Avastin is currently approved in combination with paclitaxel chemotherapy for first-line treatment of advanced HER2-negative breast cancer. This approval was based on results of the Phase III E2100 study and granted under the FDA's accelerated approval program, which allows provisional approval of medicines for cancer or other life-threatening diseases. Currently, the effectiveness of Avastin in metastatic breast cancer is based on an improvement in PFS.

Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease, said Genentech.

Hal Barron, executive vice president of global development and chief medical officer of Genentech, said: "We look forward to working with the FDA to evaluate the data from more than 2,600 women with advanced breast cancer who participated in these studies that showed Avastin in combination with various chemotherapies helped them live longer without the disease worsening."

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The other application is based on the Phase III RIBBON-1 trial, which evaluated Avastin in combination with Xeloda (capecitabine; Roche), or taxane- or anthracycline-based chemotherapy. The two groups demonstrated improvements in PFS of 45% and 55%, respectively, with the addition of Avastin.

Avastin is an IgG1 monoclonal antibody specifically directed to the vascular endothelial growth factor (VEGF). The VEGF protein is an essential component of the angiogenesis pathway critical for blood vessel formation facilitating tumor growth, invasion and metastasis. Avastin is already approved for the treatment of metastatic HER-2-negative breast cancer in combination with paclitaxel. Indeed, it is a multi-blockbuster drug for Genentech and Roche, with sales of $4.8 billion in 2008.

Breast cancer is the most common cancer in women worldwide, with incidence in the seven major markets forecast to be over 455,000 in 2009. HER-2-positive patients account for 20-25% of the total population and have a poorer prognosis owing to more aggressive tumors, greater lymph node involvement, and a higher rate of recurrence and mortality than those with HER-2-negative tumors.

The FDA had previously granted accelerated approval to Avastin in combination with paclitaxel in this indication, based on a 5.9 month PFS extension shown in the Phase III E2100 trial. Under the FDA's accelerated approval program, drugs can be made available on the market on the basis of preliminary evidence of patient benefit. While Avastin has not been shown to improve overall survival, it has demonstrated an improvement in PFS and there were no unexpected side effects. As such, these latest applications for Avastin stand an excellent chance of gaining FDA approval, and may serve to boost the drug's sales and reaffirm its status as a blockbuster for Roche and Genentech.

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Reach was a global, multi-center, randomized, open-label, Phase III study sponsored by Genentech, Biogen Idec and Roche that enrolled 552 patients with previously treated (relapsed or refractory) CD20-positive CLL who had not previously received Rituxan (Rituxan-naive).

Both studies evaluated Rituxan plus fludarabine and cyclophosphamide (FC) chemotherapy compared with FC chemotherapy alone. The primary endpoint for both studies was progression-free survival and secondary endpoints were overall survival, event-free survival, duration of response, response rate, complete response and toxicity.

The FDA has not requested any new data to complete its review of these applications. Genentech and Biogen Idec will continue final label discussions with the FDA and are committed to making Rituxan in combination with FC an FDA-approved option for people with CLL.

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"We look forward to working with the FDA to evaluate the data from more than 2,600 women with advanced breast cancer who participated in these studies that showed Avastin in combination with various chemotherapies helped them live longer without the disease worsening," said Hal Barron, M.D., executive vice president, Global Development and chief medical officer.

AVADO and RIBBON 1 demonstrated that Avastin plus commonly used chemotherapies (taxane, anthracycline-based or capecitabine chemotherapy) increased the time women lived without the disease growing or spreading, compared to the chemotherapies alone. In these studies, adverse events were consistent with those previously reported for Avastin and no new Avastin safety signals were observed. Data from AVADO and RIBBON 1 are being submitted as part of Genentech's effort to convert the accelerated approval to a full approval.

Avastin in Previously Untreated Advanced HER2-Negative Breast Cancer

Avastin has been evaluated in three separate international, multicenter, randomized Phase III clinical studies of women who have not previously received treatment for advanced HER2-negative breast cancer (E2100, AVADO and RIBBON 1).

