Physicians, Patients React to FDA Committee Vote against Bevacizumab in Breast Cancer

Bevacizumab (Avastin, Genentech) has been a popular first-line treatment for metastatic breast cancer since 2008, when the US Food and Drug Administration (FDA) granted special, fast-track approval for use in combination with paclitaxel. The accelerated approval was based on positive early findings from the E2100 trial, which showed that the addition of bevacizumab added 5.5 months of progression-free survival (PFS) over paclitaxel alone. But two additional trials—AVADO and RIBBON 1—failed to confirm this magnitude of benefit, and on July 21, 2010, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 12 to 1 to withdraw approval for the advanced breast cancer indication.

Should the FDA accept the panel’s recommendation on September 17, one oncologist who will mourn the loss of bevacizumab is Steven Vogl, MD, of Bronx, New York.

“I give the majority of my advanced breast cancer patients bevacizumab with a taxane, usually weekly paclitaxel, and my experience has tended to be more like that in E2100,” he said, referring to a high likelihood of response and durable remissions.

Vogl said without third-party coverage for the drug, essentially all his patients will have to do without it. “The cost is unconscionable,” he maintained. “Today, two of my patients spent hours while getting chemotherapy discussing how they might get Avastin if the FDA changes the label. They are very worried.”

One of these women is Lori Baur of Sleepy Hollow, New York. Vogl prescribed bevacizumab in March 2009 after a second primary (triple-negative) breast cancer spread to the liver, lungs, and brain. The drug has produced substantial tumor shrinkage. “The tumors in my brain are no longer visible. From research I’ve done, it seems that Avastin can penetrate the brain, while other agents I have taken cannot,” she said in an interview with The Oncology Nurse. She believes bevacizumab may be particularly helpful in triple-negative tumors, judging from her own response and that of other triple-negative patients she has heard from. “Maybe coverage could be determined on a case-by-case basis,” Baur suggested.

“I’m just 41 years old and I have an aggressive cancer that I am afraid will rebound if I go off Avastin. I want to be around a while longer, and this is frightening,” she said. “I don’t think the FDA should take this drug away from patients who are responding to it. In my case, at the pace it’s helping, Avastin has been almost a miracle drug.”

Elizabeth Thompson, senior vice president of medical and scientific affairs for Susan G. Komen for the Cure, has a similar point of view. “We are reviewing the recommendation of the advisory panel before deciding whether we will take a position before the FDA,” she said. “But we do hope that those women who are currently being treated with Avastin for breast cancer will continue to have access to it and that third- party payers continue to fund the use of this drug for women who are being treated with it.”

Some see it differently

Unfortunately, robust responders such as Baur may be the exception, according to the ODAC, which emphasized the lack of a survival benefit and undue toxicity in making its recommendation. Not all patients are disagreeing with the panel.

“I’m really not seeing that this has a benefit for patients,” Natalie Compagni Portis, the patient representative on the committee, said during the meeting in Gaithersburg, Maryland. “Hope is very important, but to offer hope that isn’t substantiated I don’t think is responsible.”

Patients want beneficial options only

Musa Mayer, of New York, a breast cancer survivor, patient advocate, and creator of AdvancedBC.org, has been following more than 1000 women living with metastatic breast cancer through her blog, BCMets.org, and has found reaction to the ODAC recommendation to be mixed. “It depends on the patient’s personal experience with the drug—its activity and toxicity, and of course, there’s the issue of cost,” she said. Due to the lack of a survival benefit, many women have not been persuaded that bevacizumab is a good option for them, she said, especially considering the potential for serious toxicity.

These responses show “that patients do not necessarily argue for more options, but for more beneficial options—drugs that are better than what we have now or at least provide a unique benefit,” she claimed. Although prolongation of PFS is important, she agreed with the ODAC that it is only meaningful when it is lengthy and does not impair quality of life, and this is not the case for many patients. “Avastin is not a benign drug, so it better provide real benefit, and there is no good evidence of that.”

She acknowledged that some patients do have robust and durable responses to treatment with bevacizumab, but these patients need to be identified prior to treatment. Patient advocates have been “pressing hard,” she said, on Genentech to mine the data for clues, which may lie in the presence of particular mutations of the vascular endothelial growth factor, some scientists believe. “We are hoping that Genentech will take this as an incentive to start looking more urgently at who responds. It may turn out to be a good drug for a subset but we don’t know that, and it should not be on the market until we do,” she said.

The hope is that a search for relevant markers and diagnostics will become part of drug development. Streamlined testing and targeted treatment is not only the ideal, but has become the only approach that makes sense, according to Mayer, who is calling for drugs to “no longer be introduced in a mass way, but in a more selective way.”

Views are changing

Oncologists can expect patients to respond as individuals, and patient advocacy groups to hold various points of view on the committee recommendations, reminded Eric P. Winer, MD, Director of the Breast Oncology Center at Dana-Farber Cancer Institute, Boston. “The advocacy community is broad and heterogeneous. Some feel strongly that only drugs that lead to substantial improvement in survival need to be approved but others accept more modest benefits. You can’t generalize.”

But he acknowledged that thinking has been shifting toward a more conservative stance on new agents. “I think we are in a slightly different time when it comes to patients’ perceptions of cancer treatments,” he told The Oncology Nurse. “My sense for several years has been that patients are less interested in drugs that offer very marginal improvements, whether for themselves or for women in general. There was a time when patients would say, ‘I want to do absolutely everything I can, even if the benefit is tiny.’ Now, patients have a better understanding of what it all means, and they are evaluating their choices in a different way.”