title: Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma.
abstract: BACKGROUND
  Combined BRAF and MEK inhibition, as compared with BRAF inhibition alone, delays the emergence of resistance and reduces toxic effects in patients who have melanoma with BRAF V600E or V600K mutations.
  
  
  METHODS
  In this phase 3 trial, we randomly assigned 423 previously untreated patients who had unresectable stage IIIC or stage IV melanoma with a BRAF V600E or V600K mutation to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily) or dabrafenib and placebo. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, response duration, and safety. A preplanned interim overall survival analysis was conducted.
  
  
  RESULTS
  The median progression-free survival was 9.3 months in the dabrafenib-trametinib group and 8.8 months in the dabrafenib-only group (hazard ratio for progression or death in the dabrafenib-trametinib group, 0.75; 95% confidence interval [CI], 0.57 to 0.99; P=0.03). The overall response rate was 67% in the dabrafenib-trametinib group and 51% in the dabrafenib-only group (P=0.002). At 6 months, the interim overall survival rate was 93% with dabrafenib-trametinib and 85% with dabrafenib alone (hazard ratio for death, 0.63; 95% CI, 0.42 to 0.94; P=0.02). However, a specified efficacy-stopping boundary (two-sided P=0.00028) was not crossed. Rates of adverse events were similar in the two groups, although more dose modifications occurred in the dabrafenib-trametinib group. The rate of cutaneous squamous-cell carcinoma was lower in the dabrafenib-trametinib group than in the dabrafenib-only group (2% vs. 9%), whereas pyrexia occurred in more patients (51% vs. 28%) and was more often severe (grade 3, 6% vs. 2%) in the dabrafenib-trametinib group.
  
  
  CONCLUSIONS
  A combination of dabrafenib and trametinib, as compared with dabrafenib alone, improved the rate of progression-free survival in previously untreated patients who had metastatic melanoma with BRAF V600E or V600K mutations. (Funded by GlaxoSmithKline; Clinical Trials.gov number, NCT01584648.).
authors.affiliation: The authors' affiliations are listed in the Appendix.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.forename: Daniil
authors.initials: D
authors.lastname: Stroyakovskiy
authors.forename: Helen
authors.initials: H
authors.lastname: Gogas
authors.forename: Evgeny
authors.initials: E
authors.lastname: Levchenko
authors.forename: Filippo
authors.initials: F
authors.lastname: de Braud
authors.forename: James
authors.initials: J
authors.lastname: Larkin
authors.forename: Claus
authors.initials: C
authors.lastname: Garbe
authors.forename: Thomas
authors.initials: T
authors.lastname: Jouary
authors.forename: Axel
authors.initials: A
authors.lastname: Hauschild
authors.forename: Jean Jacques
authors.initials: JJ
authors.lastname: Grob
authors.forename: Vanna
authors.initials: V
authors.lastname: Chiarion Sileni
authors.forename: Celeste
authors.initials: C
authors.lastname: Lebbe
authors.forename: Mario
authors.initials: M
authors.lastname: Mandalà
authors.forename: Michael
authors.initials: M
authors.lastname: Millward
authors.forename: Ana
authors.initials: A
authors.lastname: Arance
authors.forename: Igor
authors.initials: I
authors.lastname: Bondarenko
authors.forename: John B A G
authors.initials: JB
authors.lastname: Haanen
authors.forename: Johan
authors.initials: J
authors.lastname: Hansson
authors.forename: Jochen
authors.initials: J
authors.lastname: Utikal
authors.forename: Virginia
authors.initials: V
authors.lastname: Ferraresi
authors.forename: Nadezhda
authors.initials: N
authors.lastname: Kovalenko
authors.forename: Peter
authors.initials: P
authors.lastname: Mohr
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Probachai
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.forename: Paul
authors.initials: P
authors.lastname: Nathan
authors.forename: Caroline
authors.initials: C
authors.lastname: Robert
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: DeMarini
authors.forename: Jhangir G
authors.initials: JG
authors.lastname: Irani
authors.forename: Michelle
authors.initials: M
authors.lastname: Casey
authors.forename: Daniele
authors.initials: D
authors.lastname: Ouellet
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Martin
authors.forename: Ngocdiep
authors.initials: N
authors.lastname: Le
authors.forename: Kiran
authors.initials: K
authors.lastname: Patel
authors.forename: Keith
authors.initials: K
authors.lastname: Flaherty
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D005334:Fever / Q000139:chemically induced; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009154:Mutation; D010091:Oximes / Q000008:administration & dosage* / Q000009:adverse effects; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D011728:Pyridones / Q000008:administration & dosage* / Q000009:adverse effects; D011744:Pyrimidinones / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D007093:Imidazoles; D010091:Oximes; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases; C561627:dabrafenib