Angiogenesis inhibition: quo vadis

Abstract

Angiogenesis Inhibitors: Quo VadisTracy Batchelor, M.D., Massachusetts General Hospital, Harvard Medical SchoolThe United States Food and Drug Administration has approved 10 anti-angiogenic drugs for over 12 types of cancer since 2001. Bevacizumab, a monoclonal antibody that binds the vascular endothelial growth factor (VEGF)-A ligand, received accelerated approval in the United States as monotherapy for recurrent glioblastoma in 2009. This approval was based on radiographic response rates in two prospective studies. However, bevacizumab did not improve overall survival in two subsequent, randomized phase III trials in patients with newly diagnosed glioblastoma. To date, no survival benefit for newly diagnosed or recurrent glioblastoma patients has been demonstrated in randomized phase III trials of 3 different anti-angiogenic agents (bevacizumab, cediranib, cilengitide). Controversy remains regarding the mechanism of action of this class of agents in glioblastoma and whether survival will ultimately be extended by these expensive and potentially toxic biologics/drugs. Combinations of anti-angiogenic drugs with other drugs may be required to improve survival, similar to other solid cancers. These trials are ongoing. A challenging aspect of anti-angiogenic drug development in glioblastoma is the lack of validated biomarkers of tumor response and tumor resistance. Moreover, defining tumor response and tumor progression in the setting of anti-VEGF therapy has highlighted the limitations of conventional imaging endpoints in this disease. Revised response criteria for anti-angiogenic agents have been developed and incorporated into prospective clinical trials. Magnetic resonance imaging (MRI) and positron emission tomography (PET) techniques that may accurately predict response and progression are under development. Angiogenesis Inhibitors: Quo Vadis Tracy Batchelor, M.D., Massachusetts General Hospital, Harvard Medical School The United States Food and Drug Administration has approved 10 anti-angiogenic drugs for over 12 types of cancer since 2001. Bevacizumab, a monoclonal antibody that binds the vascular endothelial growth factor (VEGF)-A ligand, received accelerated approval in the United States as monotherapy for recurrent glioblastoma in 2009. This approval was based on radiographic response rates in two prospective studies. However, bevacizumab did not improve overall survival in two subsequent, randomized phase III trials in patients with newly diagnosed glioblastoma. To date, no survival benefit for newly diagnosed or recurrent glioblastoma patients has been demonstrated in randomized phase III trials of 3 different anti-angiogenic agents (bevacizumab, cediranib, cilengitide). Controversy remains regarding the mechanism of action of this class of agents in glioblastoma and whether survival will ultimately be extended by these expensive and potentially toxic biologics/drugs. Combinations of anti-angiogenic drugs with other drugs may be required to improve survival, similar to other solid cancers. These trials are ongoing. A challenging aspect of anti-angiogenic drug development in glioblastoma is the lack of validated biomarkers of tumor response and tumor resistance. Moreover, defining tumor response and tumor progression in the setting of anti-VEGF therapy has highlighted the limitations of conventional imaging endpoints in this disease. Revised response criteria for anti-angiogenic agents have been developed and incorporated into prospective clinical trials. Magnetic resonance imaging (MRI) and positron emission tomography (PET) techniques that may accurately predict response and progression are under development.