Targeted Oncology

, Volume 4, Issue 4, pp 297–305 | Cite as

Axitinib—a selective inhibitor of the vascular endothelial growth factor (VEGF) receptor

  • Ronan J. Kelly
  • Olivier RixeEmail author


An improved understanding of the molecular biology involved in many solid tumors has led to the development of novel targeted agents. Axitinib is a potent and selective inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases 1, 2, and 3. This review presents preclinical and clinical data available for axitinib, including findings from key phase II clinical trials in a wide variety of tumors including melanomas and renal, pancreatic, thyroid, breast, lung, and colorectal carcinomas. The differences between axitinib and other VEGFR inhibitors are explored and details of the possible use of blood pressure elevation and erythropoietin blood levels as predictive markers of VEGF/VEGFR pathway inhibition are outlined. Ongoing Phase III studies in pancreatic and metastatic renal cell carcinoma should help to determine the optimum utilization of these agents at the appropriate stage of disease.


Axitinib VEGF receptor inhibitor Renal cell carcinoma Pancreatic carcinoma Tyrosine kinese inhibitor 


Conflict of interest statement

No funds were received in support of this review and no benefits in any form have been or will be received from a commercial party related to the subject of this article.


  1. 1.
    Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407:249–257CrossRefPubMedGoogle Scholar
  2. 2.
    Rini BI, Small EJ (2005) Biology and clinical development of vascular endothelial growth factor-targeted therapy in renal cell carcinoma. J Clin Oncol 23:1028–1043CrossRefPubMedGoogle Scholar
  3. 3.
    Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23:1011–1027CrossRefPubMedGoogle Scholar
  4. 4.
    Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676CrossRefPubMedGoogle Scholar
  5. 5.
    Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246:1306–1309CrossRefPubMedGoogle Scholar
  6. 6.
    Cross MJ, Dixelius J, Matsumoto T, Claesson-Welsh L (2003) VEGF-receptor signal transduction. Trends Biochem Sci 28:488–494CrossRefPubMedGoogle Scholar
  7. 7.
    Nilsson M, Heymach JV (2006) Vascular endothelial growth factor (VEGF) pathway. J Thorac Oncol 1:768–770CrossRefPubMedGoogle Scholar
  8. 8.
    Terman BI, Carrion ME, Kovacs E, Rasmussen BA, Eddy RL, Shows TB (1991) Identification of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene 6:1677–1683PubMedGoogle Scholar
  9. 9.
    Sait SN, Dougher-Vermazen M, Shows TB, Terman BI (1995) The kinase insert domain receptor gene (KDR) has been relocated to chromosome 4q11–>q12. Cytogenet Cell Genet 70:145–146CrossRefPubMedGoogle Scholar
  10. 10.
    Shibuya M (2002) Vascular endothelial growth factor receptor family genes: when did the three genes phylogenetically segregate? Biol Chem 383:1573–1579CrossRefPubMedGoogle Scholar
  11. 11.
    Takahashi T, Shibuya M (1997) The 230 kDa mature form of KDR/Flk-1 (VEGF receptor-2) activates the PLC-gamma pathway and partially induces mitotic signals in NIH3T3 fibroblasts. Oncogene 14:2079–2089CrossRefPubMedGoogle Scholar
  12. 12.
    Rugo HS, Herbst RS, Liu G et al (2005) Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J Clin Oncol 23:5474–5483CrossRefPubMedGoogle Scholar
  13. 13.
    Hu-Lowe DD, Zou HY, Grazzini ML et al (2008) Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res 14:7272–7283CrossRefPubMedGoogle Scholar
  14. 14.
    Wilmes LJ, Pallavicini MG, Fleming LM et al (2007) AG-013736, a novel inhibitor of VEGF receptor tyrosine kinases, inhibits breast cancer growth and decreases vascular permeability as detected by dynamic contrast-enhanced magnetic resonance imaging. Magn Reson Imaging 25:319–327CrossRefPubMedGoogle Scholar
