FDA's Hamburg to make final decision on Avastin's indication for metastatic breast cancer

In the face of dozens of pink-clad demonstrators at the gates of FDA and many heartfelt pleas from women with metastatic breast cancer, an advisory committee to the agency voted unanimously at the end of June to hold firm in its recommendation that approval for Avastin (bevacizumab, Genentech/Roche) for breast cancer be withdrawn.

FDA head Margaret Hamburg is supposed to make a final decision at a later date.

Avastin will remain on the market, either way. It is also approved for advanced lung, colon, kidney, and brain (glioblastoma) cancers. But breast-cancer patients and doctors at the meeting cited fears that if the approval for breast cancer were withdrawn, payers will no longer cover that treatment. Avastin is said to cost $50,000 to $100,000 per year. Medicare has said it will continue coverage.

At issue at the meeting was the use of Avastin in combination with paclitaxel for patients who have not received chemotherapy for metastatic HER2 negative breast cancer.

The 2-day meeting and vote of the Oncologic Drugs Advisory Committee (ODAC) were held in response to the appeal made by Genentech, the drug’s sponsor, of the committee’s recommendation last year that approval be withdrawn.

At the opening session, about 30 women with breast cancer make individual statements pleading for continued approval, saying, often through tears, that Avastin had given them years of life and a chance to see graduations, weddings, and other life-cycle landmarks.

In light of the fact that some women seem to be doing well on the drug, one question that some patients and their physicians raised was whether there might be people who are “super-responders,” despite what the statistics show.

Patricia Keegan, MD, director of FDA’s Center for Drug Evaluation and Research (CDER), Division of Biologic Oncology Products, said, “I think the best we can say about the super-responders is that if you look at the controlled clinical trials, we’re not seeing a group that looks like this.”

The issue is made even more difficult by the fact that the European Medicines Agency, Europe’s counterpart to FDA, and the prestigious National Comprehensive Cancer Network have continued to recommend Avastin for breast cancer.

In sessions that sounded like legal proceedings, in which each side asked hard, detailed questions of the other, Genentech not only disagreed with FDA’s findings but accused the agency of changing the specifications by which the studies would be considered to show benefit.

Among other things, the process unfoldilng with the advisory committee will serve to illustrate difficult issues embedded in the accelerated approval process. In February 2008, FDA granted accelerated approval for Avastin’s use in treating metastatic breast cancer, based in great part on a National Cancer Institute-supported study that found no overall survival benefit from using Avastin in combination with paclitaxel. It did show, however, an estimated 5.5 months’ improvement in median progression-free survival. It also showed increased toxicity and toxic death, according to FDA.

In December 2007, ODAC voted 5 to 4 that the data were not sufficient for a favorable risk/benefit decision for use of the drug with paclitaxel for first-line treatment for patients with metastatic breast cancer. Nevertheless, FDA granted accelerated approval 2 months later.

But 2 studies presented since that time, meant to confirm a benefit for Avastin use, did not do so, according to FDA. In light of their conclusions, FDA’s CDER changed its thinking.

John Jenkins, MD, director of the CDER Office of New Drugs, said, “When we approved Avastin for breast cancer, we understood that the indication would be subject to the accelerated withdrawal procedures if clinical benefit was not confirmed. Accelerated withdrawal is a fundamental part of the accelerated approval pathway and serves as backstop to protect the public from continued marketing of the drug if clinical benefit is not confirmed.”

The advisory committee agreed, stating for the second time that the risk/benefit ratio had shifted against the drug’s use for the indication.

As the committee members voted, a row of breast-cancer survivors stood up in the audience, facing the committee, silently at first. Then they began to protest, shouting that they had no alternative and that Avastin had given them time.