Genentech Study Showed That Avastin Helped People with Newly Diagnosed Glioblastoma Live Longer without Their Disease Worsening When Added to Radiation and Chemotherapy

Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced results from the positive Phase III AVAglio study. The study showed Avastin® (bevacizumab) in combination with radiation and temozolomide chemotherapy reduced the risk of cancer worsening or death (progression-free survival; PFS) by 36 percent compared to radiation and temozolomide chemotherapy plus placebo (HR=0.64; p<0.0001) in people with newly diagnosed glioblastoma, the most common and aggressive form of primary brain cancer. PFS assessed by trial investigators was a co-primary endpoint for the study. The interim results for overall survival (OS), the other co-primary endpoint, did not reach statistical significance (HR=0.89; p=0.2135). Final data on OS are expected in 2013. The data were presented today at the 17th Annual Meeting of the Society for Neuro-Oncology in Washington, D.C.

No new safety findings were observed in the AVAglio study and adverse events were consistent with those seen in previous trials of Avastin across tumor types for approved indications. Adverse events of special interest (all Grades) that occurred more often in the Avastin arm compared to the radiation and chemotherapy arm (>2 percent increased incidence) were bleeding in mucous/skin linings (26.7 percent vs. 8.9 percent) or other regions of the body excluding the brain (11.6 percent vs. 8.1 percent), high blood pressure (37.5 percent vs. 13 percent), too much protein in the urine (proteinuria; 14 percent vs. 4 percent) and blood clots (arterial thromboembolic; 5.0 percent vs. 1.6 percent).

Avastin is currently approved in the United States under the U.S. Food and Drug Administration’s (FDA) accelerated approval program for the treatment of adults with glioblastoma who have progressive disease following prior therapy. In glioblastoma, it is approved for use as a single therapy and not in combination with other therapies. The effectiveness of Avastin is based on improvement in objective response rate. Currently, no data are available from randomized controlled trials demonstrating improvement in disease-related symptoms or increased survival with Avastin in glioblastoma.

“People with newly diagnosed glioblastoma have few treatment options and need new medicines,” said Hal Barron M.D., chief medical officer and head of Global Product Development. “An important outcome from the AVAglio study was that patients who received Avastin plus radiation and chemotherapy lived significantly longer without their disease getting worse, and we plan to discuss these data with regulatory authorities.”

The results of the Phase III AVAglio trial were presented in Plenary Session 5 by Professor Olivier Chinot, AVAglio principal investigator, President of Association des Neuro-Oncologue d'Expression Française (ANOEF), and head of the neuro-oncology department, University Hospital Timone, Marseille, France (Abstract OT-03, Saturday, November 17, 10:45 a.m. Eastern Time).

AVAglio Study Results

Primary endpoints:

• The 36 percent reduction in the risk of disease worsening or death can also be referred to as a 56 percent improvement in PFS (HR=0.64; p<0.0001).
• A 4.4 month improvement in median PFS was observed when people with newly diagnosed glioblastoma received Avastin in combination with radiation and chemotherapy compared to those who received radiation and chemotherapy plus placebo (10.6 months vs. 6.2 months, respectively).
• Interim results for OS did not reach statistical significance (HR=0.89; p=0.2135). Final data on OS are expected in 2013.

Secondary endpoints:

• An independent review committee assessment of PFS showed a 39 percent reduction in the risk of disease worsening or death, which can also be referred to as a 64 percent improvement in PFS (HR=0.61; p<0.0001). This was consistent with the magnitude of benefit assessed by the trial investigators.
• The one-year survival rate was 66 percent for the placebo arm versus 72 percent in the Avastin arm (p=0.052).
• Adverse events (Grade 3-5) of special interest occurred in 28.7 percent of patients in the Avastin arm compared to 15.2 percent of patients in the radiation and chemotherapy plus placebo arm. Adverse events (Grade 3-5) of special interest that occurred more often (>2 percent increased incidence) in the Avastin arm compared to the control arm were high blood pressure (10.3 percent vs. 2.0 percent) and too much protein in the urine (proteinuria; 3.7 percent vs. 0 percent).

