Tuesday, Jul 20, 2010
Gaithersburg, Md. -- July 20, 2010 --Genentech, Inc., a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), announced today that the U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) voted 12 to one that use of Avastin® (bevacizumab) in combination with paclitaxel for previously untreated (first-line) advanced HER2-negative breast cancer be removed from Avastin's U.S. label. The committee's vote does not affect the current availability of Avastin for people with advanced HER2-negative breast cancer in the United States. The FDA is expected to make a decision on the first-line use of Avastin in combination with certain types of chemotherapy in the United States for advanced breast cancer by September 17, 2010.
"We are disappointed by the committee's recommendation and believe Avastin should continue to be an option for women with this incurable disease," said Sandra Horning, M.D., senior vice president, global head, Clinical Development Hematology/Oncology. "We will continue to discuss the data from the more than 2,400 women who participated in three Phase III studies with the FDA. This recommendation does not impact Avastin's approved uses for other cancer types."
The recommendation also does not impact the use of Avastin for advanced breast cancer in other countries.
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. The effectiveness of Avastin in advanced breast cancer is based on an improvement in progression-free survival (PFS). Avastin is not approved for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease. Currently, there are no data available showing that Avastin improves disease-related symptoms or survival in HER2-negative advanced breast cancer.
In November 2009, the company submitted two supplemental Biologics License Applications (sBLAs) to the FDA based on the AVADO and RIBBON 1 studies as part of the company's effort to convert the accelerated approval to a full approval.
The ODAC reviewed data from all three studies (E2100, AVADO and RIBBON 1), which showed that Avastin plus commonly used chemotherapies (taxane-based, anthracycline-based or capecitabine chemotherapy) increased the time women lived without the disease growing or spreading (PFS), compared to the chemotherapies alone. In these studies, adverse events were generally consistent with those previously reported for Avastin and no new safety signals were observed.
Across the studies, the most common adverse events associated with Avastin treatment were high blood pressure (10.4 percent vs. 1.2 percent) and proteinuria (2.6 percent vs. 0 percent). The incidence of severe adverse events known to be associated with Avastin treatment included arterial thromboembolic events (1.9 percent vs. 0.3 percent), bleeding (1.6 percent vs. 0.4 percent), febrile neutropenia (5.0 percent vs. 3.5 percent), fistula (0.4 percent vs. 0.3 percent), gastrointestinal (GI) perforation (0.5 percent vs. 0.3 percent), left ventricular systolic dysfunction (LVSD) (1.5 percent vs. 0.2 percent), neutropenia (8.0 percent vs. 7.1 percent), sensory neuropathy (9.7 percent vs. 8.5 percent) and venous thromboembolic events (3.0 percent vs. 3.8 percent). In clinical trials across cancer types, serious and sometimes fatal side effects in people given Avastin included gastrointestinal perforation, surgery and wound healing complications, and severe bleeding.
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:
Avastin is a prescription only medicine that is a solution for intravenous infusion. Avastin is designed to interfere with the ability of a tumor to develop and maintain blood vessels, a process known as angiogenesis. Angiogenesis is thought to be critical to a tumor's ability to grow and spread in the body (metastasize). One of the most important factors of controlling angiogenesis is VEGF (Vascular Endothelial Growth Factor), a protein produced by normal cells and overproduced by cancer cells. Avastin is a biologic antibody that directly binds to the VEGF protein thereby interfering with the tumor blood supply. Avastin specifically inhibits the interaction of VEGF with receptors on blood vessel cells and does not bind receptors on normal or cancer cells. 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:
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 side effect 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. In a controlled clinical trial,in patients with advanced colorectal cancer who had surgery during the course of treatment, the incidence of wound healing complications, including serious and fatal complications, was 15 percent for patients who received Avastin and 4 percent for patients who did not receive Avastin. 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 having surgery and wound healing problems following surgery has not been determined. 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 five times more often in people who received Avastin compared to patients who received only chemotherapy. 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.
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 that led to kidney problems (nephrotic syndrome) 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. Women should be advised to discontinue nursing or discontinue treatment with Avastin, taking into account the importance of Avastin to the mother.
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), increased white blood cells (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.
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 member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.