Anlotinib: a novel multi-targeting tyrosine kinase inhibitor in clinical development

Guoshuang Shen, Fangchao Zheng, Dengfeng Ren, Feng Du, Qiuxia Dong, Ziyi Wang, Fuxing Zhao, Raees Ahmad, Jiuda Zhao, Guoshuang Shen, Fangchao Zheng, Dengfeng Ren, Feng Du, Qiuxia Dong, Ziyi Wang, Fuxing Zhao, Raees Ahmad, Jiuda Zhao

Abstract

Anlotinib is a new, orally administered tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptors (PDGFR), and c-kit. Compared to the effect of placebo, it improved both progression-free survival (PFS) and overall survival (OS) in a phase III trial in patients with advanced non-small-cell lung cancer (NSCLC), despite progression of the cancer after two lines of prior treatments. Recently, the China Food and Drug Administration (CFDA) approved single agent anlotinib as a third-line treatment for patients with advanced NSCLC. Moreover, a randomized phase IIB trial demonstrated that anlotinib significantly prolonged the median PFS in patients with advanced soft tissue sarcoma (STS). Anlotinib also showed promising efficacy in patients with advanced medullary thyroid carcinoma and metastatic renal cell carcinoma (mRCC). The tolerability profile of anlotinib is similar to that of other tyrosine kinase inhibitors that target VEGFR and other tyrosine kinase-mediated pathways; however, anlotinib has a significantly lower incidence of grade 3 or higher side effects compared to that of sunitinib. We review the rationale, clinical evidence, and future perspectives of anlotinib for the treatment of multiple cancers.

Keywords: Anlotinib; NSCLC; STS; Tyrosine kinase inhibitor; VEGFR.

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The authors declare that they have no competing interests.

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Figures

Fig. 1
Fig. 1
Mechanism of action of anlotinib
Fig. 2
Fig. 2
Treatment-related adverse events associated with 2-week on/1-week off anlotinib 12 mg/day. Adverse events reported in all patients (n = 21) in a phase I trial [21]. HFS hand-foot skin reaction, ALT alanine aminotransferase, ME myocardial enzymes