About the AVAglio Study

AVAglio is a Phase III, randomized, double-blind, placebo controlled trial that assessed the efficacy and safety profile of Avastin in combination with radiation and temozolomide chemotherapy following surgery or biopsy in patients with newly diagnosed glioblastoma. Patients were randomized to receive either:

• Avastin plus radiation and temozolomide chemotherapy for six weeks followed by a four-week break. Patients then received Avastin and temozolomide for up to six cycles, followed by Avastin alone until disease progression.
• Radiation, temozolomide and placebo for six weeks followed by a four-week break. Patients then received temozolomide and placebo for up to six cycles, followed by placebo until disease progression.

The co-primary endpoints of the study were OS and PFS as assessed by trial investigators. Secondary endpoints included PFS as assessed by an independent review committee, one- and two-year survival rates, health-related quality of life measures, and safety profile.

By meeting its co-primary endpoint of PFS, AVAglio is the first positive Phase III study in newly diagnosed glioblastoma since 2005.

About Glioblastoma

Glioma (cancer of the glial cells) is the most common type of malignant primary brain tumor (a tumor that originates in the brain), accounting for approximately one-third of all cases diagnosed. Glioblastoma (or glioblastoma multiforme) is the most common and the most aggressive type of glioma, affecting approximately 10,000 people per year in the United States. Glioblastoma tumors have among the highest levels of vascular endothelial growth factor (VEGF) of any solid tumor.

About Avastin

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 that plays an important role throughout the lifecycle of the tumor to develop and maintain blood vessels, a process known as angiogenesis. Avastin is designed to interfere with the tumor blood supply by directly binding to the VEGF protein to prevent interactions with receptors on blood vessel 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 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 (2.4 percent to 0.3 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 metastatic 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 four 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 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 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 2.6 percent of people. Too much protein in the urine that led to kidney problems was seen in less than one 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 five 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 three percent of people, and severe reactions occurred in 0.2 percent 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 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.

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.

Glioblastoma

In the glioblastoma clinical trial AVF3708g, the most common side effects in people who received Avastin alone were infection (occurred in 55 percent of people), tiredness (occurred in 45 percent of people), headache (occurred in 37 percent of people), high blood pressure (occurred in 30 percent of people), nosebleeds (occurred in 19 percent of people), and diarrhea (occurred in 21 percent of people). Some of these common side effects were severe to life-threatening or fatal: infection (occurred in 10 percent of people), tiredness (occurred in 4 percent of people), headache (occurred in 4 percent of people), high blood pressure (occurred in 8 percent of people), and diarrhea (occurred in 1 percent of people). Two fatalities were possibly related to Avastin: one from bleeding in the abdomen, and one from severely reduced white blood cell counts that led to infection.

People who received Avastin alone or Avastin plus irinotecan* (chemotherapy) experienced mild to life-threatening side effects including bleeding (occurred in 40 percent of people), nosebleeds (occurred in 26 percent of people), bleeding in the brain (occurred in 5 percent of people), high blood pressure (occurred in 32 percent of people), blood clots in the veins of the body (occurred in 8 percent of people), stroke or heart problems (occurred in 6 percent of people), surgery and wound healing problems (occurred in 6 percent of people), too much protein in the urine (occurred in 4 percent of people), the development of a hole in the stomach, small intestine or large intestine (occurred in 2 percent of people), and nervous system and vision disturbances (occurred in 1 percent of people). People who received Avastin alone or Avastin plus irinotecan (chemotherapy) experienced severe to fatal side effects including bleeding (occurred in 2 percent of people), bleeding in the brain (occurred in 1 percent of people), high blood pressure (occurred in 5 percent of people), blood clots in the veins of the body (occurred in 7 percent of people), stroke or heart problems (occurred in 3 percent of people), surgery and wound healing problems (occurred in 3 percent of people), too much protein in the urine (occurred in 1 percent of people), and the development of a hole in the stomach, small intestine or large intestine (occurred in 2 percent of people). Bleeding within the brain occurred in eight of 163 people; two people had severe to life threatening bleeding.

* Avastin is not approved for use for glioblastoma in combination with irinotecan

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 member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.