Genentech Submits Supplemental Biologics License Application for Avastin(R) in Relapsed Metastatic Colorectal Cancer

SOUTH SAN FRANCISCO, Calif., Dec. 19 /PRNewswire-FirstCall/ -- Genentech, Inc. announced today that the company has submitted a supplemental Biologics License Application (sBLA) with the U.S. Food and Drug Administration (FDA) for Avastin(R) (bevacizumab) in combination with 5-fluorouracil (5-FU)-based chemotherapy for patients with relapsed, metastatic colorectal cancer. Avastin is currently approved as a first-line treatment of metastatic colorectal cancer in combination with intravenous 5-FU-based chemotherapy.

The sBLA submission is based on results of a randomized, controlled, multicenter Phase III trial (E3200) of 829 patients with advanced or metastatic colorectal cancer (CRC) whose disease progressed following previous treatment with 5-FU and irinotecan-based chemotherapy. The study showed that patients who received Avastin plus the 5-FU-based chemotherapy regimen known as FOLFOX4 (oxaliplatin/5-FU/leucovorin) had a 25 percent reduction in the risk of death (hazard ratio of 0.75), the primary endpoint, which is equivalent to a 33 percent improvement in overall survival, compared to patients who received FOLFOX4 alone.

"Data from this study showed that adding Avastin to chemotherapy is an important treatment for patients with relapsed metastatic CRC," said Hal Barron M.D., senior vice president, development and chief medical officer at Genentech. "We continue to investigate Avastin in clinical trials in more than 20 cancer types, and plan to work closely with the FDA during the review process for this potential new indication in relapsed metastatic CRC."

In the E3200 study, adverse events were similar to those seen in previous trials of Avastin plus FOLFOX4; however, increases in the incidence of Grade 3 and 4 sensory neuropathy and Grade 3 and 4 nausea and vomiting were observed. Adverse events that were consistent with those observed in previous Avastin studies included Grade 3 and 4 hypertension, bleeding, diarrhea, gastrointestinal perforation, and arterial thromboembolic events. There was no significant increase in the incidence of Grade 3 and 4 venous thromboembolic events or proteinuria events with the addition of Avastin to FOLFOX4 in this study.

About the E3200 Study

This Phase III study was a randomized, controlled, multicenter trial that enrolled 829 patients with advanced colorectal cancer who had previously received both a 5-FU-based therapy and irinotecan, either alone or concurrently, for advanced disease or if their disease had relapsed within six months of concluding adjuvant treatment with these chemotherapy agents. The patients enrolled in this trial were randomized to receive treatment with the FOLFOX4 regimen with or without Avastin. Randomization to a third arm of the study evaluating single-agent Avastin was closed in March 2003 on the recommendation of the Data Monitoring Committee overseeing the study, when review of early results suggested that overall survival for patients in the single-agent Avastin arm appeared to be inferior to that of patients treated in the other two arms. The trial did not include a placebo arm that would allow for the assessment of Avastin monotherapy compared to placebo.

The trial was sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health, and conducted by a network of researchers led by the Eastern Cooperative Oncology Group (ECOG). Genentech provided Avastin for the trial under the Cooperative Research and Development Agreement (CRADA) with the NCI for the clinical development of Avastin, as well as financial support for data management.

About Colorectal Cancer

According to the American Cancer Society, more than 150 patients die every day from colorectal cancer in the United States. Colorectal cancer is the second leading cause of cancer death in the United States and the third most frequently diagnosed cancer. The ACS estimates there will be 145,290 new cases of colorectal cancer diagnosed and 56,290 colorectal cancer deaths in 2005.

About Avastin

Avastin is a therapeutic antibody designed to inhibit Vascular Endothelial Growth Factor (VEGF), a protein that plays an important role in tumor angiogenesis and maintenance of existing tumor vessels. By inhibiting VEGF, Avastin is designed to interfere with the blood supply to a tumor, a process that is thought to be critical to a tumor's growth and metastasis. For full prescribing information and boxed warnings on Avastin and information about angiogenesis, visit http://www.gene.com/ . For more information on Avastin, visit http://www.avastin.com/ .

