Two drugs being evaluated by the FDA slowed the development of treatment resistance in persons with metastatic malignant melanoma positive for the BRAF protein.
Approximately 50% of persons with metastatic melanoma experience tumor growth driven by mutations that keep the BRAF protein in a constant state of activation. Although BRAF inhibitors have been able to stop and reverse tumor growth in most patients, this response is usually temporary, with tumor growth resuming in 6 to 7 months, according to a statement from Massachusetts General Hospital (MGH) in Boston. The lead author of the current study, Keith Flaherty, MD, practices at the MGH Cancer Center.
In a multicenter study conducted in the United States and Australia and sponsored by pharmaceutical company GlaxoSmithKline, Flaherty and fellow investigators tested two of the company’s drugs: the BRAF inhibitor dabrafenib, and an MEK inhibitor called trametinib. BRAF is part of a cell growth pathway known as the MAPK pathway. Research has shown that the eventual resistance to melanoma treatment develops when the MAPK pathway gets turned on again through activation of MEK, another protein further down that pathway.
After phase I testing confirmed that no drug-to-drug interactions occurred between the two agents, 162 patients in the phase II portion were randomized into one of three groups receiving different dose combinations:
- two daily 150-mg doses of dabrafenib plus a 2-mg dose of trametinib, a regimen known as “combination 150/2”
- two daily 150-mg doses of dabrafenib plus a 1-mg dose of trametinib
- two daily 150-mg doses of dabrafenib only; members of this group were able to cross over to the full-dose combination treatment if cancer progression resumed.
Median progression-free survival in the combination 150/2 group was 9.4 months, compared with 5.8 months in the group of patients receiving dabrafenib alone. The rate of complete or partial response was 76% with combination 150/2 therapy and 54% with monotherapy. After 1 year of treatment, 41% of the combination 150/2 patients had no cancer progression, compared with only 9% of those receiving dabrafenib alone.
Few patients in the combination 150/2 group experienced dose-limiting toxic effects of the therapy. Cutaneous squamous cell carcinoma, a less malignant form of skin cancer, was seen in 7% of persons receiving combination 150/2 and in 19% of those receiving dabrafenib alone. However, more of the combination 150/2 patients than the monotherapy patients experienced abnormal elevation of body temperature (pyrexia), at 71% vs 26%.
Flaherty and colleagues concluded in The New England Journal of Medicine that dabrafenib and trametinib were safely combined at full monotherapy doses, and that the combination therapy significantly improved progression-free survival, nonsignificantly reduced the rate of proliferative skin lesions, and increased the rate of pyrexia among persons with metastatic melanoma with BRAF mutations.