title: Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma.
abstract: OBJECTIVE
  Dabrafenib (GSK2118436) is a potent inhibitor of mutated BRAF kinase. Our multicenter, single-arm, phase II study assessed the safety and clinical activity of dabrafenib in BRAF(V600E/K) mutation-positive metastatic melanoma (mut(+) MM).
  
  
  METHODS
  Histologically confirmed patients with stage IV BRAF(V600E/K) mut(+) MM received oral dabrafenib 150 mg twice daily until disease progression, death, or unacceptable adverse events (AEs). The primary end point was investigator-assessed overall response rate in BRAF(V600E) mut(+) MM patients. Secondary end points included progression-free survival (PFS) and overall survival (OS). Exploratory objectives included the comparison of BRAF mutation status between tumor-specific circulating cell-free DNA (cfDNA) and tumor tissue, and the evaluation of cfDNA as a predictor of clinical outcome.
  
  
  RESULTS
  Seventy-six patients with BRAF(V600E) and 16 patients with BRAF(V600K) mut(+) MM were enrolled onto the study. In the BRAF(V600E) group, 45 patients (59%) had a confirmed response (95% CI, 48.2 to 70.3), including five patients (7%) with complete responses. Two patients (13%) with BRAF(V600K) mut(+) MM had a confirmed partial response (95% CI, 0 to 28.7). In the BRAF(V600E) and BRAF(V600K) groups, median PFS was 6.3 months and 4.5 months, and median OS was 13.1 months and 12.9 months, respectively. The most common AEs were arthralgia (33%), hyperkeratosis (27%), and pyrexia (24%). Overall, 25 patients (27%) experienced a serious AE and nine patients (10%) had squamous cell carcinoma. Baseline cfDNA levels predicted response rate and PFS in BRAF(V600E) mut(+) MM patients.
  
  
  CONCLUSIONS
  Dabrafenib was well tolerated and clinically active in patients with BRAF(V600E/K) mut(+) MM. cfDNA may be a useful prognostic and response marker in future studies.
authors.affiliation: Paolo A. Ascierto, Ester Simeone, Instituto Nazionale Tumori Fondazione "G. Pascale," Napoli, Italy; David Minor, California Pacific Center for Melanoma Research and Treatment, San Francisco; Antoni Ribas, Jonsson Comprehensive Cancer Center, University of California, Los Angeles; Omid Hamid, Experimental Therapeutics/Immunotherapy, The Angeles Clinic and Research Institute, Los Angeles, CA; Anne O'Hagan, Niki Arya, Mary Guckert, Anne-Marie Martin, Jolly Mazumdar, Vicki L. Goodman, GlaxoSmithKline Oncology, Collegeville; Ravi Amaravadi, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; Kevin B. Kim, The University of Texas MD Anderson Cancer Center, Houston, TX; Celeste Lebbe, Assistance Publique-Hôpitaux de Paris, Hôpital Saint Louis, Paris, Université Paris Diderot, Paris; Jean-Jacques Grob, Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Hôpital Timone, Marseille, France; Dirk Schadendorf, University Hospital Essen, Essen; Tabea Wilhelm, Uwe Trefzer, Charité-Universitätsmedizin, Berlin, Germany; Richard F. Kefford, Georgina V. Long, Westmead Hospital and Melanoma Institute Australia, University of Sydney, Sydney, Australia.
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Ascierto
authors.forename: David
authors.initials: D
authors.lastname: Minor
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.forename: Celeste
authors.initials: C
authors.lastname: Lebbe
authors.forename: Anne
authors.initials: A
authors.lastname: O'Hagan
authors.forename: Niki
authors.initials: N
authors.lastname: Arya
authors.forename: Mary
authors.initials: M
authors.lastname: Guckert
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Grob
authors.forename: Omid
authors.initials: O
authors.lastname: Hamid
authors.forename: Ravi
authors.initials: R
authors.lastname: Amaravadi
authors.forename: Ester
authors.initials: E
authors.lastname: Simeone
authors.forename: Tabea
authors.initials: T
authors.lastname: Wilhelm
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Kim
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Martin
authors.forename: Jolly
authors.initials: J
authors.lastname: Mazumdar
authors.forename: Vicki L
authors.initials: VL
authors.lastname: Goodman
authors.forename: Uwe
authors.initials: U
authors.lastname: Trefzer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007390:International Agencies; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010091:Oximes / Q000627:therapeutic use*; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D015996:Survival Rate; D055815:Young Adult
chemical_list: D007093:Imidazoles; D010091:Oximes; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib