June 30, 2011 — The answer is still no. After an unusual 2-day public hearing, the US Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee voted unanimously against bevacizumab (Avastin, Genentech/Roche) in breast cancer.
But the manufacturer, Genentech, is fighting against this decision and requested an appeal — which was heard over the past 2 days. The company changed its tactic somewhat — whereas the previous advisory meeting considered a broadening of the original breast cancer indication, the focus this time was to ensure that the original indication remain approved.
The outcome for the breast cancer indication was again no.
The process now continues, and public comments will be accepted until July 28. The matter will not be closed until there is a final decision from the FDA commissioner, Margaret Hamburg, MD. Currently, no date has been set for this.
Until that time, the drug remains FDA approved for the breast cancer indication (i.e., in combination with paclitaxel), which was granted in 2008 on the basis of 1 clinical trial under the accelerated approval process.
This use of bevacizumab with paclitaxel was recently included as a "preferred regimen for recurrent or metastatic breast cancer," in the updated National Comprehensive Cancer Network breast cancer guidelines.
This combination of bevacizumab and paclitaxel also remains approved in Europe; an extension to this — approved just yesterday — covers the use of bevacizumab in combination with capecitabine (Xeloda, Roche) for the first-line treatment of metastatic breast cancer.
Emotionally Charged Meeting
This latest meeting had a different feel than the usual advisory committee meeting, and attracted a huge amount of media interest in the United States. It was interesting to note that the drug was referred to by its trade name throughout the meeting, even when it was being discussed by FDA officials.
The beginning of the meeting was emotionally charged. Outside the building, there was a demonstration of breast cancer patients and families in pink t-shirts holding placards proclaiming: Avastin saves lives. Inside, the meeting began with heartfelt testimonies from women with breast cancer who credited the drug with keeping them alive. There were also testimonials from husbands whose wives had breast cancer, from physicians reporting on patients who responded to the drug, and from several patient advocacy groups, the majority of which were petitioning the FDA to allow bevacizumab to remain available for the treatment of breast cancer.
The rest of the meeting focused on clinical data, and drilled down into the details of benefit and risks over and over. No matter how the data were presented by Genentech, however, FDA officials and members of the advisory committee were not swayed.
Richard Pazdur, MD, director of the Office of Oncology Drugs at the FDA, said that the data now available on bevacizumab in breast cancer come from 5 randomized clinical trials with more than 3500 patients. No trial has demonstrated a significant improvement in overall survival or in quality of life, he noted. In addition, none of the subsequent studies has confirmed the magnitude of benefit seen in the original trial in this indication — the E2100 trial of bevacizumab plus paclitaxel, which resulted in accelerated approval in 2008.
The totality of the data show that the benefits seen with bevacizumab do not outweigh the serious risks of this drug, Dr. Pazdur explained. He noted that bevacizumab has been associated with intestinal perforation and hemorrhage and that 10% of patients in clinical trials have apparently experienced bevacizumab-related mortality.
At the conclusion of the 2-day hearing, the advisory committee voted unanimously against the indication. All 6 members of the committee, including the patient representative, agreed that:
the available evidence on bevacizumab "demonstrates that the drug has not been shown to be effective for the breast cancer indication for which it has been approved"
"the drug has not been shown to be safe for the breast cancer indication for which it was approved"
the drug "has not been shown to present a clinical benefit that justifies the risks associated with the use of the product for this indication"
the drug should not remain approved while Genentech designs and conducts additional studies to verify the drug's benefit.
Committee member Mikkael Sekeres, MD, MS, from the Department of Translational Hematology and Oncology Research at Cleveland Clinic in Ohio, commenting on this last issue, said that there was nothing in the clinical data that "would make me feel comfortable about continuing to expose a lot of patients to risk without a clear benefit."
"We have tried to slice the pie in various ways, looking for benefit, looking at data from subgroups, but there is nothing to hang our hat on in these studies," he said.
Wyndham Wilson, MD, PhD, head of the lymphoma therapeutics division at the National Cancer Institute, and also on the advisory committee, emphasized the adverse events reported in the clinical trials and cited the Hippocratic oath: "First, do not harm."
