Phase 1/2 Trial Update of Dabrafenib + Trametinib for Melanoma with BRAF V600 Mutations

(ChemotherapyAdvisor) – The combination of the selective BRAF inhibitor, dabrafenib, and the MEK inhibitor, trametinib, significantly improved progression-free survival (PFS) in patients with melanoma and BRAF V600 mutations, according to a study published in the New England Journal of Medicine online September 29 to coincide with a presentation at the European Society for Medical Oncology (ESMO) in Vienna, Austria.

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.

Article

http://www.nejm.org/doi/full/10.1056/NEJMoa1210093

ESMO abstract (# LBA27_PR)