Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Review Article

Tivozanib: A New Hope for Treating Renal Cell Carcinoma

Author(s): Indu Passi, Koushal Billowria, Bhupinder Kumar and Pooja A. Chawla*

Volume 23, Issue 5, 2023

Published on: 19 September, 2022

Page: [562 - 570] Pages: 9

DOI: 10.2174/1871520622666220617103126

Price: $65

Abstract

Background: Renal cell carcinoma (RCC) is a diverse collection of malignancies with varying histological characteristics, molecular changes, prognosis, and therapeutic response. Tivozanib was first approved in March 2021 by USFDA with the brand name Fotivda. Tivozanib hydrochloride monohydrate is an oral medication that is used to treat relapsed or refractory renal cell carcinoma.

Objective: In this review, we explain renal cell carcinoma and its different types of treatment by the anti-renal carcinoma drugs.

Methods: A comprehensive literature search was conducted in the relevant databases, like ScienceDirect, PubMed, ResearchGate, and Google Scholar, to identify the studies.

Conclusion: Tivozanib is an oral VEGFR-1, VEGFR-2, and VEGFR-3 tyrosine kinase inhibitor that is extremely selective and powerful. It has much less affinity for other receptor tyrosine kinases than multi-targeted TKIs now in clinical use. Because of its long half-life in circulation, it may be able to block VEGFRs more consistently. Doserelated controllable hypertension is its most commonly seen drug-related side event. Fatigue, hoarseness, and diarrhea, which are all common side effects, are not dose-related. Because of its target specificity, tivozanib can work well with other medications that have low side effects. Blocking both the VEGF and mTOR signaling pathways at the same time provides the benefit of synergistic antitumor efficacy while also preventing treatment resistance. Thus, overall we can say that the drug tivozanib is suitable for treatment in patients with renal cell carcinoma and can be investigated in multi-center clinical trials.

Keywords: Renal cell carcinoma (RCC), vascular endothelial growth factor receptor (VEGFR), tyrosine kinase inhibitor (TKI), angiogenesis, tivozanib, malignancies.

