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The investigational agent cediranib demonstrated considerable activity in recurrent glioblastoma in preliminary results from a phase II trial, further strengthening evidence for suppression of angiogenesis as a strategy against brain tumors.
Dr. Tracy T. Batchelor reported the 6-month progression-free survival rate was 26% for 30 patients given cediranib (AZD2171, Recentin). All but two patients had progressed by the time of his presentation, but median progression-free survival reached 117 days and median overall survival reached 221 days.
Radiographic data on the first 16 consecutive patients showed 9 (56%) had partial responses to cediranib as reported by Dr. Batchelor, executive director of the Stephen E. & Catherine Pappas Center for Neuro-Oncology at the Massachusetts General Hospital Cancer Center in Boston. A preliminary analysis of the full population suggests the final rate will be 50%-60%, he said. While the results are encouraging, they come from "a small nonrandomized study and remain to be validated."
AstraZeneca, developer of cediranib, provided support to the trial, which was sponsored by the National Cancer Institute. An oral agent, cediranib targets all three receptors of the vascular endothelial growth factor (VEGF).
Bevacizumab (Avastin), an antiangiogenic agent that inhibits VEGF also produced unprecedented response and progression-free survival rates in a phase II trial reported at the same meeting.
Findings from that earlier phase II trial showed 15 of 35 grade IV patients (43%) and 20 of 33 with grade III disease (61%) were progression free at 6 months. All told, 59% (40 of 68 patients) had a partial response. Bevacizumab is approved in combination with chemotherapy for metastatic colorectal cancer and unresectable locally advanced, recurrent, or metastatic nonsquamous non-small cell lung cancer.
In a discussion, Dr. Timothy Cloughesy said both studies raise important questions about the role of VEGF in brain tumors and how best to use anti-VEGF therapies. Also, cediranib and bevacizumab seem to have antitumor effects that go beyond VEGF inhibition, noted Dr. Cloughesy, director of the neuro-oncology program at the University of California, Los Angeles, and member of the scientific advisory board of Genentech, maker of bevacizumab.
Dr. Batchelor made extensive use of monthly magnetic resonance imaging (MRI) in the cediranib study, from which data on normalization of tumor vessels and inhibition of edema was published earlier this year (Cancer Cell 2007;11:83-95). "The vascular network is dilated, disorganized, and leaky," he said, showing images of significant, but temporary, decline in vessel diameters. Cediranib also reduced permeability, which in turn controlled edema, as documented by MRI and clinical data.
Dr. Batchelor reported that five patients never went on steroids before or during the trial. Of 11 patients who required steroids at some point, 8 had their dose reduced and 3 stopped steroids. All patients who progressed and stopped taking cediranib required steroids immediately after stopping.
Serial biomarker assessments showed levels of bFGF, SDF1a, and circulating endothelial cells rose before tumors progressed and cediranib was halted.
At a daily dose of 45 mg, most patients needed antihypertension therapy and occasional drug holidays, but no one had an intracerebral hemorrhage, which has been a concern with antiangiogenesis agents. Of the first 16 patients, 10 had dose-limiting toxicity.
Batchelor T. et al. A phase II trial of AZD2171 (cediranib), an oral pan-VEGF receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. Abstract 2001.
Commentary |
AZD2171, a potent, oral pan-VEGF-receptor tyrosine kinase inhibitor, represents another approach to antiangiogenic therapy in patients with malignant glioma. This phase II study reports on 30 patients with recurrent glioblastoma multiforme. Of note, 6-month progression-free survival was 28% with AZD2171, and 9 of the first 16 evaluable patients had partial responses. This data is provocative. It will be interesting to see additional studies of this agent in combination with chemotherapy, which may be an even better approach. Interestingly, tumors that fail therapy with one antiangiogenic regimen responded to an alternative one. These agents do not work in the same way, and mechanisms of resistance to one may not affect a second agent with a different mechanism of action. This report and the abstract by Goli et al. make clear that the potential benefits of antiangiogenic therapy extend to malignant glioma. We need to learn whether these agents can be used in newly diagnosed patients to have an impact on survival. — Henry S. Friedman, M.D.
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