Last week, the U.S. Food and Drug Administration (FDA) approved the use of cobimetinib (Cotellic) in combination with vemurafenib (Zelboraf) for treating certain patients with advanced melanoma that has spread to other parts of the body or that cannot be removed by surgery. Specifically, this combination of targeted therapeutics is approved to treat only those patients with melanoma whose tumors test positive for BRAF V600E or BRAF V600K gene mutations.
Melanoma is the most lethal form of skin cancer: It accounts for less than 2 percent of all U.S. skin cancer cases, 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 in August 2011 for treating patients with melanoma positive for the BRAF V600E mutation. 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 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 is 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 alone. Specifically, the median progression-free survival was 12.3 months among those receiving the combination versus 7.2 months among those receiving single-agent vemurafenib. In addition, patients who received the combination of 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 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.
Moreover, as our basic understanding of the biology of cancer continues to grow, it is highly likely that this recent announcement will not be the last combination of targeted anticancer therapeutics to be approved by the FDA.
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