Current Treatment Options for HCC: From Pharmacokinetics to Efficacy and Adverse Events in Liver Cirrhosis

Author(s): Giovanni Galati*, Antonio Fabio Massimo Vainieri*, Claudia Angela Maria Fulgenzi, Stefano Di Donato, Marianna Silletta, Paolo Gallo, Angelo Onorato, Umberto Vespasiani-Gentilucci, Antonio Picardi

Journal Name: Current Drug Metabolism

Volume 21 , Issue 11 , 2020


Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Background: Hepatocellular carcinoma (HCC) is among the world’s most common cancers. For over ten years, the only medical treatment for it has been the multikinase inhibitor Sorafenib. Currently, however, other first or second-line therapeutic options have also shown efficacy against HCC, such as multikinase inhibitors (Regorafenib, Lenvatinib, and Cabozantinib), a monoclonal antibody against the vascular endothelial growth factor receptor 2 (Ramucirumab), and immune-checkpoint inhibitors (Nivolumab, Pembrolizumab, Ipilimumab).

Aim: The aim of this paper is to review the metabolic pathways of drugs that have been tested for the treatment of HCC and the potential influence of liver failure over those pathways.

Methods: The Food and Drug Administration (FDA)’s and European Medicines Agency (EMA)’s datasheets, results from clinical trials and observational studies have been reviewed.

Results: This review summarizes the current knowledge regarding targets, metabolic pathways, drug interactions, and adverse events of medical treatments for HCC in cirrhotic patients.

Conclusion: The new scenario of systemic HCC therapy includes more active drugs with different metabolic pathways and different liver adverse events. Clinical and pharmacological studies providing more data on the safety of these molecules are urgently needed.

Keywords: Hepatocellular carcinoma, multikinase inhibitors, immune-checkpoint inhibitors, pharmacokinetics, pharmacodynamics, metabolism, liver cirrhosis.

[1]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
Valery, P.C.; Laversanne, M.; Clark, P.J.; Petrick, J.L.; McGlynn, K.A.; Bray, F. Projections of primary liver cancer to 2030 in 30 countries worldwide. Hepatology, 2018, 67(2), 600-611.
[http://dx.doi.org/10.1002/hep.29498] [PMID: 28859220]
[3]
Yang, J.D.; Hainaut, P.; Gores, G.J.; Amadou, A.; Plymoth, A.; Roberts, L.R. A global view of hepatocellular carcinoma: Trends, risk, prevention and management. Nat. Rev. Gastroenterol. Hepatol., 2019, 16(10), 589-604.
[http://dx.doi.org/10.1038/s41575-019-0186-y] [PMID: 31439937]
[4]
Pennisi, G.; Celsa, C.; Giammanco, A.; Spatola, F.; Petta, S. The Burden of Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease: Screening Issue and Future Perspectives. Int. J. Mol. Sci., 2019, 20(22), 5613.
[http://dx.doi.org/10.3390/ijms20225613] [PMID: 31717576]
[5]
European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J. Hepatol., 2018, 69(1), 182-236.
[PMID: 29628281]
[6]
Geschwind, J-F.H. Locoregional Therapy for Patients With Hepatocellular Carcinoma. Gastroenterol. Hepatol. (N. Y.), 2015, 11(10), 698-700.
[PMID: 27330497]
[7]
Akateh, C.; Black, S.M.; Conteh, L.; Miller, E.D.; Noonan, A.; Elliott, E.; Pawlik, T.M.; Tsung, A.; Cloyd, J.M. Neoadjuvant and adjuvant treatment strategies for hepatocellular carcinoma. World J. Gastroenterol., 2019, 25(28), 3704-3721.
[http://dx.doi.org/10.3748/wjg.v25.i28.3704] [PMID: 31391767]
[8]
Yamamoto, M.; Arii, S.; Sugahara, K.; Tobe, T. Adjuvant oral chemotherapy to prevent recurrence after curative resection for hepatocellular carcinoma. Br. J. Surg., 1996, 83(3), 336-340.
[http://dx.doi.org/10.1002/bjs.1800830313] [PMID: 8665186]
[9]
Ono, T.; Yamanoi, A.; Nazmy El Assal, O.; Kohno, H.; Nagasue, N. Adjuvant chemotherapy after resection of hepatocellular carcinoma causes deterioration of long-term prognosis in cirrhotic patients: Metaanalysis of three randomized controlled trials. Cancer, 2001, 91(12), 2378-2385.
[http://dx.doi.org/10.1002/1097-0142(20010615)91:12<2378::AID-CNCR1271>3.0.CO;2-2] [PMID: 11413528]
[10]
Wang, J.; He, X.D.; Yao, N.; Liang, W.J.; Zhang, Y.C. A meta-analysis of adjuvant therapy after potentially curative treatment for hepatocellular carcinoma. Can. J. Gastroenterol., 2013, 27(6), 351-363.
[http://dx.doi.org/10.1155/2013/417894] [PMID: 23781519]
[11]
Lai, E.C.; Lo, C.M.; Fan, S.T.; Liu, C.L.; Wong, J. Postoperative adjuvant chemotherapy after curative resection of hepatocellular carcinoma: A randomized controlled trial. Arch. Surg., 1998, 133(2), 183-188.
[http://dx.doi.org/10.1001/archsurg.133.2.183] [PMID: 9484732]
[12]
Verbeeck, R.K. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur. J. Clin. Pharmacol., 2008, 64(12), 1147-1161.
[http://dx.doi.org/10.1007/s00228-008-0553-z] [PMID: 18762933]
[13]
Tam, Y.K. Individual variation in first-pass metabolism. Clin. Pharmacokinet., 1993, 25(4), 300-328.
[http://dx.doi.org/10.2165/00003088-199325040-00005] [PMID: 8261714]
[14]
Tillement, J.P.; Lhoste, F.; Giudicelli, J.F. Diseases and drug protein binding. Clin. Pharmacokinet., 1978, 3(2), 144-154.
[http://dx.doi.org/10.2165/00003088-197803020-00004] [PMID: 25156]
[15]
García-Morillas, M.; Gil-Extremera, B.; Caracuel-Ruiz, M.D. Differential effects of hepatic cirrhosis on the plasma protein binding of drugs. Int. J. Clin. Pharmacol. Res., 1984, 4(5), 327-333.
[PMID: 6519849]
[16]
Elbekai, R.H.; Korashy, H.M.; El-Kadi, A.O.S. The effect of liver cirrhosis on the regulation and expression of drug metabolizing enzymes. Curr. Drug Metab., 2004, 5(2), 157-167.
[http://dx.doi.org/10.2174/1389200043489054] [PMID: 15078193]
[17]
Lu, Y.; Cederbaum, A.I. CYP2E1 and oxidative liver injury by alcohol. Free Radic. Biol. Med., 2008, 44(5), 723-738.
[http://dx.doi.org/10.1016/j.freeradbiomed.2007.11.004] [PMID: 18078827]
[18]
Pena, M.A.; Horga, J.F.; Zapater, P. Variations of pharmacokinetics of drugs in patients with cirrhosis. Expert Rev. Clin. Pharmacol., 2016, 9(3), 441-458.
[http://dx.doi.org/10.1586/17512433.2016.1135733] [PMID: 26696448]
[19]
Thakkar, N.; Slizgi, J.R.; Brouwer, K.L.R. Effect of Liver Disease on Hepatic Transporter Expression and Function. J. Pharm. Sci., 2017, 106(9), 2282-2294.
[http://dx.doi.org/10.1016/j.xphs.2017.04.053] [PMID: 28465155]
[20]
Morgan, D.J.; McLean, A.J. Clinical pharmacokinetic and pharmacodynamic considerations in patients with liver disease. An update. Clin. Pharmacokinet., 1995, 29(5), 370-391.
[http://dx.doi.org/10.2165/00003088-199529050-00005] [PMID: 8582120]
[21]
Levine, W.G. Biliary excretion of drugs and other xenobiotics. Annu. Rev. Pharmacol. Toxicol., 1978, 18, 81-96.
