FDA Decides Against Bevacizumab for Breast Cancer, Europe Differs

Zosia Chustecka

December 16, 2010

December 16, 2010 — The US Food and Drug Administration (FDA) has announced that it will take the first steps to remove the indication for bevacizumab (Avastin; Genentech/Roche) in metastatic breast cancer.

The decision was announced in a press briefing today. Janet Woodcock, MD, director of the Center for Drug Evaluation and Research, told journalists that this was a "difficult decision."

This will not have an immediate effect on physicians or patients, FDA officials commented. The indication has not yet been withdrawn — this is only the first step in a process, and so there will be time for to physicians and patients to discuss and consider other treatment options, they said.

The decision is based on the totality of data, including 3 trials in first-line treatment of metastatic breast cancer — E2100, Avado, and Ribbon-1 — as well as the EVF 2119 trial for second-line treatment in this setting. The FDA concluded that patients treated with bevacizumab did not live any longer than patients who were not taking it, Dr. Woodcock said. But they were at greater risk for adverse effects, including adverse effects that are unique to bevacizumab, such as perforations, which can be life-threatening.

Other serious and potentially life-threatening adverse effects include the risk for stroke, wound healing complications, and organ damage or failure. The drug has also been linked with the neurological condition reversible posterior leukoencephalopathy syndrome, which is characterized by high blood pressure, headaches, confusion, seizures, and vision loss from swelling of the brain, she noted.


Earlier this year, the FDA's Oncologic Drugs Advisory Committee voted 12 to 1 to remove the indication, given the drug's risks vs its benefit, she said.

Dr. Woodcock repeated several times that there was no improvement in overall survival with bevacizumab in any of the 4 trials that were considered. "The drug did not prolong life in patients with metastatic breast cancer, and yet it added to the risk of serious adverse effects, that's the bottom line," she said.

She also emphasized that the FDA did not consider cost when making this decision.

The FDA's sister agency, the Centers for Medicare and Medicaid Services, has not made any changes to its reimbursement policy as yet, and is waiting for the resolution of this process before it makes any moves.

The FDA is working with the manufacturer, Genentech/Roche, to try to identify a group of patients who may respond particularly well to the drug, Dr. Woodcock added.

Richard Pazdur, MD, director of the Office of Oncology Drug Products, who oversaw the original accelerated approval for this indication, said the decision was a disappointment. But he emphasized that on consideration of all the data, the agency decided that risks outweigh benefits for this indication.

Denise Esposito, JD, deputy director of the Office of Regulatory Policy, emphasized that today's announcement is not a withdrawal of the indication, but marks the beginning of a process that may take some time. The manufacturer can request a hearing and present new data, and Genentech has issued a statement to say that it will in fact request a hearing with the FDA. That process could take up to the end of January, but there may be other steps after that, depending on the outcome of the hearing.

European Decision

Also today, the European Medicines Agency (EMA) announced its decision on the same issue.

In contrast to the US decision, the EMA announced that the approved indication for bevacizumab in metastatic breast cancer remains in Europe, but only for use in combination with paclitaxel (as it was in the original study, the E2100 trial, that led to the original approval.)

Other combinations, such as with docetaxel or capecitabine, are not approved. These combinations were tested in the Avado and Ribbon-1 trials, and they showed much less benefit. In fact, some of these new data "add uncertainty about the effect on overall survival and a detrimental effect on overall survival cannot be excluded," the EMA said.

However, for the combination of bevacizumab and paclitaxel that remains approved, the benefits continue to outweigh the risks, the agency said. "The available data have convincingly shown to prolong progression-free survival of breast cancer patients without negative effect on the overall survival."

This contrasts with the view of the FDA, and several journalists at the briefing asked why different conclusions were drawn by the 2 agencies on the basis of the same data. Dr. Pazdur said the FDA can only explain its own decision and cannot comment on action taken by the EMA.

Frenzy of Activity as Decision Loomed

The days building up to the much anticipated decision saw a frenzy of activity, with commentators, politicians, and patients warning of dire consequences if the decision was negative.

Much of the focus has been on the high price of the drug, with commentators warning that a decision to rescind the approval will be a sign of rationing of healthcare in the United States.

The decision will set a standard and will be a "major test of the credibility of the promises the Obama administration has made about the future of Medicare under health reform," writes Sally Pipes on an investors Web site.

It is a "life or death" decision for many breast cancer patients, warned an op-ed piece on the Washington Examiner Web site.

Five Congressmen had written to the FDA commissioner to express "serious concerns" about the decision, which they view as a "large-scale intrusion into Americans' lives and their personal health care decisions that have previously been left up to a patient and their health care provider."

"We fail to see why this Administration would want to remove a viable treatment option that has the support of thousands of doctors and patients around the country. Limiting access to this treatment is unthinkable and we are struggling to see any justification other than cost," the Congressmen wrote.

The letter was highlighted on a political Web site, which also carried the headline: "Countdown to Death Panels for Breast Cancer Drug Avastin."

A petition to the FDA from breast cancer patients and concerned supporters had gathered nearly 9500 signatures and urged the agency to allow the drug to remain approved. The petition is headed by Christi Turnage, a 4-year triple-negative breast cancer survivor who has been metastatic for more than 2 years and was highlighted in a YouTube video by her 19-year-old son. Both garnered considered press coverage, including television exposure.

Insurance Denied

One of the main concerns over the decision has been the likely subsequent loss of medical insurance coverage for the use of bevacizumab in the treatment of metastatic breast cancer. Now that this treatment is no longer approved, using bevacizumab for metastatic breast cancer becomes an "off-label" use, and insurance companies can choose whether or not to cover it — and the prediction is that they won't.

In fact, even before the decision was announced, several medical insurance companies had already changed their policy regarding bevacizumab in breast cancer.

These included Regence Blue Shield, the largest regional plan in the Pacific Northwest, which recently published a new policy that listed use of bevacizumab in breast cancer as "medically unnecessary."

Indication Denied in Britain

Last week, the indication of bevacizumab in metastatic breast cancer was denied coverage by the National Health Service in England and Wales by the National Institute for Health and Clinical Excellence (NICE).

In this indication, the drug offers "limited and uncertain benefit" for patients and does not lead to any significant extension of life, according to a press report.

Sir Andrew Dillon, chief executive of NICE, said, "We know that it's immensely important for breast cancer patients whose disease has spread to prolong their lives as much as possible. Unfortunately, we did not receive any evidence from the manufacturer to show that bevacizumab can significantly lengthen a patient's life or, importantly, offer a better quality of life than existing treatments.

"Although the data seemed to show that the drug may slow the growth and spread of the cancer, the size of this effect varied between studies," Dillon pointed out. "Furthermore, it was extremely unclear that the benefits in terms of slowing tumor growth translated into benefits on overall survival, which is what really matters for patients."


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