Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial.
BACKGROUND
Dabrafenib, an inhibitor of mutated BRAF, has clinical activity with a manageable safety profile in studies of phase 1 and 2 in patients with BRAF(V600)-mutated metastatic melanoma. We studied the efficacy of dabrafenib in patients with BRAF(V600E)-mutated metastatic melanoma.


METHODS
We enrolled patients in this open-label phase 3 trial between Dec 23, 2010, and Sept 1, 2011. This report is based on a data cutoff date of Dec 19, 2011. Patients aged 18 years or older with previously untreated, stage IV or unresectable stage III BRAF(V600E) mutation-positive melanoma were randomly assigned (3:1) to receive dabrafenib (150 mg twice daily, orally) or dacarbazine (1000 mg/m(2) intravenously every 3 weeks). Patients were stratified according to American Joint Committee on Cancer stage (unresectable III+IVM1a+IVM1b vs IVM1c). The primary endpoint was investigator-assessed progression-free survival and was analysed by intention to treat; safety was assessed per protocol. This study is registered with ClinicalTrials.gov, number NCT01227889.


RESULTS
Of the 733 patients screened, 250 were randomly assigned to receive either dabrafenib (187 patients) or dacarbazine (63 patients). Median progression-free survival was 5·1 months for dabrafenib and 2·7 months for dacarbazine, with a hazard ratio (HR) of 0·30 (95% CI 0·18-0·51; p<0·0001). At data cutoff, 107 (57%) patients in the dabrafenib group and 14 (22%) in the dacarbazine group remained on randomised treatment. Treatment-related adverse events (grade 2 or higher) occurred in 100 (53%) of the 187 patients who received dabrafenib and in 26 (44%) of the 59 patients who received dacarbazine. The most common adverse events with dabrafenib were skin-related toxic effects, fever, fatigue, arthralgia, and headache. The most common adverse events with dacarbazine were nausea, vomiting, neutropenia, fatigue, and asthenia. Grade 3-4 adverse events were uncommon in both groups.


CONCLUSIONS
Dabrafenib significantly improved progression-free survival compared with dacarbazine.


BACKGROUND
GlaxoSmithKline.
University Hospital, Schleswig-Holstein, Department of Dermatology, Kiel, Germany. ahauschild@dermatology.unikiel.de
Axel
A
Hauschild
Jean-Jacques
JJ
Grob
Lev V
LV
Demidov
Thomas
T
Jouary
Ralf
R
Gutzmer
Michael
M
Millward
Piotr
P
Rutkowski
Christian U
CU
Blank
Wilson H
WH
Miller
Eckhart
E
Kaempgen
Salvador
S
Martín-Algarra
Boguslawa
B
Karaszewska
Cornelia
C
Mauch
Vanna
V
Chiarion-Sileni
Anne-Marie
AM
Martin
Suzanne
S
Swann
Patricia
P
Haney
Beloo
B
Mirakhur
Mary E
ME
Guckert
Vicki
V
Goodman
Paul B
PB
Chapman
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D003606:Dacarbazine / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D010091:Oximes / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf; D016896:Treatment Outcome; D055815:Young Adult
D018906:Antineoplastic Agents, Alkylating; D007093:Imidazoles; D010091:Oximes; D003606:Dacarbazine; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib