Genentech Data Showed That People With Metastatic Colorectal ...

-- First Phase III Study to Appraise Continued Avastin Through Different Lines of Therapy --

CHICAGO--(BUSINESS WIRE)--Jun 3, 2012 - Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced results from ML18147, a Phase III study in metastatic colorectal cancer (mCRC) that evaluated Avastin^? (bevacizumab) continued with second-line chemotherapy in people who received initial Avastin plus first-line chemotherapy.

The study met its primary endpoint of a significant increase in overall survival (OS). In the study, the relative risk of death was reduced by 19 percent for people who continued with Avastin plus second-line chemotherapy compared to those who received chemotherapy alone (HR=0.81, p=0.0062). People who continued with Avastin plus second-line chemotherapy also experienced a significant improvement in progression-free survival (PFS, the time a person lives without the disease getting worse); the risk of their cancer progressing was reduced by 32 percent (HR=0.68, p<0.0001). Adverse events (AEs) in ML18147 were consistent with those seen in previous pivotal trials of Avastin across tumor types.

?Our study design was based on previous research showing that sustained VEGF inhibition achieved and maintained anti-tumor activity,? said Hal Barron M.D., chief medical officer and head, Global Product Development. ?While conventional practice is to change treatment completely at disease progression, the continued use of Avastin with a new chemotherapy regimen in this study resulted in patients living longer, compared to a new chemotherapy regimen alone.?

These results were featured in a press briefing on Saturday, June 2, at the 48th Annual Meeting of the American Society of Clinical Oncology. Full results will be presented in the ASCO Gastrointestinal (Colorectal) Cancer Oral Abstracts session by Professor Dirk Arnold, the ML18147 principal investigator and associate professor of medicine at the Department of Hematology and Oncology, Martin Luther University Halle-Wittenberg, Halle, Germany (Abstract CRA3503, Sunday, June 3, 10:45 a.m. CDT).

ML18147 Study Results

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• People with mCRC who received Avastin in combination with standard chemotherapy in both the first- and second-line settings had a median OS of 11.2 months compared to 9.8 months for people who received chemotherapy alone.
• Median PFS was 5.7 months compared to 4.1 months.
• OS and PFS were calculated from the time patients were randomized to the second-line treatment.
• Select AEs (Grade 3-5) that occurred more often in the Avastin arm compared to the chemotherapy alone arm after randomization were high blood pressure (2 percent vs. 1 percent), bleeding (2 percent vs. <1 percent), gastrointestinal perforations (a hole in the stomach or intestine; 2 percent vs. <1 percent) and blood clots in the vein (5 percent vs. 3 percent).

About the ML18147 Study

ML18147 was a randomized, open-label, Phase III multicenter, multinational trial evaluating the efficacy and safety profile of Avastin plus standard second-line chemotherapy in 820 patients with mCRC whose disease had progressed following Avastin plus standard first-line chemotherapy (irinotecan or oxaliplatin-based). Patients were randomized at progression to one of two treatment arms:

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• Arm A: Chemotherapy* plus Avastin (equivalent of 2.5 mg/kg i.v. per week)
• Arm B: Chemotherapy* alone
  *Depending on the first-line chemotherapy backbone (fluoropyrimidine/irinotecan-based or fluoropyrimidine/oxaliplatin-based), the chemotherapy backbone was switched in the second-line setting.

The primary endpoint of the study was OS measured from the time patients were randomized to the second-line treatment. The secondary efficacy endpoints of the study included PFS, overall response rate and safety profile.

About Colorectal Cancer

According to the American Cancer Society, colorectal cancer is the third most commonly diagnosed cancer in both men and women in the United States and the third leading cause of cancer deaths. In 2012, more than 143,000 people will be diagnosed and nearly 52,000 individuals will die from the disease in the United States. If colorectal cancer spreads (metastasizes) to distant organs, such as the lungs or the liver, five-year survival declines to 12 percent.

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 vascular endothelial growth factor (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.

Avastin is approved for first- or second-line treatment of metastatic colorectal cancer 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 in combination with carboplatin and paclitaxel, and metastatic renal cell carcinoma in combination with interferon alfa.

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.

First-line Metastatic Colorectal Cancer

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

Second-line Metastatic Colorectal Cancer

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

First-line Advanced Non-Squamous Non-Small Cell Lung Cancer

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

Metastatic Kidney Cancer

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

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.

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Contact: Genentech
Media Contact:
Holli Dickson, 650-922-1269
Advocacy Contact:
Sonali Padhi, 650-467-0842
Investor Contacts:
Thomas Kudsk Larsen, 650-467-2016
Karl Mahler, 011 41 61 687 8503

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Posted: June 2012

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