Skip to main content
Premium Trial:

Request an Annual Quote

FDA Approves New MEK/BRAF Inhibitor Option for Melanoma Patients with BRAF V600E, V600K Mutations


NEW YORK (GenomeWeb) – A newly approved melanoma treatment combining Genentech's MEK inhibitor Cotellic (cobimetinib) with the BRAF inhibitor Zelboraf (vemurafenib) is the latest option for advanced melanoma patients with BRAF mutations.

The US Food and Drug Administration approved the Cotellic/Zelboraf combination this week for melanoma patients with BRAF V600E or V600K mutations, whose disease has spread or cannot be surgically removed. Roche subsidiary Genentech developed Cotellic in collaboration with Exelixis.

Zelboraf was the first melanoma treatment that Genentech launched in 2011 for advanced melanoma patients with BRAF V600E mutations. The latest approval of Zelboraf in combination with Cotellic expands the use of the drug into patients with BRAF V600K mutations.

Approximately half of advanced melanoma patients have BRAF mutations, mostly V600E, while V600K mutations are comparatively rare. With the 2011 approval of Zelboraf, the FDA also approved Roche's qPCR-based Cobas 4800 BRAF V600 Mutation Test for identifying patients with such mutations who would respond best to treatment. According to Roche's website, the test can gauge less-common V600K and V600D mutations in addition to V600E mutations.

In the Phase III CoBRIM study, which led to Cotellic's approval this week, patients had their BRAF mutation status determined by the same Roche test. Roche spokesperson Emmy Wang told GenomeWeb that some patients had a V600K mutation in the so-called CoBRIM study, and "data from the study will be provided to the FDA to update the label for the Cobas test."

In approving the new combination, the FDA advised healthcare providers to "confirm the presence of BRAF V600E or V600K mutation in their patients' tumor specimens using one of the available FDA approved tests prior to starting treatment."

The Cotellic/Zelboraf duo is the second MEK/BRAF inhibitor option for melanoma patients. The FDA last year approved the combination of the BRAF inhibitor Tafinlar (dabrafenib) and the MEK inhibitor Mekinist (trametinib) for melanoma patients with BRAF V600E and V600K mutations. The FDA approved these drugs — which were initially developed by GlaxoSmithKline and then acquired by Novartis — as single agents in 2013, alongside THxID BRAF, another qPCR-based companion diagnostic developed by BioMérieux.

In a statement about Cotellic's approval, Richard Pazdur, director of the Office of Hematology and Oncology Products in FDA's drug division noted that research has improved the field's understanding of how adept cancer cells are at developing resistance to targeted therapies. "Combining two or more treatments addressing different cancer-causing targets may help to address this challenge," Pazdur said. Zelboraf and Cotellic inhibit the BRAF and MEK enzymes, respectively, which reside in the same pathway that can encourage the growth of cancer when there are abnormalities.

"Today's approval provides a new targeted treatment that, when added to vemurafenib, demonstrates greater benefit than vemurafenib alone in patients with BRAF mutation-positive melanoma," Pazdur said.

The FDA granted Cotellic priority review and orphan drug designation, and considered data from the coBRIM study. In that trial, 495 patients with BRAF V600 mutation-positive melanoma received Zelboraf, and then were randomized to receive Cotellic or placebo. Patients taking Cotellic in addition to Zelboraf on average delayed their disease progression for 12.3 months compared to 7.2 months for those on Zelboraf plus placebo.

Around two-thirds of patients receiving the combination therapy lived 17 months longer after starting treatment, compared to only half of patients receiving Zelboraf as a single agent. More patients receiving Cotellic/Zelboraf (70 percent) saw their tumors completely or partially shrink compared to those on the Zelboraf/placebo arm (50 percent). 

Adding Cotellic to Zelboraf caused common side effects, such as diarrhea, sensitivity to ultraviolet light, and nausea, as well as severe adverse events such as cardiomyopathy, new skin tumors, retinal detachment, and liver damage.

Genentech has priced Cotellic at $6,600 per month, while the monthly cost of Zelboraf is $11,000. "When considering the cost of Cotellic, we took into consideration that it would be used with Zelboraf and potentially other medicines in the future, and priced Cotellic less than other recently approved cancer medicines," Wang said.

The $17,600 per month price tag for the Cotellic/Zelboraf regimen is $1,300 above the monthly cost of Tafinlar ($7,600) and Mekinist ($8,700) combination. Still, Wang highlighted that Genentech has 350 employees helping patients gain access to drugs when they can't afford them or have insurance difficulties.