Phase 1/2 Trial Update of Dabrafenib + Trametinib for Melanoma with BRAF V600 Mutations
The Phase 1/2 study sought to address the challenge of resistance to therapy with BRAF kinase inhibitors, which results in reactivation of the mitogen-activated protein kinase (MAPK) pathway, noted Keith T. Flaherty, MD, of Massachusetts General Hospital Cancer Center, Boston, MA, and colleagues.
The open-label trial combined dabrafenib and trametinib, a selective MAPK kinase (MEK) inhibitor, in 247 patients with metastatic melanoma and BRAF V600E/K positive mutations who had not previously received a BRAF or MEK inhibitor. The investigators evaluated the pharmacokinetic activity and safety of oral dabrafenib 75 or 150mg/bid and trametinib 1, 1.5, or 2mg/day in 85 patients.
Subsequently, 162 patients were randomly assigned to receive dabrafenib 150mg/bid monotherapy and dabrafenib 150mg/bid in combination with trametinib 1mg or 2mg/day.
Incidence of cutaneous squamous cell carcinoma was observed in 7% of patients receiving dabrafenib 150mg/trametinib 2mg, compared with 19% in the monotherapy dabrafenib monotherapy arm (P=0.09). Median PFS was 9.4 months in the dabrafenib 150mg/trametinib 2mg arm vs 5.8 months in the monotherapy arm (HR for progression or death 0.39; 95% CI, 0.25 to 0.62; P<0.001). Rate of complete or partial response was 76% with the combination therapy vs 54% with monotherapy (P=0.03).
In patients receiving dabrafenib 150mg/trametinib 2mg, pyrexia occurred in 71% of patients vs 26% in the dabrafenib monotherapy arm, with dose-limiting toxic effects infrequently observed in the combination arm.
Among patients who received the combination, 41% had not progressed 12 months after treatment initiation vs 9% in the monotherapy arm, said Georgina V. Long, MD, PhD, of Westmead Hospital and the Melanoma Institute Australia, in presenting the results at ESMO.
The study was funded by GlaxoSmithKline.