[http://dx.doi.org/10.1146/annurev.pa.18.040178.000501] [PMID: 348071]
[22]
Dreisbach, A.W.; Lertora, J.J.L. The effect of chronic renal failure on hepatic drug metabolism and drug disposition. Semin. Dial., 2003, 16(1), 45-50.
[http://dx.doi.org/10.1046/j.1525-139X.2003.03011.x] [PMID: 12535300]
[23]
Korashy, H.M.; Elbekai, R.H.; El-Kadi, A.O.S. Effects of renal diseases on the regulation and expression of renal and hepatic drug-metabolizing enzymes: A review. Xenobiotica, 2004, 34(1), 1-29.
[http://dx.doi.org/10.1080/00498250310001638460] [PMID: 14742134]
[24]
Nolin, T.D.; Frye, R.F.; Matzke, G.R. Hepatic drug metabolism and transport in patients with kidney disease. Am. J. Kidney Dis., 2003, 42(5), 906-925.
[http://dx.doi.org/10.1016/j.ajkd.2003.07.019] [PMID: 14582035]
[25]
Pichette, V.; Leblond, F.A. Drug metabolism in chronic renal failure. Curr. Drug Metab., 2003, 4(2), 91-103.
[http://dx.doi.org/10.2174/1389200033489532] [PMID: 12678690]
[26]
Heimbach, J.K.; Kulik, L.M.; Finn, R.S.; Sirlin, C.B.; Abecassis, M.M.; Roberts, L.R.; Zhu, A.X.; Murad, M.H.; Marrero, J.A. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology, 2018, 67(1), 358-380.
[http://dx.doi.org/10.1002/hep.29086] [PMID: 28130846]
[27]
Vogel, A.; Cervantes, A.; Chau, I.; Daniele, B.; Llovet, J.M.; Meyer, T.; Nault, J-C.; Neumann, U.; Ricke, J.; Sangro, B.; Schirmacher, P.; Verslype, C.; Zech, C.J.; Arnold, D.; Martinelli, E. ESMO Guidelines Committee. Hepatocellular Carcinoma: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up. Ann. Oncol., 2018, 29(Suppl. 4), iv238-iv255.
[http://dx.doi.org/10.1093/annonc/mdy308]
[29]
Keating, G.M.; Santoro, A. Sorafenib: A review of its use in advanced hepatocellular carcinoma. Drugs, 2009, 69(2), 223-240.
[http://dx.doi.org/10.2165/00003495-200969020-00006] [PMID: 19228077]
[30]
Strumberg, D.; Richly, H.; Hilger, R.A.; Schleucher, N.; Korfee, S.; Tewes, M.; Faghih, M.; Brendel, E.; Voliotis, D.; Haase, C.G.; Schwartz, B.; Awada, A.; Voigtmann, R.; Scheulen, M.E.; Seeber, S.; Phase, I. Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J. Clin. Oncol., 2005, 23(5), 965-972.
[http://dx.doi.org/10.1200/JCO.2005.06.124] [PMID: 15613696]
[31]
Adnane, L.; Trail, P.A.; Taylor, I.; Wilhelm, S.M. Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol., 2006, 407, 597-612.
[http://dx.doi.org/10.1016/S0076-6879(05)07047-3] [PMID: 16757355]
[32]
Liu, L.; Cao, Y.; Chen, C.; Zhang, X.; McNabola, A.; Wilkie, D.; Wilhelm, S.; Lynch, M.; Carter, C. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res., 2006, 66(24), 11851-11858.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-1377] [PMID: 17178882]
[33]
Chen, K-F.; Tai, W-T.; Liu, T-H.; Huang, H-P.; Lin, Y-C.; Shiau, C-W.; Li, P-K.; Chen, P-J.; Cheng, A-L. Sorafenib overcomes TRAIL resistance of hepatocellular carcinoma cells through the inhibition of STAT3. Clin. Cancer Res., 2010, 16(21), 5189-5199.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-3389] [PMID: 20884624]
[34]
Swamy, S.G.; Kameshwar, V.H.; Shubha, P.B.; Looi, C.Y.; Shanmugam, M.K.; Arfuso, F.; Dharmarajan, A.; Sethi, G.; Shivananju, N.S.; Bishayee, A. Targeting multiple oncogenic pathways for the treatment of hepatocellular carcinoma. Target. Oncol., 2017, 12(1), 1-10.
[http://dx.doi.org/10.1007/s11523-016-0452-7] [PMID: 27510230]
[35]
Tai, W-T.; Cheng, A-L.; Shiau, C-W.; Huang, H-P.; Huang, J-W.; Chen, P-J.; Chen, K-F. Signal transducer and activator of transcription 3 is a major kinase-independent target of sorafenib in hepatocellular carcinoma. J. Hepatol., 2011, 55(5), 1041-1048.
[http://dx.doi.org/10.1016/j.jhep.2011.01.047] [PMID: 21354226]
[36]
Sonntag, R.; Gassler, N.; Bangen, J-M.; Trautwein, C.; Liedtke, C. Pro-apoptotic Sorafenib signaling in murine hepatocytes depends on malignancy and is associated with PUMA expression in vitro and in vivo. Cell Death Dis., 2014, 5e1030
[http://dx.doi.org/10.1038/cddis.2013.557] [PMID: 24481444]
[37]
Chen, M-L.; Yan, B-S.; Lu, W-C.; Chen, M-H.; Yu, S-L.; Yang, P-C.; Cheng, A-L. Sorafenib relieves cell-intrinsic and cell-extrinsic inhibitions of effector T cells in tumor microenvironment to augment antitumor immunity. Int. J. Cancer, 2014, 134(2), 319-331.
[http://dx.doi.org/10.1002/ijc.28362] [PMID: 23818246]
[38]
Cao, M.; Xu, Y.; Youn, J.I.; Cabrera, R.; Zhang, X.; Gabrilovich, D.; Nelson, D.R.; Liu, C. Kinase inhibitor Sorafenib modulates immunosuppressive cell populations in a murine liver cancer model. Lab. Invest., 2011, 91(4), 598-608.
[PMID: 21321535]
[39]
Strumberg, D.; Clark, J.W.; Awada, A.; Moore, M.J.; Richly, H.; Hendlisz, A.; Hirte, H.W.; Eder, J.P.; Lenz, H-J.; Schwartz, B. Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: A review of four phase I trials in patients with advanced refractory solid tumors. Oncologist, 2007, 12(4), 426-437.
[http://dx.doi.org/10.1634/theoncologist.12-4-426] [PMID: 17470685]
[40]
Awada, A.; Hendlisz, A.; Gil, T.; Bartholomeus, S.; Mano, M.; de Valeriola, D.; Strumberg, D.; Brendel, E.; Haase, C.G.; Schwartz, B.; Piccart, M.; Phase, I. Phase I safety and pharmacokinetics of BAY 43-9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours. Br. J. Cancer, 2005, 92(10), 1855-1861.
[PMID: 15870716]
[41]
Clark, J.W.; Eder, J.P.; Ryan, D.; Lathia, C.; Lenz, H-J. Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43-9006, in patients with advanced, refractory solid tumors. Clin. Cancer Res., 2005, 11(15), 5472-5480.
[http://dx.doi.org/10.1158/1078-0432.CCR-04-2658] [PMID: 16061863]
[42]
Moore, M.; Hirte, H.W.; Siu, L.; Oza, A.; Hotte, S.J.; Petrenciuc, O.; Cihon, F.; Lathia, C.; Schwartz, B.; Phase, I. Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43-9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors. Ann. Oncol., 2005, 16(10), 1688-1694.
[PMID: 16006586]
[43]
Lettieri, J. T.; Mazzu, A. L.; Huang, L.; Lathia, C. D. Effect of Hepatic Impairment on Sorafenib Pharmacokinetics: Results of a Multicenter, Open-Label, Single-Dose, Phase I Trial JCO, 2011, 29(15), 2580-2580.
