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Axitinib: A Review in Advanced Renal Cell Carcinoma

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Abstract

Axitinib (Inlyta®) is a potent, selective inhibitor of vascular endothelial growth factor receptor-1, -2 and -3. This article reviews the clinical efficacy and tolerability of axitinib in patients with previously-treated advanced renal cell carcinoma (RCC), as well as summarizing its pharmacological properties. Axitinib was effective in the second-line treatment of advanced RCC, according to the results of the pivotal, phase III AXIS trial. Median progression-free survival (PFS) was significantly prolonged with axitinib versus sorafenib (primary endpoint; independent review committee assessment); this PFS benefit was seen in patients who had received prior treatment with cytokines or sunitinib. The objective response rate was also significantly higher with axitinib than with sorafenib, with no significant between-group difference in median overall survival. Axitinib had a manageable tolerability profile in the AXIS trial, with the most commonly reported treatment-related adverse events including diarrhoea, hypertension, fatigue, decreased appetite, nausea, dysphonia, hand-foot syndrome and hypothyroidism. In conclusion, axitinib is an important option in previously-treated patients with advanced RCC.

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References

  1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): kidney cancer (version 1.2016). 2015. http://www.nccn.org/. Accessed 17 Sept 2015.

  2. Garcia-Roig M, Ortiz N, Lokeshwar V. Molecular marker for predicting treatment response in advanced renal cell carcinoma: does the promise fulfill clinical need? Curr Urol Rep. 2014;15:375.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Lam JS, Leppert JT, Belldegrun AS, et al. Novel approaches in the therapy of metastatic renal cell carcinoma. World J Urol. 2005;23(3):202–12.

    Article  CAS  PubMed  Google Scholar 

  4. Chen Y, Tortorici MA, Garrett M, et al. Clinical pharmacology of axitinib. Clin Pharmacokinet. 2013;52(9):713–25.

    Article  CAS  PubMed  Google Scholar 

  5. Tzogani K, Skibeli V, Westgaard I, et al. The European Medicines Agency approval of axitinib (Inlyta) for the treatment of advanced renal cell carcinoma after failure of prior treatment with sunitinib or a cytokine: summary of the scientific assessment of the Committee for Medicinal Products for Human Use. Oncologist. 2015;20(2):196–201.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Pfizer. Inlyta® (axitinib) tablets for oral administration: US prescribing information. 2014. http://www.inlyta.com. Accessed 17 Sept 2015.

  7. European Medicines Agency. Inlyta (axitinib): EU summary of product characteristics. 2015. http://www.ema.europa.eu. Accessed 17 Sept 2015.

  8. Hu-Lowe DD, Zou HY, Grazzini ML, et al. 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. 2008;14(22):7272–83.

    Article  CAS  PubMed  Google Scholar 

  9. Inai T, Mancuso M, Hashizume H, et al. Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol. 2004;165(1):35–52.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Wilmes LJ, Pallavicini MG, Fleming LM, et al. 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. 2007;25(3):319–27.

    Article  CAS  PubMed  Google Scholar 

  11. Miyazaki A, Miyake H, Fujisawa M. Molecular mechanism underlying cytotoxic activity of axitinib in sunitinib-resistant human renal cell carcinoma ACHN cells [abstract no. MP39-20 ]. J Urol. 2015;193(Suppl 4):e462.

    Article  Google Scholar 

  12. Mukohara T, Nakajima H, Mukai H, et al. Effect of axitinib (AG-013736) on fatigue, thyroid-stimulating hormone, and biomarkers: a phase I study in Japanese patients. Cancer Sci. 2010;101(4):963–8.

    Article  CAS  PubMed  Google Scholar 

  13. Liu G, Rugo HS, Wilding G, et al. Dynamic contrast-enhanced magnetic resonance imaging as a pharmacodynamic measure of response after acute dosing of AG-013736, an oral angiogenesis inhibitor, in patients with advanced solid tumors: results from a phase I study. J Clin Oncol. 2005;23(24):5464–73.

    Article  CAS  PubMed  Google Scholar 

  14. Fujiwara Y, Kiyota N, Chayahara N, et al. Management of axitinib (AG-013736)-induced fatigue and thyroid dysfunction, and predictive biomarkers of axitinib exposure: results from phase I studies in Japanese patients. Invest New Drugs. 2012;30(3):1055–64.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Ruiz-Garcia A, Houk BE, Pithavala YK, et al. Effect of axitinib on the QT interval in healthy volunteers. Cancer Chemother Pharmacol. 2015;75(3):619–28.

