SILVER SPRING, Maryland (EGMN)–The results of two phase II studies support accelerated approval of the anti-angiogenesis drug bevacizumab as a treatment for refractory glioblastoma multiforme, a U.S. federal advisory panel unanimously agreed at a March 31 meeting.
The U.S. Food and Drug Administration’s Oncologic Drugs Advisory Committee (ODAC) voted 10 to 0 that the objective responses seen in the studies were strong enough to serve as a surrogate that was “reasonably likely” to predict clinical benefit as a treatment for patients with previously treated glioblastoma. The responses were based on MRI changes in patients treated with bevacizumab.
Marketed by Genentech, Inc., bevacizumab is under accelerated review for approval in the United States as a single agent for the treatment of patients with previously treated glioblastoma. Initially approved in 2004 as a first-line treatment for metastatic colorectal cancer, bevacizumab is a recombinant humanized monoclonal antibody that inhibits the vascular endothelial growth factor (VEGF). This can reduce tumor vascularization as well as capillary permeability. Glioblastomas express high levels of VEGF, and develop an extensive network of tumor blood vessels.
Under the FDA’s accelerated review program, preliminary data that are considered likely to predict clinical benefit can be the basis of provisional approval of drugs for serious or life-threatening diseases, particularly when few treatment options are available. Currently, lomustine and carmustine—including carmustine as an adjunct to surgery—are approved for treating previously treated glioblastoma.
Genentech submitted data from two single-arm studies of patients with previously treated glioblastoma: a company-sponsored multicenter, open label phase II study of 167 patients (85 on bevacizumab alone and 82 on bevacizumab plus irinotecan), who had been treated with surgery, radiation, and temozolomide, and had relapsed for the first or second time; and a supportive study independently conducted and sponsored by the U.S. National Cancer Institute of 56 patients with recurrent high-grade gliomas, treated with bevacizumab alone.
One-half of patients were on corticosteroids at baseline in the Genentech study. In both studies, bevacizumab was administered every two weeks, by IV infusion at a dose of 10 mg/kg.
In the Genentech study, the primary endpoint, objective response, as determined by MRIs, was achieved by 25.9% of patients in the bevacizumab-only arm, with a median duration of response (a secondary endpoint) among responders of 4.2 months, according to the FDA analysis of the data.
Almost all (99%) patients in the bevacizumab-only arm had an adverse event: 26% had a serious adverse event
Almost 5% discontinued the drug because of an adverse event. Common adverse events affecting more than 20% of patients included fatigue (45%), headache (38%), and hypertension (30%). Epistaxis occurred in about 20% of patients in both treatment arms.
In both treatment arms combined, almost 40% of the patients had bleeding/hemorrhage and 5% had CNS hemorrhage, which were induced by bevacizumab. Other reported adverse events included wound healing complications (6%), venous thromboembolic event (8%), and arterial thromboembolic event (6%). Two deaths were considered possibly related to the drug: a case of neutropenic sepsis in a patient in the bevacizumab-only arm and a retroperitoneal hemorrhage in the combination arm.
In the NCI study, the objective response rate was 19.6%, with a median duration of response among responders of 3.9 months, according to the FDA.
There were no complete responses in either study.
Among the issues raised by FDA staff members at the meeting were the single-arm design of the studies and use of historical controls. In addition, the FDA has not used objective response as the basis of an accelerated approval for glioblastoma treatments.
Moreover, because bevacizumab neutralizes VEGF-induced vascular permeability and stabilizes the blood-brain barrier, it reduces extravasation of fluid into the brain—reducing edema and the need for corticosteroids. Therefore, the FDA staff held that it is unclear whether improvements in MRIs associated with a reduced need for steroids could be due to the drug’s effect on the tumor, or represented a reduction in edema and/or radiation-induced necrosis.
Several ODAC panelists said a reduction in steroids was a meaningful improvement because of the adverse effects of steroids.
The acting chair of the panel, Dr. Wyndham Wilson, chief of the lymphoma therapeutics section, metabolism branch, at NCI’s Center for Cancer Research, said that he considered a response rate of 20% to 25% to be “very robust,” and that “the totality of data raised a reasonable likelihood of clinical benefit.”
Dr. Jay Loeffler, chair of the department of radiation oncology, Massachusetts General Hospital, Boston, said that the drug “represents a new generation of molecules to treat our patients with brain tumors,” and that he believed that benefit would be increased when the drug is used with radiation and chemotherapy in the initial treatment of glioblastomas.
He was among the several panel members who said they thought a large phase III trial, planned by Genentech and combining bevacizumab with radiation therapy and temozolomide in newly diagnosed patients with glioblastoma, would be positive.
For accelerated drug approvals, the company must confirm the benefits in a trial after approval.
Bevacizumab is approved in the United States for first- and second-line treatment of metastatic colorectal cancer in combination with intravenous 5-flourouracil-based chemotherapy and for the first-line treatment of unresectable, locally advanced, recurrent or metastatic, nonsquamous, non-small cell lung cancer (NSCLC) in combination with carboplatin and paclitaxel. It also received accelerated approval for treatment in combination with paclitaxel of metastatic HER2-negative breast cancer in patients not previously treated with chemotherapy.
The company expects the FDA to make a decision on approval by May 5.
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