Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Pazopanib

The Newest Tyrosine Kinase Inhibitor for the Treatment of Advanced or Metastatic Renal Cell Carcinoma

  • 1251 Accesses

  • 5 Citations

Abstract

Treatment options for renal cell carcinoma (RCC) have multiplied in the past 5 years. Pazopanib is the third tyrosine kinase inhibitor (TKI) and the sixth targeted therapy that has received US FDA approval for the treatment of advanced or metastatic RCC. The primary mechanism of action of pazopanib in RCC is through its antiangiogenic properties via inhibition of the intracellular tyrosine kinase of vascular endothelial growth factor receptor and platelet-derived growth factor receptor. A placebo-controlled phase III study demonstrated that pazopanib significantly improved response rates and progression-free survival (PFS) in both treatment-naïve and cytokine-pretreated patients. Among treatment-naïve patients, the response rate was 32% and PFS was 11.1 months. In cytokine-pretreated patients, the response rate and PFS were 29% and 7.4 months, respectively. Common adverse effects of pazopanib include diarrhoea, hypertension and elevation of liver enzymes. Overall, the adverse effect profile of pazopanib is similar to that of other TKIs used for the treatment of RCC, but variation in the incidence and severity may exist. Pazopanib has an increased propensity to cause hepatotoxicity, which may be fatal in rare cases. Hepatic function must be monitored closely with dose interruption and/or reduction if elevation of hepatic function tests occurs. Pazopanib is administered on an empty stomach at a dose of 800 mg daily until disease progression, but dose reduction may be required in patients with baseline elevation of hepatic function tests, particularly total bilirubin. The minimum dose recommended for baseline hepatic dysfunction or toxicity is 200 mg daily. The potential for drug interactions exists for pazopanib. It is a substrate of cytochrome P450 (CYP) 3A4, P-glycoprotein and breast cancer resistance protein, and it weakly inhibits CYP3A4, CYP2C8 and CYP2D6, and potently inhibits UGT1A1 and OATP1B1. Currently, no study has directly compared pazopanib with other first- or second-line therapies in RCC. However, published clinical trials of pazopanib show similar efficacy outcomes to those of other targeted therapies. Therefore, pazopanib may be considered a first-line treatment option among other therapies including sunitinib, temsirolimus, and bevacizumab plus interferon-α. After failure of cytokine therapy, pazopanib is a treatment option as well as sorafenib or bevacizumab. No study has evaluated pazopanib treatment after failure of another targeted therapy. Future studies will further clarify the comparative efficacy of pazopanib with other agents as well as optimal sequencing with other agents. If similar efficacy is seen among the TKIs, it is likely that varying incidences of adverse effects may be analysed to tailor therapy according to the patient’s individual co-morbidities and preferences.

This is a preview of subscription content, log in to check access.

Table I
Table II
Table III
Table IV

References

  1. 1.

    Society AC. Cancer facts and figures 2010. Atlanta (GA): American Cancer Society, 2010

  2. 2.

    DeVita VT, Lawrence TS, Rosenberg SA, editors. DeVita, Hellman, and Rosenberg’s cancer: principles and practice of oncology. 8th ed. Philadelphia (PA): Lippincott Williams & Wilkins, 2008

  3. 3.

    Clark PE. The role of VHL in clear-cell renal cell carcinoma and its relation to targeted therapy. Kidney Int 2009 Nov; 76(9): 939–45

  4. 4.

    Gotink KJ, Verheul HM. Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action? Angiogenesis 2010 Mar; 13(1): 1–14

  5. 5.

    Rini BI. Metastatic renal cell carcinoma: many treatment options, one patient. J Clin Oncol 2009 Jul 1; 27(19): 3225–34

  6. 6.

    Harris PA, Boloor A, Cheung M, et al. Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl] amino]-2-m ethyl-benzenesulfonamide (pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor. J Med Chem 2008 Aug 14; 51(15): 4632–40

  7. 7.

    GlaxoSmith Kline. Votrient (pazopanib) tablets: full prescribing information. Research Triangle Park (NC): GlaxoSmithKline, 2010

  8. 8.

    Hurwitz HI, Dowlati A, Saini S, et al. Phase I trial of pazopanib in patients with advanced cancer. Clin Cancer Res 2009 Jun 15; 15(12): 4220–7

  9. 9.