References

    1. Persson C, Sjöblom T, Groen A, Kappert K, Engström U, Hellman U, et al. Preferential oxidation of the second phosphatase domain of receptor-like PTP-α revealed by an antibody against oxidized protein tyrosine phosphatases. Proc Natl Acad Sci U S A. 2004;101:1886–1891. doi: 10.1073/pnas.0304403101.
    1. Hojjat-Farsangi M. Small-molecule inhibitors of the receptor tyrosine kinases: promising tools for targeted cancer therapies. Int J Mol Sci. 2014;15:13768–13801. doi: 10.3390/ijms150813768.
    1. Hubbard SR, Miller WT. Receptor tyrosine kinases: mechanisms of activation and signaling. Curr Opin Cell Biol. 2007;19:117–123. doi: 10.1016/j.ceb.2007.02.010.
    1. Arora A, Scholar EM. Role of tyrosine kinase inhibitors in cancer therapy. J Pharmacol Exp Ther. 2005;315:971–979. doi: 10.1124/jpet.105.084145.
    1. Ferguson FM, Gray NS. Kinase inhibitors: the road ahead. Nat Rev Drug Discov. 2018;17:353–377. doi: 10.1038/nrd.2018.21.
    1. Hasskarl J. Sorafenib. Small molecules in oncology. Springer: Berlin; 2014;2:61–70.
    1. Chow LQM, Eckhardt SG. Sunitinib: from rational design to clinical efficacy. J Clin Oncol. 2007;25:884–896. doi: 10.1200/JCO.2006.06.3602.
    1. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, 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;27:3312–3318. doi: 10.1200/JCO.2008.19.5511.
    1. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:3584–3590. doi: 10.1200/JCO.2008.20.1293.
    1. Li J, Qin S, Xu R, Yau TC, Ma B, Pan H, et al. 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;16:619–629. doi: 10.1016/S1470-2045(15)70156-7.
    1. Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:303–312. doi: 10.1016/S0140-6736(12)61900-X.
    1. van der Graaf WT, Blay JY, Chawla SP, Kim DW, Bui-Nguyen B, Casali PG, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379:1879–1886. doi: 10.1016/S0140-6736(12)60651-5.
    1. von Mehren M, Lor Randall R, Benjamin RS, Boles S, Bui MM, Ganjoo KN, et al. National comprehensive cancer network soft tissue sarcoma guidelines. Version 2. 2018. 2018.
    1. Casali PG, Abecassis N, Bauer S, Biagini R, Bielack S, Bonvalot S, et al. Soft tissue and visceral sarcomas: ESMO–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;00:1–11. 10.1093/annonc/mdy096. [Epub ahead of print].
    1. Lewin J, Puri A, Quek R, Ngan R, Alcasabas AP, Wood D, et al. Management of sarcoma in the Asia-Pacific region: resource-stratified guidelines. Lancet Oncol. 2013;14:e562–e570. doi: 10.1016/S1470-2045(13)70475-3.
    1. Xie C, Wan X, Quan H, Zheng M, Fu L, Li Y, et al. Preclinical characterization of anlotinib, a highly potent and selective vascular endothelial growth factor receptor-2 inhibitor. Cancer Sci. 2018;109:1207–1219. doi: 10.1111/cas.13536.
    1. Taurin S, Yang CH, Reyes M, Cho S, Jarboe EA, Werner TL, et al. Abstract 3244: treatment of endometrial cancer cells with a new small tyrosine kinase inhibitor targeting mutated fibroblast growth factor receptor-2. Cancer Res. 2017;77(13 Supplement):3244. doi: 10.1158/1538-7445.AM2017-3244.
    1. Lin B, Song X, Yang D, Bai D, Yao Y, Lu N, et al. Anlotinib inhibits angiogenesis via suppressing the activation of VEGFR2, PDGFRβ and FGFR1. Gene. 2018;654:77–86. doi: 10.1016/j.gene.2018.02.026.
    1. Taurin S, Yang CH, Reyes M, Cho S, Coombs DM, Jarboe EA, et al. Endometrial cancers harboring mutated fibroblast growth factor receptor 2 protein are successfully treated with a new small tyrosine kinase inhibitor in an orthotopic mouse model. Int J Gynecol Cancer. 2018;28:152–160.
    1. Zhong CC, Chen F, Yang JL, Jia WW, Li L, Cheng C, et al. Pharmacokinetics and disposition of anlotinib, an oral tyrosine kinase inhibitor, in experimental animal species. Acta Pharmacol Sin. 2018;39:1048–1063. doi: 10.1038/aps.2017.199.
    1. Sun Y, Niu W, Du F, Du C, Li S, Wang J, et al. Safety, pharmacokinetics, and antitumor properties of anlotinib, an oral multi-target tyrosine kinase inhibitor, in patients with advanced refractory solid tumors. J Hematol Oncol. 2016;9:105. doi: 10.1186/s13045-016-0332-8.
    1. Werner Theresa Louise, Kannapel Esther, Chen Judy, Chen Melissa, Cohen Adam Louis. Safety and PK results from a phase Ib study of AL3818 (anlotinib) hydrochloride in subjects with ovarian, cervical, and endometrial cancers. Journal of Clinical Oncology. 2017;35(15_suppl):e17071–e17071. doi: 10.1200/JCO.2017.35.15_suppl.e17071.
