SILVER SPRING, MD. – In a series of three unanimous votes, a Food and Drug Administration advisory panel supported the agency’s decision to withdraw approval of bevacizumab for metastatic breast cancer.
Panelists voted 6-0 on June 29 that the available evidence does not show bevacizumab (Avastin) to be safe or effective for the first-line treatment of women with metastatic HER2-negative breast cancer, in combination with paclitaxel.
Their decision came at the conclusion of an unprecedented 2-day hearing requested by bevacizumab manufacturer Genentech Inc., a subsidiary of Roche, which appealed the FDA’s proposal in December 2010 to withdraw the accelerated approval of the antiangiogenesis agent for this indication.
The proposed withdrawal is based on subsequent studies failing to confirm a benefit in progression-free survival that was associated with the treatment in an open-label, multicenter, randomized trial. In addition, serious treatment-related adverse events, including deaths, led the FDA to conclude that bevacizumab has an unfavorable risk-benefit profile for this indication.
“In the absence of clinical benefit, I don’t think any toxicity is acceptable,” said one of the panel members, Dr. Wyndham Wilson, chief of the lymphoma therapeutics section, in the Center for Cancer Research at the National Cancer Institute, Bethesda, Md.
Along with other panelists, he contended that the studies did not show any clinically meaningful improvements in progression-free or overall survival. In another 6-0 vote, the panel agreed that the two subsequent studies – the AVADO and RIBBON1 trials – failed to verify the benefit for the breast cancer indication that was seen in the earlier study.
And the panel voted 6-0 that the FDA should not continue the approval of the breast cancer indication, while the sponsor designs and conducts additional studies intended to verify the drug’s clinical benefit.
With these votes, the panel of outside experts from the Oncologic Drugs Advisory Committee – a group that included a biostatistician, a patient representative and four oncologists – agreed with the FDA’s grounds for recommending that the drug be withdrawn for this indication.
Subsequent to the hearing, the FDA announced that it will take comments until July 28. The final decision will be made by FDA Commissioner Dr. Margaret Hamburg after that date.
Because bevacizumab is approved for kidney, colon, brain, and lung cancer, the decision will not affect its availability on the market, but insurance coverage for the costly treatment would be unlikely.
The FDA based its accelerated approval on the E2100 study, which found that median progression-free survival (PFS), the primary end point, was 5.5 months longer among the women treated with a combination of bevacizumab and paclitaxel (Taxol) than among those treated with paclitaxel alone, which was significant.
But in the AVADO study, median progression-free survival was less than a month longer among the patients in the two bevacizumab plus docetaxel arms, compared with those on docetaxel alone. In RIBBON1, the median was 1.2 months longer when taxane/anthracycline was added to bevacizumab.
None of the studies found a benefit in overall survival, the gold standard. Nor did they show improvement in quality of life. In addition bevacizumab was associated with serious adverse events.
At the hearing, Genentech maintained that the E2100 study was a well-conducted “highly influential” study that had robust results, and was not invalidated by the two follow-up studies, which met their primary end points for progression-free survival, with differences that carried statistically significant P values.
The company said that no new safety signals were seen in the studies, that the drug’s adverse event profile is well-known, and that effects like proteinuria and hypertension are generally manageable. It contended that bevacizumab combined with paclitaxel had a favorable risk-benefit profile as a first-line treatment of metastatic breast cancer –and that its safety profile was in line with other first-line metastatic breast cancer treatments.
The company also said that access to the treatment should be maintained for women with triple-negative metastatic breast cancer, as they have few treatment options.
But FDA officials explained that based on the overall data, the agency decided that the benefits do not outweigh serious and potentially life-threatening risks, which can include intestinal perforations, impaired wound healing, and hemorrhages.
Bevacizumab, an antiangiogenic agent marketed as Avastin, binds to vascular endothelial growth factor (VEGF), thereby working to cut off blood flow to tumors. It is approved in 84 countries as a first-line treatment of metastatic breast cancer, and approval in combination with paclitaxel was retained by the European Medicines Agency earlier this year.
Genentech officials argued that bevacizumab fulfills an unmet need for treatments for this population of patients. In the last 30 years, they noted, gemcitabine plus paclitaxel has been the only other nonhormonal regimen approved in the United States as a first-line treatment of HER2-negative or HER2 unspecified metastatic breast cancer.