  15. 15.
    Yang JC, Haworth L, Sherry RM et al (2003) A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427–434CrossRefPubMedGoogle Scholar
  16. 16.
    Escudier B, Eisen T, Stadler WM et al (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134CrossRefPubMedGoogle Scholar
  17. 17.
    Motzer RJ, Michaelson MD, Redman BG et al (2006) Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 24:16–24CrossRefPubMedGoogle Scholar
  18. 18.
    Motzer RJ, Hutson TE, Tomczak P et al (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124CrossRefPubMedGoogle Scholar
  19. 19.
    Rixe O, Bukowski RM, Michaelson MD et al (2007) Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study. Lancet Oncol 8:975–984CrossRefPubMedGoogle Scholar
  20. 20.
    Rixe O, Meric J-B, Bloch J et al (2005) Surrogate markers of activity of AG-013736, a multi-target tyrosine kinase receptor inhibitor, in metastatic renal cell cancer (RCC). J Clin Oncol 23:3003 (Meeting Abstracts)Google Scholar
  21. 21.
    Rini BI, Wilding GT, Hudes G et al (2007) Axitinib (AG-013736; AG) in patients (pts) with metastatic renal cell cancer (RCC) refractory to sorafenib. J Clin Oncol 25:5032 (Meeting Abstracts)Google Scholar
  22. 22.
    Burris HA 3rd, Moore MJ, Andersen J et al (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15:2403–2413PubMedGoogle Scholar
  23. 23.
    Moore MJ, Goldstein D, Hamm J et al (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960–1966CrossRefPubMedGoogle Scholar
  24. 24.
    Philip PA, Benedetti J, Fenoglio-Preiser C et al (2007) Phase III study of gemcitabine [G] plus cetuximab [C] versus gemcitabine in patients [pts] with locally advanced or metastatic pancreatic adenocarcinoma [PC]: SWOG S0205 study. J Clin Oncol 25:LBA4509 (Meeting Abstracts)CrossRefGoogle Scholar
  25. 25.
    Korc M (2003) Pathways for aberrant angiogenesis in pancreatic cancer. Mol Cancer 2:8CrossRefPubMedGoogle Scholar
  26. 26.
    Seo Y, Baba H, Fukuda T, Takashima M, Sugimachi K (2000) High expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarcinoma. Cancer 88:2239–2245CrossRefPubMedGoogle Scholar
  27. 27.
    Niedergethmann M, Hildenbrand R, Wostbrock B et al (2002) High expression of vascular endothelial growth factor predicts early recurrence and poor prognosis after curative resection for ductal adenocarcinoma of the pancreas. Pancreas 25:122–129CrossRefPubMedGoogle Scholar
  28. 28.
    Kindler HL, Niedzwiecki D, Hollis D et al (2007) A double-blind, placebo-controlled, randomized phase III trial of gemcitabine (G) plus bevacizumab (B) versus gemcitabine plus placebo (P) in patients (pts) with advanced pancreatic cancer (PC): A preliminary analysis of Cancer and Leukemia Group B (CALGB. J Clin Oncol 25:4508 (Meeting Abstracts)Google Scholar
  29. 29.
    Spano JP, Chodkiewicz C, Maurel J et al (2008) Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomised phase II study. Lancet 371:2101–2108CrossRefPubMedGoogle Scholar
  30. 30.
    Phase II study of AG-013736 in combination with docetaxel versus docetaxel alone for patients with metastatic breast cancer. 2006 July 25. Accessed on 15 Oct 2009
  31. 31.
    Rugo HS, Stopeck A, Joy AA et al (2007) A randomized, double-blind phase II study of the oral tyrosine kinase inhibitor (TKI) axitinib (AG-013736) in combination with docetaxel (DOC) compared to DOC plus placebo (PL) in metastatic breast cancer (MBC). J Clin Oncol 25:1003 (Meeting Abstracts)CrossRefGoogle Scholar
  32. 32.