    1. Sun W, Wang Z, Chen R, Huang C, Sun R, Hu X, et al. Influences of anlotinib on cytochrome P450 enzymes in rats using a cocktail method. Biomed Res Int. 2017;2017:3619723.
    1. van Erp NP, Gelderblom H, Guchelaar HJ. Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009;35:692–706. doi: 10.1016/j.ctrv.2009.08.004.
    1. Han B, Li K, Zhao Y, Li B, Cheng Y, Zhou J, et al. Anlotinib as a third-line therapy in patients with refractory advanced non-small-cell lung cancer: a multicentre, randomised phase II trial (ALTER0302) Br J Cancer. 2018;118:654–661. doi: 10.1038/bjc.2017.478.
    1. Han B, Li K, Wang Q, et al. Third-line treatment: a randomized, double-blind, placebo-controlled phase III ALTER-0303 study—efficacy and safety of anlotinib treatment in patients with refractory advanced NSCLC. J Clin Oncol. 2017;35(15_suppl):9053. doi: 10.1200/JCO.2017.35.15_suppl.9053.
    1. Han B, Li K, Wang Q, Zhao Y, Zhang L, Shi J, et al. Efficiency of anlotinib as 3rd line treatment in patients with different EGFR gene status, an exploratory subgroup analysis of ALTER0303 trial. J Thorac Oncol. 2017;12:S2275. doi: 10.1016/j.jtho.2017.09.1632.
    1. Li K, Han B, Wang Q, Zhang L, Shi J, Wang Z, et al. OS outcomes to anlotinib in patients (pts) with refractory NSCLC of both wild-type (WT) and mutant EGFR. J Clin Oncol. 2018;36(15_suppl):e21013. doi: 10.1200/JCO.2018.36.15_suppl.e21013.
    1. Cheng Y, Han B, Li K, Wang Q, Zhang L, Shi J, et al. Subgroup analysis of histology in ALTER0303: anlotinib hydrochloride as 3rd line and further line treatment in refractory advanced NSCLC patients (pts) J Clin Oncol. 2018;36(15_suppl):9080. doi: 10.1200/JCO.2018.36.15_suppl.9080.
    1. Shi J, Han B, Li K, Wang Q, Zhang L, Wang Z, et al. Subgroup analysis of elderly patients (pts) in ALTER0303: Anlotinib hydrochloride as 3rd-line and further line treatment in refractory advanced NSCLC pts from a randomized, double-blind, placebo-controlled phase III ALTER0303 trial. J Clin Oncol. 2018;36(15_suppl):e21181. doi: 10.1200/JCO.2018.36.15_suppl.e21181.
    1. Wang Q, Han B, Li K, Zhang L, Shi J, Wang Z, et al. Efficiency of anlotinib as 3rd line treatment in patients (pts) from a randomized, double-blind, placebo-controlled phase III trial, an exploratory subgroup analysis of ALTER0303 trial for the previous therapy strategy effect. J Clin Oncol. 2018;36(15_suppl):e21182. doi: 10.1200/JCO.2018.36.15_suppl.e21182.
    1. China Food and Drug Administration, Approved drugs, Anlotinib [internet]. . Accessed 8 May 2018.
    1. Cheng Y, Wu Y, Lu S, Zhou C, Wang C, Wang L, et al. Chinese Society of Clinical Oncology (CSCO) guidelines for diagnosis and treatment of primary lung cancer. Version 1. 2018. 2018.
    1. Sleijfer S, Ray-Coquard I, Papai Z, Le Cesne A, Scurr M, Schöffski 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;27:3126–3132. doi: 10.1200/JCO.2008.21.3223.
    1. Cassier PA, Gelderblom H, Stacchiotti S, Thomas D, Maki RG, Kroep JR, et al. Efficacy of imatinib mesylate for the treatment of locally advanced and/or metastatic tenosynovial giant cell tumor/pigmented villonodular synovitis. Cancer. 2012;118:1649–1655. doi: 10.1002/cncr.26409.
    1. Stacchiotti S, Negri T, Libertini M, Conca E, Castelli C, Tazzari M, et al. Sunitinib malate in solitary fibrous tumor (SFT) Ann Oncol. 2012;23:3171–3179. doi: 10.1093/annonc/mds143.
    1. Valentin T, Fournier C, Penel N, Bompas E, Chaigneau L, et al. Sorafenib in patients with progressive malignant solitary fibrous tumors: a subgroup analysis from a phase II study of the French Sarcoma Group (GSF/GETO) Investig New Drugs. 2013;31:1626–1627. doi: 10.1007/s10637-013-0023-z.
    1. Butrynski JE, D'Adamo DR, Hornick JL, Dal Cin P, Antonescu CR, Jhanwar SC, et al. Crizotinib in ALKrearranged inflammatory myofibroblastic tumor. N Engl J Med. 2010;363:1727–1733. doi: 10.1056/NEJMoa1007056.
    1. Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, Camidge DR, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014;370:1189–1197. doi: 10.1056/NEJMoa1311107.
    1. Tap WD, Jones RL, Van Tine BA, Chmielowski B, Elias AD, Adkins D, et al. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet. 2016;388:488–497. doi: 10.1016/S0140-6736(16)30587-6.
