The U.S. Food and Drug Administration (FDA) announced today that the agency is recommending removing the breast cancer indication from the label for bevacizumab (Avastin?, Genentech/Roche) because the drug has not been shown to be safe and effective for that use.

The FDA is making this recommendation after reviewing the results of four clinical studies of bevacizumab in women with HER2-negative, metastatic breast cancer and determining that the data indicate that the drug does not prolong progression-free overall survival in breast cancer patients or provide a sufficient ? clinically meaningful – benefit in slowing disease progression to outweigh the significant risk to patients with breast cancer. These risks include severe high blood pressure; bleeding and hemorrhage; the development of perforations (or “holes”) in the body, including in the nose, stomach, and intestines; and heart attack or heart failure.

European position
The decision to start the process to remove the breast cancer indication contradicts the decision by the European Medicines Agency which today confirmed that the benefits of bevacizumab in combination with paclitaxel outweigh its risks and that this combination remains a valuable treatment option for patients suffering from metastatic breast cancer The European position follows a review (Article 20/EC 726/2004), of bevacizumab in combination with taxanes, where the Committee concluded that bevacizumab should no longer be used in combination with another taxane, docetaxel.

FDA Review and Process
In July 2010, after reviewing all available data an independent advisory committee, composed primarily of oncologists, voted 12-1 to remove the breast cancer indication from the bevacizumab label.

“After careful review of the clinical data, we are recommending that the breast cancer indication for bevacizumab be removed based on evidence from four independent studies,” Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “Subsequent studies failed to confirm the benefit observed in the original trial. None of the studies demonstrated that patients receiving bevacizumab lived longer and patients receiving bevacizumab experienced a significant increase in serious side effects. The limited effects of bevacizumab combined with the significant risks led us to this difficult decision. The results of these studies are disappointing. We encourage the company to conduct additional research to identify if there may be select groups of patients who might benefit from this drug.”

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Removing the breast cancer indication from the bevacizumab label will be a process. This is the first step. The drug itself is not being removed from the market and today’s action will not have any immediate impact on its use in treating breast cancer. Today’s action will not affect the approvals for colon, kidney, brain, and lung cancers.

Oncologists currently treating patients with bevacizumab for metastatic breast cancer should use their medical judgment when deciding whether a patient should continue treatment with the drug or consider other therapeutic options.

The agency has informed Genentech of its proposal to withdraw marketing approval of the drug for breast cancer. Genentech has not agreed to remove the breast cancer indication voluntarily, so the agency has issued a Notice of Opportunity for a Hearing, which permits Genentech to request a public hearing if it wishes to contest the agency’s determination. The company has 15 days to request a hearing; if it does not do so, the hearing will be waived, and FDA will begin proceedings to remove the breast cancer indication.

Bevacizumab is a recombinant humanized monoclonal antibody directed against the vascular endothelial growth factor (VEGF), a pro-angiogenic cytokine. It binds to VEGF and inhibits VEGF receptor binding, thereby preventing the growth and maintenance of tumor blood vessels, a process known as angiogenesis. [1] (Illustration: The bond between bevacizumab, the antibody in the anti-tumor drug bevacizumab, and the VEGF)

Accelerated approval
Bevacizumab, in combination with chemotherapy (paclitaxel), was approved in February 2008 under the FDA’s accelerated approval program, based on the results of a pivotal Phase III study known as “E2100,” which evaluated the drug in patients who had not received chemotherapy for their metastatic HER2-negative breast cancer. Under the accelerated approval program, a drug may be approved based on clinical data that suggest the drug has a meaningful clinical benefit, with more information being needed to confirm this. The program provides earlier patient access to promising new drugs to treat serious or life-threatening conditions while confirmatory clinical trials are conducted.

The positive results observed in the E2100 clinical trial, conducted by the Eastern Cooperative Oncology Group (ECOG), caused a ripple of excitement in the breast cancer community by showing a twofold increase in progression-free survival (PFS) in patients treated with paclitaxel plus bevacizumab versus paclitaxel alone. However, other clinical trials failed to confirm or build on the results of E2100.

After the accelerated approval of bevacizumab for breast cancer, Genentech completed additional clinical trials and submitted the data from those studies to the FDA. These data showed only a small effect on “progression-free survival” without evidence of an improvement in overall survival or a clinical benefit to patients sufficient to outweigh the risks. The small increase in “progression-free survival” reflects a small, temporary effect in slowing tumor growth.

Bevacizumab has also been associated with several other serious and potentially life-threatening side effects including the risk of stroke, wound healing complications, organ damage or failure; and the development of a neurological condition called reversible posterior leukoencephalopathy syndrome (RPLS), characterized by high blood pressure, headaches, confusion, seizures, and vision loss from swelling of the brain. On the basis of all available data relating to the use of bevacizumab to treat metastatic breast cancer, the agency has determined that the risks of the drug outweigh the benefits for this use.

FDA is open to working with Genentech on any proposals to conduct additional studies of bevacizumab in patients with metastatic breast cancer designed to identify a population of patients in which the drug’s benefits exceed the risks.

Also read:European Medicines Agency’s Review of Bevacizumab in Metastatic Breast Cancer Contradicts US FDA Assessment

[1] Ranieri G, Patruno R, Ruggieri E, Montemurro S, et al. Vascular Endothelial Growth Factor (VEGF) As a Target of Bevacizumab in Cancer: From the Biology to the Clinic. Curr Med Chem. 2006;13:1845-1857.

For more information:
FDA: Bevacizumab Information
NCI: Breast Cancer Full Prescribing information (US): Bevacizumab

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