BACKGROUND: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.).