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

^aMassachusetts General Hospital, Boston, Massachusetts, USA; ^bDepartment of Solid Tumor Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA

Key Words. NSCLC • VEGFR • EGFR • Vandetanib • Bevacizumab • Erlotinib

Correspondence: Correspondence: Nathan A. Pennell, M.D., Ph.D., Department of Solid Tumor Oncology, R-35, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA. Telephone: 216-445-9282; Fax: 216-445-9464; e-mail: penneln{at}ccf.org

Received December 12, 2008; accepted for publication February 23, 2009.

Disclosures: Nathan A. Pennell: None; Thomas J. Lynch, Jr.: Consultant/advisory role: Genentech Inc., OSI Pharmaceuticals Inc., AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Roche, ImClone Systems Incorporated, Serono. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers.

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 both VEGFR and EGFR signaling are currently under investigation, 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 early clinical studies. Ongoing phase II and phase III trials will determine the clinical potential of a number of dual inhibition strategies in the treatment of advanced NSCLC.