Dual EGFR/VEGF pathway inhibition: a promising strategy for patients with EGFR-mutant NSCLC.

The vascular endothelial growth factor (VEGF) pathway has been recognized as a key mediator of angiogenesis to support tumorigenesis. Multiple therapeutic agents targeting VEGF and VEGF receptor (VEGFR) have been developed and approved for use in non-small cell lung cancers (NSCLCs). Preclinical studies have shown that the VEGF and epidermal growth factor receptor (EGFR) pathways share common downstream signaling, and these pathways can function exclusively of one another during oncogenesis. In EGFR-mutant NSCLCs, upregulated EGFR signaling increases VEGF through hypoxia-independent mechanisms, and elevated VEGF, in turn, contributes to the emergence of resistance to EGFR tyrosine kinase inhibitors (TKIs). In clinical trials, the addition of anti-VEGF therapy to EGFR TKIs significantly improved clinical outcomes. In recently reported large randomized studies, the addition of bevacizumab or ramucirumab to EGFR TKIs significantly improved progression-free survival in TKI-naive EGFR-mutant NSCLC patients. This article reviews the preclinical and clinical data supporting dual inhibition of EGFR and VEGF in EGFR-mutant NSCLC as a way to improve patient outcomes.