Genentech will have a hearing with the FDA, and EMA’s conclusions are under EC review.

As most have expected given all the evidence and increased regulatory vigilance of marketed drugs, both the FDA and EMA have issued statements on removing breast cancer from Avastin’s label. FDA says that the drug has not been shown to be safe and effective for this disease, calling for it to be pulled from the market for breast cancer treatment with any chemotherapy.

EMA made a slightly less harsh recommendation to the European Commission that, to treat breast cancer, Avastin should only be used in combination with paclitaxel and not with docetaxel. Both agencies also made recommendations against Avastin NDAs looking to expand its use into more breast cancer settings along with additional chemotherapies.

Roche, which commercializes the drug, reported $6 billion in 2009 sales, accounting for 12.7% of last year’s total revenues. If FDA and EMA’s findings do get the medication off the market for breast cancer, the firm could lose about $1 billion.

Avastin was granted provisional approval by the FDA as a treatment for Her2-negative breast cancer in combination with paclitaxel in February 2008. Genentech, which is owned by Roche and manufactures Avastin, has not agreed to remove breast cancer from Avastin’s label voluntarily, so the FDA has issued a Notice of Opportunity for a Hearing.

Genentech says that it will indeed request a hearing. Until the conclusion of these proceedings, Avastin remains FDA-approved for use in combination with paclitaxel for metastatic Her2-negative breast cancer.

FDA cautions oncologists treating patients with Avastin for metastatic breast cancer to use their medical judgment when deciding whether a patient should continue treatment with the drug or consider other therapeutic options.

“After careful review of the clinical data, we are recommending that the breast cancer indication for Avastin 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 Avastin lived longer, and patients receiving Avastin experienced a significant increase in serious side effects.”

These risks include severe high blood pressure; bleeding and hemorrhage; the development of perforations in the body including in the nose, stomach, and intestines; stroke, heart attack, or heart failure; organ damage or failure; and the development of a neurological condition called reversible posterior leukoencephalopathy syndrome (RPLS), FDA reports. RPLS is characterized by high blood pressure, headaches, confusion, seizures, and vision loss from swelling of the brain.

Dr. Woodcock calls the recent conclusions disappointing and encourages the company to conduct additional research to identify if there may be select groups of patients who might benefit from this drug.

The EMA Committee for Medicinal Products for Human Use (CHMP), on the other hand, concluded that the benefits of Avastin in combination with paclitaxel outweigh the risks. It stated that the available data have convincingly shown that the drug prolongs progression-free survival without a negative effect on the overall survival.

EMA’s investigation of Avastin breast cancer began after data from a study suggested that Avastin in combination with docetaxel may have a negative impact on overall survival of breast cancer patients. The study was submitted to the agency to support an application to extend Avastin’s breast cancer indication to include combination therapy with capecitabine.

Combination therapy of Avastin and docetaxel for metastatic breast cancer was approved in September 2009 and now stands to be revoked. For Avastin in combination with capecitabine, the committee found that although the data showed a modest increase in progression-free survival, no clinically relevant effects were observed on other endpoints such as overall survival or health-related quality of life.

Therefore the committee concluded that the new indication should not be approved.

FDA also issued complete responses on applications for the first-line use of Avastin in combination with other chemotherapies in metastatic breast cancer as well as for the second-line use of Avastin plus chemotherapy in metastatic breast cancer.

Avastin’s potential to be used in multiple cancer settings was touted as being a big part of why Roche doled out $46.8 billion to take full control of Genentech, which discovered the drug. Since the acquisition, Avastin has failed in hormone-refractory prostate cancer and advanced stomach cancer late-stage trials. Roche has managed to add brain and kidney cancers to the label, which already included colorectal and lung cancers as well as the provisional breast cancer indication.

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