title: Profile of vemurafenib-induced severe skin toxicities.
abstract: BACKGROUND
  Vemurafenib, a BRAF inhibitor, is commonly associated with skin toxicity. The impact of severe forms is unknown.
  
  
  OBJECTIVE
  To determine the rate of permanent vemurafenib discontinuation due to grade 3-4 skin toxicity, features of these toxicities, their recurrence rate after a switch to dabrafenib and their impact on overall survival.
  
  
  METHODS
  Retrospective cohort study of 131 patients treated with vemurafenib for melanoma between November 2010 and December 2014. Data on skin toxicities, the need for vemurafenib adjustment and the impact of switching to dabrafenib were collected. Regarding survival analysis, a conditional landmark analysis was performed to correct lead-time bias.
  
  
  RESULTS
  Among the 131 vemurafenib-treated patients, 26% developed grade 3-4 skin toxicity. Forty-four percent of them permanently discontinued their treatment, mainly due to rash and classic skin adverse reactions (Steven-Johnson syndrome, Drug Reaction with Eosinophilia and Systemic Symptoms). Conversely, photosensitivity and carcinomas rarely required treatment adjustment. Grade 3-4 rashes were associated with clinical or biological abnormalities in 94% of patients. Among the 10 patients who subsequently switched to dabrafenib, skin toxicity recurred only in one patient. Overall survival was significantly prolonged in case of severe skin toxicity emerging within the first 4 (P = 0.014) and 8 weeks (P = 0.038) on vemurafenib, with only a trend at 12 weeks (P = 0.052). Median overall survival was also prolonged in case of severe rash.
  
  
  CONCLUSIONS
  In this study, vemurafenib was continued in 56% of patients with grade 3-4 skin toxicity, which was associated with prolonged overall survival when emerging within the first 4 and 8 weeks of treatment. While developing severe skin adverse reactions permanently contraindicates vemurafenib use, other rashes should lead to retreatment attempts with dose reduction. In case of recurrence, dabrafenib seems to be an interesting option. For other skin toxicities, including photosensitivity and cutaneous carcinoma, treatment adjustment is usually not needed.
authors.affiliation: Department of Dermatology, Nantes University Hospital, INSERM U892-CNRS U6299, CIC Biothérapie INSERM 0503, Nantes, France.
authors.forename: L
authors.initials: L
authors.lastname: Peuvrel
authors.affiliation: Department of Dermatology, Nantes University Hospital, INSERM U892-CNRS U6299, CIC Biothérapie INSERM 0503, Nantes, France.
authors.forename: G
authors.initials: G
authors.lastname: Quéreux
authors.affiliation: Department of Dermatology, Nantes University Hospital, INSERM U892-CNRS U6299, CIC Biothérapie INSERM 0503, Nantes, France.
authors.forename: M
authors.initials: M
authors.lastname: Saint-Jean
authors.affiliation: Department of Dermatology, Nantes University Hospital, INSERM U892-CNRS U6299, CIC Biothérapie INSERM 0503, Nantes, France.
authors.forename: A
authors.initials: A
authors.lastname: Brocard
authors.affiliation: Department of Epidemiology and Biostatistics, Nantes University Hospital, INSERM U892-CNRS U6299, CIC Biothérapie INSERM 0503, Nantes, France.
authors.forename: J M
authors.initials: JM
authors.lastname: Nguyen
authors.affiliation: Department of Dermatology, Nantes University Hospital, INSERM U892-CNRS U6299, CIC Biothérapie INSERM 0503, Nantes, France.
authors.forename: A
authors.initials: A
authors.lastname: Khammari
authors.affiliation: Department of Dermatology, Nantes University Hospital, INSERM U892-CNRS U6299, CIC Biothérapie INSERM 0503, Nantes, France.
authors.forename: A C
authors.initials: AC
authors.lastname: Knol
authors.affiliation: Department of Dermatology, Nantes University Hospital, INSERM U892-CNRS U6299, CIC Biothérapie INSERM 0503, Nantes, France.
authors.forename: E
authors.initials: E
authors.lastname: Varey
authors.affiliation: Department of Dermatology, Nantes University Hospital, INSERM U892-CNRS U6299, CIC Biothérapie INSERM 0503, Nantes, France.
authors.forename: B
authors.initials: B
authors.lastname: Dréno
mesh_terms: D000368:Aged; D001706:Biopsy; D004305:Dose-Response Relationship, Drug; D003875:Drug Eruptions / Q000175:diagnosis*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D012720:Severity of Illness Index; D012867:Skin / Q000187:drug effects* / Q000473:pathology; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects*; D000077484:Vemurafenib
chemical_list: D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib