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U.S. Department of Health and Human Services

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Vemurafenib

On August 17, 2011, the U. S. Food and Drug Administration approved vemurafenib tablets (ZELBORAF, 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 (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 assigned to vemurafenib, 960 mg orally twice daily, and 338 were 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% 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 and 4.5 months for the vemurafenib and dacarbazine arms, respectively. Overall survival was significantly improved in patients receiving vemurafenib compared to those receiving dacarbazine (HR=0.44; 95% CI: 0.33, 0.59; p< 0.0001, log-rank test).  The median survival of patients receiving vemurafenib had not been reached (95% CI: 9.6 months, not reached) and was 7.9 months (95% 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% CI: 0.20, 0.33; p<0.0001, log-rank test). The median PFS was 5.3 (95% CI: 4.9, 6.6) and 1.6 months (95% CI: 1.6, 1.7) in the vemurafenib and dacarbazine arms, respectively. Overall response rate (complete plus partial response rates) was 48.4% (95% CI: 41.6%, 55.2%) and 5.5% (95% CI: 2.8%, 9.3%) in the vemurafenib and dacarbazine arms, respectively.
 
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% (95% CI: 43%, 61%), with a median response duration of 6.5 months (95% CI: 5.6, not reached).
 
The most common adverse reactions (≥30%) 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% 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 reactions, sometimes severe, reported in vemurafenib-treated patients 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.
Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202429s000lbl.pdf
 
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).