"Withdrawal is indicated," he argued. "To not do that you would have to have compelling evidence." The confirmatory clinical trials (RIBBON and AVADO) were "extremely well done . . . but they did not show any reasonable benefit, there was no clinically meaningful improvement in progression-free survival, and there was no evidence that the drug was of benefit."
Contrast Between Emotions and Data
Striking in its contrast were the highly emotional testimonials about the drug and the cold analytical dissection of the data.
Women who have benefited from the drug argued that bevacizumab should remain available, because although it might not work in all women, it does work in some; in fact, some respond very well. One of the patients testifying was first treated with bevacizumab in 2007; she said her "quality of life is nothing short of miraculous."
However, 2 of the patient advocates pointed out that testimonials come from women who benefited from the drug, whereas all the women who had not benefited or who had died were not at the meeting.
For every woman who has shown a great response to bevacizumab, and who has benefited with a life extension, there is at least 1 woman, if not 2, who has died sooner as a result of taking this drug, said Diane Zuckerman, PhD, president of the National Research Center for Women and Families, who supported the FDA's decision to rescind the approval.
History . . . is written by the winners.
The same point was made in a blog post on the hearing, written by Frederick Tucker, MD, from Fredricksburg Oncology, in Virginia, on the Citizen Oncologist Web site. "The testimonials we hear are only from those who do well, a self-selected population. History, it is said, is written by the winners."
Dr. Tucker highlighted a key issue behind the testimonials — the suggestion that there is a group of breast cancer patients who respond particularly well to bevacizumab, and that the drug should remain available to them.
The suggestion is that these "super responders" have tumors that are somehow biologically different, and respond more profoundly to bevacizumab, perhaps because of raised levels of vascular endothelial growth factor, the growth factor targeted by the drug, Dr. Tucker wrote. There have also been suggestions that the drug has a greater response in triple-negative tumors and in patients with a BRCA mutation.
"But as yet there are no facts to support this," Dr. Tucker pointed out. "The Center for Drug Evaluation and Research was asked specifically if they thought there were subgroups that did respond well to [bevacizumab]. Their answer was a succinct no. There was nothing in the data accumulated in the 5 trials to suggest that one group of patients might do better with the drug than another."
The contrast between emotions and data was highlighted by Len Lichtenfield, MD, deputy chief medical officer for the American Cancer Society, who was blogging and tweeting live from the meeting. "Clearly we are in a place where emotion meets science, and the FDA's decision will prove to be a difficult one," he noted.
After the vote — unanimously in favor of withdrawing the breast cancer indication — there were protests from survivors, with women loudly voicing their disagreement; one said that this shouldn't be happening in the United States of America. "I could not sit there and hear the cries without feeling their pain and anguish," Dr. Lichtenfield wrote.
"The anxiety of breast cancer patients currently using [bevacizumab] is palpable and understandable," Dr. Tucker acknowledged. "The data say that they will do just as well without it, but to ask them to give up the drug is to ask them to make a leap of faith that I doubt I would be willing to make."
Oncologists in the United States have been struggling with this issue for nearly a year now, and have been reviewing other treatment options for metastatic breast cancer. This struggle will intensify when the final FDA decision is announced because withdrawal of the breast cancer indication will make it difficult for these patients to continue to use the drug.
Because bevacizumab is approved for use in other cancers, it could be used off-label for breast cancer, but would likely no longer be covered by medical insurance, so patients would have to pay out of pocket. At a cost of $8000 a month, few would be able to afford it.
An estimated 17,000 women in the United States are thought to be taking bevacizumab for breast cancer.
At the hearing, Dr. Zuckerman proposed a solution: "I would ask that Genentech continue its research into identifying the women who do benefit from bevacizumab . . . but as the company has already made so much money from the drug, I would ask that the company make the drug available for free to the women who are on it and are benefiting from it."
Bevacizumab is the best-selling anticancer drug in history, with annual sales of around $6 billion, around $1 billion of which is from the breast cancer indication.
Medscape Medical News © 2011 WebMD, LLC
Send comments and news tips to firstname.lastname@example.org.
Cite this: Avastin for Breast Cancer: FDA Answer Is Still No - Medscape - Jun 30, 2011.