Tyrosine Kinase Inhibitors of Vascular Endothelial Growth Factor Receptors in Clinical Trials: Current Status and Future Directions

Abstract

Abstract Learning Objectives After completing this course, the reader will be able to: Discuss the mechanism of action of tyrosine kinase inhibitors of VEGFRs that are in clinical trials.Describe the current status of clinical development and the early clinical results observed with these small molecule inhibitors of VEGFRs.Discuss the optimal study design for evaluation of these compounds, the criteria for patient selection, and the optimal modalities of combination with other drugs.Discuss the differences in the design of clinical trials between chemotherapeutics and target-based agents. Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com Angiogenesis plays a central role in the process of tumor growth and metastatic dissemination. The vascular endothelial growth factor (VEGF) family of peptide growth factors and receptors are key regulators of this process. Agents directed either against VEGF or VEGF receptors (VEGFRs) have been developed. The tyrosine kinase inhibitors of VEGFRs are low-molecular-weight, ATP-mimetic proteins that bind to the ATP-binding catalytic site of the tyrosine kinase domain of VEG-FRs, resulting in blockade of intracellular signaling. Several of these agents are currently in different phases of clinical development. Large randomized phase III trials have demonstrated the efficacy of sunitinib and sorafenib in the treatment of patients affected by gastrointestinal stromal tumors and renal cancer refractory to standard therapies, respectively. Positive results also have been reported with the combination of ZD6474 and chemotherapy in previously treated non-small cell lung cancer patients. For other agents, such as vatalanib, contrasting outcomes in metastatic colorectal cancer patients have been reported: the final results of these trials are expected in 2006. However, several key questions remain to be addressed, regarding the choice of an adequate dose or schedule, the presence of “off-target” effects, the safety of long-term administration, and the research of new clinical end points or methodological approaches for the optimal clinical development of these agents.