Saturday, May 30, 2009

Genentech Announces Full Results from First Phase III Study of Avastin in Early-Stage Colon Cancer

Study Does not Meet Endpoint; However, Results Suggest Future Trials May Hold Promise for Avastin as Adjuvant Colon Cancer Treatment

Orlando, Fla. -- May 30, 2009 --

Genentech, Inc. today announced results from a Phase III study of Avastin® (bevacizumab) plus six months of chemotherapy following surgery in patients with early-stage (adjuvant) colon cancer (NSABP C-08). The study showed the addition of one year of Avastin to chemotherapy did not result in a statistically significant improvement in overall disease-free survival (DFS), the primary endpoint, compared to chemotherapy alone after surgery. Patients who received Avastin plus chemotherapy had a lower risk of the cancer returning during the year of treatment, however, the improvement diminished over the course of the study. No new safety signals for Avastin were observed.


The data were featured during a press briefing today at the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO), and will be presented on May 31, 2009.


Overall in the study, there was a 12 percent improvement in DFS that was not statistically significant (hazard ratio=0.89, p=0.15; risk reduction of 11 percent). In the first year of the study, while patients received Avastin in addition to a standard six months of adjuvant chemotherapy, DFS improved by 67 percent compared to chemotherapy alone (hazard ratio=0.60; risk reduction of 40 percent). However, this early improvement in DFS began to diminish after the first year, and overall DFS was not improved.


"During the year that patients received Avastin treatment there was a 40 percent lower risk of cancer returning; however, this initial improvement over chemotherapy alone gradually diminished over time," said Norman Wolmark, M.D., Chairman, National Surgical Adjuvant Breast and Bowel Project (NSABP). "These results suggest longer durations of Avastin treatment should be considered for future studies in early-stage colon cancer to further reduce the risk of the cancer coming back."


"We believe the C-08 results support the theory that Avastin may be an important medicine to help prevent early-stage colon cancer from returning and spreading to other parts of the body," said Hal Barron, M.D., executive vice president, Global Development and chief medical officer, Genentech. "The results are encouraging and reaffirm our commitment to fully evaluate the role of blocking the VEGF protein in early-stage cancer with ongoing and future studies of Avastin."


Efficacy Results

Treatment Phase

Observational Phase

Overall
Results

Years Post-Randomization

1 Year

1.5 Years

2 Years

2.5 Years

3 Years

Disease-Free Survival (DFS)
Risk Reduction (%)
Percent Improvement (%)
Hazard Ratio
p-value



40

67
0.60
0.0004



26

35
0.74
0.004



19

23
0.81
0.02



15

18
0.85
0.05



13

15
0.87
0.08



11

12
0.89
0.15


NSABP C-08 included a comprehensive safety analysis that showed no new or unexpected safety events related to Avastin in the study. Specific severe (Grade 3 or greater) adverse events (AEs) that occurred with increased frequency in patients who received Avastin versus chemotherapy alone were: hypertension (12 percent vs. 1.8 percent), pain (11.1 percent vs. 6.3 percent), proteinuria (2.7 percent vs. 0.8 percent) and wound-healing complications (1.7 percent vs. 0.3 percent).


About the Study
The C-08 study was conducted by the NSABP and sponsored by the National Cancer Institute (NCI) under a Cooperative Research and Development Agreement between Genentech and NCI. NSABP C-08 was a randomized multi-center Phase III study designed to evaluate the effect of FOLFOX (5-fluorouracil, leucovorin and oxaliplatin) chemotherapy with or without Avastin on DFS in patients with surgically-resected Stage II or III adenocarcinoma of the colon. DFS was measured from the date of randomization to the date of any type of cancer recurrence or death from any cause. Patients enrolled in the two-arm study were randomized after surgery to receive either FOLFOX chemotherapy alone for six months or FOLFOX in combination with Avastin (intravenously every two weeks) for six months, followed by an additional six months of Avastin monotherapy. Patients continue to be followed for overall survival, a secondary endpoint of the study.


About Adjuvant Cancer Therapy
Surgical removal of a tumor is typically the standard treatment for colon cancer that has not spread (metastasized) to other parts of the body. Often surgery is followed by an additional treatment (adjuvant therapy) to eliminate stray cancer cells that may have spread through the bloodstream before the tumor was removed. These cancer cells cannot be detected and have the potential to establish and grow into new tumors. The goal of adjuvant therapy given after the primary treatment for early-stage cancer is to increase the chance for a cure. Advanced cancers that have extensively spread throughout body are often incurable.


