Combined Inhibition of the VEGFR and EGFR Signaling Pathways in the Treatment of NSCLC

Multitargeted agents represent the next generation of targeted therapies in solid tumors. The benefits of individually targeting the vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) signaling pathways have been clinically validated in recent years in a number of solid tumor types including non-small cell lung cancer (NSCLC). Given the heterogeneity of this tumor type and potential crosstalk between these key signaling pathways (which are known to play a critical role in tumor growth, metastasis, and angiogenesis), dual inhibition of the VEGFR and EGFR signaling pathways has the potential to offer additional clinical benefits in NSCLC. A number of approaches to inhibiting bothVEGFRandEGFRsignalingarecurrentlyunderinvestigation, including monotherapy with a multitargeted tyrosine kinase inhibitor (e.g., vandetanib, AEE788, XL647, BMS-690514) or a combination of single-targeted therapies (e.g., bevacizumab, cetuximab, erlotinib, gefitinib). Preclinical and early clinical data (phase I and II trials) support combined inhibition of the VEGFR and EGFR pathways in NSCLC. Overall, combined inhibition strategies are well tolerated and have shown promise in earlyclinicalstudies.OngoingphaseIIandphaseIIItrials willdeterminetheclinicalpotentialofanumberofdualinhibition strategies in the treatment of advanced NSCLC. The Oncologist 2009;14:399–411