Graphical Abstract

[1]
Motzer, R.J.; Bander, N.H.; Nanus, D.M. Renal-cell carcinoma. N. Engl. J. Med., 1996, 335(12), 865-875.
[http://dx.doi.org/10.1056/NEJM199609193351207] [PMID: 8778606]
[2]
Jonasch, E.; Gao, J.; Rathmell, W.K. Renal cell carcinoma. BMJ, 2014, g4797.
[http://dx.doi.org/10.1136/bmj.g4797] [PMID: 25385470]
[3]
Ljungberg, B.; Campbell, S.C.; Choi, H.Y.; Jacqmin, D.; Lee, J.E.; Weikert, S.; Kiemeney, L.A. The epidemiology of renal cell carcinoma. Eur. Urol., 2011, 60(4), 615-621.
[http://dx.doi.org/10.1016/j.eururo.2011.06.049] [PMID: 21741761]
[4]
Pantuck, A.J.; Zisman, A.; Belldegrun, A.S. The changing natural history of renal cell carcinoma. J. Urol., 2001, 166(5), 1611-1623.
[http://dx.doi.org/10.1016/S0022-5347(05)65640-6] [PMID: 11586189]
[5]
Kim, E.S. Tivozanib: First global approval. Drugs, 2017, 77(17), 1917-1923.
[http://dx.doi.org/10.1007/s40265-017-0825-y] [PMID: 28971328]
[6]
Motzer, R.J.; Nosov, D.; Eisen, T.; Bondarenko, I.; Lesovoy, V.; Lipatov, O.; Tomczak, P.; Lyulko, O.; Alyasova, A.; Harza, M.; Kogan, M.; Alekseev, B.Y.; Sternberg, C.N.; Szczylik, C.; Cella, D.; Ivanescu, C.; Krivoshik, A.; Strahs, A.; Esteves, B.; Berkenblit, A.; Hutson, T.E. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: Results from a phase III trial. J. Clin. Oncol., 2013, 31(30), 3791-3799.
[http://dx.doi.org/10.1200/JCO.2012.47.4940] [PMID: 24019545]
[7]
Motzer, R.J.; Escudier, B.; Oudard, S.; Hutson, T.E.; Porta, C.; Bracarda, S.; Grünwald, V.; Thompson, J.A.; Figlin, R.A.; Hollaender, N.; Urbanowitz, G.; Berg, W.J.; Kay, A.; Lebwohl, D.; Ravaud, A. Efficacy of everolimus in advanced renal cell carcinoma: A double-blind, randomised, placebo-controlled phase III trial. Lancet, 2008, 372(9637), 449-456.
[http://dx.doi.org/10.1016/S0140-6736(08)61039-9] [PMID: 18653228]
[8]
Rini, B.I.; Pal, S.K.; Escudier, B.J.; Atkins, M.B.; Hutson, T.E.; Porta, C.; Verzoni, E.; Needle, M.N.; McDermott, D.F. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): A phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol., 2020, 21(1), 95-104.
[http://dx.doi.org/10.1016/S1470-2045(19)30735-1] [PMID: 31810797]
[9]
Lézard, L. FOTIVDA®(tivozanib) now approved for the treatment of relapsed/refractory advanced renal cell carcinoma following two or more prior systemic therapies; Onco360® selected as specialty pharmacy partner. 2021. Available from: http://www.onco360.com/assets/Fotivda-Press-Release.pdf
[10]
Pal, S.K.; Escudier, B.J.; Atkins, M.B.; Hutson, T.E.; Porta, C.; Verzoni, E.; Needle, M.N.; Powers, D.; McDermott, D.F.; Rini, B.I. Final overall survival results from a phase 3 study to compare tivozanib to sorafenib as third-or fourth-line therapy in subjects with metastatic renal cell carcinoma. Eur. Urol., 2020, 78(6), 783-785.
[http://dx.doi.org/10.1016/j.eururo.2020.08.007] [PMID: 32938569]
[11]
Monzon, J.G.; Heng, D.Y. Management of metastatic kidney cancer in the era of personalized medicine. Crit. Rev. Clin. Lab. Sci., 2014, 51(2), 85-97.
[http://dx.doi.org/10.3109/10408363.2013.869544] [PMID: 24450515]
[12]
Jamil, M.O.; Hathaway, A.; Mehta, A. Tivozanib: Status of development. Curr. Oncol. Rep., 2015, 17(6), 24.
