FDA Plans to Remove Breast Cancer Indication from Bevacizumab's Label

The FDA has taken the first steps toward removing the metastatic breast cancer indication from the label of the cancer drug bevacizumab, which is marketed as Avastin, after data from four clinical studies indicated that the medication, when used as indicated with the chemotherapeutic agent paclitaxel, does not prolong overall survival in breast cancer patients.

The agency also said bevacizumab does not slow progression of the disease sufficiently to outweigh the significant health risks posed by the drug's side effects.

Janet Woodcock, M.D., director of the FDA's Center for Drug Evaluation and Research, said during a Dec. 16 news conference (35-page PDF; About PDFs) that the drug carries severe risks, including high blood pressure, severe bleeding and hemorrhage, the development of perforations in the body -- including in the nose, stomach and intestines -- and heart attack or heart failure.

"FDA understands that some serious risks from cancer drugs are acceptable to cancer patients as long as (the drugs) are effective at prolonging life and improving quality of life," Woodcock said. "While FDA is willing to approve a relatively toxic cancer drug, we do so only if we believe the benefits to patients outweigh the severity of the drug's side effects."

Woodcock said bevacizumab also has been associated with an increased risk of stroke; wound healing complications, including dehiscence of surgical wounds; organ damage or failure; and the development of reversible posterior leukoencephalopathy syndrome, which is characterized by hypertension, headaches, confusion, seizures and vision loss resulting from swelling of the brain.

The drug, however, is not being removed from the market, and Richard Pazdur, M.D., director of the FDA's Office of Oncology Drug Products, emphasized during the news conference that the regulatory action does not affect bevacizumab's indications for lung, brain, kidney or colorectal cancers.

The FDA's action also has no immediate effect on bevacizumab's use in treating breast cancer. According to Woodcock, physicians treating patients with bevacizumab in combination with chemotherapy for metastatic breast cancer should use their medical judgment when deciding whether to continue treatment with the drug or explore other options.

She also noted that CMS is not changing its reimbursement policies related to the drug at this time and will await the outcome of the FDA's action.

The FDA initially informed Genentech Inc. of its proposal to withdraw marketing approval of the drug for the breast cancer indication in a letter dated Dec. 16. After the manufacturer declined to remove the breast cancer indication voluntarily, the FDA issued a Notice of Opportunity for a Hearing.

Genentech, which is a member of the Basel, Switzerland-based Roche Group, said in a Dec. 16 news release that it will request a hearing within the 15-day period allotted for this process.

Genentech emphasized in its release that the European Medicines Agency, or EMA, also recently reviewed data related to bevacizumab and came to a different conclusion. The EMA said in a Dec. 16 news release that it found 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."

Bevacizumab was first approved by the FDA in 2004 in combination with IV 5-fluorouracil as a first-line treatment for patients with metastatic colorectal cancer.

In December 2007, the agency's Oncologic Drugs Advisory Committee recommended against approval of the drug in combination with paclitaxel for the first-line treatment of HER2-negative metastatic breast cancer. However, the FDA granted accelerated approval in February 2008 based on data from one randomized, controlled study that indicated patients who received bevacizumab plus paclitaxel experienced an additional progression-free survival period of more than five months compared with women treated with paclitaxel alone.

However, studies conducted after that approval indicated the drug had only a small effect on delaying the growth of cancer and no evidence of improvement in overall survival, the FDA said.

In July, the agency's advisory committee recommended 12-1 that the FDA remove the breast cancer indication from the drug's label.

Pazdur said the FDA remains willing to review data from additional studies Genentech may conduct to identify a subpopulation of patients in which the drug's benefits exceed its risks.