A Phase III study of Avastin (bevacizumab) used in combination with paclitaxel and carboplatin in first-line non-squamous, non-small cell lung cancer (NSCLC) met its primary efficacy endpoint of a reduction in the risk of death, the companies report.

The trial was sponsored by the National Cancer Institute (NCI), part of the National Institutes of Health, under a Cooperative Research and Development Agreement between NCI and Genentech, Inc., and conducted by a network of researchers led by the Eastern Cooperative Oncology Group (ECOG). Data from this study will be submitted to the annual meeting of the American Society of Clinical Oncology (ASCO), May 13-17, 2005, according to ECOG.

Overall Survival Improvement

"These results represent the first study combining a targeted biologic therapy with chemotherapy to show an overall survival improvement in the first-line non-small cell lung cancer setting, and the first time that any treatment has improved upon the standard, two-drug chemotherapy regimen in this disease," said Hal Barron, M.D., Genentech senior vice president, development and chief medical officer.

"We would like to thank our collaborators at NCI and ECOG for their work on this study, as well as the many patients and their families who made the decision to participate in this study. We plan to share these data with the FDA to discuss the possibility of filing a supplemental Biologics License Application for Avastin plus chemotherapy in first-line non-small cell lung cancer," Dr. Barron added.

This is the first Phase III study to evaluate the therapeutic antibody Avastin in combination with chemotherapy in NSCLC. This was a randomized, controlled, multicenter trial that enrolled 878 patients with previously untreated advanced NSCLC. The patients enrolled in this trial were randomized to receive treatment with paclitaxel and carboplatin chemotherapies with or without Avastin.

Adverse Events

In previous clinical experience with Avastin in combination with paclitaxel and carboplatin in NSCLC, life-threatening or fatal pulmonary bleeding was identified as a severe adverse event apparently unique to this disease.

Certain characteristics, including any significant pulmonary bleeding prior to receiving treatment with Avastin or the presence of a specific type of NSCLC called "squamous cell carcinoma" appeared to predispose patients to experiencing this adverse event. Patients with these characteristics were excluded from this Phase III study and the rate of life-threatening or fatal pulmonary bleeding was substantially reduced from prior clinical studies.

However, some patients did experience fatal pulmonary bleeding in this trial, and this event was more common in the patient group that received Avastin in combination with chemotherapy than in the patient group that received chemotherapy only. Other adverse events observed in this study were similar to those identified in previous Phase II and Phase III studies of Avastin. More detailed information about adverse events in this study will be presented at the ASCO meeting in May.

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 binding to VEGF, Avastin is designed to interfere with the blood supply to tumors, a process that is critical to tumor growth and metastasis.

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).

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, non-small cell lung 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.

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 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.

According to the World Health Organization, there are more than 1.2 million cases worldwide of lung and bronchial cancer each year, causing approximately 1.1 million deaths annually.

An estimated 173,000 people were diagnosed with lung cancer in the United States in 2004.

According to the National Cancer Institute, lung cancer is the single largest cause of cancer deaths in the United States and is responsible for nearly 30 percent of cancer deaths in this country.

NSCLC is the most common form of the disease and accounts for almost 80 percent of all lung cancers.