Avastin® (bevacizumab) in Lung Cancer

Full Prescribing Information, including Boxed WARNINGS

Avastin was the first anti-angiogenesis therapy approved by the U.S. Food and Drug Administration (FDA). It was approved in combination with carboplatin and paclitaxel for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer (NSCLC) in October 2006.

Avastin "First" in Metastatic NSCLC Avastin, in combination with chemotherapy, is the first drug in more than 10 years to improve upon standard first-line treatment, and the first targeted therapy ever to extend overall median survival beyond one year in a large, randomized clinical study.

Proposed Mechanism of Action Avastin is a therapeutic antibody (not chemotherapy) specifically designed to bind to and inhibit the vascular endothelial growth factor (VEGF) protein, a potent source of angiogenesis. Angiogenesis is a process that connects tumors to the blood supply.³ By inhibiting VEGF, Avastin may interfere with the blood supply to a tumor, which is thought to be critical to a tumor's ability to grow and spread in the body (metastasize). The effects of Avastin on tumor blood vessels may also enhance the delivery of chemotherapy drugs to the cancer.^4-6

WARNINGS

• Gastrointestinal (GI) perforation: Avastin can result in the development of a potentially serious, and sometimes fatal side effect called GI perforation, which is the development of a hole in the stomach, small intestine or large intestine. Symptoms may include abdominal pain, nausea, vomiting, constipation, and fever. Patients must stop Avastin for at least 28 days before voluntary surgery.
• 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.
• Severe bleeding: Treatment with Avastin can result in serious and sometimes fatal bleeding. This includes coughing up blood, bleeding in the stomach, vomiting blood, bleeding in the brain, nosebleeds and vaginal bleeding. People who have recently coughed up blood or have serious bleeding should not receive Avastin.

Clinical Trial Data First-Line Treatment in Metastatic NSCLC The FDA approval for this indication was based on results from E4599, a randomized, controlled, multi-center trial that enrolled 878 patients with unresectable, locally advanced, recurrent or metastatic non-squamous NSCLC. Results showed that patients receiving Avastin plus paclitaxel and carboplatin chemotherapy had a 25 percent improvement in overall survival, the trial's primary endpoint, compared to patients who received paclitaxel and carboplatin alone (based on a hazard ratio of 0.80). One-year survival was 51 percent in the Avastin plus chemotherapy arm versus 44 percent in the chemotherapy-alone arm. Median survival of patients treated with Avastin plus chemotherapy was 12.3 months, compared to 10.3 months for patients treated with chemotherapy alone.¹ In clinical trials for NSCLC, the following side effects occurred more often in people receiving Avastin plus chemotherapy than in people receiving chemotherapy alone: nosebleeds, hypertension (high blood pressure), proteinuria (too much protein in the urine, a possible sign of kidney malfunction), neutropenia (a reduced white blood cell count, which may increase the chance of developing an infection). Additional side effects included fatigue, difficulty breathing, and others.

People who took Avastin with chemotherapy had a higher risk of stroke or heart problems (blood clots) compared with people taking chemotherapy alone. Additional serious side effects seen in patients who took Avastin with chemotherapy include severe hypertension, kidney malfunction, and nervous system and vision disturbances.

The National Comprehensive Cancer Network (NCCN) recommends Avastin as a preferred therapy in combination with carboplatin and paclitaxel in appropriate patients for the first-line treatment of advanced non-squamous NSCLC, the leading cause of cancer deaths in the U.S.⁷

BOXED WARNINGS and Additional Important Safety Information People receiving Avastin may experience side effects. In clinical trials, some people treated with Avastin experienced serious and sometimes fatal 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 event occurred in more people who received Avastin than in the comparison group (0.3% to 2.4%). In some cases, GI perforation resulted in fatality. Avastin therapy should be permanently stopped if GI perforation occurs.
  
  
• 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. Surgery and wound healing problems occurred more often in people who received Avastin than in the comparison group. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who had surgery during the course of Avastin treatment was 15%, and in patients who did not receive Avastin was 4%. Avastin therapy should not be started for at least 28 days after surgery and until the surgical wound is fully healed. The length of time between stopping Avastin and having voluntary surgery without the risk of wound healing problems following surgery has not been determined. Treatment with Avastin should be stopped at least 28 days before voluntary surgery and in people with wound healing problems following surgery that require medical treatment. Treatment with Avastin should be stopped in patients with slow or incomplete wound healing.
  