    Article  CAS  PubMed  Google Scholar 

  16. Pithavala YK, Chen Y, Toh M, et al. Evaluation of the effect of food on the pharmacokinetics of axitinib in healthy volunteers. Cancer Chemother Pharmacol. 2012;70(1):103–12.

    Article  CAS  PubMed  Google Scholar 

  17. European Medicines Agency. Inlyta (axitinib): CHMP assessment report. 2012. http://www.ema.europa.eu. Accessed 17 Sept 2015.

  18. Chen Y, Rini BI, Motzer RJ, et al. Effect of renal impairment on the pharmacokinetics and safety of axitinib. Target Oncol. 2015. doi:10.1007/s11523-015-0389-2.

    Google Scholar 

  19. Tortorici MA, Toh M, Rahavendran SV, et al. Influence of mild and moderate hepatic impairment on axitinib pharmacokinetics. Invest New Drugs. 2011;29(6):1370–80.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Rini BI, Garrett M, Poland B, et al. Axitinib in metastatic renal cell carcinoma: results of a pharmacokinetic and pharmacodynamic analysis. J Clin Pharmacol. 2013;53(5):491–504.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Garrett M, Poland B, Brennan M, et al. Population pharmacokinetic analysis of axitinib in healthy volunteers. Br J Clin Pharmacol. 2014;77(3):480–92.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Pithavala YK, Tortorici M, Toh M, et al. Effect of rifampin on the pharmacokinetics of axitinib (AG-013736) in Japanese and Caucasian healthy volunteers. Cancer Chemother Pharmacol. 2010;65(3):563–70.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Chen Y, Suzuki A, Tortorici MA, et al. Axitinib plasma pharmacokinetics and ethnic differences. Invest New Drugs. 2015;33(2):521–32.

    Article  CAS  PubMed  Google Scholar 

  24. Chen Y, Jiang J, Zhang J, et al. A phase I study to evaluate the pharmacokinetics of axitinib (AG-13736) in healthy Chinese volunteers. Int J Clin Pharmacol Ther. 2011;49(11):679–87.

    Article  CAS  PubMed  Google Scholar 

  25. Brennan M, Williams JA, Chen Y, et al. Meta-analysis of contribution of genetic polymorphisms in drug-metabolizing enzymes or transporters to axitinib pharmacokinetics. Eur J Clin Pharmacol. 2012;68(5):645–55.

    Article  CAS  PubMed  Google Scholar 

  26. Pithavala YK, Tong W, Mount J, et al. Effect of ketoconazole on the pharmacokinetics of axitinib in healthy volunteers. Invest New Drugs. 2012;30(1):273–81.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Rugo HS, Herbst RS, Liu G, et al. Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J Clin Oncol. 2005;23(24):5474–83.

    Article  CAS  PubMed  Google Scholar 

  28. Rini BI, Melichar B, Ueda T, et al. Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial. Lancet Oncol. 2013;14(12):1233–42.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Rixe O, Bukowski RM, Michaelson MD, et al. Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study. Lancet Oncol. 2007;8(11):975–84.

    Article  PubMed  Google Scholar 

  30. Tomita Y, Uemura H, Fujimoto H, et al. Key predictive factors of axitinib (AG-013736)-induced proteinuria and efficacy: a phase II study in Japanese patients with cytokine-refractory metastatic renal cell carcinoma. Eur J Cancer. 2011;47(17):2592–602.

    Article  CAS  PubMed  Google Scholar 

  31. Eto M, Uemura H, Tomita Y, et al. Overall survival and final efficacy and safety results from a Japanese phase II study of axitinib in cytokine-refractory metastatic renal cell carcinoma. Cancer Sci. 2014;105(12):1576–83.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Rini BI, Wilding G, Hudes G, et al. Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J Clin Oncol. 2009;27(27):4462–8.

    Article  CAS  PubMed  Google Scholar 

  33. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931–9.

    Article  CAS  PubMed  Google Scholar 

  34. Qin S, Bi F, Jin J, et al. Axitinib versus sorafenib as a second-line therapy in Asian patients with metastatic renal cell carcinoma: results from a randomized registrational study. Onco Targets Ther. 2015;8:1363–73.

    PubMed Central  PubMed  Google Scholar 

  35. Motzer RJ, Escudier B, Tomczak P, et al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol. 2013;14(6):552–62.

    Article  CAS  PubMed  Google Scholar 

  36. Cella D, Escudier B, Rini B, et al. Patient-reported outcomes for axitinib vs sorafenib in metastatic renal cell carcinoma: phase III (AXIS) trial. Br J Cancer. 2013;108(8):1571–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Uemura H, Ou Y-C, Lim HY, et al. Phase III AXIS trial of axitinib versus sorafenib in patients with metastatic renal cell carcinoma: Asian subgroup analysis [abstract no. PLS-1]. Ann Oncol. 2012;23(8 Suppl 11):xi6.