[44]
Abou-Alfa, G.K.; Schwartz, L.; Ricci, S.; Amadori, D.; Santoro, A.; Figer, A.; De Greve, J.; Douillard, J-Y.; Lathia, C.; Schwartz, B.; Taylor, I.; Moscovici, M.; Saltz, L.B.; Phase, I.I. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J. Clin. Oncol., 2006, 24(26), 4293-4300.
[http://dx.doi.org/10.1200/JCO.2005.01.3441] [PMID: 16908937]
[45]
Furuse, J.; Ishii, H.; Nakachi, K.; Suzuki, E.; Shimizu, S.; Nakajima, K.; Phase, I. Phase I study of sorafenib in Japanese patients with hepatocellular carcinoma. Cancer Sci., 2008, 99(1), 159-165.
[PMID: 17953709]
[46]
Llovet, J.M.; Ricci, S.; Mazzaferro, V.; Hilgard, P.; Gane, E.; Blanc, J-F.; de Oliveira, A.C.; Santoro, A.; Raoul, J-L.; Forner, A.; Schwartz, M.; Porta, C.; Zeuzem, S.; Bolondi, L.; Greten, T.F.; Galle, P.R.; Seitz, J-F.; Borbath, I.; Häussinger, D.; Giannaris, T.; Shan, M.; Moscovici, M.; Voliotis, D.; Bruix, J. SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med., 2008, 359(4), 378-390.
[http://dx.doi.org/10.1056/NEJMoa0708857] [PMID: 18650514]
[47]
Cheng, A-L.; Kang, Y-K.; Chen, Z.; Tsao, C-J.; Qin, S.; Kim, J.S.; Luo, R.; Feng, J.; Ye, S.; Yang, T-S.; Xu, J.; Sun, Y.; Liang, H.; Liu, J.; Wang, J.; Tak, W.Y.; Pan, H.; Burock, K.; Zou, J.; Voliotis, D.; Guan, Z. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: A phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol., 2009, 10(1), 25-34.
[http://dx.doi.org/10.1016/S1470-2045(08)70285-7] [PMID: 19095497]
[48]
Wörns, M.A.; Weinmann, A.; Pfingst, K.; Schulte-Sasse, C.; Messow, C-M.; Schulze-Bergkamen, H.; Teufel, A.; Schuchmann, M.; Kanzler, S.; Düber, C.; Otto, G.; Galle, P.R. Safety and efficacy of sorafenib in patients with advanced hepatocellular carcinoma in consideration of concomitant stage of liver cirrhosis. J. Clin. Gastroenterol., 2009, 43(5), 489-495.
[http://dx.doi.org/10.1097/MCG.0b013e31818ddfc6] [PMID: 19247201]
[49]
Abou-Alfa, G.K.; Amadori, D.; Santoro, A.; Figer, A.; De Greve, J.; Lathia, C.; Voliotis, D.; Anderson, S.; Moscovici, M.; Ricci, S. Safety and Efficacy of Sorafenib in Patients with Hepatocellular Carcinoma (HCC) and Child-Pugh A versus B Cirrhosis. Gastrointest. Cancer Res., 2011, 4(2), 40-44.
[PMID: 21673874]
[50]
Kane, R.C.; Farrell, A.T.; Saber, H.; Tang, S.; Williams, G.; Jee, J.M.; Liang, C.; Booth, B.; Chidambaram, N.; Morse, D.; Sridhara, R.; Garvey, P.; Justice, R.; Pazdur, R. Sorafenib for the treatment of advanced renal cell carcinoma. Clin. Cancer Res., 2006, 12(24), 7271-7278.
[http://dx.doi.org/10.1158/1078-0432.CCR-06-1249] [PMID: 17189398]
[51]
Lathia, C.; Lettieri, J.; Cihon, F.; Gallentine, M.; Radtke, M.; Sundaresan, P. Lack of effect of ketoconazole-mediated CYP3A inhibition on sorafenib clinical pharmacokinetics. Cancer Chemother. Pharmacol., 2006, 57(5), 685-692.
[http://dx.doi.org/10.1007/s00280-005-0068-6] [PMID: 16133532]
[52]
Peer, C.J.; Sissung, T.M.; Kim, A.; Jain, L.; Woo, S.; Gardner, E.R.; Kirkland, C.T.; Troutman, S.M.; English, B.C.; Richardson, E.D.; Federspiel, J.; Venzon, D.; Dahut, W.; Kohn, E.; Kummar, S.; Yarchoan, R.; Giaccone, G.; Widemann, B.; Figg, W.D. Sorafenib is an inhibitor of UGT1A1 but is metabolized by UGT1A9: Implications of genetic variants on pharmacokinetics and hyperbilirubinemia. Clin. Cancer Res., 2012, 18(7), 2099-2107.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-2484] [PMID: 22307138]
[53]
Meza-Junco, J.; Chu, Q.S-C.; Christensen, O.; Rajagopalan, P.; Das, S.; Stefanyschyn, R.; Sawyer, M.B. UGT1A1 polymorphism and hyperbilirubinemia in a patient who received sorafenib. Cancer Chemother. Pharmacol., 2009, 65(1), 1-4.
[http://dx.doi.org/10.1007/s00280-009-1096-4] [PMID: 19672597]
[54]
[55]
Wilhelm, S.M.; Dumas, J.; Adnane, L.; Lynch, M.; Carter, C.A.; Schütz, G.; Thierauch, K-H.; Zopf, D. Regorafenib (BAY 73-4506): A new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int. J. Cancer, 2011, 129(1), 245-255.
[http://dx.doi.org/10.1002/ijc.25864] [PMID: 21170960]
[56]
Strumberg, D.; Schultheis, B. Regorafenib for cancer. Expert Opin. Investig. Drugs, 2012, 21(6), 879-889.
[http://dx.doi.org/10.1517/13543784.2012.684752] [PMID: 22577890]
[57]
Miura, K.; Satoh, M.; Kinouchi, M.; Yamamoto, K.; Hasegawa, Y.; Philchenkov, A.; Kakugawa, Y.; Fujiya, T. The preclinical development of regorafenib for the treatment of colorectal cancer. Expert Opin. Drug Discov., 2014, 9(9), 1087-1101.
[http://dx.doi.org/10.1517/17460441.2014.924923] [PMID: 24896071]
[58]
Mross, K.; Frost, A.; Steinbild, S.; Hedbom, S.; Büchert, M.; Fasol, U.; Unger, C.; Krätzschmar, J.; Heinig, R.; Boix, O.; Christensen, O. A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors. Clin. Cancer Res., 2012, 18(9), 2658-2667.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-1900] [PMID: 22421192]
[59]
Strumberg, D.; Scheulen, M.E.; Schultheis, B.; Richly, H.; Frost, A.; Büchert, M.; Christensen, O.; Jeffers, M.; Heinig, R.; Boix, O.; Mross, K. Regorafenib (BAY 73-4506) in advanced colorectal cancer: A phase I study. Br. J. Cancer, 2012, 106(11), 1722-1727.
[http://dx.doi.org/10.1038/bjc.2012.153] [PMID: 22568966]
[60]
George, S.; Wang, Q.; Heinrich, M.C.; Corless, C.L.; Zhu, M.; Butrynski, J.E.; Morgan, J.A.; Wagner, A.J.; Choy, E.; Tap, W.D.; Yap, J.T.; Van den Abbeele, A.D.; Manola, J.B.; Solomon, S.M.; Fletcher, J.A.; von Mehren, M.; Demetri, G.D. Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: A multicenter phase II trial. J. Clin. Oncol., 2012, 30(19), 2401-2407.
[PMID: 22614970]
[61]
Grothey, A.; Van Cutsem, E.; Sobrero, A.; Siena, S.; Falcone, A.; Ychou, M.; Humblet, Y.; Bouché, O.; Mineur, L.; Barone, C.; Adenis, A.; Tabernero, J.; Yoshino, T.; Lenz, H-J.; Goldberg, R.M.; Sargent, D.J.; Cihon, F.; Cupit, L.; Wagner, A.; Laurent, D. CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): An international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet, 2013, 381(9863), 303-312.