-- E2100: Avastin plus paclitaxel chemotherapy compared to paclitaxel chemotherapy alone (722 patients)

-- AVADO: Avastin plus docetaxel chemotherapy compared to docetaxel chemotherapy alone (736 patients)

-- RIBBON 1: Avastin plus either a taxane, anthracycline-based or capecitabine chemotherapy compared to the chemotherapies alone (622 patients in the taxane or anthracycline-based chemotherapies group, 615 patients in the capecitabine chemotherapy group)

Genentech is committed to understanding the potential role of Avastin in breast cancer and will separately submit to the FDA data from three other randomized Phase III studies of Avastin in this disease when available, including the recently announced RIBBON 2 study in patients who have previously received chemotherapy for metastatic HER2-negative breast cancer.

About Avastin

Avastin is a solution for intravenous infusion and is a biologic antibody designed to specifically bind to a protein called vascular endothelial growth factor (VEGF). VEGF plays an important role throughout the lifecycle of the tumor to develop and maintain blood vessels, a process known as angiogenesis. Avastin interferes with the tumor blood supply by directly binding to the VEGF protein to prevent interactions with receptors on blood vessel cells. Avastin does not bind to receptors on normal or cancer cells. The tumor blood supply is thought to be critical to a tumor's ability to grow and spread in the body (metastasize). For more information about angiogenesis, visit http://www.gene.com.

BOXED WARNINGS and Additional Important Safety Information

People treated with 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 potentially 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 percent to 2.4 percent). 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. 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.

Severe bleeding: Treatment with Avastin can result in serious 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 five times more often in people who received Avastin. Across cancer types, 1.2 percent to 4.6 percent 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 percent or less of people. Severe to life-threatening stroke or heart problems were seen in 2.4 percent of people. Too much protein in the urine, which led to kidney problems, was seen in less than 1 percent 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 percent to 18 percent of people, and nervous system and vision disturbances (reversible posterior leukoencephalopathy syndrome), which was seen in less than 0.1 percent of people. Infusion reactions with the first dose of Avastin were uncommon and occurred in less than 3 percent of people and severe reactions occurred in 0.2 percent of people.

Common side effects that occurred in more than 10 percent 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 percent to 21 percent of people because of side effects.

Avastin may impair fertility. 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 six months following the last dose of Avastin.

In the E2100 metastatic breast cancer trial, there was a 20.5 percent increase in severe to life-threatening and fatal side effects for Avastin plus paclitaxel chemotherapy vs. paclitaxel alone. Because mild side effects of Avastin plus paclitaxel were not studied, they are not known. Severe to life-threatening side effects that increased by 2 percent or more in people who received Avastin plus paclitaxel were numbness and tingling in the fingers and toes (24 percent vs. 18 percent), high blood pressure (16 percent vs. 1 percent), tiredness (11 percent vs. 5 percent), infection without reduced white blood cell counts (9 percent vs. 5 percent), white blood cells that contained harmful bacteria (6 percent vs. 3 percent), vomiting (6 percent vs. 2 percent), diarrhea (5 percent vs. 1 percent), bone pain (4 percent vs. 2 percent), headache (4 percent vs. 1 percent), nausea (4 percent vs. 1 percent), stroke (3 percent vs. 0 percent), dehydration (3 percent vs. 1 percent), infection (3 percent vs. 0.3 percent), rash (3 percent vs. 0.3 percent) and too much protein in the urine (3 percent vs. 0 percent). The most common severe to life-threatening and fatal side effects that increased by 5 percent or more in people who received Avastin plus paclitaxel vs. paclitaxel alone included numbness and tingling in fingers and toes (24 percent vs. 18 percent), high blood pressure (16 percent vs. 1 percent) and tiredness (11 percent vs. 5 percent). Congestive heart failure was seen in more people who received Avastin plus paclitaxel vs. paclitaxel alone (2.2 percent vs. 0.3 percent). Among people receiving prior anthracyclines, congestive heart failure was more common in people who received Avastin plus paclitaxel vs. paclitaxel alone (3.8 percent vs. 0.6 percent). Deaths due to side effects were seen in 1.7 percent (6 of 363) of people who received Avastin plus paclitaxel. Causes of death were the development of a hole in the stomach, small intestine or large intestine (2), heart attack (2) and diarrhea/abdominal pain/weakness/low blood pressure (2).

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

About Genentech

Founded more than 30 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious or life-threatening medical conditions. The company, a wholly-owned member of the Roche Group, has headquarters in South San Francisco, Calif. For additional information about the company, please visit http://www.gene.com.

SOURCE: Genentech, Inc.

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