Genentech's Zelboraf

Specialty Pharmacy Times, February 2012, Volume 3, Issue 1

The FDA approved Genentech's Zelboraf (vermurafenib) for the treatment of unresectable or metastatic melanoma with BRAF V600E mutation.

The FDA approved Genentech's Zelboraf (vermurafenib) for the treatment of unresectable or metastatic melanoma with BRAFV600E mutation.

The FDA has approved Genentech’s Zelboraf (vemurafenib) for the treatment of unresectable or metastatic melanoma with BRAFV600E mutation, as determined by the FDA-approved cobas 4800 BRAF V600 Mutation Test.1,2 Zelboraf should not be used in patients with wild-type BRAF melamona.1

Melanoma is the most common cause of death from skin disease. In 2010, the National Cancer Institute estimated 68,130 new cases of melanoma were diagnosed in the United States, with about 8700 deaths resulting from the condition. Approximately half of all late-stage melanomas exhibit a mutated BRAF protein.3

PHARMACOLOGY AND PHARMACOKINETICS

Zelboraf is a kinase inhibitor of some mutated forms of BRAF, including BRAFV600E. The mutated forms of the BRAF gene lead to activated BRAF proteins, which can result in cell proliferation, even when growth factors normally required for proliferation are absent.

Age, gender, body weight, and race did not affect the pharmacokinetics of Zelboraf.1

DOSING AND ADMINISTRATION

Zelboraf is given as 960 mg orally twice a day, with approximately 12 hours between doses. The tablets should be swallowed with a full glass of water and should not be chewed or crushed. Zelboraf can be taken with or without food.

The dose of Zelboraf may need to be reduced, interrupted, or discontinued based on prolongation of QT or symptomatic adverse drug reactions, as evaluated by Common Terminology Criteria for Adverse Events v4.0 (CTC-AE).

Reducing the dose to less than 480 mg twice daily is not recommended. Modification or interruption of treatment for cutaneous squamous cell carcinoma (cuSCC) is not recommended.1

CLINICAL TRIALS

Zelboraf was studied in 2 clinical trials. BRIM3 was a global, randomized, open-label, controlled, multicenter, Phase 3 study that compared Zelboraf with dacarbazine in 675 patients with previously untreated BRAFV600E mutation—positive, unresectable, or metastatic melanoma. The study found the risk of death to be decreased by 56% in the Zelboraf group. The Zelboraf group also had a 74% reduction in the risk of disease worsening or death. 48.4% of Zelboraf participants experienced tumor shrinkage (1% complete response and 47.4% partial response), compared with 5.5% (partial response) of the dacarbazine group.

BRIM2 was a global, single-arm, multicenter, open-label Phase 2 study of 132 patients with previously treated BRAFV600E mutation—positive, unresectable, or metastatic melanoma. The study found 52% of the Zelboraf group experienced tumor shrinkage.2

CONTRAINDICATIONS, WARNINGS, AND PRECAUTIONS

There are no contraindications to treatment with Zelboraf.

CuSCCs occurred in approximately 24% of patients using Zelboraf; dermatologic examinations should be performed prior to treatment and every 2 months during treatment. CuSCC should be managed with excision and Zelboraf should be continued without dose reduction. Discontinue Zelboraf if serious hypersensitivity reactions occur. Zelboraf should be discontinued if severe dermatologic reactions occur, including Stevens- Johnson syndrome and toxic epidermal necrolysis.

QT prolongation has been reported during treatment with Zelboraf. ECG and electrolytes should be monitored before treatment and after dose modifications. ECG should be monitored at day 15, monthly for the first 3 months, and then every 3 months thereafter. Liver enzymes should be monitored before treatment and monthly thereafter. Patients should avoid sun exposure, as Zelboraf may increase photosensitivity. Serious ophthalmologic reactions have been reported, including uveitis, iritis, and retinal vein occlusion. New primary malignant melanomas have occurred and should be managed with excision and dose continuation without modification. Zelboraf is

Pregnancy Category D. Zelboraf should not be used while breastfeeding. Patients should be confirmed for the BRAFV600E mutation prior to initiation of therapy. Zelboraf has not been studied in patients with wild-type BRAF melanoma. Concomitant use with narrow therapeutic window substrates of cytochrome P450 (CYP) 3A4, CYP1A2, or CYP2D6 should be avoided. Caution should be used when Zelboraf and warfarin are used together.

The most common adverse reactions (≥30%) are arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritis, and skin papilloma.1

Zelboraf’s approval included a Medication Guide to inform patients and health care professionals of its potential risks.3

References

1. Zelboraf complete prescribing information. www.gene.com/gene/products/information/zelboraf/pdf/pi.pdf. Accessed November 2011.

2. FDA approves Zelboraf (vemurafenib) and companion diagnostic for BRAF mutation-positive metastatic melanoma, a deadly form of skin cancer. www.gene.com/gene/news/press-releases/display.do?method=detail&id=13567. Accessed November 2011.

3. FDA approves Zelboraf and companion diagnostic test for late-stage skin cancer. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm268241.htm. Accessed November 2011.

About the Author

Monica Holmberg, PharmD, BCPS, is a pharmacist who resides in Phoenix, Arizona.