Genentech, Inc. said the US Food and Drug Administration (FDA) dealt a major blow to it by refusing to recommend its cancer drug Avastin as a treatment for breast cancer.

The Oncologic Drugs Advisory Committee (ODAC) appointed by the US FDA voted 5 to 4 that data are not sufficient to establish a favourable risk/benefit analysis for the use of Avastin (bevacizumab), in combination with paclitaxel chemotherapy, for the treatment of patients who have not received chemotherapy for their locally recurrent or metastatic HER2-negative breast cancer.

The FDA is not bound by the recommendations of its advisory committees and is expected to make a decision on the supplemental Biologics License Application requesting approval for the use of Avastin in this patient population by February 23, 2008.

"We are disappointed by the split vote of the advisory committee, as the addition of Avastin to chemotherapy showed the longest reported progression-free survival in any first-line clinical trial of patients with advanced breast cancer, and we believe progression-free survival is a meaningful endpoint for patients and physicians," said Susan Desmond-Hellmann, M.D., M.P.H., president, Product Development. "We believe that Avastin can help meet a significant unmet medical need for women with metastatic breast cancer, and we remain committed to working with the FDA to make Avastin a viable treatment option for these patients."

Breast cancer is the second most common form of cancer and the second leading cancer killer among American women. According to the American Cancer Society, an estimated 178,000 women will be diagnosed with breast cancer and approximately 40,000 will die from the disease in the US in 2007. Genentech estimates that 75 per cent of women with newly diagnosed metastatic breast cancer are HER2-negative.

Avastin was the first anti-angiogenesis therapy approved by the FDA and is currently indicated for the treatment of metastatic colorectal cancer and advanced non-squamous, non-small cell lung cancer, two of the three largest cancer killers in the US. Avastin is being studied worldwide in more than 300 clinical trials and in more than 20 different tumour types.

The E2100 trial was sponsored by the National Cancer Institute under a Cooperative Research and Development Agreement, and was conducted by a network of researchers led by the Eastern Cooperative Oncology Group (ECOG). E2100 was a multicenter, randomised and controlled clinical trial that enrolled 722 patients with previously untreated, locally recurrent or metastatic breast cancer. Patients were randomised to receive weekly treatment with paclitaxel every three out of four weeks, with or without Avastin.
Based on an independent, blinded review of patient scans, patients treated with Avastin plus paclitaxel experienced a 52 per cent reduction in the risk of disease progression or death compared to those treated with paclitaxel alone (or a hazard ratio of 0.48; p < 0.001) and a near doubling in median PFS (11.3 months versus 5.8 months). PFS represents the time patients live without their disease progressing. The independent review showed a similar magnitude of benefit relative to the initial results presented by ECOG at the American Society of Clinical Oncology annual meeting in 2005. The secondary endpoint of overall survival was longer in the Avastin-containing arm, as indicated by the hazard ratio of 0.87. This improvement did not reach statistical significance (p=0.14).

Safety findings were generally consistent with previous trials of Avastin plus chemotherapy and no new safety signals related to Avastin were observed. Grade 3/4 adverse events that occurred more often in the Avastin arm included neuropathy (due to longer time on paclitaxel treatment), hypertension, arterial thromboembolic events and proteinuria.

Avastin is a therapeutic antibody designed to specifically inhibit vascular endothelial growth factor (VEGF), a protein that plays an important role in angiogenesis and the maintenance of existing blood vessels throughout the lifecycle of a tumour. By inhibiting VEGF, Avastin is designed to interfere with the blood supply to a tumour, which is thought to be critical to a tumour's ability to grow and spread in the body (metastasize).

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. Avastin is also indicated in combination with intravenous 5-FU-based chemotherapy for second-line treatment of patients with metastatic carcinoma of the colon or rectum. On October 11, 2006, the FDA approved Avastin in combination with carboplatin and paclitaxel for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous, non-small cell lung cancer.

Avastin has a well-characterized safety profile in its approved indications. The most serious adverse events associated with Avastin across all trials were gastrointestinal perforation, wound healing complications, haemorrhage, non-GI fistula formation, arterial thromboembolic events, hypertensive crisis, reversible posterior leukoencephalopathy syndrome (RPLS), neutropenia and infection, nephrotic syndrome and congestive heart failure. The most common adverse events seen in patients receiving Avastin across all studies were asthenia, pain, abdominal pain, headache, hypertension, diarrhoea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, dyspnoea, exfoliative dermatitis and proteinuria.