[http://dx.doi.org/10.1007/s11912-015-0451-3] [PMID: 25895472]
[13]
Elfiky, A.A.; Sonpavde, G. Novel molecular targets for the therapy of renal cell carcinoma. Discov. Med., 2012, 13(73), 461-471.
[PMID: 22742652]
[14]
Badal, S.A.M.; Aiken, W.D.; Chin, S.N. Molecular targets and angiogenesis in renal cell carcinoma, a multitarget approach: Mini review. Curr. Drug Targets, 2017, 18(10), 1204-1213.
[http://dx.doi.org/10.2174/1389450117666160502152518] [PMID: 27138755]
[15]
Lopez-Beltran, A.; Cheng, L.; Vidal, A.; Scarpelli, M.; Kirkali, Z.; Blanca, A.; Montironi, R. Pathology of renal cell carcinoma: An update. Anal. Quant. Cytopathol. Histpathol., 2013, 35(2), 61-76.
[PMID: 23700715]
[16]
Petejova, N.; Martinek, A. Renal cell carcinoma: Review of etiology, pathophysiology and risk factors. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub., 2016, 160(2), 183-194.
[17]
Mikami, S.; Oya, M.; Mizuno, R.; Kosaka, T.; Ishida, M.; Kuroda, N.; Nagashima, Y.; Katsube, K.; Okada, Y. Recent advances in renal cell carcinoma from a pathological point of view. Pathol. Int., 2016, 66(9), 481-490.
[http://dx.doi.org/10.1111/pin.12433] [PMID: 27461942]
[18]
Motzer, R.J.; Hutson, T.E.; Cella, D.; Reeves, J.; Hawkins, R.; Guo, J.; Nathan, P.; Staehler, M.; de Souza, P.; Merchan, J.R.; Boleti, E.; Fife, K.; Jin, J.; Jones, R.; Uemura, H.; De Giorgi, U.; Harmenberg, U.; Wang, J.; Sternberg, C.N.; Deen, K.; McCann, L.; Hackshaw, M.D.; Crescenzo, R.; Pandite, L.N.; Choueiri, T.K. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N. Engl. J. Med., 2013, 369(8), 722-731.
[http://dx.doi.org/10.1056/NEJMoa1303989] [PMID: 23964934]
[19]
Hanna, S.C.; Heathcote, S.A.; Kim, W.Y. mTOR pathway in renal cell carcinoma. Expert Rev. Anticancer Ther., 2008, 8(2), 283-292.
[http://dx.doi.org/10.1586/14737140.8.2.283] [PMID: 18279068]
[20]
Nabi, S.; Kessler, E.R.; Bernard, B.; Flaig, T.W.; Lam, E.T. Renal cell carcinoma: A review of biology and pathophysiology. F1000 Res., 2018, 7, 307.
[http://dx.doi.org/10.12688/f1000research.13179.1] [PMID: 29568504]
[21]
Motzer, R.J.; Escudier, B.; McDermott, D.F.; George, S.; Hammers, H.J.; Srinivas, S.; Tykodi, S.S.; Sosman, J.A.; Procopio, G.; Plimack, E.R.; Castellano, D.; Choueiri, T.K.; Gurney, H.; Donskov, F.; Bono, P.; Wagstaff, J.; Gauler, T.C.; Ueda, T.; Tomita, Y.; Schutz, F.A.; Kollmannsberger, C.; Larkin, J.; Ravaud, A.; Simon, J.S.; Xu, L.A.; Waxman, I.M.; Sharma, P. Nivolumab versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med., 2015, 373(19), 1803-1813.
[http://dx.doi.org/10.1056/NEJMoa1510665] [PMID: 26406148]
[22]
Salgia, N.J.; Zengin, Z.B.; Pal, S.K. Tivozanib in renal cell carcinoma: A new approach to previously treated disease. Ther. Adv. Med. Oncol., 2020, 12, 1758835920923818.
[http://dx.doi.org/10.1177/1758835920923818] [PMID: 32547647]
[23]
Cowey, C.L. Profile of tivozanib and its potential for the treatment of advanced renal cell carcinoma. Drug Des. Devel. Ther., 2013, 7, 519-527.
[http://dx.doi.org/10.2147/DDDT.S31442] [PMID: 23818763]
[24]
Sonpavde, G.; Hutson, T.E.; Rini, B.I. Axitinib for renal cell carcinoma. Expert Opin. Investig. Drugs, 2008, 17(5), 741-748.
