FDA Approves Cobimetinib in Combination With Vemurafenib for Metastatic Melanoma

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On November 10, 2015, the U.S. Food and Drug Administration (FDA) approved the MEK inhibitor cobimetinib (Cotellic) in combination with the BRAF inhibitor vemurafenib (Zelboraf) to treat metastatic or unresectable melanoma in patients whose tumors express the BRAF V600E or V600K mutation. Approval of the combination was based on results from the phase III coBRIM study.1

“As we continue to advance our knowledge of tumor biology, we have learned that cancer cells have a remarkable ability to adapt and become resistant to targeted therapies. Combining two or more treatments addressing different cancer-causing targets may help to address this challenge,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

“[This] approval provides a new targeted treatment that, when added to vemurafenib, demonstrates greater benefit than vemurafenib alone in patients with BRAF mutation–positive melanoma,” Dr. Pazdur said.

Vemurafenib was approved in 2011 to treat patients with melanoma that has spread to other parts of the body or cannot be removed by surgery, whose tumors express the BRAF V600E mutation, as detected by an FDA-approved test. Health-care providers should confirm the presence of BRAF V600 E or V600K mutation in their patients’ tumor specimens using one of the available FDA-approved tests prior to starting treatment with cobimetinib in combination with vemurafenib.

Phase III coBRIM Study

The coBRIM study is an international, randomized, double-blind, placebo-controlled phase III trial evaluating the safety and efficacy of cobimetinib at 60 mg once daily plus vemurafenib at 960 mg twice daily compared to vemurafenib at 960 mg twice daily plus placebo. In the study, 495 patients with BRAF V600 mutation–positive unresectable locally advanced or metastatic melanoma (detected by the Cobas 4800 BRAF Mutation Test) and previously untreated for advanced disease were randomly assigned to receive vemurafenib every day on a 28-day cycle plus either cobimetinib or placebo on days 1 to 21. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent.

Investigator-assessed progression-free survival was the primary endpoint. Secondary endpoints included progression free survival as determined by independent review committee; overall response rate; objective survival; duration of response; and other safety, pharmacokinetic, and quality-of-life measures.

The study showed cobimetinib plus vemurafenib reduced the risk of progression-free survival by about one-half in people who received the combination, (P < .001), with a median progression-free survival of 12.3 months for cobimetinib plus vemurafenib compared to 7.2 months with vemurafenib alone. An interim analysis also showed the combination of cobimetinib and vemurafenib improved overall survival compared with vemurafenib alone (P = .0019). The objective response rate was higher with cobimetinib plus vemurafenib compared with vemurafenib alone (70% vs 5%, P < .001), as was the complete response rate (complete tumor shrinkage = 16% vs 10%).

The final overall survival analysis from the coBRIM study were presented earlier this month at the Society for Melanoma Research 2015 International Congress, held in San Francisco.1


1. Ascierto P, et al: coBRIM: A phase III, double-blind placebo-controlled study of vemurafenib vs vemurafenib + cobimetinib in previously untreated BRAF v600 mutation–positive patients with unresectable locally advanced or metastatic melanoma. Society for Melanoma Research 2015 Congress. Presented November 18-21, 2015.