Genentech Inc. announced that the US Food and Drug Administration (FDA) approved Avastin (bevacizumab) in combination with intravenous 5-fluorouracil (5-FU)-based chemotherapy for second-line metastatic colorectal cancer.

Avastin is also approved as a first-line treatment of metastatic colorectal cancer (CRC) in combination with intravenous 5-FU-based chemotherapy.

"Avastin is the only biologic therapy with a demonstrated survival benefit in colorectal cancer, and this new indication offers CRC patients who have received a previous treatment regimen a new option to help fight their disease," said Hal Barron, M.D., senior vice president, Development and chief medical officer at Genentech. "Avastin used in combination with chemotherapy has become an important component of care for patients with metastatic colorectal cancer. We continue to study Avastin in both the adjuvant and metastatic settings, and phase III trials in kidney, breast, pancreatic, non-small cell lung, prostate and ovarian cancers are ongoing in the hope that we may be able to help patients with other cancers as well."

The approval is based on results of a randomized, controlled, multicenter phase III trial (E3200) of 829 patients with advanced or metastatic CRC who had received previous treatment with irinotecan and 5-FU as initial therapy for metastatic disease or as adjuvant therapy. The study showed that patients who received Avastin plus the 5-FU-based chemotherapy regimen known as FOLFOX4 (oxaliplatin/5-FU/leucovorin) had a 25 per cent reduction in the risk of death (based on a hazard ratio of 0.75), the primary endpoint, which is equivalent to a 33 per cent improvement in overall survival, compared to patients who received FOLFOX4 alone. Median survival for patients receiving Avastin plus FOLFOX4 was 13.0 months, compared to 10.8 months for those receiving FOLFOX4 alone.

"Colorectal cancer is the second leading cause of cancer death in the United States, so we are encouraged by new treatments and options that are leading to increased survival for patients," said Amy E. Kelly, Co-founder and Executive Director of the Colon Cancer Alliance. "We believe Avastin is an important advance that offers hope for prolonging survival for patients, including those who have already been through first-line treatment."

In the E3200 study, the most common Grade 3-5 (non-haematologic) and Grade 4/5 (haematologic) adverse events which occurred at a higher incidence (more than or equal to 2 percent) in the Avastin plus FOLFOX4 arm, compared to the FOLFOX4 alone arm, were: diarrhoea, nausea, vomiting, dehydration, ileus, sensory neuropathy, other neurologic events, fatigue, abdominal pain, headache, hypertension and haemorrhage.

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, as well as financial support for data management.

Avastin is a therapeutic antibody designed to inhibit Vascular Endothelial Growth Factor (VEGF), a protein that plays an important role in tumour angiogenesis and maintenance of existing tumour vessels. By inhibiting VEGF, Avastin is designed to interfere with the blood supply to a tumour, a process that is thought to be critical to a tumour's growth and metastasis.

Avastin, in combination with intravenous 5-FU-based chemotherapy, is indicated for first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum. The FDA first 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). The addition of Avastin to IFL improved overall survival by 52 percent (based on a hazard ratio of 0.66). In addition, this study demonstrated an improvement in progression-free survival of more than four months (10.6 months in the Avastin/IFL arm compared to 6.2 months in the IFL-alone arm).

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, haemorrhage, arterial thromboembolic events, hypertensive crisis, nephrotic syndrome and congestive heart failure. The most common adverse events in patients receiving Avastin were asthenia, pain, abdominal pain, headache, hypertension, diarrhoea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, dyspnoea, exfoliative dermatitis, and proteinuria.

Based on data showing that VEGF may play a broad role in a range of cancers, Genentech is pursuing a broad development program for Avastin that currently includes 130 clinical trials across 25 different types of cancer. Avastin is being evaluated in Phase III clinical trials for its potential use in adjuvant and metastatic colorectal, renal cell (kidney), breast, pancreatic, non-small cell lung, prostate and ovarian cancers. Avastin is also being evaluated in earlier stage trials as a potential therapy in a variety of solid tumour cancers and haematologic malignancies. In April 2006, Genentech submitted an sBLA for Avastin plus platinum-based chemotherapy for first-line treatment of advanced non-small cell lung cancer other than predominant squamous histology. In May 2006, Genentech submitted an sBLA for Avastin in combination with taxane chemotherapy for patients who have not previously received chemotherapy for their locally recurrent or metastatic breast cancer.