[http://dx.doi.org/10.1517/13543784.17.5.741] [PMID: 18447599]
[25]
Kelly, R.J.; Rixe, O. Axitinib (AG-013736); Small Molecules in Oncology, 2010, pp. 33-44.
[26]
Sonpavde, G.; Hutson, T.E. Pazopanib: A novel multitargeted tyrosine kinase inhibitor. Curr. Oncol. Rep., 2007, 9(2), 115-119.
[http://dx.doi.org/10.1007/s11912-007-0007-2] [PMID: 17288876]
[27]
Kalpathy-Cramer, J.; Chandra, V.; Da, X.; Ou, Y.; Emblem, K.E.; Muzikansky, A.; Cai, X.; Douw, L.; Evans, J.G.; Dietrich, J.; Chi, A.S.; Wen, P.Y.; Stufflebeam, S.; Rosen, B.; Duda, D.G.; Jain, R.K.; Batchelor, T.T.; Gerstner, E.R. Phase II study of tivozanib, an oral VEGFR inhibitor, in patients with recurrent glioblastoma. J. Neurooncol., 2017, 131(3), 603-610.
[http://dx.doi.org/10.1007/s11060-016-2332-5] [PMID: 27853960]
[28]
Rini, B.I. Sorafenib. Expert Opin. Pharmacother., 2006, 7(4), 453-461.
[http://dx.doi.org/10.1517/14656566.7.4.453] [PMID: 16503817]
[29]
Hahn, O.; Stadler, W. Sorafenib. Curr. Opin. Oncol., 2006, 18(6), 615-621.
[http://dx.doi.org/10.1097/01.cco.0000245316.82391.52] [PMID: 16988583]
[30]
Rini, B.I. Temsirolimus, an inhibitor of mammalian target of rapamycin. Clin. Cancer Res., 2008, 14(5), 1286-1290.
[http://dx.doi.org/10.1158/1078-0432.CCR-07-4719] [PMID: 18316545]
[31]
Kwitkowski, V.E.; Prowell, T.M.; Ibrahim, A.; Farrell, A.T.; Justice, R.; Mitchell, S.S.; Sridhara, R.; Pazdur, R. FDA approval summary: Temsirolimus as treatment for advanced renal cell carcinoma. Oncologist, 2010, 15(4), 428-435.
[http://dx.doi.org/10.1634/theoncologist.2009-0178] [PMID: 20332142]
[32]
Yao, J.C.; Shah, M.H.; Ito, T.; Bohas, C.L.; Wolin, E.M.; Van Cutsem, E.; Hobday, T.J.; Okusaka, T.; Capdevila, J.; de Vries, E.G.; Tomassetti, P.; Pavel, M.E.; Hoosen, S.; Haas, T.; Lincy, J.; Lebwohl, D.; Öberg, K. Everolimus for advanced pancreatic neuroendocrine tumors. N. Engl. J. Med., 2011, 364(6), 514-523.
[http://dx.doi.org/10.1056/NEJMoa1009290] [PMID: 21306238]
[33]
Dunn, C.; Croom, K.F. Everolimus: A review of its use in renal and cardiac transplantation. Drugs, 2006, 66(4), 547-570.
[http://dx.doi.org/10.2165/00003495-200666040-00009] [PMID: 16597167]
[34]
Liu, M.X.; Hu, L.X.; Wang, X.W.; Zhu, H.D. Synthesis of anticancer targeted therapies drug tivozanib. In: Advanced Materials Research; Trans Tech Publications Ltd.: Bach 2012, Vol. 396, pp. 1490-1492.
[35]
Nakamura, K.; Taguchi, E.; Miura, T.; Yamamoto, A.; Takahashi, K.; Bichat, F.; Guilbaud, N.; Hasegawa, K.; Kubo, K.; Fujiwara, Y.; Suzuki, R.; Kubo, K.; Shibuya, M.; Isae, T. KRN951, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, has antitumor activities and affects functional vascular properties. Cancer Res., 2006, 66(18), 9134-9142.
[http://dx.doi.org/10.1158/0008-5472.CAN-05-4290] [PMID: 16982756]
[36]
Escudier, B.; Eisen, T.; Stadler, W.M.; Szczylik, C.; Oudard, S.; Siebels, M.; Negrier, S.; Chevreau, C.; Solska, E.; Desai, A.A.; Rolland, F.; Demkow, T.; Hutson, T.E.; Gore, M.; Freeman, S.; Schwartz, B.; Shan, M.; Simantov, R.; Bukowski, R.M. Sorafenib in advanced clear-cell renal-cell carcinoma. N. Engl. J. Med., 2007, 356(2), 125-134.
[http://dx.doi.org/10.1056/NEJMoa060655] [PMID: 17215530]
[37]
