermatology, Westmead Hospital, Sydney, Australia2University of Sydney Medical Faculty, Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: Pablo
authors.initials: P
authors.lastname: Fernandez-Peñas
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010091:Oximes / Q000008:administration & dosage; D015995:Prevalence; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D011728:Pyridones / Q000008:administration & dosage; D011744:Pyrimidinones / Q000008:administration & dosage; D012189:Retrospective Studies; D012871:Skin Diseases / Q000139:chemically induced* / Q000453:epidemiology / Q000473:pathology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013449:Sulfonamides / Q000008:administration & dosage; D000077484:Vemurafenib
chemical_list: D007093:Imidazoles; D007211:Indoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D013449:Sulfonamides; D000077484:Vemurafenib; C560077:trametinib; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib