Thursday, Jan 27, 2005
Hollywood, Fla. -- January 27, 2005 --Genentech, Inc. (NYSE: DNA) today announced that a randomized Phase III study (E3200) of Avastin (bevacizumab) plus the FOLFOX4 chemotherapy regimen (oxaliplatin/5-FU/leucovorin), compared to FOLFOX4 alone in second-line metastatic colorectal cancer patients achieved its primary endpoint of improving overall survival. These data, first announced by the National Cancer Institute (NCI) and Genentech in November 2004, were presented by Bruce J. Giantonio, M.D., of the Abramson Cancer Center at the University of Pennsylvania in Philadelphia at the Second Annual Gastrointestinal Cancers Symposium. Avastin is currently approved as a first-line treatment for metastatic colorectal cancer in combination with intravenous 5-FU-based chemotherapy.
Results from a preliminary analysis of the E3200 study demonstrated that patients receiving Avastin plus FOLFOX4 had a 26 percent reduction in the risk of death (a hazard ratio of 0.74), the primary endpoint, compared to patients who received FOLFOX4 alone. Median survival for patients receiving Avastin plus FOLFOX4 was 12.5 months, compared to 10.7 months for those receiving FOLFOX4 alone, a 17 percent improvement.
"Avastin is the only targeted therapy to demonstrate an improvement in survival in first-line metastatic colorectal cancer patients, who on average face a two-year life expectancy upon diagnosis. The data presented today show that Avastin in combination with the FOLFOX4 regimen may be an effective treatment for second-line metastatic colorectal cancer," said Gwen Fyfe, M.D., Genentech's vice president, Clinical Hematology/Oncology. "The results from this study add to the growing body of data showing that the addition of Avastin to 5-FU-based chemotherapy regimens can result in meaningful clinical benefit to patients with metastatic colorectal cancer, and we have initiated discussions with the FDA to determine a filing strategy for the use of Avastin plus FOLFOX in the second-line population."
Adverse events in this Phase III study were consistent with those seen in previous Avastin and FOLFOX4 clinical trials in metastatic colorectal cancer. The most frequent adverse events were hypertension and sensory neuropathy, with six percent of patients (17/286) in the Avastin plus FOLFOX4 arm experiencing Grade 3 or 4 hypertension compared to two percent (5/282) in the FOLFOX4 arm. Grade 3 and 4 sensory neuropathy occurred at a rate of 15 percent (44/286) in the Avastin plus FOLFOX4 arm, compared to a rate of nine percent (26/282) in the FOLFOX4 arm. The most serious adverse events were bleeding, which occurred at a rate of 2.8 percent (8/286) in the Avastin + FOLFOX4 arm and less than one percent (1/282) in the FOLFOX4 arm, gastrointestinal perforation, which occurred at a rate of one percent (3/286) in the Avastin plus FOLFOX4 arm, and thrombosis, which occurred in 4.5 percent of patients (13/286) treated with Avastin plus FOLFOX4 and compared to 2.8 percent of patients (8/282) treated with FOLFOX4.
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 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 suspended 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 that group might be lower compared to that of patients treated in the other two arms. Results from this treatment arm have not yet been disclosed.
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.
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 binding to VEGF, Avastin is designed to interfere with the blood supply to tumors, a process that is critical to tumor growth and metastasis. For full prescribing information, including Boxed Warnings for Avastin and information about Avastin and angiogenesis, visit www.gene.com or 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 of 925 patients 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). 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 6.4 months in the IFL-alone arm). The survival and PFS results observed when Avastin is added to first-line chemotherapy are the longest ever reported in a randomized, Phase III study of patients with metastatic colorectal cancer.
Last year the National Comprehensive Cancer Network (NCCN), an alliance of 19 of the world's leading cancer centers, updated their Colorectal Clinical Practice Guidelines and added Avastin in combination with 5-Fluorouracil-based regimens -- including those using oxaliplatin or irinotecan -- to its list of treatment options for first-line advanced colon or rectal cancer.
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 and non-small cell lung cancers. Avastin is also being evaluated in earlier stage trials as a potential therapy in prostate, ovarian, and several types of solid tumor cancers and hematologic malignancies and melanoma.
Avastin Safety Profile
Avastin has a well-established safety profile. In Genentech-sponsored studies, the most serious adverse events associated with Avastin were infrequent, and included 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 VEGF and Tumor Angiogenesis
The link between angiogenesis and cancer growth has been discussed by many researchers for decades. It wasn't until 1989 that a key growth factor influencing the process, VEGF, was discovered by Napoleone Ferrara, M.D., a staff scientist at Genentech. Dr. Ferrara and his team cloned VEGF, providing some of the first evidence that a specific angiogenic growth factor existed. This research was published in the journal Science in 1989. Dr. Ferrara then created a mouse antibody to this protein. In 1993, Dr. Ferrara and his team at Genentech, in a study published in Nature, demonstrated that the antibody directed against VEGF could suppress angiogenesis and tumor growth in preclinical models, providing compelling evidence that VEGF can play a critical role in tumor growth. Clinical studies with a humanized version of the antibody, Avastin, began in 1997.
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® (Rituximab), Herceptin® (Trastuzumab), Avastin (bevacizumab) and Tarceva (erlotinib), and markets all four products in the United States alone (Avastin and Herceptin), with Biogen Idec Inc. (Rituxan) or with OSI Pharmaceuticals (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. Potential oncology therapies directed at the HER pathway include a therapeutic antibody currently in Phase II trials. Also in early development are a small molecule directed at the hedgehog pathway, a soluble human protein targeting apoptosis and a humanized anti-CD20 antibody for hematology/oncology indications.
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 receives royalties or other income from companies that are licensed to market its products outside of the United States. 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, please call 1-800-821-8590 or visit www.gene.com.