    Cupisti K, Wolf A, Raffel A et al (2007) Long-term clinical and biochemical follow-up in medullary thyroid carcinoma: a single institution’s experience over 20 years. Ann Surg 246:815–821CrossRefPubMedGoogle Scholar
  33. 33.
    Gottlieb JA, Hill CS Jr (1974) Chemotherapy of thyroid cancer with adriamycin. Experience with 30 patients. N Engl J Med 290:193–197PubMedCrossRefGoogle Scholar
  34. 34.
    Shimaoka K, Schoenfeld DA, DeWys WD, Creech RH, DeConti R (1985) A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer 56:2155–2160CrossRefPubMedGoogle Scholar
  35. 35.
    Viglietto G, Maglione D, Rambaldi M et al (1995) Upregulation of vascular endothelial growth factor (VEGF) and downregulation of placenta growth factor (PlGF) associated with malignancy in human thyroid tumors and cell lines. Oncogene 11:1569–1579PubMedGoogle Scholar
  36. 36.
    Kilicarslan AB, Ogus M, Arici C, Pestereli HE, Cakir M, Karpuzoglu G (2003) Clinical importance of vascular endothelial growth factor (VEGF) for papillary thyroid carcinomas. APMIS 111:439–443CrossRefPubMedGoogle Scholar
  37. 37.
    Klein M, Picard E, Vignaud JM et al (1999) Vascular endothelial growth factor gene and protein: strong expression in thyroiditis and thyroid carcinoma. J Endocrinol 161:41–49CrossRefPubMedGoogle Scholar
  38. 38.
    Cohen EE, Rosen LS, Vokes EE et al (2008) Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study. J Clin Oncol 26:4708–4713CrossRefPubMedGoogle Scholar
  39. 39.
    Schiller JH, Larson T, Ou SI et al (2007) Efficacy and safety of axitinib (AG-013736; AG) in patients (pts) with advanced non-small cell lung cancer (NSCLC): A phase II trial. J Clin Oncol 25:7507 (Meeting Abstracts)Google Scholar
  40. 40.
    Fruehauf JP, Lutzky J, McDermott DF et al (2008) Axitinib (AG-013736) in patients with metastatic melanoma: a phase II study. J Clin Oncol 26:9006 (Meeting Abstracts)Google Scholar
  41. 41.
    Phase II study with AG-013736 combined with chemotherapy and bevacizumab in patients with metastatic colorectal cancer. 2008 April 17. Accessed 15 Oct 2009
  42. 42.
    A study combining FOLFOX or FOLFIRI with AG-013736 or avastin in patients with metastatic colorectal cancer after failure of one first line regimen. 2008 April 07. Accessed 15 Oct 2009
  43. 43.
    Randomized study of gemcitabine plus AG-013736 versus gemcitabine for advanced pancreatic cancer. 2007 May 07. Accessed 15 Oct 2009
  44. 44.
    Axitinib as second line therapy for metastatic renal cell cancer: Axis trial. 2009. Accessed 15 Oct 2009
  45. 45.
    Karaman MW, Herrgard S, Treiber DK et al (2008) A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol 26:127–132CrossRefPubMedGoogle Scholar
  46. 46.
    Rixe O, Dutcher JP, Motzer RJ (2008) Association between diastolic blood pressure ≥90 mmHg and efficacy in patients with metastatic renal cell carcinoma receiving axitinib (AG-013736). ESMO 2008 Meeting abstractGoogle Scholar
  47. 47.
    Alexandrescu DT, McClure R, Farzanmehr H, Dasanu CA (2008) Secondary erythrocytosis produced by the tyrosine kinase inhibitors sunitinib and sorafenib. J Clin Oncol 26:4047–4048CrossRefPubMedGoogle Scholar
  48. 48.
    Tam BY, Wei K, Rudge JS et al (2006) VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis. Nat Med 12:793–800CrossRefPubMedGoogle Scholar
  49. 49.
    Boutin AT, Weidemann A, Fu Z et al (2008) Epidermal sensing of oxygen is essential for systemic hypoxic response. Cell 133:223–234CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.National Cancer Institute, Medical Oncology BranchCenter for Cancer ResearchBethesdaUSA
  2. 2.Division of Hematology/OncologyUniversity of Cincinnati College of MedicineCincinnatiUSA

Personalised recommendations