  
• Severe bleeding: Treatment with Avastin can result in serious or fatal bleeding, including coughing up blood, bleeding in the stomach, vomiting of blood, bleeding in the brain, nosebleeds, and vaginal bleeding. These events occurred up to 5 times more often in people who received Avastin compared to patients who received only chemotherapy. Across cancer types, 1.2% to 4.6% of people who received Avastin experienced severe to fatal bleeding. People who have recently coughed up blood (greater than or equal to a half teaspoon of red blood) or have serious bleeding should not receive Avastin. Treatment with Avastin should be permanently stopped if serious bleeding occurs (i.e. requiring medical attention).
  
  
• In clinical trials for different cancer types, there were additional serious and sometimes fatal side effects that occurred in more people who received Avastin than in those in the comparison group. The formation of an abnormal passage from parts of the body to another part (non-GI fistula formation) was seen in 0.3% or less of people. Severe to life threatening stroke or heart problems were seen in 2.6% of people. Too much protein in the urine, which led to kidney problems, was seen in less than 1% of people. Additional serious side effects that occurred in more people who received Avastin than those in the comparison group included severe to life-threatening high blood pressure, which was seen in 5% to 18% of people, and nervous system and vision disturbances (reversible posterior leukoencephalopathy syndrome), which was seen in less than 0.1% of people. Infusion reactions with the first dose of Avastin were uncommon and occurred in less than 3% of people, and severe reactions occurred in 0.2% of people. Avastin can cause fertility issues for women. Avastin could cause a woman's ovaries to stop working and may impair her ability to have children.
  
  
• Common side effects that occurred in more than 10% of people who received Avastin for different cancer types, and at least twice the rate of the comparison group, were nosebleeds, headache, high blood pressure, inflammation of the nose, too much protein in the urine, taste change, dry skin, rectal bleeding, tear production disorder, back pain, and inflammation of the skin (exfoliative dermatitis). Across all trials, treatment with Avastin was permanently stopped in 8.4% to 21% of people because of side effects.
  
  
• Patients who are pregnant or thinking of becoming pregnant should talk with their doctor about the potential risk of loss of the pregnancy or the potential risk of Avastin to the fetus during and following Avastin therapy, and the need to continue an effective birth control method for at least 6 months following the last dose of Avastin.
  
  
• Women should be advised to discontinue nursing or discontinue drug, taking into account the importance of the drug to the mother.
  
  
• In the non-small cell lung cancer trial, the most common life-threatening to fatal side effects that increased by 2% or more in people who received Avastin vs those in the comparison group were reduced white blood cell counts (27% vs 17%), tiredness (16% vs 13%), high blood pressure (8% vs 0.7%), infection without reduced white blood cell counts (7% vs 3%), blood clots in the veins of the body (5% vs 3%), fever with reduced white blood cell counts (5% vs 2%), inflammation of the lungs (5% vs 3%), infection with severe or life-threatening reduced white blood cell counts (4% vs 2%), low sodium levels in the blood that could lead to seizure or coma (4% vs 1%), headache (3% vs 1%), and too much protein in the urine (3% vs 0%).

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

Avastin Development Program Based on data showing that VEGF may play a broad role in a range of cancers, a global development program for Avastin currently includes more than 450 clinical trials in more than 30 different tumor types, including early-stage cancers. Avastin is also being studied in combination with other targeted therapy agents in the absence of chemotherapy.

References ¹ Genentech. "Avastin. Full Prescribing Information."

² American Cancer Society. "Leading Sites of New Cancer Cases and Deaths - 2007 Estimates." Available at http://www.cancer.org/acs/groups/content/@nho/documents/document/globalfactsandfigures2007rev2p.pdf. Accessed May 7, 2007.

³ Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted antiogenic mitogen. Science. 1989;246:1306-1309.

⁴ Rosen LS. Clinical experience with angiogenesis signaling inhibitors: focus on vascular endothelial growth factor (VEGF) blockers. Cancer Control. 2002;9:36-44.

⁵ Kerbel R, Folkman J. Clinical translation of angiogenesis inhibitors. Nat Rev Cancer. 2002;2:727-739.

⁶ Jain RK. Normalizing tumor vasculature with antiangiogenic therapy: a new paradigm for combination therapy. Nat Med. 2001;7:987-989.

⁷ Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun M. Cancer statistics, 2007. CA Cancer J Clin. 2007;57:43-66.