BEVACIZUMAB IS LOOSING THE INDICATION FOR BREAST CANCER

July 21, 2010 ( UPDATED July 22, 2010 ) — The benefits of using bevacizumab (Avastin, Genentech) for breast cancer were questioned yesterday at a meeting of the US Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee, which voted nearly unanimously (12 to 1) to remove this licensed indication from the product's labeling.

Bevacizumab is licensed for use in several cancer types, so the drug is not threatened with removal from the market. And even if the approval for breast cancer is rescinded, the drug can still be used off-label, although there would be problems with coverage from medical insurance companies.

However, losing the breast cancer indication — if the FDA decides to follow the advice of its committee — is expected to lead to a substantial decrease in its use, and analysts estimate that it could lead to a loss of $1 billion from its $6 billion annual sales.

The FDA is expected to make its decision on September 17, 2010.

One breast cancer expert contacted by Medscape Medical News said she was surprised by the FDA advisory committee vote, because she considered bevacizumab to be "one of the options typically discussed with all patients with metastatic breast cancer."

Considered New Clinical Trial Data

The advisory committee considered new clinical data that had been collected by the manufacturer, Genentech, as a condition of the accelerated approval for bevacizumab in metastatic breast cancer that was granted in 2008.

That decision was considered controversial at the time, as reported by Medscape Medical News, because it was based on an improvement in progression-free survival in 1 clinical trial (the E2100 study), and the FDA advisory committee considering those data voted 5 to 4 against recommending approval.

Since then, 2 other trials have been conducted — AVADO and RIBBON-1. Both have shown a statistically significant improvement in progression-free survival, although of a much smaller magnitude than was seen in the E2100 study.

Summing up the data at yesterday's meeting, the chair of the committee, Wyndham Wilson, MD, from the National Cancer Institute, said that the improvement in progression-free survival is "a scientifically valid finding."

"But is this clinically meaningful for patients?" he asked.

There is no evidence of improvement in overall survival with bevacizumab, he noted. In contrast, other drugs that have been approved for first-line use in metastatic breast cancer have shown a survival advantage, including one from the same manufacturer, trastuzumab (Herceptin, Genentech/Roche).

In addition, "we have to take into account risks, and there are definite risks," Dr. Wilson said. He pointed out that some of the adverse effects of bevacizumab are life-threatening and that some people have died, and he reminded the committee members of the Hippocratic Oath: First do no harm.

Nearly All Votes Were No

The advisory committee voted on several questions and each time were in agreement, unanimously (13 to 0) or very nearly so (12 to 1), in their votes against bevacizumab.

They concluded that the addition of bevacizumab to chemotherapy does not represent a favorable risk/benefit scenario in the initial treatment of metastatic breast cancer.

It was the word "initial" that tipped the voting for one committee member, who said that he would like to see bevacizumab remain available as an option for use in breast cancer, but not as a first-line option.

The decision against bevacizumab was made on the basis of the 2 new studies.

In the AVADO trial, bevacizumab was added to docetaxel; the results show that it improved median progression-free survival by 0.8 months at the lower dose used (7.5 mg/kg) and by 0.88 months at the higher dose used (15 mg/kg).

In the RIBBON-1 study, bevacizumab was added to anthracycline/taxane regimens, where it improved the median progression-free survival by 1.2 months, or to capecitabine, where it improved median progression-free survival by 2.9 months.

In all of these cases, the improvement in progression-free survival was much smaller than in the E2100 trial, where bevacizumab added to paclitaxel nearly doubled median progression-free survival, from 5.8 months with paclitaxel alone to 11.3 months with the combination.

There was no statistically significant improvement in overall survival in any of the 3 trials.

One committee member who voted for accelerated approval in 2008 said that the data from E2100 — a doubling of progression-free survival and a more than doubling of the response rate — had impressed her, especially because the results came from a trial that reflected community practice. But the new data from the manufacturer-sponsored trials, which would be expected to show better results, are "very disappointing," she said. Although she had argued vociferously for bevacizumab last time around, in light of the data that have since become available, she said that "now it's really hard to see how there can be an approval for this indication."

