Combination therapy with two drugs delayed the development of treatment resistance in patients with metastatic melanoma that expresses a specific mutation in the BRAF gene.
The results of the Phase I/II study were published recently in the New England Journal of Medicine.
Jeffrey Sosman, M.D., professor of Medicine, director of the Melanoma Program and co-leader of the Signal Transduction Program, and Igor Puzanov, M.D., MSCI, associate professor of Medicine, associate director of the Phase I Program and clinical director of Renal Cancer at Vanderbilt-Ingram Cancer Center, were among the authors of the study led by Keith Flaherty, M.D., Massachusetts General Hospital Cancer Center, Boston.
Melanoma is the most deadly form of skin cancer. Nearly half of all patients with metastatic melanoma have a BRAF V600 mutation in their tumor. New drugs that target the BRAF mutation have shown effectiveness, but resistance to the BRAF inhibitors develops after a median of six to seven months and the disease progresses.
Investigators have theorized that the therapy stops working because the mitogen-activated protein kinase (MAPK) pathway gets reactivated, so there is a need to shut down potential reactivation mechanisms.
For this study, researchers from more than a dozen institutions in the United States and Australia combined a BRAF inhibitor drug with another drug that targets a different spot (MEK) in the MAPK growth-factor pathway. As part of the trial, they enrolled 162 patients divided into three groups. Patients were randomly assigned to receive the single agent BRAF inhibitor drug dabrafenib or dabrafenib plus the MEK inhibitor trametinib at one of two different doses.
After a median follow-up of 14.1 months, patients treated with the combination therapy were found to have improved progression-free survival of 9.4 months, compared with 5.8 months for the patients who received only dabrafenib. The percentage of patients who were alive and progression free at one year was also substantially higher among the combination therapy group — 41 percent vs. 9 percent for the monotherapy. Patients whose disease began to progress were allowed to crossover to the combination therapy arm.
“These results confirm previous studies about the importance of the MAPK pathway in treatment resistance,” said Sosman. “For years, we had very little to offer patients with metastatic melanoma and now we’re beginning to understand the factors that drive this disease and develop therapies for improved treatment.”
However, while the combination therapy delayed treatment resistance, it did not stop it and the disease eventually progressed.
Side effects from the combination therapy remarkably demonstrated a decrease in skin toxicity compared to the dabrafenib alone, including fewer cases of squamous cell skin cancer. However, fever and chills were greater with the combination therapy.
Two randomized, Phase III trials of the drug combination are now under way.
The study was sponsored by GlaxoSmithKline.