About the Avastin Development Program
Results are expected in 2010 from a separate Roche-sponsored international Phase III study (AVANT) assessing Avastin in combination with chemotherapy for early-stage colon cancer. The three-arm trial is evaluating Avastin in combination with the chemotherapy regimens XELOX (capecitabine and oxaliplatin) or FOLFOX chemotherapy versus FOLFOX alone.


In addition to early-stage colon cancer, Avastin is being studied as an adjuvant treatment in other early-stage diseases: HER2-negative breast cancer, HER2-positive breast cancer, and non-squamous, non-small cell lung cancer. Approximately 26,000 people are expected to participate in Avastin adjuvant studies.


The Avastin development program represents one of the most comprehensive undertakings in cancer research since chemotherapy and includes more than 450 clinical trials worldwide in approximately 30 different tumor types.


About Avastin
Avastin is a biologic antibody designed to specifically inhibit the vascular endothelial growth factor (VEGF) protein that plays an important role in the development and maintenance of blood vessels, a process known as angiogenesis. VEGF is a potent activator of angiogenesis throughout the life cycle of a tumor. By inhibiting VEGF, Avastin is designed to interfere with the blood supply to a tumor, which is thought to be critical to a tumor's ability to grow and spread in the body (metastasize). For more information on angiogenesis, visit http://www.gene.com.


Avastin is indicated for the first- and second-line treatment of metastatic colorectal cancer in combination with intravenous 5-FU based chemotherapy and for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer in combination with carboplatin and paclitaxel.


About Avastin in Metastatic Colorectal Cancer
Avastin in combination with IV 5-FU-based chemotherapy was proven to extend overall survival by 52 percent compared to chemotherapy alone in people with advanced colorectal cancer. This is one of the largest improvements in survival ever reported in a randomized Phase III advanced colorectal cancer study (hazard ratio=0.66). In a Phase III study in second-line advanced colon cancer, Avastin in combination with FOLFOX4 chemotherapy improved overall survival by 33 percent compared to chemotherapy alone (hazard ratio=0.75).


BOXED WARNINGS and Additional Important Safety Information
Patients treated with Avastin may experience side effects. In clinical trials, some patients treated with Avastin experienced serious 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 side effect occurred in 0.3 to 2.4 percent of patients and in some cases resulted in fatality. Avastin therapy should be permanently stopped in people with GI perforation.


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. In a clinical trial, 15 percent of patients with metastatic colorectal cancer who had surgery while receiving Avastin treatment had serious and fatal complications. Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Avastin therapy should be permanently stopped in patients with wound healing problems that require medical treatment. The appropriate waiting time between stopping treatment with Avastin and having surgery has not been determined.


Severe bleeding: Severe or fatal bleeding, including hemoptysis (coughing up of blood), GI bleeding, hematemesis (bloody vomit), central nervous system (CNS) hemorrhage (bleeding in the brain), epistaxis (nose bleeds), and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin. Grade 3 or higher (severe or fatal) bleeding events have occurred in 1.2 to 4.6 percent of patients receiving Avastin. In patients with previously treated glioblastoma, intracranial hemorrhage (bleeding within the brain) occurred in eight of 163 patients and two people had Grade 3 to 4 (severe) bleeding. Some people receiving Avastin with chemotherapy for lung cancer experienced hemoptysis. In some cases, this event resulted in fatality. People with serious bleeding or recent hemoptysis should not receive Avastin.


In clinical trials, additional serious side effects seen across different cancer types, in some cases resulting in fatality, included the following: formation of an abnormal passage from parts of the body to another part (non-GI fistula formation - less than 0.3 percent); stroke or heart problems (arterial thromboembolic events - 2.6 percent); high blood pressure (5 to 18 percent); nervous system and vision disturbances known as RPLS (reversible posterior leukoencephalopathy syndrome - less than 0.1 percent); severe infusion reactions (0.2 percent of people), and too much protein in the urine, which may be a sign of kidney problems, was increased.


The most common adverse reactions observed in Avastin patients at a rate of more than 10 percent and at least twice the control arm rate, were nose bleeds, headache, high blood pressure, irritation of the nose (rhinitis), protein in the urine, taste alteration, dry skin, rectal bleeding, tear production disorder (lacrimation), and inflammation of the skin (exfoliative dermatitis).


Avastin may cause problems getting pregnant. People who are pregnant or thinking of becoming pregnant should talk with their doctor about the potential risks of loss of pregnancy or the potential risk of Avastin to the fetus. Nursing mothers should not breast-feed while receiving Avastin or for a short period of time after treatment is finished.


For full Prescribing Information and Boxed WARNINGS on Avastin 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, California. For additional information about the company, please visit http://www.gene.com.


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