The current status of targeted therapy for non-small cell lung cancer.

Lung cancer accounts for more cancer-related deaths than any other malignancy in Australia and worldwide. Non-small cell lung cancer (NSCLC) accounts for about 85% of lung cancers and is associated with a 5-year survival of only 15%. Treatment with platinum-based doublets in the first-line setting and single agent chemotherapy in the second-line setting has improved survival and quality of life in patients with NSCLC. However, the benefits associated with chemotherapy are modest and serve to stress the need for novel therapeutic approaches. In the last decade a range of targeted therapies has been evaluated in NSCLC. Dramatic and often durable responses were seen in patients treated with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) gefitinib and erlotinib particularly in females, non-smokers, patients of East Asian ethnicity and those with adenocarcinomas - a group subsequently found to be enriched for tumours with activating EGFR mutations. Large randomized phase III trials have since established a role for EGFR TKI in the second- and third-line setting as well as a potential role for the monoclonal antibodies bevacizumab and cetuximab, directed at vascular endothelial growth factor and EGFR, respectively, in the combination with chemotherapy in the first-line setting. Recently it has been shown that patients with EGFR mutations may benefit from gefitinib in the first-line setting. Other promising agents under evaluation are inhibitors of the insulin-like growth factor-1 receptor and inhibitors of recently described ALK gene rearrangements.