The emerging role of vascular endothelial growth factor receptor tyrosine kinase inhibitors

In the United States, non-small cell lung cancer (NSCLC) constitutes 85% of all newly diagnosed lung cancers. Over the past 40 years, the 5-year survival rates in NSCLC have improved from 6% to 15%, with surgery remaining the most curative approach. However, resection is feasible in less than 35% of patients at diagnosis, and 40% to 50% of newly diagnosed patients present with metastatic disease. Platinum-based combination chemotherapy is standard treatment for these patients, but improvement beyond platinum doublets has not been achieved. Therefore, a clear-cut need exists for new treatment approaches for NSCLC. Targeted therapies, particularly angiogenesis inhibitors, are hoped to facilitate therapeutic progress. Neovascularization not only allows for the continued growth of the primary tumor, but also provides migrating tumor cells access to the systemic circulation, facilitating metastasis. A number of studies have shown a clear correlation between vascular endothelial growth factor (VEGF) expression, microvessel density, and impaired prognosis. Monoclonal antibodies directed against the VEGF and VEGF receptor have been studied in depth in advanced NSCLC. A randomized phase III trial evaluated the role of the anti-VEGF-A antibody bevacizumab in combination with paclitaxel and carboplatin versus chemotherapy alone in NSCLC. Based on toxicity observations from a phase II study, this trial excluded patients with squamous histology, brain metastases, or an ongoing need for therapeutic anti-coagulation or non-steroidal anti-inflammatory agents. Preliminary data confirmed a survival advantage of 12.5 months for patients in the bevacizumab arm compared with 10.2 months in the control arm (P = .0075), which showed that antiangiogenic therapies can be effective in NSCLC. Antiangiogenic therapies, including antibodies against VEGF, and, in particular, new small-molecule inhibitors of the VEGF receptor, are reviewed and discussed in detail.