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Clinical Pharmacology

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

^a Clinical Trials Unit and ^b Cellular Biology and Preclinical Models, National Cancer Institute, Napoli, Italy

Key Words. VEGFR • Angiogenesis • Tyrosine kinase inhibitors • Clinical trials

Correspondence: Francesco Perrone, M.D., Ph.D., Clinical Trials Unit, National Cancer Institute, Via Mariano Semola, 80131 Naples, Italy. Telephone: 390815903571; Fax: 390817702938; e-mail: francesco.perrone{at}uosc.fondazionepascale.it

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.

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