Pazopanib for the treatment of gynecological malignancies

Angiogenesis is a well-established therapeutic target in gynecological malignancies. Vascular growth factor (VEGF) plays a critical role in angiogenesis, but also other growth factor receptors, such as platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF), have been demonstrated to contribute to it. Pazopanib is an oral multi-targeted tyrosine kinase inhibitor (TKI) under clinical investigation in late clinical trials for the treatment of gynecological cancers. Moreover, in 2012 the Food and Drug Administration (FDA) approved pazopanib for the treatment of advanced soft-tissue sarcomas, including uterine leiomyosarcoma. This review aims to provide a complete and updated overview on results of clinical studies of pazopanib for the treatment of gynecological malignancies, highlighting the ongoing trials.

Angiogenesis; Vascular growth factor (VEGF); platelet-derived growth factor (PDGF); Pazopanib

[1] Carmeliet P., Jain R.K.: “Angiogenesis in cancer and other diseases”. Nature, 2000, 407, 249.

[2] Shih T., Lindley C.: “Bevacizumab: an angiogenesis inhibitor for the treatment of solid malignancies”. Clin. Ther., 2006, 28, 1779.

[3] Kong D.H., Kim M.R., Jang J.H., Na H.J., Lee S.: “A Review of Anti-Angiogenic Targets for Monoclonal Antibody Cancer Therapy”. Int. J. Mol. Sci., 2017, 18, pii: E1786.

[4] Hamberg P., Verweij J., Sleijfer S.: “(Pre-)clinical pharmacology and activity of pazopanib, a novel multikinase angiogenesis inhibitor”. Oncologist, 2010, 15, 539.

[5] Keisner S.V., Shah S.R.: “Pazopanib: the newest tyrosine kinase inhibitor for the treatment of advanced or metastatic renal cell carcinoma”. Drugs, 2011, 71, 443.

[6] Ferrero S., Leone Roberti Maggiore U., Aiello N., Barra F., Ditto A., Bogani G., et al.: “Pharmacokinetic drug evaluation of pazopanib for the treatment of uterine leiomyosarcomas”. Expert. Opin. Drug Metab. Toxicol., 2017, 13, 881.

[7] Nakamura M., Abe Y., Tokunaga T.: “Pathological significance of vascular endothelial growth factor A isoform expression in human cancer”. Pathol. Int., 2002, 52, 331.

[8] Zebrowski B.K., Liu W., Ramirez K., Akagi Y., Mills G.B., Ellis L.M.: “Markedly elevated levels of vascular endothelial growth factor in malignant ascites”. Ann. Surg. Oncol., 1999, 6, 373.

[9] Barra F., Lorusso D., Leone Roberti Maggiore U., Ditto A., Bogani G., Raspagliesi F., et al.: “Investigational drugs for the treatment of cervical cancer”. Expert. Opin. Investig. Drugs, 2017, 26, 389.

[10] Wang J., Taylor A., Showeil R., Trivedi P., Horimoto Y., Bagwan I., et al.: “Expression profiling and significance of VEGF-A, VEGFR2, VEGFR3 and related proteins in endometrial carcinoma”. Cytokine, 2014, 68, 94.

[11] Tejpar S., Prenen H., Mazzone M.: “Overcoming resistance to antiangiogenic therapies”. Oncologist, 2012, 17, 1039.

[12] Boudou-Rouquette P., Tlemsani C., Blanchet B., Huillard O., Jouinot A., Arrondeau J., et al.: “Clinical pharmacology, drug-drug interactions and safety of pazopanib: a review”. Expert. Opin. Drug. Metab. Toxicol., 2016, 12, 1433.

[13] Morotti M., Becker C.M., Menada M.V., Ferrero S.: “Targeting tyrosine-kinases in ovarian cancer”. Expert. Opin. Investig. Drugs, 2013, 22, 1265.

[14] Kumar R., Knick V.B., Rudolph S.K., Johnson J.H., Crosby R.M., Crouthamel M.C., 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, 6, 2012.

[15] “GlaxoSmithKline. Votrient full prescribing information”. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022465lbl.pdf

[16] Deng Y., Sychterz C., Suttle A.B., Dar M.M., Bershas D., Negash K., et al.: “Bioavailability, metabolism and disposition of oral pazopanib in patients with advanced cancer”. Xenobiotica, 2013, 43, 443.

[17] Heath E.I., Forman K., Malburg L., Gainer S., Suttle A.B., Adams 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, 30, 1566.

[18] Di Gion P., Kanefendt F., Lindauer A., Scheffler M., Doroshyenko O., Fuhr U., et al.: “Clinical pharmacokinetics of tyrosine kinase inhibitors: focus on pyrimidines, pyridines and pyrroles”. Clin. Pharmacokinet., 2011, 50, 551.

[19] Tan A.R., Gibbon D.G., Stein M.N., Lindquist D., Edenfield J.W., Martin J.C., et al.: “Effects of ketoconazole and esomeprazole on the pharmacokinetics of pazopanib in patients with solid tumors”. Cancer Chemother. Pharmacol., 2013, 71, 1635.

[20] Hurwitz H.I., Dowlati A., Saini S., Savage S., Suttle A.B., Gibson D.M., et al.: “Phase I trial of pazopanib in patients with advanced cancer”. Clin. Cancer. Res., 2009, 15, 4220.

[21] Friedlander M., Hancock K.C., Rischin D., Messing M.J., Stringer C.A., Matthys G.M., et al.: “A Phase II, open-label study evaluating pazopanib in patients with recurrent ovarian cancer”. Gynecol. Oncol., 2010, 119, 32.