  38. Ueda T, Uemura H, Tomita Y, et al. Efficacy and safety of axitinib versus sorafenib in metastatic renal cell carcinoma: subgroup analysis of Japanese patients from the global randomized phase 3 AXIS trial. Jpn J Clin Oncol. 2013;43(6):616–28.

    Article  PubMed Central  PubMed  Google Scholar 

  39. Escudier B, Rini BI, Motzer RJ, et al. Genotype correlations with blood pressure and efficacy from a randomized phase III trial of second-line axitinib versus sorafenib in metastatic renal cell carcinoma. Clin Genitourin Cancer. 2015;13(4):328–37.

    Article  PubMed  Google Scholar 

  40. Rini BI, Quinn DI, Baum M, et al. Hypertension among patients with renal cell carcinoma receiving axitinib or sorafenib: analysis from the randomized phase III AXIS trial. Target Oncol. 2015;10(1):45–53.

    Article  PubMed Central  PubMed  Google Scholar 

  41. Miyake H, Harada K-I, Imai S, et al. Non-significant impact of proteinuria on renal function in Japanese patients with metastatic renal cell carcinoma treated with axitinib. Int J Clin Oncol. 2015;20(4):796–801.

    Article  CAS  PubMed  Google Scholar 

  42. Rini BI, Escudier B, Hariharan S, et al. Long-term safety with axitinib in previously treated patients with metastatic renal cell carcinoma. Clin Genitourin Cancer. 2015. doi:10.1016/j.clgc.2015.07.001.

    Google Scholar 

  43. González Larriba JL, Espinosa E, García Carbonero I, et al. Sequential therapy in metastatic renal cell carcinoma: pre-clinical and clinical rationale for selecting a second- or subsequent-line therapy with a different mechanism of action. Cancer Metastasis Rev. 2012;31(Suppl 1):S11–7.

    Article  PubMed  Google Scholar 

  44. Escudier B, Porta C, Schmidinger M, et al. Renal cell carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(Suppl 3):iii49–56.

  45. Hirsch BR, George DJ, Harrison MR. Treatment selection in metastatic renal cell carcinoma: more confusion or a path forward? Clin Adv Hematol Oncol. 2014;12(3):163–71.

    PubMed  Google Scholar 

  46. Calvo E, Grünwald V, Bellmunt J. Controversies in renal cell carcinoma: treatment choice after progression on vascular endothelial growth factor-targeted therapy. Eur J Cancer. 2014;50(7):1321–9.

    Article  CAS  PubMed  Google Scholar 

  47. Hutson TE, Escudier B, Esteban E, et al. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2014;32(8):760–7.

    Article  CAS  PubMed  Google Scholar 

  48. Vogelzang NJ, Pal SK, Signorovitch JE, et al. Comparative effectiveness of everolimus (EVE) and axitinib (AXI) for second-line treatment of metastatic renal cell carcinoma (mRCC) in the United States: a retrospective chart review [abstract no. 500]. J Clin Oncol. 2015;33(Suppl 7).

  49. Canipari C, Haque F, Jain A, et al. Axitinib in second and further line for metastatic renal cell carcinoma [abstract no. 2600]. Eur J Cancer. 2015;51(Suppl 3):S511.

    Google Scholar 

  50. Melichar B, Poprach A, Kubackova K, et al. Efficacy and tolerability of axitinib in metastatic renal cell carcinoma (mRCC): comparison of Czech clinical registry and AXIS trial data [abstract no. 2615]. Eur J Cancer. 2015;51(Suppl 3):S516.

    Google Scholar 

  51. Ansari J, Hussain SA, Ansari A, et al. Critical appraisal of axitinib in the treatment of advanced renal cell carcinoma. Biologics. 2013;7:39–46.

    PubMed Central  CAS  PubMed  Google Scholar 

  52. Rini BI, de La Motte Rouge T, Harzstark AL, et al. Five-year survival in patients with cytokine-refractory metastatic renal cell carcinoma treated with axitinib. Clin Genitourin Cancer. 2013;11(2):107–14.

    Article  PubMed  Google Scholar 

  53. Qi W-X, He A-N, Shen Z, et al. Incidence and risk of hypertension with a novel multi-targeted kinase inhibitor axitinib in cancer patients: a systematic review and meta-analysis. Br J Clin Pharmacol. 2013;76(3):348–57.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Wood LS, Gornell S, Rini BI. Maximizing clinical outcomes with axitinib therapy in advanced renal cell carcinoma through proactive side-effect management. Community Oncol. 2012;9(2):46–55.