[http://dx.doi.org/10.1016/S0140-6736(12)61900-X] [PMID: 23177514]
[62]
Li, J.; Qin, S.; Xu, R.; Yau, T.C.C.; Ma, B.; Pan, H.; Xu, J.; Bai, Y.; Chi, Y.; Wang, L.; Yeh, K-H.; Bi, F.; Cheng, Y.; Le, A.T.; Lin, J-K.; Liu, T.; Ma, D.; Kappeler, C.; Kalmus, J.; Kim, T.W. CONCUR Investigators. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol., 2015, 16(6), 619-629.
[http://dx.doi.org/10.1016/S1470-2045(15)70156-7] [PMID: 25981818]
[63]
Demetri, G.D.; Reichardt, P.; Kang, Y-K.; Blay, J-Y.; Rutkowski, P.; Gelderblom, H.; Hohenberger, P.; Leahy, M.; von Mehren, M.; Joensuu, H.; Badalamenti, G.; Blackstein, M.; Le Cesne, A.; Schöffski, P.; Maki, R.G.; Bauer, S.; Nguyen, B.B.; Xu, J.; Nishida, T.; Chung, J.; Kappeler, C.; Kuss, I.; Laurent, D.; Casali, P.G. GRID study investigators. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): An international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet, 2013, 381(9863), 295-302.
[http://dx.doi.org/10.1016/S0140-6736(12)61857-1] [PMID: 23177515]
[64]
Zopf, D.; Heinig, R.; Thierauch, K-H.; Hirth-Dietrich, C.; Hafner, F-T.; Christensen, O.; Lin, T.; Wilhelm, S.; Radtke, M. Abstract 1666: Regorafenib (BAY 73-4506): Preclinical Pharmacology and Clinical Identification and Quantification of Its Major Metabolites. Exp. Mol. Ther., 2010, 70(8), 1666-1666.
[http://dx.doi.org/10.1158/1538-7445.AM10-1666]
[65]
Fabian, M.A.; Biggs, W.H., III; Treiber, D.K.; Atteridge, C.E.; Azimioara, M.D.; Benedetti, M.G.; Carter, T.A.; Ciceri, P.; Edeen, P.T.; Floyd, M.; Ford, J.M.; Galvin, M.; Gerlach, J.L.; Grotzfeld, R.M.; Herrgard, S.; Insko, D.E.; Insko, M.A.; Lai, A.G.; Lélias, J-M.; Mehta, S.A.; Milanov, Z.V.; Velasco, A.M.; Wodicka, L.M.; Patel, H.K.; Zarrinkar, P.P.; Lockhart, D.J. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat. Biotechnol., 2005, 23(3), 329-336.
[http://dx.doi.org/10.1038/nbt1068] [PMID: 15711537]
[66]
Frenette, C.T. The Role of Regorafenib in Hepatocellular Carcinoma. Gastroenterol. Hepatol. (N. Y.), 2017, 13(2), 122-124.
[PMID: 28450818]
[67]
Hafner, F-T.; Werner, D.; Kaiser, M. Determination of regorafenib (BAY 73-4506) and its major human metabolites BAY 75-7495 (M-2) and BAY 81-8752 (M-5) in human plasma by stable-isotope dilution liquid chromatography-tandem mass spectrometry. Bioanalysis, 2014, 6(14), 1923-1937.
[http://dx.doi.org/10.4155/bio.14.52] [PMID: 25158964]
[68]
Cerrito, L.; Ponziani, F.R.; Garcovich, M.; Tortora, A.; Annicchiarico, B.E.; Pompili, M.; Siciliano, M.; Gasbarrini, A. Regorafenib: A promising treatment for hepatocellular carcinoma. Expert Opin. Pharmacother., 2018, 19(17), 1941-1948.
[http://dx.doi.org/10.1080/14656566.2018.1534956] [PMID: 30345837]
[69]
U.S. Food and Drug Administration, C. for D. E. and. Regorafenib https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204369lbl.pdf
[70]
Kim, K.; Jha, R.; Prins, P.A.; Wang, H.; Chacha, M.; Hartley, M.L.; He, A.R. Regorafenib in advanced hepatocellular carcinoma (HCC): Considerations for treatment. Cancer Chemother. Pharmacol., 2017, 80(5), 945-954.
[http://dx.doi.org/10.1007/s00280-017-3431-5] [PMID: 28932966]
[71]
van Cutsem, E.; Sobrero, A.; Siena, S.; Falcone, A.; Ychou, M.; Humblet, Y.; Bouche, O.; Mineur, L.; Barone, C.; Adenis, A.; Argilés, G.; Yoshino, T.; Lenz, H.-J.; Goldberg, R. M.; Sargent, D. J.; Cihon, F.; Wagner, A.; Laurent, D.; Cupit, L.; Grothey, A. Regorafenib (REG) in Progressive Metastatic Colorectal Cancer (MCRC): Analysis of Age Subgroups in the Phase III CORRECT Trial J. Clin. Oncol.,, 2013, 31(15), 3636-3636.
[72]
Bruix, J.; Tak, W-Y.; Gasbarrini, A.; Santoro, A.; Colombo, M.; Lim, H-Y.; Mazzaferro, V.; Wiest, R.; Reig, M.; Wagner, A.; Bolondi, L. Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: Multicentre, open-label, phase II safety study. Eur. J. Cancer, 2013, 49(16), 3412-3419.
[http://dx.doi.org/10.1016/j.ejca.2013.05.028] [PMID: 23809766]
[73]
Bruix, J.; Qin, S.; Merle, P.; Granito, A.; Huang, Y-H.; Bodoky, G.; Pracht, M.; Yokosuka, O.; Rosmorduc, O.; Breder, V.; Gerolami, R.; Masi, G.; Ross, P.J.; Song, T.; Bronowicki, J-P.; Ollivier-Hourmand, I.; Kudo, M.; Cheng, A-L.; Llovet, J.M.; Finn, R.S.; LeBerre, M-A.; Baumhauer, A.; Meinhardt, G.; Han, G. RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet, 2017, 389(10064), 56-66.
[http://dx.doi.org/10.1016/S0140-6736(16)32453-9] [PMID: 27932229]
[74]
Finn, R.S.; Merle, P.; Granito, A.; Huang, Y-H.; Bodoky, G.; Pracht, M.; Yokosuka, O.; Rosmorduc, O.; Gerolami, R.; Caparello, C.; Cabrera, R.; Chang, C.; Sun, W.; LeBerre, M-A.; Baumhauer, A.; Meinhardt, G.; Bruix, J. Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: Additional analyses from the phase III RESORCE trial. J. Hepatol., 2018, 69(2), 353-358.
[http://dx.doi.org/10.1016/j.jhep.2018.04.010] [PMID: 29704513]
[75]
Parikh, N.D.; Singal, A.G.; Hutton, D.W. Cost effectiveness of regorafenib as second-line therapy for patients with advanced hepatocellular carcinoma. Cancer, 2017, 123(19), 3725-3731.
[http://dx.doi.org/10.1002/cncr.30863] [PMID: 28662266]
[76]
Grothey, A.; Sobrero, A.F.; Siena, S.; Falcone, A.; Ychou, M.; Humblet, Y.; Bouche, O.; Mineur, L.; Barone, C.; Adenis, A.; Argiles, G.; Yoshino, T.; Lenz, H-J.; Goldberg, R.M.; Sargent, D.J.; Cihon, F.; Wagner, A.; Cupit, L.; Laurent, D.; Van Cutsem, E. Time Profile of Adverse Events (AEs) from Regorafenib (REG) Treatment for Metastatic Colorectal Cancer (MCRC) in the Phase III CORRECT Study. J. Clin. Oncol., 2013, 31(15_suppl), 3637-3637.
