Avastin® (bevacizumab) Plus Interferon Alfa In First-Line Metastatic Kidney Cancer

Full Prescribing Information, including Boxed WARNINGS

Avastin is the first medicine approved by the U.S. Food and Drug Administration (FDA) designed to inhibit angiogenesis, a process that connects tumors to the blood supply.¹

In July 2009, Avastin was approved for the treatment of people with metastatic renal cell carcinoma in combination with interferon alfa.¹ Avastin is designed to specifically block a protein that is a key factor in the growth of most types of cancer. Avastin inhibits this protein known as vascular endothelial growth factor (VEGF), which is produced in elevated amounts in renal cell carcinoma.

The National Comprehensive Cancer Network, an alliance of 21 of the world's leading cancer centers, recommends Avastin in combination with interferon alfa as a treatment for metastatic renal cell carcinoma.²

Renal cell carcinoma is the most common form of kidney cancer and accounts for about nine out of 10 cases.³ According to the American Cancer Society, more than 57,000 people in the United States will be diagnosed with kidney cancer and nearly 13,000 will die from the disease in 2009.⁴ The number of newly diagnosed cases of renal cell carcinoma has been increasing over the last several decades.⁵

Avastin in combination with chemotherapy is also approved by the FDA to treat two of the largest causes of cancer deaths — colorectal and lung cancers.¹

How Avastin Works (Proposed Mechanism Of Action)

• Avastin is a biologic medicine (not chemotherapy) designed to inhibit the VEGF protein, an important factor in the development and maintenance of blood vessels⁶
• VEGF is a potent activator of angiogenesis known to be present throughout the lifecycle of a tumor and is critical to a tumor's ability to grow and spread (metastasize)⁶

Avastin Clinical Studies In Kidney Cancer First-Line Treatment In Metastatic Renal Cell Carcinoma

• In the Phase III study (AVOREN), patients who received Avastin plus interferon alfa had a 67 percent improvement in the time patients lived without their disease worsening (progression-free survival or PFS), compared to those who received interferon alfa alone, which can also be referred to as a 40 percent reduction in the risk of cancer progression or death (HR=0.60, 95 percent CI=0.49, 0.72, p<0.0001)^{1, 7}
  • In AVOREN, one-half of patients who received Avastin plus interferon alfa lived 10.2 months without their disease worsening, compared to 5.4 months for patients who received interferon alfa alone, corresponding to an 89 percent improvement in median PFS.¹
  • Median overall survival with Avastin plus interferon alfa was 23 months, a non-significant increase vs. 21 months in the placebo plus interferon alfa (HR=0.86, 95 percent CI=0.72, 1.04, p=0.1291)^{1, 7}
  • Tumor size decreased in 30 percent of patients who received Avastin plus interferon alfa, compared to 12 percent of patients who received interferon alfa alone (p<0.0001)^{1, 7}

Avastin Development Program

• The Avastin development program is one of the most comprehensive in cancer research since chemotherapy⁸
• Avastin is being studied worldwide in more than 450 clinical trials and in approximately 30 different tumor types, including treatment for early-stage cancers⁸
• Avastin is also being studied in combination with other targeted medicines without chemotherapy⁸

Indications Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil-based chemotherapy.¹

Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer in combination with carboplatin and paclitaxel.¹

Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.¹

Avastin Safety Patients treated with Avastin may experience side effects. In clinical trials, some patients treated with Avastin experienced serious side effects, including:

Gastrointestinal (GI) perforation: Treatment with Avastin can result in the development of a serious side effect called GI perforation, which is the development of a hole in the stomach, small intestine, or large intestine. In clinical trials, this side effect occurred in 0.3 to 2.4 percent of patients and in some cases resulted in fatality. Avastin therapy should be permanently stopped in people with GI perforation.

Surgery and wound healing problems: Treatment with Avastin can lead to slow or incomplete wound healing (for example, when a surgical incision has trouble healing or staying closed). In some cases this event resulted in fatality. In a clinical trial, 15 percent of patients with metastatic colorectal cancer who had surgery while receiving Avastin treatment had serious and fatal complications. Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Avastin therapy should be permanently stopped in patients with wound healing problems that require medical treatment. The appropriate waiting time between stopping treatment with Avastin and having surgery has not been determined.

Severe bleeding: Severe or fatal bleeding, including hemoptysis (coughing up of blood), GI bleeding, hematemesis (bloody vomit), central nervous system (CNS) hemorrhage (bleeding in the brain), epistaxis (nose bleeds), and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin. Grade 3 or higher (severe or fatal) bleeding events have occurred in 1.2 to 4.6 percent of patients receiving Avastin.

In patients with previously treated glioblastoma, intracranial hemorrhage (bleeding within the brain) occurred in eight of 163 patients and two people had Grade 3 to 4 (severe) bleeding. Some people receiving Avastin with chemotherapy for lung cancer experienced hemoptysis. In some cases, this event resulted in fatality. People with serious bleeding or recent hemoptysis should not receive Avastin.

In clinical trials, additional serious side effects seen across different cancer types, in some cases resulting in fatality, included the following: formation of an abnormal passage from parts of the body to another part (non-GI fistula formation - less than 0.3 percent); stroke or heart problems (arterial thromboembolic events - 2.6 percent); high blood pressure (5 to 18 percent); nervous system and vision disturbances known as RPLS (reversible posterior leukoencephalopathy syndrome - less than 0.1 percent); severe infusion reactions (0.2 percent), and too much protein in the urine, which may be a sign of kidney problems, was increased.

The most common adverse reactions observed in Avastin patients at a rate of more than 10 percent and at least twice the control arm rate, were nose bleeds, headache, high blood pressure, irritation of the nose (rhinitis), protein in the urine, taste alteration, dry skin, rectal bleeding, tear production disorder (lacrimation), and inflammation of the skin (exfoliative dermatitis).

Avastin may cause problems getting pregnant. People who are pregnant or thinking of becoming pregnant should talk with their doctor about the potential risks of loss of pregnancy or the potential risk of Avastin to the fetus. Nursing mothers should not breast-feed while receiving Avastin or for a short period of time after treatment is finished.

For full Prescribing Information and Boxed WARNINGS on Avastin, please visit http://www.avastin.com.

References ¹ Genentech. Avastin® (bevacizumab) Prescribing Information. May, 2009.

² NCCN Treatment Guidelines. Available at: http://nccn.org. Accessed on June 18, 2009.

³ American Cancer Society. What Is Kidney Cancer (Adult) - Renal Cell Carcinoma? Available at: http://www.cancer.org Accessed on June 18, 2009.

⁴ American Cancer Society. Cancer Facts & Figures 2009. Atlanta: American Cancer Society; 2009.

⁵ Adams, et al. Body Size and Renal Cell Cancer Incidence in a Large US Cohort Study. American Journal of Epidemiology. 2008;168:268- 277.

⁶ Ranieri G, Patruno R, Ruggieri E, et al. Vascular endothelial growth factor (VEGF) as a target of bevacizumab in cancer: from the biology to the clinic. Curr Med Chem. 2006;13:1845-1857.

⁷ Escudier B, Bellmunt J, Negrier S, et al. Slides presented at: Annual Meeting of the American Society of Clinical Oncology; May 29-June 2, 2009; Orlando, Fla.

⁸ Data on File.