title: Phototoxicity of B-RAF inhibitors: Exclusively due to UVA radiation and rapidly regressive.
abstract: BACKGROUND
  New targeted melanoma therapies such as B-RAF inhibitors have shown high and promising clinical benefit but have cutaneous side-effects, including photosensitivity, which is triggered in the UVA radiation spectrum. However, visible spectrum implication has not yet been investigated. We conducted a study to determine whether visible light also contributes to the phototoxicity action spectrum of vemurafenib. The secondary end points were to determine the time to complete regression of the phototoxicity post-vemurafenib discontinuation and whether there was a significant difference between the UVA radiation immediate reactivity cut-offs, in patients treated with vemurafenib vs. those treated with dabrafenib.
  
  
  METHODS
  This prospective, observational study included patients with B-RAF mutant metastatic melanoma: 34 patients treated with vemurafenib and 9 with dabrafenib.
  
  
  RESULTS
  The visible-light phototest results in patients treated with vemurafenib were all negative before and after 2 months of treatment. The UVA radiation phototests conducted 1 or 2 weeks post-vemurafenib discontinuation in 4 patients showed a normalised UVA-radiation reactivity cut-off. UVA radiation phototests after 2 months of treatment were conducted for all patients. The UVA radiation reactivity cut-off had been lowered for 30 patients (88%) on vemurafenib and 3 patients (33%) on dabrafenib. The median UVA radiation reactivity cut-off was 12 J/cm(2) for the patients on vemurafenib and 20 J/cm(2) for the patients on dabrafenib.
  
  
  CONCLUSIONS
  B-RAF inhibitor phototoxicity is exclusively triggered by UVA radiation and resolves rapidly post-treatment discontinuation. A significant difference between the UVA immediate reactivity cut-offs, vemurafenib vs. dabrafenib, explains the difference in the clinical photosensitivity rates reported in the clinical trials.
authors.affiliation: Clinique Dermatologique, Hôpital Hôtel-Dieu, CHU Nantes Place Alexis Ricordeau, 44093 Cedex 01 - France.
authors.forename: Romain
authors.initials: R
authors.lastname: Gabeff
authors.affiliation: Clinique Dermatologique, Hôpital Hôtel-Dieu, CHU Nantes Place Alexis Ricordeau, 44093 Cedex 01 - France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Dutartre
authors.affiliation: Clinique Dermatologique, Hôpital Hôtel-Dieu, CHU Nantes Place Alexis Ricordeau, 44093 Cedex 01 - France.
authors.forename: Amir
authors.initials: A
authors.lastname: Khammari
authors.affiliation: Clinique Dermatologique, Hôpital Hôtel-Dieu, CHU Nantes Place Alexis Ricordeau, 44093 Cedex 01 - France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Boisrobert
authors.affiliation: Clinique Dermatologique, Hôpital Hôtel-Dieu, CHU Nantes Place Alexis Ricordeau, 44093 Cedex 01 - France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Nguyen
authors.affiliation: Clinique Dermatologique, Hôpital Hôtel-Dieu, CHU Nantes Place Alexis Ricordeau, 44093 Cedex 01 - France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Quereux
authors.affiliation: Clinique Dermatologique, Hôpital Hôtel-Dieu, CHU Nantes Place Alexis Ricordeau, 44093 Cedex 01 - France.
authors.forename: Anabelle
authors.initials: A
authors.lastname: Brocard
authors.affiliation: Clinique Dermatologique, Hôpital Hôtel-Dieu, CHU Nantes Place Alexis Ricordeau, 44093 Cedex 01 - France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Saint-Jean
authors.affiliation: Clinique Dermatologique, Hôpital Hôtel-Dieu, CHU Nantes Place Alexis Ricordeau, 44093 Cedex 01 - France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Peuvrel
authors.affiliation: Clinique Dermatologique, Hôpital Hôtel-Dieu, CHU Nantes Place Alexis Ricordeau, 44093 Cedex 01 - France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Dreno
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D017484:Dermatitis, Phototoxic / Q000209:etiology* / Q000503:physiopathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use; D007211:Indoles / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods; D009361:Neoplasm Invasiveness / Q000473:pathology; D010091:Oximes / Q000009:adverse effects / Q000627:therapeutic use; D010166:Palliative Care / Q000379:methods; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000187:drug effects* / Q000235:genetics; D018570:Risk Assessment; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D013449:Sulfonamides / Q000009:adverse effects* / Q000627:therapeutic use; D016019:Survival Analysis; D016896:Treatment Outcome; D014466:Ultraviolet Rays / Q000009:adverse effects*; D000077484:Vemurafenib
chemical_list: D007093:Imidazoles; D007211:Indoles; D010091:Oximes; D013449:Sulfonamides; D000077484:Vemurafenib; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib
keywords: B-RAF inhibitors; dabrafenib; melanoma; phototoxicity; vemurafenib; visible light