Zelboraf® (vemurafenib) in Metastatic Melanoma

Zelboraf (vemurafenib) (pronounced "ZEL bor af" and "vem yoo RAF en ib") is the first and only oral, personalized medicine that is approved by the U.S. Food and Drug Administration (FDA) for the treatment of BRAF V600E mutation-positive, unresectable (inoperable) or metastatic melanoma, as determined by a FDA-approved test. Zelboraf inhibits a cancer-driving, mutated form of the BRAF protein found in approximately half of melanomas.¹

What is Melanoma?

• Melanoma is the less common, but more serious category of skin cancer that originates in the skin's pigment-producing cells known as melanocytes^{2, 3}
• The American Cancer Society (ACS) estimates more than 76,000 new cases of melanoma will be diagnosed and nearly 9,200 melanoma deaths will occur in the United States in 2012²
• When melanoma is caught early, it is generally treatable. However, when it spreads to other parts of the body (metastatic melanoma), it is the deadliest and most aggressive form of skin cancer.² A person with metastatic melanoma typically has a short life expectancy that is measured in months⁴
• Until recently, there were no major advances in treatment for metastatic melanoma for 30 years and people with the disease have had few options⁵

How Zelboraf Works (Proposed Mechanism of Action)

• Zelboraf is designed to inhibit the activity of some forms of the mutant BRAF protein, including BRAF V600E, which is found in approximately half of melanomas¹
• The BRAF protein plays a key role in normal cell growth and survival.⁶ However, mutations in BRAF (V600E mutations) cause the protein to be locked "on," leading to constant growth signals that can contribute to cancer development and growth⁷
• Zelboraf is thought to work by targeting and suppressing cells with the mutated BRAF protein and preventing the cells from growing⁷
• Zelboraf was co-developed with a FDA-approved test developed by Roche, the cobas 4800 BRAF V600 Mutation Test
• Using a diagnostic test to identify patients whose tumors carry BRAF V600E mutations and therefore may be candidates to receive Zelboraf is an example of Genentech's commitment to developing personalized approaches to cancer care

The BRAF Signaling Pathway

1) In normal cells, growth factors bind to receptors on the cell surface. This activates a protein called RAS, which in turn leads to the activation of a series of other proteins within the cell, beginning with BRAF. Eventually the signal reaches the cell nucleus, where it turns on genes that control cell growth and survival.

2) In cells that have the BRAF V600E mutation, growth signals are constantly sent into the cell, regardless of whether growth factors are present. This can drive cancer to grow and survive. Zelboraf is designed to inhibit the mutant BRAF V600E protein.

Zelboraf in Inoperable or Metastatic Melanoma with the BRAF V600E Mutation

Zelboraf demonstrated a significant improvement in overall survival compared to dacarbazine chemotherapy in a Phase III study (BRIM3) in people with previously untreated BRAF V600E mutation-positive, inoperable or metastatic melanoma. Results showed that:

• The risk of death was reduced by 56 percent for people who received Zelboraf compared to those who received dacarbazine chemotherapy (hazard ratio [HR]=0.44, p<0.0001)
• People who received Zelboraf also had a 74 percent reduced risk of the disease getting worse or death (progression-free survival, or PFS) compared to dacarbazine chemotherapy (HR=0.26, p<0.0001)

The most frequent Grade 3 adverse event observed in trials of Zelboraf was skin related and included cutaneous squamous cell carcinoma, a skin cancer treated by local excision (minor surgery done in a physician's office). Common side effects include joint pain, hair loss, tiredness, rash, nausea, sunburn or sun sensitivity, itching or warts.

Zelboraf is being co-developed under a 2006 license and collaboration agreement between Roche and Plexxikon, a member of the Daiichi Sankyo Group. Genentech and Daiichi Sankyo, Inc. will co-promote Zelboraf in the United States.

Important Safety Information

This information does not take the place of the patient talking to their doctor about their medical condition or their treatment with Zelboraf.

Zelboraf is a prescription medicine used to treat a type of skin cancer called melanoma that has spread to other parts of the body or cannot be removed by surgery, and has a certain type of abnormal "BRAF" gene.

Zelboraf may cause a type of skin cancer called cutaneous squamous cell carcinoma (cuSCC) that usually does not spread to other parts of the body. Patients should check their skin and tell their doctor about skin changes including a new wart, a skin sore or reddish bump that bleeds or does not heal, or a mole that changes size or color.

While taking Zelboraf, patients should avoid going out in the sun. When patients go outside, they should wear clothes that protect their skin, including head, face, hands, arms and legs. They should use lip balm and a broad-spectrum sunscreen with SPF 30 or higher.

Possible serious side effects of Zelboraf include severe allergic reactions; severe skin reactions; changes in the electrical activity of the heart called QT prolongation, which can potentially be life-threatening; abnormal liver function tests; eye problems; or new melanoma lesions.

Common side effects of Zelboraf include joint pain, rash, hair loss, tiredness, sunburn or sun sensitivity, nausea, itching, or warts.

These are not all of the possible side effects of Zelboraf. Patients must tell their doctor if they have any side effect that bothers them or does not go away. For more information about side effects, patients should ask their doctor or pharmacist.

Patients should call their doctor for medical advice about any side effects. Patients or their caregivers may report side effects to the FDA at 1-800-FDA-1088. They may also report side effects to Genentech at 1-888-835-2555.

Patients should read the Zelboraf full Prescribing Information and Medication Guide for additional important safety information at www.zelboraf.com.

• References

  ¹ Flaherty KT, Puzanov I, Kim K, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363:809-819.

  ² American Cancer Society. Cancer Facts and Figures 2012. http://www.cancer.org/Research/CancerFactsFigures/CancerFactsFigures/cancer-facts-figures-2012. Accessed April 29, 2012.

  ³ American Cancer Society. Skin Cancer: Melanoma. http://www.cancer.org/Cancer/SkinCancer-Melanoma/DetailedGuide/melanoma-skin-cancer-what-is-melanoma. Accessed June 29, 2011.

  ⁴ Tsao H, Atkins MB, Sober AJ. Management of cutaneous melanoma. N Engl J Med. 2004;351:998-1012.

  ⁵ Bhatia S, Tykodi SS, Thompson JA. Treatment of metastatic melanoma: An overview. Oncology. 2009;23(6):488-496.

  ⁶ Garnett MJ and Marais R. Guilty As Charged: B-RAF Is A Human Oncogene. Cancer Cell. 2004;6:313-319.

  ⁷ Bollag et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2010;467(7315):596-599.

  ⁸ McCubrey JA, Steelman LS, Chappell WH, et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 2007;1773(8):1263-1284.

  ⁹ Sebolt-Leopold JS, Herrera R. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer. 2004;4:937-947.

  ¹⁰ Data on file.