title: BRAF inhibitor activity in V600R metastatic melanoma.
abstract: Activating mutations in the BRAF gene occur in approximately 50% of melanomas. More than 70% of BRAF mutations are V600E and 10-30% are V600K. Potent and selective BRAF inhibitors have demonstrated significant clinical benefits in patients with V600E and V600K BRAF-mutated melanoma. V600R mutations constitute approximately 3-7% of all BRAF mutations and the activity of BRAF inhibitors in patients with this mutation is unknown. We have treated 45 patients with V600 mutated melanoma including patients with V600R mutation between July 2011 and October 2012 with the selective BRAF inhibitor dabrafenib (n=43) or vemurafenib (n=2) via a compassionate access programme. The overall response rate was 50% for the whole population with a progression-free survival of 5.5 months. Five objective responses were seen in six assessable patients with V600R BRAF mutation (n=9). Our experience suggests that patients with V600R BRAF mutations can be treated successfully with oral BRAF inhibitors, and molecular diagnostic assays should include detection of this type of mutation.
authors.affiliation: Melanoma Institute Australia and Westmead Hospital, University of Sydney, 40 Rocklands Road, North Sydney, New South Wales, Australia.
authors.forename: Oliver
authors.initials: O
authors.lastname: Klein
authors.forename: Arthur
authors.initials: A
authors.lastname: Clements
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Menzies
authors.forename: Sandra
authors.initials: S
authors.lastname: O'Toole
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001120:Arginine / Q000235:genetics; D057176:Compassionate Use Trials; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D020125:Mutation, Missense; D009362:Neoplasm Metastasis; D010091:Oximes / Q000008:administration & dosage / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014633:Valine / Q000235:genetics; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D001120:Arginine; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D014633:Valine; C561627:dabrafenib