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FDA Approval for Vemurafenib

Brand name: Zelboraf

  • Approved to treat late-stage or unresectable melanoma.

Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.

On August 17, 2011, the Food and Drug Administration (FDA) approved vemurafenib tablets (ZELBORAF, made  by Hoffmann-La Roche Inc.) for the treatment of patients with unresectable or metastatic melanoma with the BRAFV600E mutation as detected by an FDA-approved test.   

The approval was based primarily on an international randomized open-label trial in patients with previously untreated metastatic or unresectable melanoma with the BRAFV600E mutation as detected by the cobas 4800 BRAF V600 Mutation Test (made by Roche Molecular Systems, Inc.). This companion diagnostic test was approved by the FDA concurrently with vemurafenib’s approval.

The trial enrolled 675 patients; 337 patients were randomly assigned to vemurafenib, 960 mg orally twice daily, and 338 were randomly assigned to dacarbazine, 1000 mg/m2 intravenously, every three weeks. Treatment continued until disease progression, unacceptable toxicity, and/or consent withdrawal.  All patients had an ECOG performance status of 0 or 1, and 95 percent of patients had metastatic disease. The major efficacy outcome measures of the trial were overall survival (OS) and investigator-assessed progression-free survival (PFS). Other outcome measures included confirmed investigator-assessed best overall response rate.

The median follow-up at the time of the overall survival analysis was 6.2 months for patients treated with vemurafenib and 4.5 months for patients treated with dacarbazine. Overall survival was significantly improved in patients receiving vemurafenib compared with those receiving dacarbazine (HR=0.44; 95 percent CI: 0.33, 0.59; p< 0.0001, log-rank test).  The median survival of patients receiving vemurafenib had not been reached (95 percent CI: 9.6 months, not reached) and was 7.9 months (95 percent CI: 7.3, 9.6) for those receiving dacarbazine.

Progression-free survival (PFS) was also significantly improved in patients receiving vemurafenib (HR=0.26; 95 percent CI: 0.20, 0.33; p<0.0001, log-rank test). The median PFS was 5.3 months (95 percent CI: 4.9, 6.6) for patients receiving vemurafenib and 1.6 months for patients receiving dacarbazine (95 percent CI: 1.6, 1.7). Overall response rate (complete plus partial response rates) was 48.4 percent for patients receiving vemurafenib (95 percent CI: 41.6 percent, 55.2 percent) and 5.5 percent (95 percent CI: 2.8 percent, 9.3 percent) for patients receiving dacarbazine.

Vemurafenib was also evaluated in a single-arm multicenter trial that enrolled 132 patients with BRAFV600E mutation-positive metastatic melanoma who had received at least one prior systemic therapy. An independent review of treatment responses demonstrated a confirmed best overall response rate of 52 percent (95 percent CI: 43 percent, 61 percent), with a median response duration of 6.5 months (95 percent CI: 5.6, not reached).

The most common adverse reactions (at least 30 percent) in patients treated with vemurafenib were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, and nausea.  Cutaneous squamous cell carcinomas (cuSCC), including squamous cell carcinomas of the skin and keratoacanthomas, were detected in approximately 24 percent of patients treated with vemurafenib.  CuSCCs were managed with excision in clinical trials, and patients were able to continue treatment without dose adjustment. Other adverse and sometimes severe reactions reported in patients treated with vemurafenib included hypersensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, uveitis, QT prolongation, and liver enzyme laboratory abnormalities.

The recommended dose of vemurafenib is 960 mg, orally twice daily administered approximately 12 hours apart, with or without a meal.

Confirmation of BRAFV600E mutation-positive melanoma using an FDA-approved test is required before treatment with vemurafenib. Vemurafenib is not recommended for use in patients with wild-type BRAF melanoma.  The approval also contains a Medication Guide to inform health care professionals and patients of vemurafenib’s potential risks.

This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.

The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.

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  • Updated: July 3, 2013