Antiangiogenic agents in the management of non-small cell lung cancer

Abstract

Several therapies targeting angiogenesis are currently in development for non-small cell lung cancer (NSCLC). This review discusses results of recent clinical trials evaluating chemotherapy plus antiangiogenic therapy for NSCLC. Bevacizumab, an anti-VEGF antibody, is currently approved for the treatment of advanced NSCLC in combination with carboplatin and paclitaxel. Completed phase III trials evaluating bevacizumab plus chemotherapy have shown prolonged progression-free survival; however, not all trials showed significant improvement in overall survival (OS). Phase III trials of the tyrosine kinase inhibitors (TKIs) vandetanib and sorafenib and the vascular disrupting agent ASA404 also failed to improve OS compared with chemotherapy alone. Clinical trials are ongoing involving several new antiangiogenic therapies, including ramucirumab, aflibercept, cediranib, BIBF 1120, sunitinib, pazopanib, brivanib, ABT-869, axitinib, ABT-751, and NPI-2358; several of these agents have shown promising phase I/II results. Results from recently completed and ongoing phase III trials will determine if these newer antiangiogenic agents will be incorporated into clinical practice.

Keywords:

• non-small cell lung cancer
• antiangiogenic therapy
• vascular endothelial growth factor
• angiogenesis
• tyrosine kinase inhibitor
• monoclonal antibody
• chemotherapy

Disclosure of Potential Conflicts of Interest

G.R.S., N.S. and C.A. have no potential conflicts of interest to disclose.

Acknowledgments

This work was supported by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). Writing and editorial assistance was provided by Robert J. Lee, Ph.D., of MedErgy, which was contracted by BIPI for these services. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE), fully accept responsibility for content and editorial decisions, and were involved at all stages of manuscript development. The authors received no compensation related to the development of the manuscript.

Figures and Tables

Figure 1 Mechanisms of action of approved and investigational antiangiogenic agents. (A) Diagram depicting inhibition of tumor cell receptors (1) and endothelial cell and pericyte receptors (3 and 4) by TKIs and ramucirumab, targeting of VEGF (2) molecules by bevacizumab and VEGFR trap (aflibercept) and (5) disruption of vascular integrity by VDAs. (B) Receptor tyrosine kinase-activated signaling pathways involved in angiogenesis. [Part (A) reprinted with permission ^©2006 Springer; part (B) reproduced with permission of Alphamed Press, Inc. in the format Journal via Copyright Clearance Center.]

Figure 2 Efficacy outcomes from phase III trials evaluating bevacizumab in combination with chemo-therapy in patients with NSCLC. OS and PFS curves from ECOG 4599 (A) and AVAiL (B).19,20 [(A) Reprinted with permission ^©2006 Massachusetts Medical Society. (B) Reprinted by permission of ^©2011 Oxford University Press and ^©2008 American Society of Clinical Oncology. All rights reserved.]

Table 1 Phase II and III clinical trials evaluating approved and investigational antiangiogenic antibodies in combination with chemotherapy for NSCLC

Table 2 Significantly higher rates of grade ≥ 3 adverse events with bevacizumab plus chemotherapy vs. chemotherapy alone (ECOG 4599 trial)17

Table 3 Phase II and III clinical trials testing aflibercept (VEGF trap) and ASA404 in combination with chemotherapy for NSCLC

Table 4 Phase II and III clinical trials testing investigational TKIs in combination with chemotherapy for NSCLC