Abstract
Pazopanib inhibits multiple receptor tyrosine kinases, through which it mediates antiangiogenic and antitumour effects.
The clinical efficacy of oral pazopanib in patients with metastatic soft tissue sarcoma (STS) was demonstrated in a randomized, double-blind, placebo-controlled, phase III trial (PALETTE), generally confirming the findings of an earlier, noncomparative phase II study.
In the multicentre PALETTE trial, pazopanib 800 mg once daily significantly prolonged median progression-free survival (PFS; primary endpoint) ≈3-fold relative to placebo (4.6 vs 1.6 months) in adults with progressive metastatic STS following standard chemotherapy.
According to subgroup analyses, pazopanib provided benefit over placebo in terms of PFS regardless of whether the tumour was low/intermediate or high grade and regardless of tumour histology (leiomyosarcoma, synovial sarcoma, other STS), although patients with adipocytic STS were among those excluded from the PALETTE trial, as sufficient benefit had not been shown with the drug in patients with adipocytic STS in the phase II study.
At final analysis of the PALETTE trial, median overall survival was ≈2 months longer with pazopanib than with placebo, although this between-group difference was not statistically significant.
Oral pazopanib generally had no detrimental effect on health-related quality of life and had an acceptable tolerability profile in patients with STS in the PALETTE trial, with adverse events generally being grade 1 or 2 in severity.
Similar content being viewed by others
References
Sinha S, Peach AHS. Diagnosis and management of soft tissue sarcoma. BMJ 2010 Dec 29; 341: c7170
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012 Jan/Feb; 62(1): 10–29
Clark MA, Fisher C, Judson I, et al. Soft-tissue sarcomas in adults. N Engl J Med 2005 Aug 18; 353(7): 701–11
Schöffski P. Pazopanib in the treatment of soft tissue sarcoma. Expert Rev Anticancer Ther 2012 Jun; 12(6): 711–23
Grimer R, Judson I, Peake D, et al. Guidelines for the management of soft tissue sarcomas. Sarcoma 2010; 2010: 506182
Casali PG, Blay JY. Soft tissue sarcomas: ESMO clinical practice guidelines for diagnosis, treatment and follow-up [published erratum appears in Ann Oncol 2010 Aug; 21 (8): 1736]. Ann Oncol 2010 May; 21 Suppl. 5: 198–203
National Comprehensive Cancer Network®. NCCN clinical practice guidelines in oncology (NCCN Guidelines®): soft tissue sarcoma, version 2.2012 [online]. Available from URL: http://www.nccn.org/professionals/physician_gls/f_ guidelines.asp [Accessed 2012 Aug 1
Quesada J, Amato R. The molecular biology of soft-tissue sarcomas and current trends in therapy. Sarcoma 2012; 2012: 849456
Sleijfer S, Van Der Graaf WTA, Blay JY. Angiogenesis inhibition in non-GIST soft tissue sarcomas. Oncologist 2008 Nov; 13(11): 1193–200
US Food and Drug Administration. Votrient (pazopanib) tablets: US prescribing information [online]. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022465s-010S-012lbl.pdf [Accessed 2012 Oct 8
European Medicines Agency. Votrient film-coated tablets: summary of product characteristics [online]. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001141/WC500094272.pdf [Accessed 2012 Oct 8
GlaxoSmithKline. New anti-cancer agent Votrient® 200 mg tablets approval in Japan for the treatment of malignant soft tissue tumors — molecular targeted drugs for the first time appear in malignant soft tissue tumors [media release; in Japanese]. 2012 Sep 28 [online]. Available from URL: http://glaxosmithkline.co.jp/press/press/2012_07/P1000749.html
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 1; 6(7): 2012–21
Podar K, Tonon G, Sattler M, et al. The small-molecule VEGF receptor inhibitor pazopanib (GW786034B) targets both tumor and endothelial cells in multiple myeloma. PNAS 2006 Dec 19; 103(51): 19478–83
Harris PA, Boloor A, Cheung M, et al. Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl] amino]-2-methyl-benzenesulfonamide (pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor. J Med Chem 2008 Aug; 51(15): 4632–40
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
Tailor TD, Hanna G, Yarmolenko PS, et al. Effect of pazopanib on tumor microenvironment and liposome delivery. Mol Cancer Ther 2010 Jun; 9(6): 1798–808
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
US Food and Drug Administration Center for Drug Evaluation and Research. Clinical pharmacology and bio-pharmaceutics review(s) [online]. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022465s000_ClinPharmR.pdf [Accessed 2012 Jun 25
Heath EI, Chiorean EG, Sweeney CJ, et al. A phase I study of the pharmacokinetic and safety profiles of oral pazopanib with a high-fat or low-fat meal in patients with advanced solid tumors. Clin Pharmacol Ther 2010 Dec; 88(6): 818–23
Heath EI, Forman K, Malburg L, et al. A phase I pharmacokinetic and safety evaluation of oral pazopanib dosing administered as crushed tablet or oral suspension in patients with advanced solid tumors. Invest New Drugs 2012 Aug; 30(4): 1566–74
van der Graaf WTA, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2012 May 19; 379(9829): 1879–86
Sleijfer S, Ray-Coquard I, Papai Z, et al. Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European Organisation for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC Study 62043). J Clin Oncol 2009 Jul 1; 27(19): 3126–32
Sleijfer S, Van Glabbeke MM, Lamers C, et al. Soluble factors (SF) associated with efficacy and toxicity of pazopanib (PZB) in advanced soft tissue sarcoma (STS) patients (pts): an EORTC-STBSG study [abstract]. J Clin Oncol 2010 May 20; 28 (15 Suppl. 1)
Van Der Graaf WTA, Blay JY, Chawla SP, et al. PALETTE: final overall survival (OS) data and predictive factors for OS of EORTC 62072/GSK VEG110727, a randomized double-blind phase III trial of pazopanib versus placebo in advanced soft tissue sarcoma (STS) patients [abstract no. 10009]. J Clin Oncol 2012; 30 Suppl.
Coens C, van der Graaf WTA, Blay JY, et al. Final results of health-related quality of life (HRQOL) results from PALETTE: a randomized double-blind phase III trial of pazopanib versus placebo in patients with soft tissue sarcoma (STS) whose disease has progressed during or following prior chemotherapy. An EORTC STBSG global network study (EORTC 62072) [poster no. 1493P]. European Organisation for Research and Treatment of Cancer; 2012 Sep 28–Oct 2; Vienna
US Food and Drug Administration. FDA briefing document. Oncologic Drugs Advisory Committee Meeting: NDA 22465/S-010 pazopanib (Votrient®) GlaxoSmithKline [online]. Available from URL: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM296299.pdf [Accessed 2012 Jun 28]
Phase II study of GW786034 in patients with relapsed or refractory advanced or metastatic soft tissue sarcoma [online]. Available from URL: http://www.cancer.gov/clinicaltrials/search/view?cdrid=459498&version=Health Professional [Accessed Oct 5]
GlaxoSmithKline. PALETTE: academic vs regulatory analysis. London: GlaxoSmithKline, 2011. (Data on file)
Rahman AM, Yusuf SW, Ewer MS. Anthracycline-induced cardotoxicity and the cardiac-sparing effect of liposomal formulation. Int J Nanomedicine 2007; 2(4): 567–83
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
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Deeks, E.D. Pazopanib. Drugs 72, 2129–2140 (2012). https://doi.org/10.2165/11209950-000000000-00000
Published:
Issue Date:
DOI: https://doi.org/10.2165/11209950-000000000-00000