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  • Review Article
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An overview of small-molecule inhibitors of VEGFR signaling

Nature Reviews Clinical Oncology volume 6, pages 569–579 (2009)Cite this article

Abstract

VEGFR inhibitors are in broad use for the treatment of metastatic renal-cell carcinoma, gastrointestinal stromal tumors and hepatocellular carcinoma and in development in a number of other oncology indications, including colorectal cancer, non-small-cell lung cancer, pancreatic cancer, thyroid malignancies, ovarian cancer, breast cancer and sarcomas. This Review outlines the structure–activity relationships of the 44 VEGFR inhibitors currently in development. An overview of the pharmacokinetic profile of each molecule and its stage in development is provided. Phase III clinical trials being conducted for licensing of these agents for specific indications and phase III developmental efficacy trials are described in detailed tables that include the disease studied, trial design including combination therapy, study end points, and projected or final accrual. The relative frequency of on-target and off-target adverse events observed in 3,060 patients is described for a subset of agents in development in clinical trials sponsored by the National Cancer Institute. No interagent comparisons were undertaken and no data from pharmaceutical pharmacovigilance databases were used. The on-target effects seem to be mechanistically based and predicted by VEGFR inhibition. Small-molecule inhibitors of angiogenesis are active in a wide variety of malignancies and fill a unique niche for cancer therapeutics.

Key Points

  • Small-molecule inhibitors of VEGFRs are in clinical development both as single agents and in combination with other cancer therapies; these agents are licensed for use in a limited number of indications

  • Small-molecule inhibitors of VEGFRs are often designed to inhibit other receptors as well, so these agents have a varied adverse-event profile and spectrum of activity

  • Sunitinib and sorafenib are indicated for the treatment of renal-cell carcinoma; sunitinib is also used to treat gastrointestinal stromal cell tumors and sorafenib is also used to treat hepatocellular carcinoma

  • Toxic effects of VEGFR inhibitors include hypertension, proteinuria, hemorrhage and/or bleeding, hypothyroidism, fistula, bowel perforation, left ventricular diastolic dysfunction, thrombotic microangiopathy, reversible posterior leukoencephalopathy syndrome and arterial thrombosis

  • The off-target toxic effects of VEGFR inhibitors are attributed to their split kinase activity (which can be on-target for a specific kinase inhibitor), comorbid illness or complication caused by the cancer

  • The identification of biomarkers to personalize treatment with angiogenesis inhibitors, such as VEGFR inhibitors, is a pressing medical need

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Figure 1: The role of VEGFR signaling in tumor angiogenesis.

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Authors and Affiliations

  1. Division of Cancer Treatment and Diagnosis, Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA

    S. Percy Ivy

  2. Division of Cancer Treatment and Diagnosis, Pharmaceutical Management Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA

    Jeannette Y. Wick

  3. PSI International, Inc., Fairfax, VA, USA

    Bennett M. Kaufman

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Ivy, S., Wick, J. & Kaufman, B. An overview of small-molecule inhibitors of VEGFR signaling. Nat Rev Clin Oncol 6, 569–579 (2009). https://doi.org/10.1038/nrclinonc.2009.130

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