New Glaxo 2 Drug Combo Delays Treatment Resistance in Patients with Advanced Melanoma

Researchers indicate that they've discovered a two-drug combination that delays treatment resistance in patients who are suffering from advanced melanoma.

The study authors said that by targeting different points in the same growth-factor pathway, the kinase inhibitor drugs dabrafenib and trametinib delayed the development of drug resistance in patients with BRAF-positive metastatic melanoma.

Melanoma is the most serious and often deadly form of skin cancer. In half of patients with melanoma that has spread, tumor growth is caused by genetic mutations that keep the BRAF protein, which is part of the MAPK cell growth pathway, constantly activated. Drugs that inhibit BRAF activity can rapidly stop and reverse tumor growth in 90 percent of patients. However the response is usually temporary in most cases, and tumor growth resumes in six or seven months.

Past research suggests that this drug resistance develops because the MAPK pathway gets turned back on through activation of MEK, another protein that is part of the MAPK pathway.

Lead author Dr. Keith Flaherty of the Massachusetts General Hospital Cancer Center said:

"We investigated this (drug) combination because of research we and others have conducted into the molecular underpinnings of resistance to BRAF inhibitor therapy."

Phase 1 and 2 of the study was sponsored by GlaxoSmithKline, which developed both drugs.

Dr. Flaherty added:

"We found that adding the MEK inhibitor trametinib to BRAF inhibitor dabrafenib clearly delays the emergence of resistance. In fact, the combination was at least twice as effective as BRAF inhibition alone."

The study was conducted at 14 sites in both the United States and Australia, an included 162 patients who received different dose combinations of the drugs: two daily 150mg doses of dabrafenib plus one 2mg dose of trametinib, 150mg dabrafenib plus 1mg of trametinib, or treatment with dabrafenib alone.

Patients who received dabrafenib alone were able to receive the full-dose combination treatment if their cancer resumed progression.

Treatment with both combinations of dabrafenib and trametinib led to a four-month longer delay in drug resistance than treatment with dabrafenib alone.

After a year of treatment, 41 percent of patients receiving the full dose combination treatment had no progression of their melanoma, compared to 9 percent of those who received dabrafenib alone.

The study was presented Saturday at the European Society for Medical Oncology meeting in Vienna, and a simultaneous publication in the New England Journal of Medicine.

The drug combination is now being tested in a larger phase 3 study, which the U.S. Food and Drug Administration requires for approval.