Dual Targeting of the Vascular Endothelial Growth Factor and Epidermal Growth Factor Receptor Pathways: Rationale and Clinical Applications for Non-Small-Cell Lung Cancer

The vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) pathways represent 2 clinically validated targets for non–small-cell lung cancer (NSCLC), and there is strong biologic rationale for therapeutic approaches targeting both pathways in NSCLC and other diseases. These 2 pathways are interrelated, as VEGF is known to be downregulated by EGFR inhibition through hypoxia-inducible factor 1α–dependent and hypoxia-inducible factor 1α–independent mechanisms. Furthermore, acquired resistance to EGFR inhibitors is associated with increased levels of VEGF, and dual VEGF/EGFR inhibition has demonstrated activity in the presence of EGFR tyrosine kinase inhibitor–resistant disease. This approach is being investigated clinically using combinations of drugs that target the pathways separately, such as erlotinib and bevacizumab, or individual drugs that target both pathways, such as vandetanib. Randomized phase II studies in previously treated patients with NSCLC suggest that dual VEGF/EGFR inhibition might be more active than targeting either pathway alone and that the combination could also enhance the efficacy of chemotherapy. Phase III clinical trials are currently in progress to determine whether dual VEGF/EGFR inhibition, alone or in combination with chemotherapy, should become a standard therapeutic option for patients with NSCLC.