Avastin study shows significant improvement in patients with metastatic colorectal cancer

Genentech, Inc. and Roche have announced that the New England Journal of Medicine published the first Phase III study of an anti-angiogenesis cancer therapy, showing that the addition of Avastin™ (bevacizumab) to the IFL chemotherapy regimen (5-FU/Leucovorin/ CPT-11) significantly extended survival in patients with first-line (previously untreated) metastatic colorectal cancer. These data, first presented at the American Society of Clinical Oncology (ASCO) meeting in 2003, were the first positive results from a Phase III trial of a therapy that works by preventing the formation of new blood vessels, a process called angiogenesis.

Based on the results from this Phase III study, the U.S. Food and Drug Administration (FDA) approved Avastin on February 26, 2004, to be used in combination with intravenous 5-Fluorouracil-based chemotherapy as a treatment for patients with first-line -- or previously untreated -- metastatic cancer of the colon or rectum. Avastin is the first FDA-approved cancer therapy designed to inhibit Vascular Endothelial Growth Factor (VEGF), a key mediator of angiogenesis.

This study showed an extension in the median survival of patients treated with Avastin plus the IFL chemotherapy regimen by approximately five months, compared to patients treated with the IFL chemotherapy regimen alone (20.3 months versus 15.6 months). The survival and progression free survival (PFS) results observed when Avastin was added to first-line chemotherapy are among the longest ever reported in a randomized, Phase III study of patients with metastatic colorectal cancer.

"The New England Journal of Medicine publication of the Avastin pivotal study is significant because it is the first published trial of its kind," said Herbert I. Hurwitz, M.D., the study's lead author and assistant professor, Division of Medical Oncology, Duke University Medical Center. "This study is also significant because the survival improvement was observed in a broad group of patients enrolled in the trial."

An improvement in survival was shown across all patient populations studied, including groups analyzed by age, sex, race, Eastern Cooperative Oncology Group (ECOG) performance status, location of primary tumor, prior adjuvant therapy, number of metastatic sites and tumor burden. Additional data on these subset analyses will be presented at the ASCO annual meeting this weekend in New Orleans, La.

"We learned last year that adding Avastin to chemotherapy supported the long-held scientific theory that affecting the blood supply of tumors can be utilized to help patients in their fight against colorectal cancer," said Hal Barron, M.D., Genentech's senior vice president, Development, and Chief Medical Officer. "One year later, Avastin is approved in the United States as a first-line treatment for metastatic colorectal cancer patients, and we continue to study Avastin in a variety of cancers and in combination with both chemotherapies and targeted therapies."

Last year enrollment was completed in the Phase III ECOG clinical trial evaluating Avastin as a second-line therapy in combination with the FOLFOX regimen (oxaliplatin/5-FU/Leucovorin). Enrollment was recently completed in two additional Phase III ECOG clinical trials, evaluating Avastin as a first-line treatment in combination with chemotherapy for metastatic breast and advanced non-small cell lung cancers. Clinical trials combining Avastin with other targeted therapies continue, and data from clinical studies combining Avastin with the investigational therapy Tarceva™ (erlotinib) in non-small cell lung cancer and renal cell carcinoma will be presented at the ASCO meeting this weekend.

About the Study
The New England Journal of Medicine publication focused on the pivotal Phase III Avastin trial, which enrolled 923 patients with first-line metastatic colorectal cancer. Eight hundred and thirteen patients were randomized to receive Avastin plus the IFL chemotherapy regimen or the IFL regimen plus Avastin placebo. A third arm of the study treated 110 patients with Avastin plus 5-FU/Leucovorin chemotherapy. This arm was dropped, as pre-specified by the trial protocol, once the relative safety of the IFL regimen plus Avastin combination was established.

The trial met its primary endpoint of improving survival rates of patients treated with Avastin plus the IFL chemotherapy regimen compared to those treated with IFL chemotherapy and placebo.

The trial also met its secondary endpoints by improving progression-free survival (PFS), response rate and duration of response. This study demonstrated the largest improvement in PFS reported in a randomized, Phase III study of metastatic colorectal cancer (10.6 months in the Avastin/IFL arm compared to 6.2 months in the IFL-alone arm).

In the pivotal trial, the most serious adverse events that occurred with Avastin included gastrointestinal perforations and wound healing complications, which were uncommon. The most common severe adverse events in this trial included hypertension, which was managed with oral medications; nosebleeds; and asymptomatic proteinuria. Adverse events observed in other trials with Avastin included hemorrhage, congestive heart failure and thromboembolism.

About VEGF and Tumor Angiogenesis
The link between angiogenesis and cancer growth has been discussed by many researchers for decades, but it was not until 1989 that a key growth factor influencing the process, Vascular Endothelial Growth Factor (VEGF), was discovered by Napoleone Ferrara, M.D., a Genentech Fellow. 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 Avastin
Avastin is a therapeutic antibody designed to inhibit 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. Avastin received approval by the U.S. Food and Drug Administration (FDA) on February 26, 2004, to be used in combination with intravenous 5-Flourouracil-based chemotherapy as a treatment for first-line metastatic colorectal cancer. For full prescribing information, Boxed Warnings on Avastin and information about angiogenesis, visit http://www.gene.com. For more information about Avastin, visit http://www.avastin.com.

Earlier this 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-Flourouracil-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 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 various cancers, including 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, as well as in hematologic malignancies and melanoma.

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