ODAC Upholds Vote to Revoke Avastin's Breast Cancer Indication

After 2 days of emotional pleas from patients and a wealth of clinical data from scientists, an FDA advisory committee unanimously recommended Wednesday that the agency withdraw the breast cancer indication for Avastin.

In doing so, the Oncology Drugs Advisory Committee (ODAC) members voted 6-0 to uphold the panel’s controversial finding nearly a year ago that the world’s best-selling cancer drug posed a greater risk of harming breast cancer patients than benefiting them.

Genentech, whose appeal of last year’s ruling set the stage for this week’s hearing, contended that a subset of patients benefit from Avastin and that the drug should remain on the market while further studies are conducted.

The matter will now go to FDA Commissioner Margaret A. Hamburg, MD, who will make the final decision after the posthearing comment period ends July 28.

Until Hamburg makes her decision, Avastin remains an approved use for the treatment of HER2-negative metastatic breast cancer in combination with paclitaxel, according to Genentech. The outcome will not affect the drug’s other approved indications for metastatic colorectal cancer, non—small cell lung cancer, glioblastoma, and metastatic kidney cancer.

Nevertheless, the vote Wednesday is a blow to Genentech, a member of the Roche Group, which reportedly realized $7 billion in annual sales of the drug.

The FDA had granted Avastin an accelerated approval for metastatic breast cancer in 2009 based on the promising results of a single trial that showed a significant benefit in progression-free survival (PFS).

However, subsequent trials that evaluated Avastin in combination with other chemotherapeutic agents failed to confirm the original PFS results and showed no improvement in overall survival in patients receiving Avastin.

In this week’s hearing, the ODAC panel focused on 3 pivotal questions that would ultimately determine Avastin’s fate.

The first 2 questions dealt with whether the subsequent Avastin trials had produced compelling evidence to support the clinical benefit of Avastin for the breast cancer indication for which the drug received accelerated approval.

In the discussion sessions that preceded the vote, several panel members indicated that the AVADO and RIBBON1 studies, while well-executed, failed to confirm any clinical benefit of Avastin in women with breast cancer, and more importantly, most agreed that the drug has not demonstrated a clinical benefit that justifies the risks associated with its use.

“We can’t tolerate a 13% increase in toxicities,” said ODAC panel member Mikkael A. Sekeres, MD, MS, associate professor of medicine and director of the Leukemia Program at Cleveland Clinic’s Taussig Cancer Center in Ohio. Other panelists concurred, indicating that the evidence demonstrates a high risk to patients without any clinical benefit.

Serious adverse events include severe high blood pressure, hemorrhaging, heart attack or heart failure, and the development of perforations, including in the nose, stomach, and intestines, according to the National Center for Biotechnology Information.

ODAC members voted unanimously in response to the first 2 questions that the data failed to verify the clinical benefit that justifies the risk of Avastin in women with breast cancer.

Nevertheless, the third and most difficult question, according to one panelist, dealt with whether the FDA should continue the approval of the breast cancer indication while the sponsor conducts additional studies intended to verify Avastin’s clinical benefit. This question generated the most discussion between the panelists, Genentech, and members from the FDA Center for Drug Evaluation and Research (CDER) in the audience.

An industry representative and nonvoting member of the ODAC panel, Gregory Curt, MD, the US medical science lead of emerging products at AstraZeneca Oncology in Garrett Park, Maryland, asked how CDER would feel about continuing the breast cancer indication if the sponsor was able to identify a subset of patients that may benefit from therapy for additional study.

The deputy director of the division of biologic oncology products at CDER, Patricia Keegan, MD, said that CDER prefers to make decisions on a subgroup analysis based on data and that no data exist to indicate that a specific group of patients would respond differently.

In the end, the panelists voted against continuing the approval of the breast cancer indication. Despite its decision to revoke the approval, the panel encouraged Genentech to conduct additional studies to prove a clinical benefit for Avastin in these patients.

Ultimately, the panelists felt that the FDA should have the authority to reverse its decision in light of new data. Brent Logan, PhD, associate professor of biostatistics at the Medical College of Wisconsin in Milwaukee, summed it up by explaining, “The accelerated approval process should not indicate a change in the approval standard.”