[77]
Belum, V. R.; Wu, S.; Lacouture, M. E. Risk of Hand-Foot Skin Reaction with the Novel Multikinase Inhibitor Regorafenib: A Meta-analysis. Invest. New Drugs, 2013, 31(4), 1078-1086.
[PMID: 23700287]
[78]
de Man, F.M.; Hussaarts, K.G.A.M.; de With, M.; Oomen-de Hoop, E.; de Bruijn, P.; van Halteren, H.K.; van der Burg-de Graauw, N.C.H.P.; Eskens, F.A.L.M.; van Gelder, T.; van Leeuwen, R.W.F.; Mathijssen, R.H.J. Influence of the Proton Pump Inhibitor Esomeprazole on the Bioavailability of Regorafenib: A Randomized Crossover Pharmacokinetic Study. Clin. Pharmacol. Ther., 2019, 105(6), 1456-1461.
[http://dx.doi.org/10.1002/cpt.1331] [PMID: 30570132]
[80]
U.S. Food and Drug Administration, C. for D. E. and. FDA Approves Lenvatinib for Unresectable Hepatocellular Carcinoma Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206947s007lbl.pdf
[81]
Brose, M.S.; Worden, F.P.; Newbold, K.L.; Guo, M.; Hurria, A. Effect of Age on the Efficacy and Safety of Lenvatinib in Radioiodine-Refractory Differentiated Thyroid Cancer in the Phase III SELECT Trial. J. Clin. Oncol., 2017, 35(23), 2692-2699.
[http://dx.doi.org/10.1200/JCO.2016.71.6472] [PMID: 28613956]
[82]
Motzer, R.J.; Hutson, T.E.; Glen, H.; Michaelson, M.D.; Molina, A.; Eisen, T.; Jassem, J.; Zolnierek, J.; Maroto, J.P.; Mellado, B.; Melichar, B.; Tomasek, J.; Kremer, A.; Kim, H-J.; Wood, K.; Dutcus, C.; Larkin, J. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: A randomised, phase 2, open-label, multicentre trial. Lancet Oncol., 2015, 16(15), 1473-1482.
[http://dx.doi.org/10.1016/S1470-2045(15)00290-9] [PMID: 26482279]
[83]
Kudo, M.; Finn, R.S.; Qin, S.; Han, K-H.; Ikeda, K.; Piscaglia, F.; Baron, A.; Park, J-W.; Han, G.; Jassem, J.; Blanc, J.F.; Vogel, A.; Komov, D.; Evans, T.R.J.; Lopez, C.; Dutcus, C.; Guo, M.; Saito, K.; Kraljevic, S.; Tamai, T.; Ren, M.; Cheng, A-L. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial. Lancet, 2018, 391(10126), 1163-1173.
[http://dx.doi.org/10.1016/S0140-6736(18)30207-1] [PMID: 29433850]
[84]
Capozzi, M.; De Divitiis, C.; Ottaiano, A.; von Arx, C.; Scala, S.; Tatangelo, F.; Delrio, P.; Tafuto, S. Lenvatinib, a molecule with versatile application: From preclinical evidence to future development in anti-cancer treatment. Cancer Manag. Res., 2019, 11, 3847-3860.
[http://dx.doi.org/10.2147/CMAR.S188316] [PMID: 31118801]
[85]
Gauglhofer, C.; Sagmeister, S.; Schrottmaier, W.; Fischer, C.; Rodgarkia-Dara, C.; Mohr, T.; Stättner, S.; Bichler, C.; Kandioler, D.; Wrba, F.; Schulte-Hermann, R.; Holzmann, K.; Grusch, M.; Marian, B.; Berger, W.; Grasl-Kraupp, B. Up-regulation of the fibroblast growth factor 8 subfamily in human hepatocellular carcinoma for cell survival and neoangiogenesis. Hepatology, 2011, 53(3), 854-864.
[http://dx.doi.org/10.1002/hep.24099] [PMID: 21319186]
[86]
Gao, L.; Wang, X.; Tang, Y.; Huang, S.; Hu, C-A.A.; Teng, Y. FGF19/FGFR4 signaling contributes to the resistance of hepatocellular carcinoma to sorafenib. J. Exp. Clin. Cancer Res., 2017, 36(1), 8.
[http://dx.doi.org/10.1186/s13046-016-0478-9] [PMID: 28069043]
[87]
Okamoto, K.; Ikemori-Kawada, M.; Jestel, A.; von König, K.; Funahashi, Y.; Matsushima, T.; Tsuruoka, A.; Inoue, A.; Matsui, J. Distinct binding mode of multikinase inhibitor lenvatinib revealed by biochemical characterization. ACS Med. Chem. Lett., 2014, 6(1), 89-94.
[http://dx.doi.org/10.1021/ml500394m] [PMID: 25589937]
[88]
Matsuki, M.; Hoshi, T.; Yamamoto, Y.; Ikemori-Kawada, M.; Minoshima, Y.; Funahashi, Y.; Matsui, J. Lenvatinib inhibits angiogenesis and tumor fibroblast growth factor signaling pathways in human hepatocellular carcinoma models. Cancer Med., 2018, 7(6), 2641-2653.
[http://dx.doi.org/10.1002/cam4.1517] [PMID: 29733511]
[89]
Dubbelman, A-C.; Nijenhuis, C.M.; Jansen, R.S.; Rosing, H.; Mizuo, H.; Kawaguchi, S.; Critchley, D.; Shumaker, R.; Schellens, J.H.M.; Beijnen, J.H. Metabolite profiling of the multiple tyrosine kinase inhibitor lenvatinib: A cross-species comparison. Invest. New Drugs, 2016, 34(3), 300-318.
[http://dx.doi.org/10.1007/s10637-016-0342-y] [PMID: 27018262]
[90]
Inoue, K.; Asai, N.; Mizuo, H.; Fukuda, K.; Kusano, K.; Yoshimura, T. Unique metabolic pathway of [(14)C]lenvatinib after oral administration to male cynomolgus monkey. Drug Metab. Dispos., 2012, 40(4), 662-670.
[http://dx.doi.org/10.1124/dmd.111.043281] [PMID: 22207053]
[91]
Dubbelman, A.; Rosing, H.; Mergui-Roelvink, M.; Gupta, A.; Verbel, D.; Sellecchia, R.; Fan, J.; Thompson, G.; Shumaker, R.; Huitema, A.; Beijnen, J.; Schellens, J. A Mass Balance Study of C-14-Lenvatinib (E7080) in Patients with Advanced Solid Tumours or Lymphomas. Br. J. Clin. Pharmacol., 2013, 76(3), 831-831.
[PMID: 22845008]
[92]
Hussein, Z.; Mizuo, H.; Hayato, S.; Namiki, M.; Shumaker, R. Clinical Pharmacokinetic and Pharmacodynamic Profile of Lenvatinib, an Orally Active, Small-Molecule, Multitargeted Tyrosine Kinase Inhibitor. Eur. J. Drug Metab. Pharmacokinet., 2017, 42(6), 903-914.
[http://dx.doi.org/10.1007/s13318-017-0403-4] [PMID: 28236116]
[93]
Shumaker, R.; Aluri, J.; Fan, J.; Martinez, G.; Ren, M.; Chen, K. Evaluation of the effects of formulation and food on the pharmacokinetics of lenvatinib (E7080) in healthy volunteers. Int. J. Clin. Pharmacol. Ther., 2014, 52(4), 284-291.
[http://dx.doi.org/10.5414/CP201937] [PMID: 24548978]
[94]
Boss, D.S.; Glen, H.; Beijnen, J.H.; Keesen, M.; Morrison, R.; Tait, B.; Copalu, W.; Mazur, A.; Wanders, J.; O’Brien, J.P.; Schellens, J.H.M.; Evans, T.R.J. A phase I study of E7080, a multitargeted tyrosine kinase inhibitor, in patients with advanced solid tumours. Br. J. Cancer, 2012, 106(10), 1598-1604.