    Kumar R, Knick VB, Rudolph SK, et al. Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther 2007 Jul; 6(7): 2012–21

  10. 10.

    Bayer HealthCare Pharmaceuticals Inc. Nexavar® (sorafenib) tablets: full prescribing information. Wayne (NJ): Bayer HealthCare Pharmaceuticals Inc., 2009

  11. 11.

    Pfizer Labs. Sutent® (sunitinib) capsules: full prescribing information. New York: Pfizer Labs, 2010

  12. 12.

    National Comprehensive Cancer Network. Clinical practice guidelines in oncology: kidney cancer, V.2.2010 [online]. Available from URL: http://www.nccn.org/professionals/physician_gls/-PDF/kidney.pdf [Accessed 2010 Jun 21]

  13. 13.

    Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010 Feb 20; 28(6): 1061–8

  14. 14.

    Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009 Aug 1; 27(22): 3584–90

  15. 15.

    Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007 Dec 22; 370(9605): 2103–11

  16. 16.

    Rini BI, Halabi S, Rosenberg JE, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 2008 Nov 20; 26(33): 5422–8

  17. 17.

    Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007 May 31; 356(22): 2271–81

  18. 18.

    Escudier B, Eisen T, Stadler WM, et al. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol 2009 Jul 10; 27(20): 3312–8

  19. 19.

    Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003 Jul 31; 349(5): 427–34

  20. 20.

    Atkins MB, Hidalgo M, Stadler WM, et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 2004 Mar 1; 22(5): 909–18

  21. 21.

    Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA 2006 Jun 7; 295(21): 2516–24

  22. 22.

    Motzer RJ, Escudier B, Oudard S, et al. Efficacy of ever-olimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008 Aug 9; 372(9637): 449–56

  23. 23.

    Hutson TE, Davis ID, Machiels JP, et al. Efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma. J Clin Oncol 2010 Jan 20; 28(3): 475–80

  24. 24.

    Plimack ER, Jonasch E, Bekele BN, et al. Sunitinib in papillary renal cell carcinoma (pRCC): results from a single-arm phase II study [abstract no. 325]. ASCO 2010 Genitourinary Cancers Symposium; 2010 Mar 5–7; San Francisco (CA)

  25. 25.

    Motzer RJ, Hudes G, Wilding G, et al. Phase I trial of sunitinib malate plus interferon-alpha for patients with metastatic renal cell carcinoma. Clin Genitourin Cancer 2009 Jan; 7(1): 28–33

  26. 26.

    Ryan CW, Goldman BH, Lara Jr PN, et al. Sorafenib with interferon alfa-2b as first-line treatment of advanced renal carcinoma: a phase II study of the Southwest Oncology Group. J Clin Oncol 2007 Aug 1; 25(22): 3296–301

  27. 27.

    Feldman DR, Baum MS, Ginsberg MS, et al. Phase I trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 2009 Mar 20; 27(9): 1432–9

  28. 28.

    Sosman J. Updated results of phase I trial of sorafenib (S) and bevacizumab (B) in patients with metastatic renal cell cancer (mRCC) [abstract]. J Clin Oncol 2008; 26 Suppl.: 5011

  29. 29.

    Di Lorenzo G, Carteni G, Autorino R, et al. Phase II study of sorafenib in patients with sunitinib-refractory metastatic renal cell cancer. J Clin Oncol 2009 Sep 20; 27(27): 4469–74

  30. 30.

    Kumar R, Crouthamel MC, Rominger DH, et al. Myelosuppression and kinase selectivity of multikinase angiogenesis inhibitors. Br J Cancer 2009 Nov 17; 101(10): 1717–23

  31. 31.

    Routhouska S, Gilliam AC, Mirmirani P. Hair depigmentation during chemotherapy with a class III/V receptor tyrosine kinase inhibitor. Arch Dermatol 2006 Nov; 142(11): 1477–9

  32. 32.

    Sideras K, Menefee ME, Burton JK, et al. Effect of pazopanib on hair and skin hypopigmentation: a series of three patients [abstract]. J Clin Oncol 2010; 28 Suppl.: e13602

  33. 33.

