Friday, Dec 11, 2009

Avastin Plus Commonly Used Chemotherapies Improved Progression-Free Survival in Women Previously Treated with Chemotherapy for Advanced Breast Cancer

San Antonio -- December 11, 2009 --

Genentech, Inc. , a wholly owned member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced results from a Phase III study (RIBBON 2) of Avastin® (bevacizumab) in women who had previously been treated with initial (first-line) chemotherapy for advanced HER2-negative breast cancer and needed additional (second-line) treatment. The study showed that women who received Avastin in combination with a commonly used chemotherapy had a 28 percent improvement in the likelihood of living without the disease getting worse (progression-free survival or PFS), compared with those who received chemotherapy alone (hazard ratio=0.78; p=0.0072). The doctors treating the women in the study chose the type of chemotherapy used in combination with Avastin and the chemotherapies were assessed together in the primary endpoint analysis of PFS. No new safety signals were observed in this study and adverse events were similar to those previously reported for Avastin studies in advanced breast cancer and other indications.

"It's important for women with advanced breast cancer whose disease has worsened after their first treatment to have as many treatment choices as possible," said Dr. Adam Brufsky, M.D. , Medical Director of the Women's Cancer Center, University of Pittsburgh Medical Center and principal investigator of the study. "This is the first Phase III study that showed an anti-angiogenic medicine combined with chemotherapy extended the time women with advanced HER2-negative disease, whose initial chemotherapy had stopped working, lived without the cancer worsening. "

The 28 percent improvement in PFS observed in RIBBON 2 can also be referred to as a 22 percent reduction in the risk of cancer progression or death (hazard ratio=0.78; p=0.0072). Patients who received Avastin plus chemotherapy had a median PFS of 7.2 months compared to 5.1 months for those who received chemotherapy alone.

Results of the RIBBON 2 study were featured today during a press briefing at the 32nd Annual San Antonio Breast Cancer Symposium. Full results will be presented this afternoon (Abstract #42 — Friday, December 11, 2009, 3:00 p.m. — 3:15 p.m. CST, Exhibit Hall D).

"RIBBON 2 is the fourth Phase III trial in this disease that showed the combination of Avastin and standard chemotherapies delayed the spread or growth of tumors more than the chemotherapies alone," said Hal Barron, M.D., executive vice president, Global Development and chief medical officer, Genentech. "We look forward to discussing these data with the FDA."

Avastin is currently approved in combination with paclitaxel chemotherapy as a first-line treatment for women who have not received chemotherapy for advanced HER2-negative breast cancer. This approval was based on results of the Phase III E2100 study and granted under the U.S. Food and Drug Administration's (FDA) accelerated approval program, which allows provisional approval of medicines for cancer or other life-threatening diseases. 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. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Avastin in breast cancer.

About RIBBON 2 (AVF3693g)
RIBBON 2 is an international, multicenter, randomized, double-blind, placebo-controlled clinical study of 684 patients with metastatic HER2-negative breast cancer who had previously received chemotherapy alone for metastatic disease. The trial evaluated the combination of either Avastin or placebo with an investigator's choice of chemotherapy, including taxanes (paclitaxel, protein-bound paclitaxel or docetaxel), gemcitabine, capecitabine or vinorelbine. Depending on the type of chemotherapy used, Avastin was administered every two or three weeks until disease progression. PFS was defined as the time from randomization to disease progression or death as assessed by the treating physicians in the study.

Table 1. Results for Primary Endpoint of Investigator-Assessed Progression-Free Survival

 

Avastin Plus Chemotherapies vs. Chemotherapies Alone

 

(459 patients)

(225 patients)

Progression-Free Survival
Overall PFS Improvement
Risk Reduction
Hazard Ratio
p-value

28%
22%
0.78
p=0.0072

Median PFS

7.2 months

5.1 months



Table 2. Results for Secondary Endpoints

Overall Response Rate

 

Avastin Plus Chemotherapies
(362 patients)

Chemotherapies Alone
(179 patients)

Overall Response Rate
p-value (not statistically significant at alpha=0.01)

39.5%

29.6%

p=0.0193

PFS By Chemotherapy Type vs. Chemotherapy Type Alone

 

Avastin Plus Taxanes vs. Taxanes Alone
(304 patients)

Avastin Plus Gemcitabine vs. Gemcitabine Alone
(160 patients)

Avastin Plus Capecitabine vs. Capecitabine Alone
(144 patients)

Avastin Plus
Vinorelbine vs. Vinorelbine Alone
(76 patients)

Hazard Ratio

0.64

0.90

0.73

1.42

Overall Survival (not statistically significant at this interim analysis with 57% of events)

Avastin Plus Chemotherapies
(459 patients)

Chemotherapies Alone
(225 patients)

Hazard Ratio
p-value (not statistically significant)

0.90
p=0.3741

Specific severe (Grade 3 or 4) adverse events that occurred at a rate of at least 2 percent more often in patients who received Avastin plus chemotherapy versus chemotherapy alone were low white blood cell count, high blood pressure and too much protein in the urine. Deaths during the study due to adverse events were observed more frequently with the chemotherapies alone.


Table 3. Selected Grade 3 or Greater Adverse Events

 

Avastin Plus Chemotherapies

Chemotherapies Alone

≥ Grade 3 Neutropenia* (low white blood cell count)

17.7% (81/458)

14.5% (32/221)

≥ Grade 3 Hypertension* (high blood pressure)

9.0% (41/458)

0.5% (1/221)

≥ Grade 3 Proteinuria* (too much protein in the urine)

3.1% (14/458)

0.5% (1/221)

Adverse Events Leading to Death

1.3% (6/458)

2.3% (5/221)

* No Grade 5 events

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.

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