Potential role of multi-targeted tyrosine kinase inhibitors in non-small-cell lung cancer

Treatment outcomes for patients with metastatic non-small-cell lung cancer (NSCLC) are poor with chemotherapy. In recent years, novel agents that target specific, aberrant molecular pathways in NSCLC have been under evaluation in clinical trials. To date, just two targeted agents have impacted the natural history of the disease--erlotinib and bevacizumab--each of which targets a single molecule in a signalling pathway involved in NSCLC. While modest, the activity of these single-target agents results in improved clinical outcomes, highlighting the potential of agents that target biological pathways in patients with NSCLC. However, as NSCLC is a highly heterogeneous disease, it is likely that agents with multiple targets (e.g. sunitinib, sorafenib, ZD6474, AZD2171 and AMG 706) may have greater activity than those with single-target activity through inhibition of other pathways that may act as salvage or escape mechanisms for malignant cells. New multi-targeted therapeutic agents currently undergoing clinical evaluation have shown promise as single agents, and preclinical studies have indicated that this efficacy may be due at least in part to the inhibition of multiple pathways that may result in a synergistic antitumour effect.