US FDA commissioner's hammer falls on Avastin; breast cancer use revoked
This article was originally published in SRA
US Food and Drug Administration commissioner Margaret Hamburg has rescinded the agency's approval for Genentech's Avastin (bevacizumab) as a treatment for HER2-negative metastatic breast cancer (MBC), after deciding that follow-up studies had failed to show that the drug is a safe and effective therapy for the disease1.
Dr Hamburg's decision follows the vote by a first-of-its-kind FDA advisory committee hearing in June to withdraw the MBC indication from Avastin's labelling because of the poor results from the follow-up trials2. Genentech had requested the hearing after an FDA assessment of the follow-up findings resulted in the agency recommending in December 2010 that the MBC labelling be removed.
The follow-up studies had been carried out by Genentech to meet the requirements of the FDA's accelerated approval pathway, under which the breast cancer indication was approved. This pathway enables drugs to be marketed for life-threatening conditions for which there is an unmet medical need as long as confirmatory studies verify that a medicine truly is effective for the intended use. Genentech's follow-up studies, however, failed to demonstrate that Avastin prolonged overall survival in MBC and did not confirm the magnitude of benefit in delaying tumour growth originally observed in an earlier study, nor did the trials demonstrate an improvement in quality of life, Dr Hamburg said.
Genentech's accelerated approval had been granted in February 2008. The FDA agreed to permit South San Francisco-based company, a unit of Roche, to market Avastin, which is approved for use in several other cancers, for MBC based on the positive observations seen in the company's E2100 study. The E2100 study showed a 52% increase in progression-free survival (PFS), with an observed 5.5-month difference in median PFS in patients treated with the recombinant, humanised monoclonal antibody.
However, the follow-up studies not only failed to back Avastin's effectiveness in treating MBC it also confirmed the very serious adverse events associated with the use of the drug. The adverse events included high blood pressure, bleeding and haemorrhaging, heart attack or heart failure, and the development of perforations in different parts of the body, such as the nose, stomach and intestines, with some of those effects resulting in death, said Dr Hamburg during an 18 November media briefing.
In that light, Dr Hamburg said she "did not feel that I could really advocate for maintaining the indication for Avastin for metastatic breast cancer".
In the cases of Avastin's other approved indications – lung, kidney, brain and certain types of advanced colon cancers – "the scientific demonstration of benefit has been sufficient to balance what are the recognized serious risks of use," Dr Hamburg said.
Coming to the conclusion that Avastin in MBC did not provide a meaningful clinical benefit to patients was a difficult process, she said.
"As a doctor, as a woman and as a parent, I recognize how frightening and difficult it is to receive the diagnosis of metastatic breast cancer and to begin preparing for what may be very trying times ahead," Dr Hamburg said, adding that selecting a treatment is "one of the most daunting and important challenges patients face".
"I feel deeply for these women suffering from breast cancer and all that that involves who are seeking therapies that may work for them," she said.
But ultimately, it is the FDA's responsibility to put aside any preconceived beliefs that "I, or patients or physicians, may hold, and take a hard look at the objective evidence," Dr Hamburg wrote in her 69-page opinion outlining her decision.
"We may hope" that the promise seen in early studies of a drug may hold true later, she said.
"But if the evidence does not show that, FDA cannot, and should not, continue to approve it," Dr Hamburg declared.
She pointed out that the option to withdraw an indication is an "essential component" of the accelerated approval process – a possibility companies are well aware of before they start down that pathway, which was created in 1992.
Dr Hamburg stressed, however, that because Avastin is available on the US market for other indications, physicians can keep prescribing it for MBC.
"If an individual patient sits down with their physician, goes over the risks and benefits, and the determination is made that they want to continue to pursue therapy with Avastin, presumably with paclitaxel or another cancer chemotherapeutic agent, that is a decision that they can make," Dr Hamburg said, acknowledging the FDA has no jurisdiction when it comes to the practice of medicine, which is overseen by individual states in the US.
She also noted that the Centers for Medicare & Medicaid Services has stated it would continue to reimburse Avastin in MBC, at least for the time being. Some big insurers, though, already have stopped paying for the drug for use in breast cancer, including several Blue Cross Blue Shield affiliates.
Shortly after Dr Hamburg's decision was revealed on 18 November, the Ovarian Cancer National Alliance expressed concern that the removal of the MBC indication from Avastin's labelling could negatively affect women with ovarian cancer, for whom the drug is used off-label, insisting that those patients could be denied insurance coverage for the medicine3.
The group noted that national compendia, including the National Comprehensive Cancer Network treatment guidelines, include Avastin as a treatment for ovarian cancer.
The Susan G Komen for the Cure organisation urged that women "successfully" using Avastin should continue to have access to the drug and have it covered by third-party payers4. The breast cancer patient advocacy group said Dr Hamburg's decision on Avastin "underscores the need for aggressive research". The organisation called for more work on biomarkers aimed at identifying which patients will benefit from certain treatments.
Dr Hamburg said it would be "valuable for further studies to be done" in identifying subgroups of patients for which Avastin and other potential breast cancer drugs may work best.
Dr Hal Barron, chief medical officer and head of global product development at Genentech, said the company plans to start a new Phase III study of Avastin in combination with paclitaxel in previously untreated MBC patients and will evaluate a potential biomarker that may help identify which people might derive a more substantial benefit from the drug5.
"I think that it is extremely important that we continue to pursue strategies that might make appropriate safe and effective therapies available to women with metastatic breast cancer," Dr Hamburg said.
References
1. FDA press release, 18 November 2011, www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm280536.htm
2. Genentech details argument with FDA over Avastin in breast cancer, Scrip Regulatory Affairs, 27 January 2011
3. Ovarian Cancer National Alliance press release, 18 November 2011, www.ovariancancer.org/2011/11/18/2011-11-18-ovarian-cancer-advocates-troubled-by-fda-decision-on-avastin-and-breast-cancer/
4. Susan G Komen for the Cure press release, 18 November 2011, www5.komen.org/KomenNewsArticle.aspx?id=19327353969
5. Genentech press release, 18 November 2011, www.gene.com/gene/news/press-releases/display.do?method=detail&id=13687