A Combination of Targeted Therapeutics for Melanoma Patients

The U.S. Food and Drug Administration approval provides a new option for patients whose disease is driven by mutations in the BRAF gene.

The U.S. Food and Drug Administration (FDA) has approved the molecularly targeted therapeutic cobimetinib (Cotellic) for use in combination with another molecularly targeted therapeutic, vemurafenib (Zelboraf), for treating certain patients with melanoma that has advanced or cannot be removed by surgery.

The combination of molecularly targeted therapeutics is intended for patients whose tumors tests positive for BRAF gene mutations – specifically BRAF V600E or BRAF V600K mutations. The combination therapy was shown to increase the time before disease progressed for patients in a randomized, double-blind, placebo-controlled, phase III clinical trial.

Melanoma is the most lethal form of skin cancer: It accounts for less than 2 percent of all cases of skin cancer in the United States but the majority of skin cancer deaths. The growth of about 50 percent of melanomas is fueled by a BRAF V600E or BRAF V600K gene mutation.

The anticancer therapeutics in this new treatment combination target two different components of the BRAF signaling pathway.

Vemurafenib, which targets BRAF V600E and blocks the BRAF signaling pathway, was approved by the FDA for treating patients with melanoma positive for the BRAF V600E mutation in August 2011. Even though vemurafenib benefits many of these patients, about half of the melanomas that respond to treatment become resistant to vemurafenib and disease progresses in about six to seven months.

Because several of the ways in which vemurafenib resistance arises involve reactivation of the BRAF signaling pathway, researchers looked to combine molecularly targeted therapeutics that block different components of the pathway. Cobimetinib targets MEK, which is downstream of BRAF in the signaling pathway.

According to the FDA announcement, its approval of cobimetinib was based on results from the phase III coBRIM clinical trial, which showed that patients with advanced melanoma positive for either the BRAF V600E or V600K mutation who received cobimetinib and vemurafenib had a delay in the amount of time it took for their disease to progress compared with those who received vemurafenib and placebo. Specifically, median progression-free survival was 12.3 months among those receiving the combination versus 7.2 months among those receiving vemurafenib and placebo. In addition, patients who received the combination of molecularly targeted therapeutics were more likely to respond to treatment and to be alive 17 months after starting treatment.

The approval of cobimetinib for use with vemurafenib to treat advanced BRAF mutation-positive advanced melanoma is not the first combination of BRAF- and MEK-targeted therapeutics to be approved for this use by the FDA. In January 2014, the FDA approved the BRAF-targeted agent dabrafenib (Tafinlar) and the MEK-targeted agent trametinib (Mekinist) for the same use.

As our basic understanding of the biology of cancer continues to grow, it is highly likely that this recent approval will not be the last combination of molecularly targeted anticancer therapeutics to be approved by the FDA.

The FDA approval was rendered on Nov. 10, 2015.