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Advisory panel votes down bevacizumab for metastatic breast cancer
The FDA’s Oncologic Drugs Advisory Committee voted 5-4 that progression-free survival alone is not a measure of direct clinical benefit and should not be used as a basis for FDA approval of bevacizumab for the first-line treatment of metastatic breast cancer.
The FDA will make a regulatory decision at a later date, and has historically followed a panel’s advice.
In one study, patients who received first-line paclitaxel treatment with bevacizumab (Avastin, Genentech) had a significant increase in progression-free survival, but this was coupled with an increase in grade-3 to grade-5 adverse effects.
Bevacizumab is indicated for first- and second-line treatment of colorectal cancer and for first-line treatment of unresectable, locally advanced, recurrent or metastatic nonsquamous non–small cell lung cancer.
Although the gold standard for oncology drug trials is usually overall survival, progression-free survival has been a primary endpoint for approval of several agents used in metastatic breast cancer.
Some panel members noted that progression-free survival is a more meaningful endpoint than overall survival in first-line metastatic breast cancer because of the differences in previous treatment and second-line and third-line treatments.
Although the panel members agreed that progression-free survival can be an adequate endpoint, this particular study raised too many questions, primarily concerning toxicity and data measurement.
“We have to look at the data in totality,” said panel member Aman Buzdar, MD, professor of medicine in the department of breast medical oncology at The University of Texas M.D. Anderson Cancer Center. “This study turned out to be positive but was not designed for FDA approval. There is no perfect study, but there were major shortcomings in this study. We have to keep that in mind.”
E2100
The decision was based primarily on data from the E2100 trial, in which patients with untreated metastatic breast cancer were randomly assigned to paclitaxel plus bevacizumab or paclitaxel alone. The primary endpoint was progression-free survival.
Patients who received bevacizumab had a 5.5-month increase in median progression-free survival, which was consistent across several patient subgroups. Secondary endpoints included overall survival, objective response rate, quality of life and safety.
There was a 1.7-month improvement in overall survival in the bevacizumab arm, but this was not significant. The objective response rate was 49.8% in the bevacizumab arm vs. 22.2% in the paclitaxel-alone arm.
Patients in the bevacizumab arm also had an increased rate of grade-3 to -5 adverse events: 71.1% vs. 50.6% in the paclitaxel arm. The most common events were grade-3 sensory neuropathy and hypertension.
Data from another study discussed, AVF2119g, showed that when bevacizumab was used in a second- or third-line setting, the objective response rate increased twofold. The progression-free survival primary endpoint, however, was not met.
“Even with the lack of a survival advantage, I would have been willing to vote yes if there were not too many questions on how progression was determined particularly given that there were increased toxicities observed with the combination,” said panel chair Maha Hussain, MD, professor of medicine and urology at the University of Michigan. “But there are just too many uncertainties.” – by Emily Shafer