Eskens, F.A.; de Jonge, M.J.; Bhargava, P.; Isoe, T.; Cotreau, M.M.; Esteves, B.; Hayashi, K.; Burger, H.; Thomeer, M.; van Doorn, L.; Verweij, J. Biologic and clinical activity of tivozanib (AV-951, KRN-951), a selective inhibitor of VEGF receptor-1, -2, and -3 tyrosine kinases, in a 4-week-on, 2-week-off schedule in patients with advanced solid tumors. Clin. Cancer Res., 2011, 17(22), 7156-7163.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-0411] [PMID: 21976547]
[38]
Cotreau, M.M.; Siebers, N.M.; Miller, J.; Strahs, A.L.; Slichenmyer, W. Effects of ketoconazole or rifampin on the pharmacokinetics of tivozanib hydrochloride, a vascular endothelial growth factor receptor tyrosine kinase inhibitor. Clin. Pharmacol. Drug Dev., 2015, 4(2), 137-142.
[http://dx.doi.org/10.1002/cpdd.145] [PMID: 27128217]
[39]
Haberkorn, B.C.; Eskens, F.A. Structure, development, preclinical and clinical efficacy of tivozanib (KRN-951, AV-951). Future Oncol., 2013, 9(1), 13-20.
[http://dx.doi.org/10.2217/fon.12.167] [PMID: 23252559]
[40]
Fountzilas, C.; Gupta, M.; Lee, S.; Krishnamurthi, S.; Estfan, B.; Wang, K.; Attwood, K.; Wilton, J.; Bies, R.; Bshara, W.; Iyer, R. A multicentre phase 1b/2 study of tivozanib in patients with advanced inoperable hepatocellular carcinoma. Br. J. Cancer, 2020, 122(7), 963-970.
[http://dx.doi.org/10.1038/s41416-020-0737-6] [PMID: 32037403]
[41]
Mehta, A.; Sonpavde, G.; Escudier, B. Tivozanib for the treatment of renal cell carcinoma: Results and implications of the TIVO-1 trial. Future Oncol., 2014, 10(11), 1819-1826.
[http://dx.doi.org/10.2217/fon.14.120] [PMID: 25325825]
[42]
Fishman, M.N.; Srinivas, S.; Hauke, R.J.; Amato, R.J.; Esteves, B.; Cotreau, M.M.; Strahs, A.L.; Slichenmyer, W.J.; Bhargava, P.; Kabbinavar, F.F. Phase Ib study of tivozanib (AV-951) in combination with temsirolimus in patients with renal cell carcinoma. Eur. J. Cancer, 2013, 49(13), 2841-2850.
[http://dx.doi.org/10.1016/j.ejca.2013.04.019] [PMID: 23726267]
[43]
Escudier, B.; Porta, C.; Eisen, T.; Belsey, J.; Gibson, D.; Morgan, J.; Motzer, R. The role of tivozanib in advanced renal cell carcinoma therapy. Expert Rev. Anticancer Ther., 2018, 18(11), 1113-1124.
[http://dx.doi.org/10.1080/14737140.2018.1508348] [PMID: 30084668]
[44]
Reckova, M.; Mego, M.; Svetlovska, D.; Miskovska, V.; Obertova, J.; Sycova-Mila, Z.; Palacka, P.; Rajec, J.; Liskova, S.; Mardiak, J.; Phase, I.I. Study of everolimus (E) in refractory germ cell tumors (GCTS). Ann. Oncol., 2012, 23, ix293.
[http://dx.doi.org/10.1016/S0923-7534(20)33358-5]
[45]
Bhargava, P.; Robinson, M.O. Development of second-generation VEGFR tyrosine kinase inhibitors: Current status. Curr. Oncol. Rep., 2011, 13(2), 103-111.
[http://dx.doi.org/10.1007/s11912-011-0154-3] [PMID: 21318618]
[46]
Jacob, A.; Shook, J.; Hutson, T.E. Tivozanib, a highly potent and selective inhibitor of VEGF receptor tyrosine kinases, for the treatment of metastatic renal cell carcinoma. Future Oncol., 2020, 16(28), 2147-2164.
[http://dx.doi.org/10.2217/fon-2020-0443] [PMID: 32692256]
[47]