[22] Pignata S., Lorusso D., Scambia G., Sambataro D., Tamberi S., Cinieri S., et al.: “Pazopanib plus weekly paclitaxel versus weekly paclitaxel alone for platinum-resistant or platinum-refractory advanced ovarian cancer (MITO 11): a randomised, open-label, phase 2 trial”. Lancet. Oncol., 2015, 16, 561.

[23] Richardson D., Sill M., Cho J.K., Pearl M.L., Kehoe S.M., Hanjani P., et al.: “A randomised placebo controlled phase IIb trial of weekly paclitaxel plus/minus pazopanib in persistent or recurrent ovarian cancer”. Int. J. Gynecol. Cancer, 2014, 24, 17.

[24] du Bois A., Floquet A., Kim J.W., Rau J., del Campo J.M., Friedlander M., et al.: “Incorporation of pazopanib in maintenance therapy of ovarian cancer”. J. Clin. Oncol., 2014, 32, 3374.

[25] Monk B.J., Mas Lopez L., Zarba J.J., Oaknin A., Tarpin C., Termrungruanglert W., et al.: “Phase II, open-label study of pazopanib or lapatinib monotherapy compared with pazopanib plus lapatinib combination therapy in patients with advanced and recurrent cervical cancer”. J. Clin. Oncol., 2010, 28, 3562.

[26] Boom L.E., Ottevanger P.B., Reyners A., Kroep J.R., Witteveen P., Lalisang R., et al.: “A DGOG open-label multicenter phase II study of pazopanib in metastatic and locally advanced hormone-resistant endometrial cancer”. Ann. Oncol., 2016, 27, 858PD.

[27] Sleijfer S., Ray-Coquard I., Papai Z., Le Cesne A., Scurr M., Schoffski P., 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, 27, 3126.

[28] van der Graaf W.T., Blay J.Y., Chawla S.P., Kim D.W., Bui-Nguyen B., Casali P.G., et al.: “Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial”. Lancet, 2012, 379, 1879.

[29] Campos S.M., Brady W.E., Moxley K.M., O'Cearbhaill R.E., Lee P.S., DiSilvestro P.A., et al.: “A phase II evaluation of pazopanib in the treatment of recurrent or persistent carcinosarcoma of the uterus: a gynecologic oncology group study”. Gynecol. Oncol., 2014, 133, 537.

[30] Kim J.W., Mahner S., Wu L.Y., Shoji T., Kim B.G., Zhu J.Q., et al.: “Pazopanib maintenance therapy in East Asian women with advanced epithelial ovarian cancer: results from AGO-OVAR16 and an East Asian study”. Int. J. Gynecol. Cancer, 2018, 28, 2.

[31] Dinkic C., Eichbaum M., Schmidt M., Grischke E.M., Gebauer G., Fricke H.C., et al.: “Pazopanib (GW786034) and cyclophosphamide in patients with platinum-resistant, recurrent, pre-treated ovarian cancer - Results of the PACOVAR-trial”. Gynecol. Oncol., 2017, 146, 279.

[32] Benson C., Ray-Coquard I., Sleijfer S., Litiere S., Blay J.Y., Le Cesne A., et al.: “Outcome of uterine sarcoma patients treated with pazopanib: A retrospective analysis based on two European Organisation for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group (STBSG) clinical trials 62043 and 62072”. Gynecol. Oncol., 2016, 142, 89.

[33] Nishikawa T., Hasegawa K., Yabuno A., Yoshida H., Yasuda M., Kozawa E., et al.: “Pazopanib as a second line treatment for uterine and ovarian carcinosarcoma: a single institutional study”. J. Gynecol. Oncol., 2017, 28, e25.

[34] Stark D., Nankivell M., Pujade-Lauraine E., Kristensen G., Elit L., Stockler M., et al.: “Standard chemotherapy with or without bevacizumab in advanced ovarian cancer: quality-of-life outcomes from the International Collaboration on Ovarian Neoplasms (ICON7) phase 3 randomised trial”. Lancet. Oncol., 2013, 14, 236.

[35] Coleman R.L., Brady M.F., Herzog T.J., Sabbatini P., Armstrong D.K., Walker J.L., et al.: “Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinumsensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial”. Lancet Oncol., 2017, 18, 779.

[36] Pujade-Lauraine E., Hilpert F., Weber B., Reuss A., Poveda A., Kristensen G., et al.: “Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA openlabel randomized phase III trial”. J. Clin. Oncol., 2014, 32, 1302.

[37] du Bois A., Kristensen G., Ray-Coquard I., Reuss A., Pignata S., Colombo N., et al.: “Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): a randomised, double-blind, placebo-controlled phase 3 trial”. Lancet Oncol., 2016, 17, 78.

[38] Judson I., Verweij J., Gelderblom H., Hartmann J.T., Schoffski P., Blay J.Y., et al.: “Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial”. Lancet Oncol., 2014, 15, 415.

[39] Hensley M.L., Maki R., Venkatraman E., Geller G., Lovegren M., Aghajanian C., et al.: “Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial”. J. Clin. Oncol., 2002, 20, 2824.

[40] Maki R.G., Wathen J.K., Patel S.R., Priebat D.A., Okuno S.H., Samuels B., et al.: “Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002 [corrected]”. J. Clin. Oncol., 2007, 25, 2755.

[41] Sanfilippo R., Grosso F., Jones R.L., Banerjee S., Pilotti S., D'Incalci M., et al.: “Trabectedin in advanced uterine leiomyosarcomas: a retrospective case series analysis from two reference centers”. Gynecol. Oncol., 2011, 123, 553.