Pharmacology Update

Vemurafenib Tablets (Zelboraf™)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationships relevant to this field of study.

A kinase inhibitor for late-stage melanoma and its companion diagnostic test have been approved by the FDA. Vemurafenib is specifically for patients with melanoma whose tumor expresses a gene mutation called BRAF V600E. It is the second drug approved for late-stage melanomas after the monoclonal antibody, ipili-mumab (Yervoy™). Vemurafenib was reviewed under the FDA's priority review program. The drug is marketed by Genentech as Zelboraf™.


Vemurafenib is indicated for the treatment of unresectable or metastatic melanoma with BRAF mutation as detected by the FDA-approved test (cobas® 4800 BRAF V600 Mutation Test).


The recommended dose is 960 mg (4x 240 mg) taken orally twice daily.1 The tablets should be swallowed whole with or without a meal. Dose reduction, interruption, or discontinuation may be required if adverse reactions occur, however dose reduction below 480 mg twice daily is not recommended.

Vemurafenib is available as 240 mg tablets.

Potential Advantages

Vemurafenib has been shown to improve overall and progression-free survival compared to dacarbazine in patients with mutation positive metastatic melanoma.1,2

Potential Disadvantages

Common adverse events (30% or higher) include arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma.1 Cutaneous squamous cell carcinoma and keratoacanthomas have been reported. These tend to occur with a median time of 7 to 8 weeks of therapy and approximately one-third of patients experienced more than one occurrence. Close to 40% of patients required dose modification due to adverse effects.2 Vemurafenib is not recommended in patients with uncorrectable electrolyte abnormalities or long QT syndrome, or for those who are on drugs that may prolong QT interval.1 The drug is a moderate inhibitor of CYP1A2, a weak inhibitor of CYP2D6, and an inducer of CYP3A4. Concomitant use with substrates with narrow therapeutic windows for these isoenzymes is not recommended.1


Vemurafenib is a potent inhibitor of some mutated forms of BRAF, particularly BRAFT V600E. The efficacy and safety of vemurafenib was shown in a Phase 3 randomized trial comparing it with dacarbazine (n = 675).1,2 Patients with unresectable, previously untreated stage IIIC, or stage IV melanoma and positive for BRAF V600 mutation were randomized to vemurafenib (960 mg twice daily) or dacarbazine (1000 mg/m2 intravenously on day 1 every 3 weeks). The efficacy endpoints were overall survival, investigator-assessed progression-free survival, and confirmed investigator-assessed best overall response rate. After a median follow-up of 6.2 months in the vemurafenib group (n = 337) and 4.5 months in the dacarbazine group (n = 338), the number of deaths were 23% and 36%, respectively (hazard ratio [95% CI] 0.44 [0.33,0.59]; P < 0.0001). The hazard ratio for progression-free survival was 0.26 (0.20, 0.33). The confirmed investigator-assessed best overall response rate was 48.4% with vemurafenib compared to 5.5% for dacarbazine.3 Responses were partial as there were two complete responses in the vemurafenib group and none in the dacarbazine group. Seventy-five percent of responses occurred by month 1.6 of treatment. Adverse event related dose modification or interruption occurred in 38% of patients on vemurafenib compared to 16% for dacarbazine. Cutaneous squamous cell carcinoma, keratoacanthoma, or both occurred in 18% of vemurafenib-treated patients.2 Some evidence of acquired clinical resistance to vemurafenib has been reported.4

Clinical Implications

Late-stage melanoma carries a poor prognosis and is the leading cause of death from skin disease with median survival ranging from 8 to 18 months.5 BRAF V600E mutation is found in 50% to 60% of melanoma. Vemurafenib represents an important treatment for this disease in patients with the BRAF mutation. Earlier this year, the FDA approved ipilimumab that also has been shown to improve survival in patients with this disease with previously treated unresectable or metastatic melanoma.


1. Zelboraf Prescribing Information. San Francisco, CA: Genentech; August 2011.

2. Chapman PB, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-2516.

3. Accessed on Sept. 25, 2011.

4. Shi H, et al. Combinatorial treatments that overcome PDGFRB-driven resistance of melanoma cells to V600EB-RAF inhibition. Cancer Res 2011;71:5067-5074.

5. Balch DM, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009;27:6199-6206.