Combined Targeted Therapy Safe and Effective in Metastatic Melanoma

Combined Targeted Therapy Safe and Effective in Metastatic Melanoma

Treatment with a combination of two targeted agents—dabrafenib, which targets BRAF, and trametinib, which targets MEK—in patients with metastatic melanoma and BRAF V600 mutations was safe and improved progression-free survival, according to the results of a study published in the New England Journal of Medicine.

Of the more than one million new diagnoses of skin cancer each year, roughly 68,000 involve melanoma. More than 8,000 people die of melanoma each year in the United States. Melanoma is dangerous because it is more likely than other types of skin cancer to spread (metastasize) to other parts of the body.

Much new cancer research has been focused on targeted therapies, which are anticancer drugs that interfere with specific pathways involved in cancer cell growth or survival. Targeted therapies provide an opportunity to deliver more individualized and more effective cancer therapy.

The BRAF gene is known to play a part in cell growth, and mutations in BRAF are common in several types of cancer. Approximately half of all melanomas carry a specific BRAF mutation known as V600E. This mutation produces an abnormal version of the BRAF protein that stimulates cancer growth. Researchers are exploring BRAF-targeted drugs. It may also be possible to control the effects of an abnormal BRAF protein by blocking other proteins that work with it. MEK is one of these proteins, and drugs that inhibit MEK are also being explored for the treatment of melanoma.

Two new targeted therapies have shown promise in the treatment of advanced melanoma—dabrafenib targets BRAF, while trametinib targets MEK. Because resistance to BRAF-targeted drugs is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway, researchers are evaluating the combination of BRAF and MEK inhibitors in the treatment of melanoma.

Researchers conducted an open-label study that included 247 patients with metastatic melanoma and BRAF V600E mutations. First, they evaluated the safety and activity of combining dabrafenib and trametinib in 85 patients. Then they randomly assigned 162 patients to receive either a combination of dabrafenib and trametinib or dabrafenib alone.

The results indicated that the combination of the two targeted agents was safe. Secondary skin cancers occurred in 7 percent of patients receiving the combination, compared to 19 percent receiving dabrafenib alone. Fever was more common in the combination group—71 percent compared to 26 percent in the dabrafenib group.

The median progression-free survival was 9.4 months in the combination group, compared to 5.8 months in the dabrafenib group. What’s more—the rate of complete or partial response was 76 percent in the combination group compared with 54 percent in the dabrafenib group.

The researchers concluded that dabrafenib and trametinib were safely combined at their full doses—and significantly improved progression-free survival.


Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations. New England Journal of Medicine. Published early online September 29, 2012. DOI: 10.1056/NEJMoa1210093

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