Hutson, T.E.; Nosov, D.; Eisen, T.; Lipatov, O.N.; Tomczak, P.; Alyasova, A.; Harza, M.; Kogan, M.; Alexseev, B.Y.; Szczylik, C.; Strahs, A.L. Subgroup analyses of a phase III trial comparing tivozanib hydrochloride versus sorafenib as initial targeted therapy for patients (pts) with metastatic renal cell carcinoma (mRCC). J. Clin. Oncol., 2013, 31(6), 354-354.
[48]
Rini, B.I.; Atkins, M.B.; Escudier, B.J.; Hutson, T.E.; Koralewski, P.; McDermott, D.F.; Pal, S.K.; Needle, M.N.; Porta, C. Tivo-3: A phase 3, randomized, controlled, multi-center, open-label study to compare tivozanib hydrochloride to sorafenib in subjects with refractory advanced renal cell carcinoma (RCC). J. Clin. Oncol., 2019, 37(7), 541-541.
[49]
Westerman, M.E.; Wood, C.G. Editorial Commentary: Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): A phase 3, multicentre, randomised, controlled, open-label study. Ann. Transl. Med., 2020, 8(16), 1037.
[http://dx.doi.org/10.21037/atm.2020.03.217] [PMID: 32953837]
[50]
Motzer, R.J.; Nosov, D.; Eisen, T.; Bondarenko, I.N.; Lesovoy, V.; Lipatov, O.N.; Tomczak, P.; Lyulko, A.A.; Alyasova, A.; Harza, M.; Kogan, M.; Alexeev, B.Y.; Sternberg, C.N.; Szczylik, C.; Zhang, J.; Strahs, A.L.; Esteves, B.; Slichenmyer, W.J.; Berkenblit, A.; Hutson, T.E. Tivozanib versus sorafenib as initial targeted therapy for patients with advanced renal cell carcinoma: Results from a phase III randomized, open-label, multicenter trial. J. Clin. Oncol., 2012, 30(15), 277S.
[http://dx.doi.org/10.1200/jco.2012.30.15_suppl.4501]
[51]
Manz, K.M.; Fenchel, K.; Eilers, A.; Morgan, J.; Wittling, K.; Dempke, W.C.M. Efficacy and safety of approved first-line tyrosine kinase inhibitor treatments in metastatic renal cell carcinoma: A network meta-analysis. Adv. Ther., 2020, 37(2), 730-744.
[http://dx.doi.org/10.1007/s12325-019-01167-2] [PMID: 31838709]
[52]
Nosov, D.A.; Esteves, B.; Lipatov, O.N.; Lyulko, A.A.; Anischenko, A.A.; Chacko, R.T.; Doval, D.C.; Strahs, A.; Slichenmyer, W.J.; Bhargava, P. Antitumor activity and safety of tivozanib (AV-951) in a phase II randomized discontinuation trial in patients with renal cell carcinoma. J. Clin. Oncol., 2012, 30(14), 1678-1685.
[http://dx.doi.org/10.1200/JCO.2011.35.3524] [PMID: 22493422]
[53]
Kalathil, S.G.; Wang, K.; Hutson, A.; Iyer, R.; Thanavala, Y. Tivozanib mediated inhibition of c-Kit/SCF signaling on Tregs and MDSCs and reversal of tumor induced immune suppression correlates with survival of HCC patients. OncoImmunology, 2020, 9(1), 1824863.
[http://dx.doi.org/10.1080/2162402X.2020.1824863] [PMID: 33101775]
[54]
Hudes, G.; Carducci, M.; Tomczak, P.; Dutcher, J.; Figlin, R.; Kapoor, A.; Staroslawska, E.; Sosman, J.; McDermott, D.; Bodrogi, I.; Kovacevic, Z.; Lesovoy, V.; Schmidt-Wolf, I.G.; Barbarash, O.; Gokmen, E.; O’Toole, T.; Lustgarten, S.; Moore, L.; Motzer, R.J. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med., 2007, 356(22), 2271-2281.
[http://dx.doi.org/10.1056/NEJMoa066838] [PMID: 17538086]
[55]
Guo, S.; Pang, X.; Peng, L.; Zhan, M.; Fan, L.; Gong, Y.; Kang, F.; Chen, Y. Design, synthesis and biological evaluation of deuterated tivozanib for improving pharmacokinetic properties. Bioorg. Med. Chem. Lett., 2015, 25(11), 2425-2428.
[http://dx.doi.org/10.1016/j.bmcl.2015.03.088] [PMID: 25908516]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy