Untargeted Use of Targeted Therapy

Lung cancer is the leading cause of cancer death in men and women and frequently presents as advanced disease. The majority of lung cancers are of the non-small cell type, for which chemotherapy has demonstrated modest survival benefits at all stages of disease. Clearly, more effective therapies are needed. Agents that alter critical molecular cell growth pathways, so-called targeted therapies, are a growing area of research and development. Targeted therapies including drugs directed at the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) have recently established a role in the treatment of advanced stage non-small cell lung cancer (NSCLC). These drugs and many others are undergoing investigation, either as single agents or in combination with cytotoxics or other targeted therapies, with dual goals of improved efficacy and reduced toxicity. Although progress has been made in target identification for lung cancer treatment, the ability to select groups of NSCLC patients who benefit from these therapies based on predictive markers remains a challenge. Ongoing studies correlating potential predictive biomarkers with patient outcome are designed to refine the use of developing targeted therapies, that is, to provide a rational basis for “targeted use of targeted therapies.” Despite some recent breakthroughs in identifying molecular signatures predictive of benefit, much remains to be learned. Using erlotinib and bevacizumab as prime examples, this chapter will review a dilemma currently facing both basic scientists and clinical investigators engaged in the study of NSCLC, namely how to develop and test paradigms for individualizing patient therapy.