FDA Reviewers Question Safety and Efficacy of Bevacizumab (Avastin) in Breast Cancer

ROCKVILLE, Md., Dec. 4 -- Adding bevacizumab (Avastin) to paclitaxel (Taxol) for treatment of metastatic breast cancer did not extend overall survival, but did increase toxicity by more than 20% and mortality by 1.7%, FDA staffers said.
Their analysis was presented in a briefing document prepared for tomorrow's Oncology Drugs Advisory Committee meeting during which Genentech's request for approval of bevacizumab in combination with paclitaxel for first-line treatment of locally recurrent or metastatic breast cancer will be considered.
The FDA reviewers said the combination treatment did add 5.5 months to median progression-free survival, but overall survival was 26.5 months for women who received combination therapy versus 24.8 months for those in the paclitaxel-alone arm, which did not achieve statistical significance.
Moreover, the reviewers presented a long list of increased toxicities with the combination therapy, including "hypertension, proteinuria, arterial and venous thrombosis, congestive heart failure, bowel perforation, and death."
They also noted one death in the bevacizumab arm in a trial of 722 women sponsored by the National Cancer Institute and conducted by Eastern Cooperative Oncology Group -- a 64-year-old woman who suffered a bowel perforation, a known side effect of bevacizumab therapy. The study investigators and the company contend that the death was due to the woman's cancer, but the FDA reviewers ruled it as treatment related.
In its briefing documents Genentech argued that some of the toxicities were related to paclitaxel treatment, noting that women in the bevacizumab arm were exposed to longer paclitaxel therapy because they had longer progression-free survival (the study drugs were stopped when disease progressed). The FDA reviewers conceded that that might contribute to the significantly higher toxicities seen in the combination arm, but they remained skeptical.
Although the reviewers did not state that the drug should not be approved for breast cancer, the overall tone of the analysis was negative.
Genentech first sought a breast cancer indication for bevacizumab in 2006, on the basis of the increase in progression-free survival. But the FDA, which has been reluctant to approve drugs on the basis of progression-free survival alone, asked for more data.
In their analysis, the FDA reviewers said that it was possible that "a bevacizumab survival effect, if it exists, is being obscured by subsequent treatment and/or crossover." But, they added, because "post-protocol anticancer therapy information was not collected, any conclusions in this regard would be purely speculative."
The FDA reviewers said, too, that other breast cancer drugs -- specifically trastuzumab (Herceptin) and capecitabine (Xeloda) -- face the same crossover challenge, yet "demonstrated prolongation of life."
Bevacizumab is already approved for colon and lung cancer.