Sunday, Jun 1, 2003
Chicago -- June 1, 2003 --Genentech, Inc. (NYSE: DNA) today announced that a randomized Phase III study in previously-untreated metastatic colorectal cancer patients evaluating Avastin® (bevacizumab, rhuMAb-VEGF) plus chemotherapy versus chemotherapy alone met its primary endpoint of improving overall survival, as measured by a hazard ratio. Patients receiving Avastin plus chemotherapy had a 50 percent increase in their chance for survival compared to patients who received chemotherapy alone. Conversely, this corresponds to a hazard ratio of 0.65 (p=0.00003). The overall survival data suggest a stronger patient benefit than anticipated, as the study was designed to detect a hazard ratio of 0.75, or a 33 percent increase in chance for survival.
This benefit represents an extension in the median survival of patients treated with Avastin plus chemotherapy by approximately five months, compared to patients treated with chemotherapy alone (20.3 months versus 15.6 months). The study was presented at the 39th annual American Society of Clinical Oncology (ASCO) meeting by Herbert I. Hurwitz, M.D. of the Duke University Medical Center.
The median time to disease progression increased 71 percent from 6.2 months in the chemotherapy arm to 10.6 months in the Avastin plus chemotherapy arm (p<0.00001), and Avastin plus chemotherapy was also shown to improve overall response rates from 35 percent in the group receiving chemotherapy alone to 45 percent with Avastin plus chemotherapy (p=0.0029). The duration of response increased from 7.1 months with chemotherapy to 10.4 months with Avastin plus chemotherapy (p=0.0014).
"The primary and secondary efficacy endpoints, as well as the safety profile, exceeded what the study was designed to demonstrate, and open the door to a potentially new way to treat cancer by inhibiting angiogenesis," said Susan D. Hellmann, M.D., M.P.H., Genentech's executive vice president, Development and Product Operations, and chief medical officer. "The positive results from this clinical trial are an important milestone in the fight against colorectal cancer, and we want to recognize the contributions of the numerous investigators and the courage of the hundreds of patients who participated in this study."
Genentech is currently discussing plans for the filing of a Biologics License Application with the U.S. Food and Drug Administration.
Avastin is an investigational therapeutic antibody designed to inhibit Vascular Endothelial Growth Factor (VEGF), a protein that plays a critical role in tumor angiogenesis (the formation of new blood vessels to the tumor) and maintenance of existing tumor blood vessels. By inhibiting VEGF, Avastin is designed to interfere with the blood supply to tumors, a process that is critical to tumor growth and metastasis.
"The results of this Phase III study showed that adding Avastin to standard chemotherapy resulted in a significant improvement in how long metastatic colorectal cancer patients lived, how well their tumors shrank, and how long their tumor growth remained under control," said Dr. Hurwitz. "Importantly, these clinical benefits were seen in all groups of patients -- young and old. In addition, there were very few side effects, and those observed in this study were generally mild and manageable, especially compared to standard chemotherapies. Further clinical study is warranted to determine if and how Avastin may be useful in other settings."
Avastin Metastatic Colorectal Cancer Trial Overview and Safety Results
This multi-center, Phase III study enrolled more than 900 patients, and randomized 800 patients to receive either Avastin plus the standard of care chemotherapy (5-FU/Leucovorin/CPT-11, called IFL, n=403) or the IFL regimen plus an Avastin placebo (n=412). A third arm of the study treated 110 patients with Avastin plus 5-FU/Leucovorin chemotherapy. This arm was dropped, as pre-specified, once safety with the IFL regimen was established.
The addition of Avastin to chemotherapy was well tolerated. While bleeding, thrombosis, asymptomatic proteinuria and hypertension were identified in Phase II studies as safety events, of these expected events only Grade 3 hypertension, managed with oral medications, was clearly increased in this Phase III study. Grade 3 hypertension occurred in 10.9 percent of patients treated with Avastin plus chemotherapy and 2.3 percent of patients who received chemotherapy alone. Grade 3 proteinuria occurred at the same rate in both arms (0.8 percent in each group), and bleeding occurred in 3.1 percent of patients in the Avastin plus chemotherapy arm and in 2.5 percent of patients in the chemotherapy alone. The incidence of thromboembolism was 19.3 percent for Avastin plus chemotherapy compared to 16.1 percent in patients receiving chemotherapy alone. In addition, although uncommon, gastrointestinal perforation was limited to the Avastin plus chemotherapy arm and may be increased by the addition of Avastin to chemotherapy.
About VEGF and Tumor Angiogenesis
For decades the link between angiogenesis and cancer growth has been discussed by many researchers, but 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.
"As a scientist, it is extremely rewarding to see a discovery from the lab develop into a treatment that has improved survival for metastatic colorectal cancer patients in a Phase III study," said Dr. Ferrara. "These results validate the work of many scientists, both within and outside of Genentech, which demonstrate the role VEGF and angiogenesis play in the growth of cancer."
Genentech's research on VEGF has since expanded beyond cancer and includes the development of an antibody fragment similar to Avastin, called Lucentis (rhuFAB V2). Lucentis is in Phase III studies for certain forms of age-related macular degeneration, the leading cause of blindness in the United States.
Comprehensive Clinical Trial Program
Based on preclinical and clinical studies showing that VEGF plays a broad role in a range of cancers, Genentech is pursuing a late-stage clinical development program with Avastin evaluating its potential use in metastatic colorectal, renal cell (kidney), breast and non-small cell lung cancers. To date, more than 2,000 patients have been treated with Avastin in clinical studies.
Results from a second Genentech study in metastatic colorectal cancer are expected later this year. The second colorectal cancer trial enrolled 200 patients who are not optimal candidates for CPT-11 as a first-line treatment and randomized patients to receive either 5-FU/Leucovorin chemotherapy alone or in combination with Avastin.
Last year, a Phase III study of Avastin plus Xeloda® (capecitabine) in refractory metastatic breast cancer patients did not meet its primary endpoint.
In October 2001, a Phase II study with Avastin in metastatic renal cell carcinoma conducted by the National Cancer Institute (NCI) was stopped early for efficacy reasons after it was shown that time to disease progression was delayed approximately two and a half times longer in patients treated with high dose Avastin. Results from this study were presented at last year's ASCO meeting. Based on the positive data observed in this trial, two Phase III trials in metastatic kidney cancer are scheduled to begin enrollment this year.
In addition, Phase III Eastern Cooperative Oncology Group (ECOG) studies continue to evaluate Avastin in second-line metastatic colorectal, first-line metastatic non-small cell lung, and first-line metastatic breast cancer. Additional studies are ongoing through the NCI in more than 20 different tumor types.
Preliminary data from additional studies with Avastin in non-small cell lung, prostate, colorectal, breast, melanoma and pancreatic cancers will also be presented at ASCO.
For further information about Avastin clinical trials, please call 888-662-6728.
About Colorectal Cancer
According to the American Cancer Society (ACS), colorectal cancer is the second leading cause of cancer death in the United States and the third most frequently diagnosed cancer. The ACS estimates that 147,500 new cases of colorectal cancer will be diagnosed in the United States in 2003.
Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes biotherapeutics for significant unmet medical needs. Fifteen of the currently approved biotechnology products originated from or are based on Genentech science. Genentech manufactures and commercializes ten biotechnology products in the United States. The company has headquarters in South San Francisco, California and is traded on the New York Stock Exchange under the symbol DNA. For press releases and additional information about the company, please visit http://www.gene.com.