The FDA approved Avastin on February 26, 2004 as a first-line treatment for metastatic colorectal cancer in combination with intravenous 5-FU-based chemotherapy. Approval was based on data from two trials. The pivotal trial was a large, placebo-controlled, randomized study that demonstrated a prolongation in the median survival of patients treated with Avastin plus the IFL (5-FU/leucovorin/CPT-11) chemotherapy regimen by approximately five months, compared to patients treated with the IFL chemotherapy regimen alone (20.3 months versus 15.6 months). The addition of Avastin to IFL improved overall survival by 52 percent (based on a hazard ratio of 0.66). In addition, this study demonstrated an improvement in progression-free survival (PFS) of more than four months (10.6 months in the Avastin/IFL arm compared to 6.2 months in the IFL-alone arm).

Based on data showing that VEGF may play a broad role in a range of cancers, Genentech is pursuing a late-stage clinical development program with Avastin evaluating its potential use in adjuvant and metastatic colorectal, renal cell (kidney), breast, pancreatic, non-small cell lung, prostate and ovarian cancers. Avastin is also being evaluated in earlier stage trials as a potential therapy in a variety of solid tumor cancers and hematologic malignancies. For further information about Avastin clinical trials, please call 888-662-6728.

Avastin Safety Profile

Avastin has a well-established safety profile. In Genentech-sponsored studies, the most serious adverse events associated with Avastin were gastrointestinal perforation, wound healing complications, hemorrhage, arterial thromboembolic events, hypertensive crisis, nephrotic syndrome and congestive heart failure. The most common Grade 3-4 adverse events (occurring in greater than two percent of patients in the Avastin arm, compared to the control group) were asthenia, pain, hypertension, diarrhea and leukopenia. The most common adverse events (occurring in greater than two percent of patients in the Avastin arm, compared to the control group) of any severity were asthenia, pain, abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, dyspnea, exfoliative dermatitis and proteinuria.

About Genentech BioOncology

Genentech is committed to changing the way cancer is treated by establishing a broad oncology portfolio of innovative, targeted therapies with the goal of improving patients' lives. The company is the leading provider of anti-tumor therapeutics in the United States. Genentech is leading clinical development programs for Rituxan(R) (Rituximab), Herceptin(R) (Trastuzumab), Avastin(R) (bevacizumab), and Tarceva(R) (erlotinib), and markets all four products in the United States, either alone (Avastin and Herceptin) or with Biogen Idec Inc. (Rituxan) or OSI Pharmaceuticals, Inc. (Tarceva). Genentech has licensed Rituxan, Herceptin, and Avastin and OSI Pharmaceuticals has licensed Tarceva to Roche for sale by the Roche Group outside of the United States.

The company has a robust pipeline of potential oncology therapies with a focus on four key areas: angiogenesis, apoptosis (i.e., programmed cell death), the HER pathway, and B-cell biology. A therapeutic antibody directed at the HER pathway is currently in Phase II trials, and in early development, are a small molecule directed at the hedgehog pathway and a therapy targeting apoptosis.

Genentech is a leading biotechnology company that discovers, develops, manufactures, and commercializes biotherapeutics for significant unmet medical needs. A considerable number of the currently approved biotechnology products originated from, or are based on, Genentech science. Genentech manufactures and commercializes multiple biotechnology products directly in the United States and licenses several additional products to other companies. The company has headquarters in South San Francisco, Calif., and is traded on the New York Stock Exchange under the symbol DNA. For additional information about the company, please visit http://www.gene.com/ .

For full prescribing information, including Boxed Warnings for Avastin, Rituxan, and Herceptin, or for Tarceva full prescribing information, please call 800-821-8590 or visit http://www.gene.com/ .

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