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Lessons from phase III clinical trials on anti-VEGF therapy for cancer

Abstract

In randomized phase III trials two anti-vascular endothelial growth factor (VEGF) approaches have yielded survival benefit in patients with metastatic cancer. In one approach, the addition of bevacizumab, a VEGF-specific antibody, to standard chemotherapy improved overall survival in colorectal and lung cancer patients and progression-free survival in breast cancer patients. In the second approach, multitargeted tyrosine kinase inhibitors that block VEGF receptor and other kinases in both endothelial and cancer cells, demonstrated survival benefit in gastrointestinal stromal tumor and renal-cell-carcinoma patients. By contrast, adding bevacizumab to chemotherapy failed to increase survival in patients with previously treated and refractory metastatic breast cancer. Furthermore, addition of vatalanib, a kinase inhibitor developed as a VEGF receptor-selective agent, to chemotherapy did not show a similar benefit in metastatic colorectal cancer patients. These contrasting responses raise critical questions about how these agents work and how to combine them optimally. We summarize three of the many potential mechanisms of action of anti-VEGF agents, and also discuss progress relating to the identification of potential biomarkers for anti-VEGF-agent efficacy in humans.

Key Points

  • Based on the results of the phase III trials completed to date, bevacizumab can increase median survival when combined with standard chemotherapy, but not when used as monotherapy

  • Anti-VEGF therapy with bevacizumab can increase overall survival and/or progression-free survival in colorectal, breast and lung cancer patients when combined with cytotoxic agents

  • Improved survival has been observed with broad-spectrum multitargeted tyrosine kinase inhibitors (e.g. sorafenib, sunitinib) when used in monotherapy

  • In colorectal cancer patients, vatalanib, a VEGF-receptor-selective tyrosine kinase inhibitor, does not confer the same survival advantage as bevacizumab when combined with chemotherapy

  • Anti-VEGF therapy can prune and 'normalize' tumor vasculature, and decrease the number of circulating endothelial cells and progenitor cells

  • There is an urgent need to identify biomarkers to guide anti-VEGF therapy and combination therapies using anti-VEGF agents

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Figure 1: Schematic representation of direct targeting of cancer, endothelial and perivascular cells by anti-VEGF agents
Figure 2: Potential mechanisms of action of bevacizumab on tumor vasculature

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Acknowledgements

The authors thank the members of the Steele Lab, especially Y Boucher, E di Tomaso, D Fukumura, K Kozak, S Kozin, L Munn, and T Padera. We also thank T Batchelor, H Chen, V Natarajan, W Novotny, L Rosen, A Ryan, J Samson, C Willett, and J Wood for their helpful comments on this manuscript. The authors' work is supported by grants from the National Cancer Institute.

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Correspondence to Rakesh K Jain.

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RK Jain is a consultant to, and recipient of a research grant, from AstraZeneca. The authors’ work is supported by grants from the National Cancer Institute. RK Jain has at one time been a consultant (as a Scientific Advisory Board member) for Novartis, SK Bio-Pharmaceuticals, and GLG Life Tech Ltd.

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Supplementary Table 1

Agents that may inhibit angiogenesis by indirect mechanisms of action. (DOC 36 kb)

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Jain, R., Duda, D., Clark, J. et al. Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nat Rev Clin Oncol 3, 24–40 (2006). https://doi.org/10.1038/ncponc0403

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