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US FDA plans to withdraw approval of Avastin to treat metastatic breast cancer

South San Francisco, CaliforniaSaturday, December 18, 2010, 10:00 Hrs  [IST]

Genentech, a member of the Roche Group, confirmed that following the reviews of Avastin (bevacizumab) in metastatic breast cancer by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), the following regulatory announcements were made by the individual health authorities.

The FDA notified Genentech of its "Proposal to Withdraw Marketing Approval" of Avastin for first-line treatment of metastatic HER2-negative breast cancer in combination with paclitaxel and issued a "Notice of Opportunity for a Hearing" (NOOH). An NOOH is the mechanism FDA uses to provide a company an opportunity for a hearing on a proposal to withdraw an indication. Genentech will request a hearing. If FDA grants a hearing, there is no set date for when this would occur. Until the conclusion of these proceedings, Avastin remains FDA-approved for use in combination with paclitaxel for the first-line treatment of metastatic HER2-negative breast cancer.

The FDA also issued Complete Responses on Avado and Ribbon1 for the first-line use of Avastin in combination with other chemotherapies in metastatic breast cancer and a Complete Response on Ribbon2 for the second-line use of Avastin plus chemotherapy in metastatic breast cancer. The FDA's decision does not impact Avastin's availability for its approved uses for other cancer types in the United States.

EMA/European Committee for Medicinal Products for Human Use (CHMP) update: the EMA has confirmed that Avastin in combination with paclitaxel has been convincingly shown to enable women with metastatic breast cancer to live longer without their disease getting worse (progression-free survival). The EMA has also stated that “the benefits of this combination outweigh its risks and that this combination remains a valuable treatment option for patients suffering from metastatic breast cancer.”

Paclitaxel is the chemotherapy most frequently used in Europe and also most frequently partnered with Avastin for the first-line treatment of metastatic breast cancer. The CHMP, which is part of EMA, recommended the removal of the combination of Avastin with docetaxel from the label based on uncertainty about the benefit of the combination and also recommended against a label extension with capecitabine. A European Commission decision on this opinion will be issued in due course. The CHMP opinion does not affect the other approved uses of Avastin in the European Union for advanced colorectal, kidney and lung cancer.


“We are pleased that the EMA has confirmed the benefits of Avastin with paclitaxel and that Avastin will continue to be available for women with metastatic breast cancer living within the European Union,” said Hal Barron, MD, chief medical officer and head, Global Product Development. “We believe women living in the United States with metastatic HER2-negative breast cancer should also have Avastin as a treatment option, and, therefore, we will request a hearing with the FDA.”

Until the conclusion of the proceedings with FDA, Avastin remains approved for use in combination with paclitaxel for the first-line treatment of metastatic HER2-negative breast cancer in the United States. The effectiveness of Avastin in metastatic HER2-negative breast cancer is based on an improvement in progression-free survival in the E2100 study. There is no data available showing that Avastin improves disease-related symptoms or survival in metastatic HER2-negative breast cancer. Avastin is not approved for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease.

Avastin is a prescription-only medicine that is a solution for intravenous infusion. It is a biologic antibody designed to specifically bind to a protein called VEGF (vascular endothelial growth factor) that plays an important role throughout the lifecycle of the tumour to develop and maintain blood vessels, a process known as angiogenesis. Avastin interferes with the tumour 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 tumour blood supply is thought to be critical to a tumour's ability to grow and spread in the body (metastasize).

Avastin is approved for first- and second-line treatment of metastatic Colorectal Cancer (mCRC) in combination with intravenous 5-FU-based chemotherapy, first-line treatment of unresectable, locally advanced, recurrent or metastatic, non-squamous, Non-Small Cell Lung Cancer (NSCLC) in combination with carboplatin and paclitaxel, and metastatic renal cell carcinoma in combination with interferon alfa.

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 per cent to 2.4 per cent). 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 per cent for patients who received Avastin and four per cent 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 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 five times more often in people who received Avastin compared to patients who received only chemotherapy. Across cancer types, 1.2 per cent to 4.6 per cent 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 per cent or less of people. Severe to life-threatening stroke or heart problems were seen in 2.4 per cent of people. Too much protein in the urine that led to kidney problems was seen in less than one per cent 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 five per cent to 18 per cent of people, and nervous system and vision disturbances (reversible posterior leukoencephalopathy syndrome), which was seen in less than 0.1 per cent of people. Infusion reactions with the first dose of Avastin were uncommon and occurred in less than three per cent of people, and severe reactions occurred in 0.2 per cent of people.