    Article  Google Scholar 

  55. Rini BI, Schiller JH, Fruehauf JP, et al. Diastolic blood pressure as a biomarker of axitinib efficacy in solid tumors. Clin Cancer Res. 2011;17(11):3841–9.

    Article  CAS  PubMed  Google Scholar 

  56. Rini BI, Melichar B, Fishman MN, et al. Axitinib dose titration: analyses of exposure, blood pressure and clinical response from a randomized phase II study in metastatic renal cell carcinoma. Ann Oncol. 2015;26(7):1372–7.

    CAS  PubMed  Google Scholar 

  57. Chen Y, Rini BI, Bair AH, et al. Population pharmacokinetic-pharmacodynamic modelling of 24-h diastolic ambulatory blood pressure changes mediated by axitinib in patients with metastatic renal cell carcinoma. Clin Pharmacokinet. 2015;54(4):397–407.

    Article  CAS  PubMed  Google Scholar 

  58. Maitland ML, Bakris GL, Black HR, et al. Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors. J Natl Cancer Inst. 2010;102(9):596–604.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. National Institute for Health and Care Excellence. Axitinib for treating advanced renal cell carcinoma after failure of prior systemic treatment. 2015. https://www.nice.org.uk/guidance/ta333/resources/guidance-axitinib-for-treating-advanced-renal-cell-carcinoma-after-failure-of-prior-systemic-treatment-pdf. Accessed 17 Sept 2015.

  60. Petrou P. Cost-effectiveness analysis of axitinib through a probabilistic decision model. Expert Opin Pharmacother. 2015;16(8):1233–43.

    Article  PubMed  Google Scholar 

  61. Rini BI, Tomita Y, Melichar B, et al. Overall survival analysis from a randomized phase II study of axitinib with or without dose titration for first-line metastatic renal cell carcinoma [abstract no. 4545 plus poster]. J Clin Oncol. 2015;33(Suppl).

  62. Hutson TE, Lesovoy V, Al-Shukri S, et al. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol. 2013;14(13):1287–94.

    Article  CAS  PubMed  Google Scholar 

  63. Hutson TE, Al-Shukri S, Stus VP, et al. Overall survival analysis from a randomised phase III trial of axitinib vs sorafenib as first-line therapy in patients with metastatic renal cell carcinoma [abstract no. 2509]. Eur J Cancer. 2015;51(Suppl 3):S476.

    Google Scholar 

  64. Yousaf N, Larkin J. Axitinib in advanced renal-cell carcinoma. Lancet Oncol. 2013;14(13):1245–6.

    Article  PubMed  Google Scholar 

  65. Choueiri TK, Michaelson MD, Posadas EM, et al. A phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) in combination with axitinib in patients with metastatic renal cell carcinoma [abstract no. 426]. J Clin Oncol. 2015;33(Suppl 7).

  66. Voss MH, Plimack ER, Rini BL, et al. DART study: a phase 2 randomized trial of dalantercept plus axitinib versus placebo plus axitinib in advanced clear cell renal cell carcinoma (RCC): results from part 1 [abstract no. 407]. J Clin Oncol. 2015;33(Suppl 7).

  67. Haas NB, Manola J, Uzzo RG, et al. Initial results from ASSURE (E2805): adjuvant sorafenib or sunitinib for unfavourable renal carcinoma, an ECOG-ACRN-led, NCTN phase III trial [abstract no. 403]. J Clin Oncol. 2015;33(Suppl 7).

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Acknowledgments

During the peer review process, the manufacturer of axitinib was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

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    Gillian M. Keating

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Correspondence to Gillian M. Keating.

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The preparation of this review was not supported by any external funding.

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Gillian Keating is a salaried employee of Adis/Springer, is responsible for the article content and declares no relevant conflict of interest.

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The manuscript was reviewed by: J.P. Dutcher, Cancer Research Foundation, Chappaqua, NY, USA; S. Négrier, Université de Lyon, Centre Léon Bérard, Lyon, France; O. Rixe, Division of Hematology/Oncology, University of New Mexico Cancer Center, Albuquerque, NM, USA; M. Schmidinger, Department of Medicine I, Clinical Division of Oncology, Comprehensive Cancer Centre, Medical University of Vienna, Vienna, Austria.

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Keating, G.M. Axitinib: A Review in Advanced Renal Cell Carcinoma. Drugs 75, 1903–1913 (2015). https://doi.org/10.1007/s40265-015-0483-x

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