November 29, 2004
Phase III Results Show Avastin Plus FOLFOX4 Chemotherapy Significantly Extend Survival in Second-Line Metastatic Colorectal Cancer
SOUTH SAN FRANCISCO, Calif. and BASEL, Switzerland, Nov. 29
/PRNewswire-FirstCall/ -- Genentech, Inc. and Roche (SWX Zurich) today announced that a randomized Phase III study of Avastin(TM) (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.
Results from an interim analysis demonstrated that patients receiving Avastin plus FOLFOX4 had a 26 percent reduction in the risk of death, a hazard ratio of 0.74, 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. A preliminary assessment of the safety profile suggested that Avastin could be combined safely with FOLFOX4 and adverse events observed in this study were consistent with other clinical trials in which Avastin was combined with chemotherapy.
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. According to ECOG, preliminary study results will be presented during the ASCO Gastrointestinal Cancers Symposium, January 27-29, 2005, in Hollywood, Fla.
"Avastin is the first and only targeted therapy to demonstrate improvements in survival in both first- and second-line metastatic colorectal cancer," said Hal Barron, M.D., Genentech senior vice president, development and chief medical officer. "This is the first Phase III study to evaluate Avastin in combination with an oxaliplatin-based chemotherapy regimen in patients with metastatic colorectal cancer. This study provides additional evidence that adding Avastin to chemotherapy results in a significant survival benefit for patients with either untreated or relapsed metastatic colorectal cancer. We plan to share these Phase III results with the FDA to discuss the filing of a supplemental Biologics License Application for this combination in this setting of metastatic colorectal cancer."
This Phase III study was a randomized, controlled, multicenter trial that enrolled 829 patients with advanced colorectal cancer who had previously received a fluorouracil-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 on the other two arms. Results from this treatment arm have not yet been disclosed.
A preliminary assessment of the safety profile suggested that Avastin could be combined safely with FOLFOX4 and treatment toxicities observed in this study were consistent with adverse events observed in other clinical trials in which Avastin was combined with chemotherapy. Adverse events included neuropathy attributed to FOLFOX4 and hypertension, managed with oral medications, and bleeding attributed to Avastin(1).
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 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). 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.
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, melanoma and several types of solid tumor cancers and hematologic malignancies. Additionally, Avastin is being studied in combination with Tarceva(TM) (erlotinib) in Phase II trials in both renal cell carcinoma and relapsed non-small cell lung cancer.
Avastin Safety Profile
In Genentech-sponsored studies in several tumor types, the most serious adverse events associated with Avastin use were gastrointestinal perforation, wound healing complications, hemorrhage, hypertensive crisis, nephrotic syndrome, congestive heart failure and arterial thromboembolic events including cerebrovascular accidents (stroke), myocardial infarctions, transient ischemic attacks, and angina. Other common adverse events were asthenia, pain, hypertension, diarrhea, leukopenia, 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 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. Approximately 147,000 new cases of colorectal cancer will be diagnosed in the United States in 2004.
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(TM) (bevacizumab) and Tarceva(TM) (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, Avastin and 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/.
Roche in Oncology
Within the last five years the Roche Group, including its members Genentech in the United States and Chugai in Japan, has become the world's leading provider of anti-cancer treatments, supportive care products and diagnostics. Its oncology business includes an unprecedented five products with survival benefit in different major tumor indications: Xeloda and Herceptin in advanced stage breast cancer, MabThera in non-Hodgkin's lymphoma, Avastin in colorectal carcinoma and Tarceva in non-small cell lung cancer and pancreatic carcinoma.
In the United States Herceptin, MabThera, Avastin and Tarceva are marketed either by Genentech alone or together with its partners Biogen Idec Inc. (MabThera) and OSI (Tarceva). Outside of the United States, Roche and its Japanese partner Chugai are responsible for the marketing of these medicines.
The Roche oncology portfolio also includes NeoRecormon (anemia in various cancer settings), Bondronat (prevention of skeletal events in breast cancer and bone metastases patients, hypercalcemia of malignancy), Kytril (chemotherapy and radiotherapy-induced nausea and vomiting) and Roferon-A (hairy cell and chronic myeloid leukemia, Kaposi's sarcoma, malignant melanoma, renal cell carcinoma). CERA is the most recent demonstration of Roche's commitment to anemia management. The Roche Group's cancer medicines generated sales of more than 5.6 billion Swiss francs in the first nine months of 2004.
In addition to the medicines, Roche is developing new diagnostic tests that will have a significant impact on disease management for cancer patients in the future. With a broad portfolio of tumor markers for prostate, colorectal, liver, ovarian, breast, stomach, pancreas and lung cancer, as well as a range of molecular oncology tests, Roche will continue to be the leader in providing cancer-focused treatments and diagnostics.
Roche has four research sites (two in the United States and one each in Germany and Japan) and five development sites (two in the United States and one each in UK, Australia and Switzerland).
For full prescribing information, including Boxed Warnings for Avastin, please call 1-800-821-8590 or visit http://www.gene.com/.
CONTACT: Media: Neil Cohen, +1-650-225-8681, Investors: Kathee Littrell, +1-650-225-1034, or, Advocacy: Cheya Pope, +1-650-225-6334, all of Genentech; or Media: Martin McInally, +41 61 688 98 48, for Roche.
(1) Giantonio BJ et al. The addition of bevacizumab (anti-VEGF) to FOLFOX4 in previously treated advanced colorectal cancer (advCRC): An updated interim toxicity analysis of the Eastern Cooperative Oncology Group (ECOG) study E3200. ASCO Gastrointestinal 2004 Cancer Symposium (abstract #241).
CONTACT: Media: Neil Cohen, +1-650-225-8681, Investors: Kathee Littrell,+1-650-225-1034, or, Advocacy: Cheya Pope, +1-650-225-6334, all of Genentech;or Media: Martin McInally, +41 61 688 98 48, for Roche
Web site: http://www.gene.com/