Common side effects that occurred in more than 10 per cent 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 per cent to 21 per cent 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 trial in metastatic breast cancer, there was a 20.5 per cent 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 two per cent or more in people who received Avastin plus paclitaxel were numbness and tingling in the fingers and toes (24 per cent vs. 18 per cent), high blood pressure (16 per cent vs. 1 per cent), tiredness (11 per cent vs. 5 per cent), infection without reduced white blood cell counts (9 per cent vs. 5 per cent), increased white blood cells (6 per cent vs. 3 per cent), vomiting (6 per cent vs. 2 per cent), diarrhea (5 per cent vs. 1 per cent), bone pain (4 per cent vs. 2 per cent), headache (4 per cent vs. 1 per cent), nausea (4 per cent vs. 1 per cent), stroke (3 per cent vs. 0 per cent), dehydration (3 per cent vs. 1 per cent), infection (3 per cent vs. 0.3 per cent), rash (3 per cent vs. 0.3 per cent) and too much protein in the urine (3 per cent vs. 0 per cent). Congestive heart failure was seen in more people who received Avastin plus paclitaxel vs. paclitaxel alone (2.2 per cent vs. 0.3 per cent).

Among people receiving prior anthracyclines, congestive heart failure was more common in people who received Avastin plus paclitaxel vs. paclitaxel alone (3.8 per cent vs. 0.6 per cent). Deaths due to side effects were seen in 1.7 per cent (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 diarrhoea/abdominal pain/weakness/low blood pressure (2).

In the first-line metastatic colorectal cancer trial, the most common severe to life-threatening side effects that increased by two per cent or more in people who received Avastin plus IFL (chemotherapy) vs. IFL (chemotherapy) alone were weakness (10 per cent vs. 7 per cent), abdominal pain (8 per cent vs. 5 per cent), pain (8 per cent vs. 5 per cent), high blood pressure (12 per cent vs. 2 per cent), blood clots in the veins of the body (9 per cent vs. 5 per cent), blood clots inside the abdomen (3 per cent vs. 1 per cent), a brief loss of consciousness (3 per cent vs. 1 per cent), diarrhea (34 per cent vs. 25 per cent), constipation (4 per cent vs. 2 per cent), reduced white blood cell counts (37 per cent vs. 31 per cent), and reduced white blood cell counts that may increase the chance of infection (21 per cent vs. 14 per cent).

In the second-line metastatic colorectal cancer trial, the most common severe to life-threatening and fatal side effects that increased by two per cent or more in people who received Avastin plus FOLFOX4 (chemotherapy) vs. FOLFOX4 (chemotherapy) alone were diarrhea (18 per cent vs. 13 per cent), nausea (12 per cent vs. 5 per cent), vomiting (11 per cent vs. 4 per cent), dehydration (10 per cent vs. 5 per cent), blockage of the bowel (4 per cent vs. 1 per cent), numbness and tingling in fingers and toes (17 per cent vs. 9 per cent), nervous system disturbances (5 per cent vs. 3 per cent), tiredness (19 per cent vs. 13 per cent), abdominal pain (8 per cent vs. 5 per cent), headache (3 per cent vs. 0 per cent), high blood pressure (9 per cent vs. 2 per cent), and severe bleeding (5 per cent vs. 1 per cent).

In the non-small cell lung cancer trial, the most common life-threatening to fatal side effects that increased by two per cent or more in people who received Avastin vs. those in the comparison group were reduced white blood cell counts (27 per cent vs. 17 per cent), tiredness (16 per cent vs. 13 per cent), high blood pressure (8 per cent vs. 0.7 per cent), infection without reduced white blood cell counts (7 per cent vs. 3 per cent), blood clots in the veins of the body (5 per cent vs. 3 per cent), fever with reduced white blood cell counts (5 per cent vs. 2 per cent), inflammation of the lungs (5 per cent vs. 3 per cent), infection with severe or life-threatening reduced white blood cell counts (4 per cent vs. 2 per cent), low sodium levels in the blood that could lead to seizure or coma (4 per cent vs. 1 per cent), headache (3 per cent vs. 1 per cent), and too much protein in the urine (3 per cent vs. 0 per cent).

In the metastatic kidney cancer trial, the most common severe to fatal side effects that increased by two per cent or more in people who received Avastin vs. those in the comparison group included tiredness (13 per cent vs. 8 per cent), weakness (10 per cent vs. 7 per cent), too much protein in the urine (7 per cent vs. 0 per cent), high blood pressure (6 per cent vs. 1 per cent), and severe bleeding (3 per cent vs. 0.3 per cent).

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.

 
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