Angiogenesis Inhibitors and Vascular Disrupting Agents in Non-Small Cell Lung Cancer

A.      Rossi; P.      Maione; M.   L.   Ferrara; P.   C.   Sacco; C.      Schettino; M.   A.   Bareschino; C.      Gridelli

Abstract

Most patients diagnosed with non-small cell lung cancer (NSCLC) have advanced disease. Chemotherapy has apparently reached a plateau of effectiveness in improving survival in this subgroup of patients. Considerable efforts have been initiated to identify novel targets for new biological agents which may be safely and effectively administered to NSCLC patients. New blood vessel formation, known as angiogenesis, is a fundamental event in the process of tumor growth and metastatic dissemination. The vascular endothelial growth factor (VEGF) and its receptors play an essential role in tumor proliferation. Approaches to limit VEGF activity include monoclonal antibodies (mAbs) and small molecules inhibiting the corresponding receptor-tyrosine kinase activity. Bevacizumab, an anti-VEGF recombinant humanized mAb, is the first targeted agent which, when combined with chemotherapy, has shown superior efficacy versus chemotherapy alone as first-line treatment of advanced NSCLC. Future clinical developments of bevacizumab in NSCLC treatment include the combination with other targeted therapies in advanced disease, and the integration into the combined modality approaches for the treatment of early and locally advanced disease stages. Vandetanib, a small molecule targeting VEGF tyrosine-kinase activity, due to first indications of antitumor activity and the excellent toxicity profile seems to be a promising agent for the treatment of advanced NSCLC. Other antiangiogenic drugs, such as sorafenib, sunitinib, VEGF Trap and a new class named ‘vascular disrupting agents’, which includes ASA404, are being tested in ongoing clinical trials which will further define their role in the management of NSCLC.

Keywords: NSCLC, bevacizumab, ZD6474, sorafenib, sunitinib, VEGF Trap, vascular disrupting agents, ASA404