title: Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations.
abstract: Resistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted a phase 1 and 2 trial of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor.
  
  
  
  In this open-label study involving 247 patients with metastatic melanoma and BRAF V600 mutations, we evaluated the pharmacokinetic activity and safety of oral dabrafenib (75 or 150 mg twice daily) and trametinib (1, 1.5, or 2 mg daily) in 85 patients and then randomly assigned 162 patients to receive combination therapy with dabrafenib (150 mg) plus trametinib (1 or 2 mg) or dabrafenib monotherapy. The primary end points were the incidence of cutaneous squamous-cell carcinoma, survival free of melanoma progression, and response. Secondary end points were overall survival and pharmacokinetic activity.
  
  
  
  Dose-limiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg of dabrafenib and 2 mg of trametinib (combination 150/2). Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P=0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). Median progression-free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P<0.001). The rate of complete or partial response with combination 150/2 therapy was 76%, as compared with 54% with monotherapy (P=0.03).
  
  
  
  Dabrafenib and trametinib were safely combined at full monotherapy doses. The rate of pyrexia was increased with combination therapy, whereas the rate of proliferative skin lesions was nonsignificantly reduced. Progression-free survival was significantly improved. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01072175.).
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, USA.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.forename: Jeffery R
authors.initials: JR
authors.lastname: Infante
authors.forename: Adil
authors.initials: A
authors.lastname: Daud
authors.forename: Rene
authors.initials: R
authors.lastname: Gonzalez
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Sosman
authors.forename: Omid
authors.initials: O
authors.lastname: Hamid
authors.forename: Lynn
authors.initials: L
authors.lastname: Schuchter
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cebon
authors.forename: Nageatte
authors.initials: N
authors.lastname: Ibrahim
authors.forename: Ragini
authors.initials: R
authors.lastname: Kudchadkar
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.forename: Gerald
authors.initials: G
authors.lastname: Falchook
authors.forename: Alain
authors.initials: A
authors.lastname: Algazi
authors.forename: Karl
authors.initials: K
authors.lastname: Lewis
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.forename: Igor
authors.initials: I
authors.lastname: Puzanov
authors.forename: Peter
authors.initials: P
authors.lastname: Lebowitz
authors.forename: Ajay
authors.initials: A
authors.lastname: Singh
authors.forename: Shonda
authors.initials: S
authors.lastname: Little
authors.forename: Peng
authors.initials: P
authors.lastname: Sun
authors.forename: Alicia
authors.initials: A
authors.lastname: Allred
authors.forename: Daniele
authors.initials: D
authors.lastname: Ouellet
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Kim
authors.forename: Kiran
authors.initials: K
authors.lastname: Patel
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Weber
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D005334:Fever / Q000139:chemically induced; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009154:Mutation; D010091:Oximes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D011728:Pyridones / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011744:Pyrimidinones / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D007093:Imidazoles; D010091:Oximes; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases; C561627:dabrafenib