[http://dx.doi.org/10.1038/bjc.2012.154] [PMID: 22516948]
[95]
Yamada, K.; Yamamoto, N.; Yamada, Y.; Nokihara, H.; Fujiwara, Y.; Hirata, T.; Koizumi, F.; Nishio, K.; Koyama, N.; Tamura, T.; Phase, I. Phase I dose-escalation study and biomarker analysis of E7080 in patients with advanced solid tumors. Clin. Cancer Res., 2011, 17(8), 2528-2537.
[http://dx.doi.org/10.1158/1078-0432.CCR-10-2638] [PMID: 21372218]
[96]
Benet, L.Z.; Hoener, B.A. Changes in plasma protein binding have little clinical relevance. Clin. Pharmacol. Ther., 2002, 71(3), 115-121.
[http://dx.doi.org/10.1067/mcp.2002.121829] [PMID: 11907485]
[97]
Dubbelman, A-C.; Rosing, H.; Nijenhuis, C.; Huitema, A.D.R.; Mergui-Roelvink, M.; Gupta, A.; Verbel, D.; Thompson, G.; Shumaker, R.; Schellens, J.H.M.; Beijnen, J.H. Pharmacokinetics and excretion of (14)C-lenvatinib in patients with advanced solid tumors or lymphomas. Invest. New Drugs, 2015, 33(1), 233-240.
[http://dx.doi.org/10.1007/s10637-014-0181-7] [PMID: 25377392]
[98]
Shumaker, R.; Aluri, J.; Fan, J.; Martinez, G.; Pentikis, H.; Ren, M. Influence of hepatic impairment on lenvatinib pharmacokinetics following single-dose oral administration. J. Clin. Pharmacol., 2015, 55(3), 317-327.
[http://dx.doi.org/10.1002/jcph.398] [PMID: 25204557]
[99]
Ikeda, M.; Okusaka, T.; Mitsunaga, S.; Ueno, H.; Tamai, T.; Suzuki, T.; Hayato, S.; Kadowaki, T.; Okita, K.; Kumada, H. Safety and Pharmacokinetics of Lenvatinib in Patients with Advanced Hepatocellular Carcinoma. Clin. Cancer Res., 2016, 22(6), 1385-1394.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-1354] [PMID: 26500236]
[100]
Nakamichi, S.; Nokihara, H.; Yamamoto, N.; Yamada, Y.; Honda, K.; Tamura, Y.; Wakui, H.; Sasaki, T.; Yusa, W.; Fujino, K.; Tamura, T. A phase 1 study of lenvatinib, multiple receptor tyrosine kinase inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother. Pharmacol., 2015, 76(6), 1153-1161.
[http://dx.doi.org/10.1007/s00280-015-2899-0] [PMID: 26530955]
[101]
Llovet, J.M.; Di Bisceglie, A.M.; Bruix, J.; Kramer, B.S.; Lencioni, R.; Zhu, A.X.; Sherman, M.; Schwartz, M.; Lotze, M.; Talwalkar, J.; Gores, G.J. Panel of Experts in HCC-Design Clinical Trials. Design and endpoints of clinical trials in hepatocellular carcinoma. J. Natl. Cancer Inst., 2008, 100(10), 698-711.
[http://dx.doi.org/10.1093/jnci/djn134] [PMID: 18477802]
[102]
Tamai, T.; Hayato, S.; Hojo, S.; Suzuki, T.; Okusaka, T.; Ikeda, K.; Kumada, H. Dose Finding of Lenvatinib in Subjects With Advanced Hepatocellular Carcinoma Based on Population Pharmacokinetic and Exposure-Response Analyses. J. Clin. Pharmacol., 2017, 57(9), 1138-1147.
[http://dx.doi.org/10.1002/jcph.917] [PMID: 28561918]
[103]
Ikeda, K.; Kudo, M.; Kawazoe, S.; Osaki, Y.; Ikeda, M.; Okusaka, T.; Tamai, T.; Suzuki, T.; Hisai, T.; Hayato, S.; Okita, K.; Kumada, H. Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma. J. Gastroenterol., 2017, 52(4), 512-519.
[http://dx.doi.org/10.1007/s00535-016-1263-4] [PMID: 27704266]
[104]
Anticancer agent lenvatinib phase Ⅲ trial results published in New England Journal of Medicine | News Release:2015 Eisai Co., Ltd., 2015. .Available from: https://www.eisai.com/news/news201508.html
[105]
Yagishita, H.; Minami, S.; Akamine, Y.; Kato, S.; Iijima, K.; Miura, M. Drug interactions between warfarin and lenvatinib in a patient with the CYP2C9*1/*3 and VKORC1-1639G/A genotype. J. Clin. Pharm. Ther., 2019, 44(6), 977-980.
[http://dx.doi.org/10.1111/jcpt.13030] [PMID: 31468576]
[106]
Benson, A.B.; D’Angelica, M.I.; Abbott, D.E.; Abrams, T.A.; Alberts, S.R.; Anaya, D.A.; Anders, R.; Are, C.; Brown, D.; Chang, D.T.; Cloyd, J.; Covey, A.M.; Hawkins, W.; Iyer, R.; Jacob, R.; Karachristos, A.; Kelley, R.K.; Kim, R.; Palta, M.; Park, J.O.; Sahai, V.; Schefter, T.; Sicklick, J.K.; Singh, G.; Sohal, D.; Stein, S.; Tian, G.G.; Vauthey, J-N.; Venook, A.P.; Hammond, L.J.; Darlow, S.D. Guidelines Insights: Hepatobiliary Cancers, Version 2.2019. J. Natl. Compr. Canc. Netw., 2019, 17(4), 302-310.
[http://dx.doi.org/10.6004/jnccn.2019.0019] [PMID: 30959462]
[107]
FDA, C. for D. E. and. FDA Approves cabozantinib for Hepatocellular Carcinoma Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/208692s003lbl.pdf
[108]
European Medicines Agency. Available from: Https://www.ema.europa.eu/en/medicines/human/epar/Cometriq
[109]
Lacy, S.A.; Miles, D.R.; Nguyen, L.T. Clinical Pharmacokinetics and Pharmacodynamics of Cabozantinib. Clin. Pharmacokinet., 2017, 56(5), 477-491.
[http://dx.doi.org/10.1007/s40262-016-0461-9] [PMID: 27734291]
[111]
Nguyen, L.; Holland, J.; Ramies, D.; Mamelok, R.; Benrimoh, N.; Ciric, S.; Marbury, T.; Preston, R.A.; Heuman, D.M.; Gavis, E.; Lacy, S. Effect of Renal and Hepatic Impairment on the Pharmacokinetics of Cabozantinib. J. Clin. Pharmacol., 2016, 56(9), 1130-1140.
[http://dx.doi.org/10.1002/jcph.714] [PMID: 26865195]
[112]
Lacy, S.; Hsu, B.; Miles, D.; Aftab, D.; Wang, R.; Nguyen, L. Metabolism and Disposition of Cabozantinib in Healthy Male Volunteers and Pharmacologic Characterization of Its Major Metabolites. Drug Metab. Dispos., 2015, 43(8), 1190-1207.
[http://dx.doi.org/10.1124/dmd.115.063610] [PMID: 26015560]
[113]
Kurzrock, R.; Sherman, S.I.; Ball, D.W.; Forastiere, A.A.; Cohen, R.B.; Mehra, R.; Pfister, D.G.; Cohen, E.E.W.; Janisch, L.; Nauling, F.; Hong, D.S.; Ng, C.S.; Ye, L.; Gagel, R.F.; Frye, J.; Müller, T.; Ratain, M.J.; Salgia, R. Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J. Clin. Oncol., 2011, 29(19), 2660-2666.
