On May 5, 2009, the U.S. Food and Drug Administration granted accelerated approval to bevacizumab injection (Avastin, Genentech, Inc.) as a single agent for patients with glioblastoma, with progressive disease following prior therapy. The approval was based on demonstration of durable objective response rates observed in two single-arm trials, AVF3708g and NCI 06-C-0064E.
AVF3708g was an open-label, multi-center, randomized trial of patients with previously treated glioblastoma. Patients received bevacizumab (10 mg/kg IV) alone orbevacizumab plus irinotecan every 2 weeks until disease progression or unacceptable toxicity was noted. All patients received prior radiotherapy and temozolomide. Patients completed radiotherapy at least 8 weeks prior to receiving bevacizumab. Patients with active brain hemorrhage were excluded. Only efficacy data from the bevacizumab monotherapy arm (N=85) was used to support drug approval.
The efficacy of bevacizumab was demonstrated using response assessment based on WHO radiographic criteria. In addition, all responding patients must have had stable or decreasing corticosteroid use. Responses were observed in 25.9% (95% CI: 17.0%, 36.1%) of the patients. Median response duration was 4.2 months (95% CI: 3.0, 5.7 months). Radiologic assessment was performed using MR imaging (T1 and T2/FLAIR). MRI does not necessarily distinguish between tumor, edema and radiation necrosis.
NCI 06-C-0064E was a single arm, single site study of bevacizumab for the treatment of patients with previously treated gliomas. The study enrolled 56 patients with glioblastoma. All patients had documented disease progression after receiving temozolomide and radiation therapy. Patients received bevacizumab (10 mg/kg IV) every 2 weeks until disease progression or unacceptable toxicity was noted.
The objective response rate from the NCI 06-C-0064E study was 19.6% (95% CI: 10.9%, 31.3%), using the same response criteria as in AVF3708g. Median response duration was 3.9 months (95% CI: 2.4, 17.4).
Safety data was provided for study AVF3708g. In patients receiving bevacizumab monotherapy, the most frequently reported adverse events of any grade were infection, fatigue, headache, hypertension, epistaxis, and diarrhea. Bevacizumab was discontinued due to adverse events in 4.8% of patients. Two deaths (one retroperitoneal hemorrhage and one neutropenic infection) were possibly related to bevacizumab.
Grade 3-5 bevacizumab-related adverse events included bleeding/hemorrhage, CNS hemorrhage, hypertension, venous and arterial thromboembolic events, wound-healing complications, proteinuria, gastrointestinal perforation and reversible posterior leukoencephalopathy (RPLS). The attribution of certain adverse events (e.g., CNS hemorrhage, wound healing complications, and thromboembolic events) to either bevacizumab, underlying disease status or both cannot be determined due to single arm, non-comparative study design.
Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available through Drugs@ FDA
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Date created: May 6, 2009