Another committee member, Jean Grem, MD, FACP, from the University of Nebraska Medical Center in Omaha, wondered if the FDA "made a mistake" in issuing the accelerated approval in 2008. FDA officials were quick to counter that it was not a mistake — it was a decision that was warranted because of the data that were available at that time, and there are "more comprehensive data available now."

Dr. Wilson agreed, and said that the current discussions "show that the system is working." The accelerated approval was granted on the condition that more trials would be conducted, and these are now being reviewed, he pointed out.

Mikkael Sekeres, MD, MS, from the Cleveland Clinic Taussig Cancer Institute in Ohio, argued that bevacizumab failed to demonstrate a clinically meaningful benefit, and said that "an improvement in progression-free survival of 1 month is a Pyrrhic victory at best."

The patient representative on the committee, Natalie Compagni Portis, said there were not enough positives from bevacizumab; she was not convinced of benefit and was concerned about toxicity. She acknowledged that giving patients hope is important, but "to offer hope that is not substantiated is not responsible."

Genentech issued a statement saying that it was "disappointed with the committee's recommendation." The company believes the drug "should continue to be an option for women with this incurable disease," and will continue to discuss the data from clinical trials with the FDA.

This decision does not affect the approved uses of bevacizumab in other cancer types, the company noted. The drug is approved for use in colorectal cancer, nonsmall-cell lung cancer, and renal cell carcinoma. It has also received accelerated approval for use in glioblastoma multiforme, but this has also been controversial, as previously reported by Medscape Medical News.

Since its initial approval in 2004, the package insert for bevacizumab has been updated several times, with safety information being added about arterial thromboembolic events (in 2004), gastrointestinal perforation (in 2006), reversible posterior leukoencephalopathy syndrome and nasal septum perforation (in 2006), and nongastrointestinal fistula formation (in 2007).

One issue that was not really touched upon during the advisory committee meeting was that of cost, but the high cost of bevacizumab is of great concern among oncologists. In a recent essay, the total cost of therapy with bevacizumab for metastatic breast cancer was estimated to be $90,816, as reported by Medscape Medical News, and the authors and other experts question such high costs for drugs that offer minimal or nonexistent survival benefit. However, Genentech has taken issue with this figure, and told Medscape Medical News that it has limited the annual cost of bevacizumab to approximately $57,000.

Reaction From Breast Cancer Expert

Asked for her reaction to the news from the advisory meeting, Edith Perez, MD, professor of medicine and deputy director of the Mayo Clinic Cancer Center in Jacksonville, Florida, said she was surprised that the committee had voted to revoke the approval for bevacizumab in breast cancer.

"I was surprised, as all 3 studies reviewed had statistical improvements in the response rate and progression-free survival (albeit not survival differences), with what we felt were acceptable potential for side effects in the context of advanced breast cancer," she told Medscape Medical News.

The finding of no impact on overall survival is a "tough issue," she added. "Survival is a critically important issue and we would like all our treatments to improve survival, but we know that is not the case for most agents, in breast cancer and in other diseases."

"In terms of patients care, I think that objective response and progression-free survival are very important — especially if not accompanied by serious adverse events," she added.

The results from the AVADO and RIBBON-1 trials have been known for many months, Dr. Perez pointed out, adding: "Our practice has continued in terms of considering this agent as one of the options for patient treatment — in practice for patients with advanced disease and in the context of clinical trials for patients with resected early-stage breast cancer."

Because the magnitude of improvement in progression-free survival was different in the 3 trials, each of which used a different backbone of chemotherapy, one option that the FDA could consider is to make a decision based on the results of each separate study, rather than an aggregate of the 3 trials, Dr. Perez said.

There are 2 more trials in progress; results have yet to be announced, she noted.

"I also think that we need to continue our work to better identify individual patients who may benefit from antiangiogenesis or other specific treatments," Dr. Perez said. "Individualized treatment options are becoming more of a reality, so one treatment might be more effective than others for certain patients."

Dr. Perez reports serving on steering committees for Bayer HealthCare and Genentech, and on an independent monitoring committee for Novartis.