[http://dx.doi.org/10.1200/JCO.2010.32.4145] [PMID: 21606412]
[114]
Nguyen, L.; Holland, J.; Miles, D.; Engel, C.; Benrimoh, N.; O’Reilly, T.; Lacy, S. Pharmacokinetic (PK) drug interaction studies of cabozantinib: Effect of CYP3A inducer rifampin and inhibitor ketoconazole on cabozantinib plasma PK and effect of cabozantinib on CYP2C8 probe substrate rosiglitazone plasma PK. J. Clin. Pharmacol., 2015, 55(9), 1012-1023.
[http://dx.doi.org/10.1002/jcph.510] [PMID: 25854986]
[115]
Kelley, R.K.; Verslype, C.; Cohn, A.L.; Yang, T-S.; Su, W-C.; Burris, H.; Braiteh, F.; Vogelzang, N.; Spira, A.; Foster, P.; Lee, Y.; Van Cutsem, E. Cabozantinib in hepatocellular carcinoma: Results of a phase 2 placebo-controlled randomized discontinuation study. Ann. Oncol., 2017, 28(3), 528-534.
[http://dx.doi.org/10.1093/annonc/mdw651] [PMID: 28426123]
[116]
Abou-Alfa, G.K.; Meyer, T.; Cheng, A-L.; El-Khoueiry, A.B.; Rimassa, L.; Ryoo, B-Y.; Cicin, I.; Merle, P.; Chen, Y.; Park, J-W.; Blanc, J-F.; Bolondi, L.; Klümpen, H-J.; Chan, S.L.; Zagonel, V.; Pressiani, T.; Ryu, M-H.; Venook, A.P.; Hessel, C.; Borgman-Hagey, A.E.; Schwab, G.; Kelley, R.K. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. N. Engl. J. Med., 2018, 379(1), 54-63.
[http://dx.doi.org/10.1056/NEJMoa1717002] [PMID: 29972759]
[117]
FDA. FDA approves ramucirumab for hepatocellular carcinoma. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125477s029lbl.pdf
[118]
Frenette, C.; Gish, R. Targeted systemic therapies for hepatocellular carcinoma: Clinical perspectives, challenges and implications. World J. Gastroenterol., 2012, 18(6), 498-506.
[PMID: 22363115]
[120]
Zhu, A.X.; Finn, R.S.; Mulcahy, M.; Gurtler, J.; Sun, W.; Schwartz, J.D.; Dalal, R.P.; Joshi, A.; Hozak, R.R.; Xu, Y.; Ancukiewicz, M.; Jain, R.K.; Nugent, F.W.; Duda, D.G.; Stuart, K. A phase II and biomarker study of ramucirumab, a human monoclonal antibody targeting the VEGF receptor-2, as first-line monotherapy in patients with advanced hepatocellular cancer. Clin. Cancer Res., 2013, 19(23), 6614-6623.
[http://dx.doi.org/10.1158/1078-0432.CCR-13-1442] [PMID: 24088738]
[121]
Newsome, B.W.; Ernstoff, M.S. The clinical pharmacology of therapeutic monoclonal antibodies in the treatment of malignancy; have the magic bullets arrived? Br. J. Clin. Pharmacol., 2008, 66(1), 6-19.
[http://dx.doi.org/10.1111/j.1365-2125.2008.03187.x] [PMID: 18503606]
[122]
Spratlin, J.L.; Cohen, R.B.; Eadens, M.; Gore, L.; Camidge, D.R.; Diab, S.; Leong, S.; O’Bryant, C.; Chow, L.Q.M.; Serkova, N.J.; Meropol, N.J.; Lewis, N.L.; Chiorean, E.G.; Fox, F.; Youssoufian, H.; Rowinsky, E.K.; Eckhardt, S.G.; Phase, I. Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J. Clin. Oncol., 2010, 28(5), 780-787.
[http://dx.doi.org/10.1200/JCO.2009.23.7537] [PMID: 20048182]
[123]
Zhu, A.X.; Park, J.O.; Ryoo, B-Y.; Yen, C-J.; Poon, R.; Pastorelli, D.; Blanc, J-F.; Chung, H.C.; Baron, A.D.; Pfiffer, T.E.F.; Okusaka, T.; Kubackova, K.; Trojan, J.; Sastre, J.; Chau, I.; Chang, S-C.; Abada, P.B.; Yang, L.; Schwartz, J.D.; Kudo, M. REACH Trial Investigators. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): A randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol., 2015, 16(7), 859-870.
[PMID: 26095784]
[124]
Zhu, A.X.; Kang, Y-K.; Yen, C-J.; Finn, R.S.; Galle, P.R.; Llovet, J.M.; Assenat, E.; Brandi, G.; Lim, H.Y.; Pracht, M.; Rau, K-M.; Merle, P.; Motomura, K.; Ohno, I.; Daniele, B.; Shin, D.; Gerken, G.; Abada, P.; Hsu, Y.; Kudo, M. REACH-2: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Ramucirumab versus Placebo as Second-Line Treatment in Patients with Advanced Hepatocellular Carcinoma (HCC) and Elevated Baseline Alpha-Fetoprotein (AFP) Following First-Line Sorafenib. J. Clin. Oncol., 2018, 36(15), 4003-4003.
[125]
Pardoll, D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer, 2012, 12(4), 252-264.
[PMID: 22437870]
[126]
Brown, Z.J.; Heinrich, B.; Steinberg, S.M.; Yu, S.J.; Greten, T.F. Safety in treatment of hepatocellular carcinoma with immune checkpoint inhibitors as compared to melanoma and non-small cell lung cancer. J. Immunother. Cancer, 2017, 5(1), 93.
[http://dx.doi.org/10.1186/s40425-017-0298-2] [PMID: 29157287]
[127]
Ringelhan, M.; Pfister, D.; O’Connor, T.; Pikarsky, E.; Heikenwalder, M. The immunology of hepatocellular carcinoma. Nat. Immunol., 2018, 19(3), 222-232.
[http://dx.doi.org/10.1038/s41590-018-0044-z] [PMID: 29379119]
[128]
Zhong, J-H.; Luo, C-P.; Zhang, C-Y.; Li, L-Q. Strengthening the case that elevated levels of programmed death ligand 1 predict poor prognosis in hepatocellular carcinoma patients. J. Hepatocell. Carcinoma, 2016, 4, 11-13.
[PMID: 28116284]
[129]
Jain, R.K. Antiangiogenesis strategies revisited: From starving tumors to alleviating hypoxia. Cancer Cell, 2014, 26(5), 605-622.
[http://dx.doi.org/10.1016/j.ccell.2014.10.006] [PMID: 25517747]
[130]
Liu, X.; Qin, S. Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Opportunities and Challenges. Oncologist, 2019, 24(1)(Suppl. 1), S3-S10.
[http://dx.doi.org/10.1634/theoncologist.2019-IO-S1-s01] [PMID: 30819826]
[131]
Wong, A.C.Y.; Ma, B. An update on the pharmacodynamics, pharmacokinetics, safety and clinical efficacy of nivolumab in the treatment of solid cancers. Expert Opin. Drug Metab. Toxicol., 2016, 12(10), 1255-1261.
[http://dx.doi.org/10.1080/17425255.2016.1223047] [PMID: 27548326]
[132]
De Mattia, E.; Cecchin, E.; Guardascione, M.; Foltran, L.; Di Raimo, T.; Angelini, F.; D’Andrea, M.; Toffoli, G. Pharmacogenetics of the systemic treatment in advanced hepatocellular carcinoma. World J. Gastroenterol., 2019, 25(29), 3870-3896.
[http://dx.doi.org/10.3748/wjg.v25.i29.3870] [PMID: 31413525]
[133]
El-Khoueiry, A.B.; Sangro, B.; Yau, T.; Crocenzi, T.S.; Kudo, M.; Hsu, C.; Kim, T-Y.; Choo, S-P.; Trojan, J.; Welling, T.H.; Meyer, T.; Kang, Y-K.; Yeo, W.; Chopra, A.; Anderson, J.; Dela Cruz, C.; Lang, L.; Neely, J.; Tang, H.; Dastani, H.B.; Melero, I. Nivolumab in Patients with Advanced Hepatocellular Carcinoma (CheckMate 040): An Open-Label, Non-Comparative, Phase 1/2 Dose Escalation and Expansion Trial. Lancet, 2017, 389(10088), 2492-2502.
