Novel therapies for non-small-cell lung cancer: a 2008 update.

Lung cancer is the leading cause of cancer death in the United States and worldwide.1,2 The 5-year survival rate of 16% remains suboptimal and far lower than 5-year survival rates for all cancers (66%) and other common cancers such as breast, colon, and prostate cancers.1 Cytotoxic chemotherapy has been the mainstay of treatment for patients with advanced small-cell lung cancer and non–small-cell lung cancer (NSCLC) for many years.3-5 Because these therapies have many toxicities that kill a substantial number of tumor cells, it is imperative that we develop biomarkers to identify patients most likely to respond to individual drugs and to develop agents with reduced toxicities. The revolution in our understanding of the molecular basis of lung cancer leads to the identification of new therapeutic targets. Among these new targets are growth factor pathways that stimulate not only tumor growth but also the growth of blood vessels that permit lung cancer growth (angiogenesis). In this supplement to Clinical Lung Cancer, the recent advances in novel therapies for lung cancer are reviewed by experts in the field. With respect to the novel targets, the epidermal growth factor (EGF) pathway for lung cancer cells and the vascular endothelial growth factor (VEGF) pathway for endothelial cells are highlighted. Horn and Sandler review the emerging data on antiangiogenic therapies for NSCLC. There are several ways to inhibit the pathway, including monoclonal antibodies (MoAbs) directed to the VEGF ligand (bevacizumab) or MoAbs to the VEGF receptor (VEGFR; eg, IMC-1121B). Many small-molecule tyrosine kinase inhibitors (TKIs) of VEGFR signaling are also being studied. Among all antiangiogenic therapies of any class, only bevacizumab (Avastin) is currently US Food and Drug Administration (FDA) approved for lung cancer therapy. Herein, Joy and Butts review the status of inhibitors of the EGF receptor (EGFR) signaling pathway. Once again, there are both MoAbs to the receptor, such as cetuximab, and small-molecule TKIs of EGFR signaling, such as erlotinib and gefitinib. The smallmolecule inhibitor erlotinib is approved for use in NSCLC by the FDA, and there are promising emerging data for cetuximab and gefitinib. There are intense studies to identify the best biomarkers to select patients for these therapies. Activating EGFR mutations appear to be excellent markers for sensitivity to EGFR TKIs. EGFR protein expression, EGFR gene copy number by fluorescence in situ hybridization, and other markers are being evaluated to assist in the selection of patients for cetuximab therapy. Pakkala and Ramalingam review studies that evaluate dual inhibition of both the EGFR and VEGFR pathways. The dual inhibition can be achieved by combining agents specific for each pathway (eg, erlotinib and bevacizumab) and by using single small-molecule TKIs that target both pathways (eg, vandetanib). Scagliotti and colleagues review recent studies focusing on the novel cytotoxic chemotherapeutic agent pemetrexed. Pemetrexed is a multitargeted antifolate that is FDA approved for use in both firstand second-line therapy for advanced NSCLC. Multiple studies have demonstrated that its activity is greater in nonsquamous carcinomas than in squamous carcinomas. The authors explore the molecular basis for this difference. Finally, West reviews the next generation of targeted therapies for advanced NSCLC. There are many promising targets, including insulin-like growth factor-1 receptor signaling; c-Met signaling; mammalian target of rapamycin; AKT and phosphatidylinositol 3-kinase signaling; and inducers of apoptosis, such as TRAIL, and agonist antibodies to DR4 or DR5. This supplement highlights the major advances in lung cancer therapy that have the potential to improve 5-year survival rates and reduce the pain and suffering experienced by patients with lung cancer.