    Xu CF, Reck BH, Xue Z, et al. Pazopanib-induced hyperbilirubinemia is associated with Gilbert’s syndrome UGT1A1 polymorphism. Br J Cancer 2010 Apr 27; 102(9): 1371–7

  34. 34.

    Xu C, Reck BH, Goodman VL, et al. Association of the hemochromatosis (HFE) gene with pazopanib-induced transaminase elevations in renal cell carcinoma [abstract]. J Clin Oncol 2010; 28 (7 Suppl.): 3019

  35. 35.

    White AJ, LaGerche A, Toner GC, et al. Apical ballooning syndrome during treatment with a vascular endothelial growth factor receptor antagonist. Int J Cardiol 2009 Jan 24; 131(3): e92–4

  36. 36.

    Rini BI, Halabi S, Rosenberg JE, et al. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol 2010 May 1; 28(13): 2137–43

  37. 37.

    Shibata S, Longmate J, Chung VM, et al. A phase I and pharmacokinetic single agent study of pazopanib (P) in patients (Pts) with advanced malignancies and varying degrees of liver dysfunction (LD) [abstract]. J Clin Oncol 2010; 28 (7 Suppl.): 2571

  38. 38.

    Miller AA, Murry DJ, Owzar K, et al. Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. J Clin Oncol 2009 Apr 10; 27(11): 1800–5

  39. 39.

    Suttle B, Ball HA, Molimard M, et al. Relationship between exposure to pazopanib (P) and efficacy in patients (pts) with advanced renal cell carcinoma (mRCC) [abstract]. J Clin Oncol 2010; 28 (7 Suppl.): 3048

  40. 40.

    Correia MA. Katzung BG. Basic & clinical pharmacology, 11e [online]. Available from URL: http://www.accessmedicine.com/content.aspx?aID=4515730 [Accessed 2009 Nov 2]

  41. 41.

    Chapter 1: clinical pharmacokinetic and pharmacodynamic concepts. In: Bauer LA. Applied clinical pharmacokinetics. 2nd ed. [online]. Available from URL: http://www.accesspharmacy.com/content.aspx?aID=3517000 [Accessed 2009 Nov 2]

  42. 42.

    Maruo Y, Iwai M, Mori A, et al. Polymorphism of UDP-glucuronosyltransferase and drug metabolism. Curr Drug Metab 2005 Apr; 6(2): 91–9

  43. 43.

    Romaine SP, Bailey KM, Hall AS, et al. The influence of SLCO1B1 (OATP1B1) gene polymorphisms on response to statin therapy. Pharmacogenomics J 2010 Feb; 10(1): 1–11

  44. 44.

    Tan AR, Jones SF, Dowlati A, et al. Phase I study of the safety, tolerability, and pharmacokinetics (PK) of weekly paclitaxel administered in combination with pazopanib (GW786034) [abstract]. J Clin Oncol 2008; 26S (May 20 Suppl.): 3552

  45. 45.

    Dejonge M, Savage S, Verweij J, et al. A phase I, open-label study of the safety and pharmacokinetics (PK) of pazopanib (P) and lapatinib (L) administered concurrently [abstract]. J Clin Oncol 2006; 24 (18S Jun 20 Suppl.): 3088

  46. 46.

    Slamon D, Gomez HL, Kabbinavar FF, et al. Randomized study of pazopanib+lapatinib vs. lapatinib alone in patients with HER2-positive advanced or metastatic breast cancer [abstract]. J Clin Oncol 2008; 26S (May 20 Suppl.): 1016

Download references

Acknowledgements

The authors would like to thank Melissa Eder, Assistant Director of the Texas Tech University Health Sciences Center Clinical Research Unit, for her assistance in the preparation of this manuscript.

No funding was received for this paper other than salary support from Texas Tech University Health Sciences Center School of Pharmacy and VA North Texas Health Care System.

Dr Shah has received honoraria for speaking engagements from Amgen and Novartis. Dr Keisner has no relevant conflicts of interest.

Author information

Correspondence to Sachin R. Shah PharmD, BCOP.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Keisner, S.V., Shah, S.R. Pazopanib. Drugs 71, 443–454 (2011). https://doi.org/10.2165/11588960-000000000-00000

Download citation

Keywords

  • Renal Cell Carcinoma
  • Bevacizumab
  • Sorafenib
  • Sunitinib
  • Lapatinib