FDA votes to recommend removal of indication for bevacizumab in metastatic breast cancer
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After 2 days of hearings, the FDA on Wednesday voted to strip the indication for bevacizumab for use in patients with metastatic breast cancer and said follow-up trials did not confirm positive PFS results observed in the E2100 trial.
Agency officials said Genentech, the manufacturer of Avastin, also failed to show clinical benefit for patients or an improvement in OS or quality of life associated with the antiangiogenic drug that would outweigh the known risks for serious toxicities.
FDA commissioner Margaret A. Hamburg, MD, will make the final decision on whether bevacizumab will retain approval for use in patients with metastatic breast cancer. Until her ruling, Avastin remains FDA approved for use in combination with paclitaxel for the first-line treatment of HER2-negative metastatic breast cancer in the United States.
The agency voted unanimously on each of three questions related to the indication (see Sidebar).
“We are here to adjudicate whether or not we feel the original study, E2100, has been confirmed. My reading of the AVADO and RIBBON-1 studies is that the magnitude of the effect is smaller than that which was the basis for approval of E2100,” said Wyndham Wilson, MD, PhD, chief of the lymphoma therapeutics section with the NCI’s Center for Cancer Research. “Simply delaying a change in a CT scan by a month or two, we would all agree, is not a major finding, unless it is accompanied by other improvements in quality of life or increased survival. It is hard for me to view this trial (E2100) as clinically relevant or important, so it is hard to look at these other trials and see them as confirmatory.”
In February 2008, the FDA granted accelerated approval for the use of bevacizumab combined with paclitaxel for first-line treatment of chemotherapy-naive patients with metastatic HER-2–negative breast cancer. The FDA based that approval on PFS results from the E2100 trial, an open-label, randomized, multicenter trial comparing paclitaxel with the combination of paclitaxel plus bevacizumab.
In that trial, assessment from an independent radiology review facility determined that bevacizumab was associated with a 5.5-month increase in PFS compared with paclitaxel alone (11.3 months vs. 5.8 months).
However, in August 2010, the FDA’s Oncologic Drugs Advisory Committee voted to remove bevacizumab’s indication as a first-line therapy for metastatic breast cancer. The committee concluded that Genentech’s follow-up studies, AVADO and RIBBON-1, had not demonstrated that bevacizumab was associated with improved quality of life or extended OS while increasing toxicity. Additionally, they said there was no evidence that PFS was a surrogate marker for extended OS.
Officials with the Center for Drug Evaluation and Research (CDER) said Genentech had downplayed the safety risks associated with bevacizumab because the company had not characterized the long-term outcomes of hypertension and proteinuria.
“These common side effects of Avastin are not benign. Hypertension does not resolve in all patients at the end of treatment with Avastin, sometimes causing a metastatic breast cancer patient to need long-term pharmacologic therapy,” CDER officials said. “Similarly, nearly 40% of patients with grade-3 proteinuria did not have evidence of resolution, and for those who did, resolution took months. Because at least half of patients receiving initial treatment for metastatic breast cancer can expect to live for several years, these risks are not acceptable in light of Avastin’s minimal or lack of effect on PFS.”
PFS results from AVADO showed only a 0.9-month improvement in PFS associated with the addition of 15 mg/kg bevacizumab. The addition of bevacizumab to anthracycline/taxane-based chemotherapy in the RIBBON-1 trial resulted in a 1.2-month improvement in PFS (HR=0.64; 95% CI, 0.52-0.80).
Genentech officials said the CDER had not established a clear, consistent standard for the showing of clinical benefit necessary to support approval for treatments in first-line metastatic breast cancer. The lack of “a clear, predictable, and consistent regulatory standard” could discourage further drug development for a disease that has few treatment available options.
“The view that Avastin presents a distinctly unfavorable safety profile does not appropriately reflect the ability of clinicians to manage Avastin’s most common side effects, or the fact that the majority of serious but rare events (including treatment-related deaths) in the first-line metastatic breast cancer studies were seen in both the treatment and chemotherapy-only arms of the studies,” company officials said. “In considering the import of the Avastin data, in light of the purposes of accelerated approval, it bears noting that Avastin’s efficacy data compare favorably to other available treatments for first-line [metastatic breast cancer], further supporting accelerated approval. These data for an alternative therapy for first-line [metastatic breast cancer] provide an instructive reference point and reinforce that the E2100 data represent a meaningful treatment effect for Avastin with paclitaxel.”
“Common risks are manageable. Avastin has been widely used, and the incidence of serious adverse events is low,” said Sandra Horning, MD, global head for clinical development at Genentech. “We have a treatment effect in PFS; we have an HR of 0.48 that represents a more than 50% reduction in progression or death. We also see a doubling of response rate. With regard to OS, if you look at the OS curves, they do favor the paclitaxel/Avastin arm for first 30 months, after which they overlap. We also see a 7.4% increase in survival at 1 year. Taken all together, this data shows that Avastin provides a clinical benefit for women with metastatic breast cancer.”
The FDA disagreed and decided that, in the absence of clinical benefit, no level of toxicity was acceptable.
Patricia Keegan, MD, director of the CDER’s Division of Biologic Oncology Products, said the trials, which involved more than 2,400 women, showed “no evidence that Avastin saves or extends lives.”
Additionally, agency staff concluded that the AVADO and RIBBON-1 trials did not confirm the clinical benefit observed in E2100; that bevacizumab has not been shown to be effective or safe in this indication; and that the FDA should withdraw approval while Genentech conducts new trials to support the drug.
Genentech plans to conduct further trials to confirm the efficacy of bevacizumab in metastatic breast cancer. – by Jason Harris
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