[134]
Xu, W.; Liu, K.; Chen, M.; Sun, J. Y.; McCaughan, G. W.; Lu, X. J.; Ji, J. Immunotherapy for hepatocellular carcinoma: Recent advances and future perspectives. Ther. Adv. Med. Oncol., 2019, 11, 1-15.
[135]
Kudo, M.; Matilla, A.; Santoro, A.; Melero, I.; Gracian, A.C.; Acosta-Rivera, M.; Choo, S.P.; El-Khoueiry, A.B.; Kuromatsu, R.; El-Rayes, B.F.; Numata, K.; Itoh, Y.; Di Costanzo, F.; Crysler, O.V.; Reig, M.; Shen, Y.; Neely, J.; Dela Cruz, C.M.; Baccan, C.; Sangro, B. Checkmate-040: Nivolumab (NIVO) in Patients (Pts) with Advanced Hepatocellular Carcinoma (AHCC) and Child-Pugh B (CPB) Status. J. Clin. Oncol., 2019, 37(4), 327-327.
[http://dx.doi.org/10.1200/JCO.2019.37.4_suppl.327]
[136]
Finkelmeier, F.; Czauderna, C.; Perkhofer, L.; Ettrich, T.J.; Trojan, J.; Weinmann, A.; Marquardt, J.U.; Vermehren, J.; Waidmann, O. Feasibility and safety of nivolumab in advanced hepatocellular carcinoma: Real-life experience from three German centers. J. Cancer Res. Clin. Oncol., 2019, 145(1), 253-259.
[http://dx.doi.org/10.1007/s00432-018-2780-8] [PMID: 30374657]
[137]
Kambhampati, S.; Bauer, K.E.; Bracci, P.M.; Keenan, B.P.; Behr, S.C.; Gordan, J.D.; Kelley, R.K. Nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh class B cirrhosis: Safety and clinical outcomes in a retrospective case series. Cancer, 2019, 125(18), 3234-3241.
[http://dx.doi.org/10.1002/cncr.32206] [PMID: 31154669]
[138]
U.S. Food and Drug Administration approves Opdivo (nivolumab) + Yervoy; (ipilimumab) for patients with hepatocellular carcinoma (HCC) previously treated with sorafenib Princeton, New Jersey: Bristol Myers Squibb Company, 2020. Available from: https://bit.ly/2THE7Zx
[139]
Yau, T.; Kang, Y-K.; Kim, T-Y.; El-Khoueiry, A.B.; Santoro, A.; Sangro, B.; Melero, I.; Kudo, M.; Hou, M-M.; Matilla, A.; Tovoli, F.; Knox, J.J.; He, A.R.; El-Rayes, B.F.; Acosta-Rivera, M.; Neely, J.; Shen, Y.; Baccan, C.; Dela Cruz, C.M.; Hsu, C. Nivolumab (NIVO) + Ipilimumab (IPI) Combination Therapy in Patients (Pts) with Advanced Hepatocellular Carcinoma (AHCC): Results from CheckMate 040. J. Clin. Oncol., 2019, 37(15), 4012-4012.
[http://dx.doi.org/10.1200/JCO.2019.37.15_suppl.4012]
[140]
Feng, Y.; Masson, E.; Dai, D.; Parker, S.M.; Berman, D.; Roy, A. Model-based clinical pharmacology profiling of ipilimumab in patients with advanced melanoma. Br. J. Clin. Pharmacol., 2014, 78(1), 106-117.
[http://dx.doi.org/10.1111/bcp.12323] [PMID: 24433434]
[141]
Wolchok, J.D.; Kluger, H.; Callahan, M.K.; Postow, M.A.; Rizvi, N.A.; Lesokhin, A.M.; Segal, N.H.; Ariyan, C.E.; Gordon, R.A.; Reed, K.; Burke, M.M.; Caldwell, A.; Kronenberg, S.A.; Agunwamba, B.U.; Zhang, X.; Lowy, I.; Inzunza, H.D.; Feely, W.; Horak, C.E.; Hong, Q.; Korman, A.J.; Wigginton, J.M.; Gupta, A.; Sznol, M. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med., 2018, 379(22), 2185.
[PMID: 31442371]
[142]
Motzer, R.J.; Tannir, N.M.; McDermott, D.F.; Arén Frontera, O.; Melichar, B.; Choueiri, T.K.; Plimack, E.R.; Barthélémy, P.; Porta, C.; George, S.; Powles, T.; Donskov, F.; Neiman, V.; Kollmannsberger, C.K.; Salman, P.; Gurney, H.; Hawkins, R.; Ravaud, A.; Grimm, M-O.; Bracarda, S.; Barrios, C.H.; Tomita, Y.; Castellano, D.; Rini, B.I.; Chen, A.C.; Mekan, S.; McHenry, M.B.; Wind-Rotolo, M.; Doan, J.; Sharma, P.; Hammers, H.J.; Escudier, B. CheckMate 214 Investigators. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N. Engl. J. Med., 2018, 378(14), 1277-1290.
[http://dx.doi.org/10.1056/NEJMoa1712126] [PMID: 29562145]
[143]
Siu, E.H-L.; Chan, A.W-H.; Chong, C.C-N.; Chan, S.L.; Lo, K-W.; Cheung, S.T. Treatment of advanced hepatocellular carcinoma: Immunotherapy from checkpoint blockade to potential of cellular treatment. Transl. Gastroenterol. Hepatol., 2018, 3, 89.
[http://dx.doi.org/10.21037/tgh.2018.10.16] [PMID: 30603725]
[144]
Longoria, T.C.; Tewari, K.S. Evaluation of the pharmacokinetics and metabolism of pembrolizumab in the treatment of melanoma. Expert Opin. Drug Metab. Toxicol., 2016, 12(10), 1247-1253.
[http://dx.doi.org/10.1080/17425255.2016.1216976] [PMID: 27485741]
[145]
Zhu, A.X.; Finn, R.S.; Edeline, J.; Cattan, S.; Ogasawara, S.; Palmer, D.; Verslype, C.; Zagonel, V.; Fartoux, L.; Vogel, A.; Sarker, D.; Verset, G.; Chan, S.L.; Knox, J.; Daniele, B.; Webber, A.L.; Ebbinghaus, S.W.; Ma, J.; Siegel, A.B.; Cheng, A-L.; Kudo, M. KEYNOTE-224 investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): A non-randomised, open-label phase 2 trial. Lancet Oncol., 2018, 19(7), 940-952.
[PMID: 29875066]
[146]
Finn, R.S.; Ryoo, B-Y.; Merle, P.; Kudo, M.; Bouattour, M.; Lim, H.Y.; Breder, V.; Edeline, J.; Chao, Y.; Ogasawara, S.; Yau, T.; Garrido, M.; Chan, S.L.; Knox, J.; Daniele, B.; Ebbinghaus, S.W.; Chen, E.; Siegel, A.B.; Zhu, A.X.; Cheng, A-L. KEYNOTE-240 investigators. Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial. J. Clin. Oncol., 2020, 38(3), 193-202.
[http://dx.doi.org/10.1200/JCO.19.01307] [PMID: 31790344]
[147]
ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US) Identifier NCT03713593, Safety and Efficacy of Lenvatinib (E7080/MK-7902) in Combination with Pembrolizumab (MK-3475) Versus Lenvatinib as First-line Therapy in Participants with Advanced Hepatocellular Carcinoma (MK-7902-002/E7080-G000-311/LEAP-002), Available from: https://clinicaltrials.gov/ct2/show/NCT03713593


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 21
ISSUE: 11
Year: 2020
Published on: 18 September, 2020
Page: [866 - 884]
Pages: 19
DOI: 10.2174/1389200221999200918141239
Price: $65

Article Metrics

PDF: 49
HTML: 2