    1. Agulnik M, Yarber JL, Okuno SH, von Mehren M, Jovanovic BD, Brockstein BE, et al. An open-label, multicenter, phase II study of bevacizumab for the treatment of angiosarcoma and epithelioid hemangioendotheliomas. Ann Oncol. 2013;24:257–263. doi: 10.1093/annonc/mds237.
    1. Chi Y, Sun Y, Cai J, Yao Y, Hong X, Fang Z, et al. Phase II study of anlotinib for treatment of advanced soft tissues sarcomas. J Clin Oncol. 2016;34(15_suppl):11005. doi: 10.1200/JCO.2016.34.15_suppl.11005.
    1. Stacchiotti S, Negri T, Zaffaroni N, Palassini E, Morosi C, Brich S, et al. Sunitinib in advanced alveolar soft part sarcoma: evidence of a direct antitumor effect. Ann Oncol. 2011;22:1682–1690. doi: 10.1093/annonc/mdq644.
    1. Chi Y, Yao Y, Wang S, Huang G, Cai Q, Shang G, et al. Anlotinib for metastasis soft tissue sarcoma: a randomized, double-blind, placebo-controlled and multi-centered clinical trial. J Clin Oncol. 2018;36(15_suppl):11503. doi: 10.1200/JCO.2018.36.15_suppl.11503.
    1. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28:1061–1068. doi: 10.1200/JCO.2009.23.9764.
    1. Motzer RJ, Hutson TE, Tomczak P, Ecklund DJ, Klingner EA, Yankey JW, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115–114. doi: 10.1056/NEJMoa065044.
    1. Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh MK, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial. J Clin Oncol. 2017;35:591–597. doi: 10.1200/JCO.2016.70.7398.
    1. Hutson TE, Lesovoy V, Al-Shukri S, Stus VP, Lipatov ON, Bair AH, et al. Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol. 2013;14:1287–1294. doi: 10.1016/S1470-2045(13)70465-0.
    1. Motzer RJ, Hutson TE, Ren M, Dutcus C, Larkin J. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol. 2016;17:e4–e5. doi: 10.1016/S1470-2045(15)00543-4.
    1. Zhou AP, Bai Y, Song Y, Li H, Xie X, Ren XB, et al. Anlotinib in metastatic renal cell carcinoma (mRCC) with a previous anti-VEGFR TKI: preliminary results from a multicenter, phase II trial. J Clin Oncol. 2016;34(15_suppl):e16082. doi: 10.1200/JCO.2016.34.15_suppl.e16082.
    1. Zhou AP, Ma J, Bai Y, Song Y, Li H, Xie X, et al. Anlotinib versus sunitinib as first line treatment for metastatic renal cell carcinoma (mRCC): preliminary results from a randomized phase II clinical trial. J Clin Oncol. 2016;34(15_suppl):4565. doi: 10.1200/JCO.2016.34.15_suppl.4565.
    1. Brose MS, Nutting CM, Jarzab B, Libby P, Thuren T, Glynn RJ, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. 2014;384:319–328. doi: 10.1016/S0140-6736(14)60421-9.
    1. Carr LL, Mankoff DA, Goulart BH, Eaton KD, Capell PT, Kell EM, et al. Phase II study of daily sunitinib in FDG-PET-positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. Clin Cancer Res. 2010;16:5260–5268. doi: 10.1158/1078-0432.CCR-10-0994.
    1. Elisei R, Schlumberger MJ, Muller SP, Schöffski P, Brose MS, Shah MH, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639–3646. doi: 10.1200/JCO.2012.48.4659.
    1. Wells SA, Jr, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30:134–141. doi: 10.1200/JCO.2011.35.5040.
    1. Bible KC, Suman VJ, Molina JR, Smallridge RC, Maples WJ, Menefee ME, et al. Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study. Lancet Oncol. 2010;11:962–972. doi: 10.1016/S1470-2045(10)70203-5.
    1. Sun Y, Chi Y, Tang P, Gao M, Ji Q, Li Z, et al. Phase II study of anlotinib for treatment of advanced medullary thyroid carcinoma. J Clin Oncol. 2016;34(15_suppl):6015. doi: 10.1200/JCO.2016.34.15_suppl.6015.
    1. Beck J, Procopio G, Bajetta E, Keilholz U, Negrier S, Szczylik C, et al. Final results of the European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study: a large open-label study in diverse community settings. Ann Oncol. 2011;22:1812–1823. doi: 10.1093/annonc/mdq651.
    1. Stadler WM, Figlin RA, McDermott DF, Dutcher JP, Knox JJ, Miller WH, et al. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer. 2010;116:1272–1280. doi: 10.1002/cncr.24864.
    1. Gore ME, Szczylik C, Porta C, Bracarda S, Bjarnason GA, Oudard S, et al. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol. 2009;10:757–763. doi: 10.1016/S1470-2045(09)70162-7.
    1. Qi WX, Shen Z, Tang LN, Yao Y. Risk of arterial thromboembolic events with vascular endothelial growth factor receptor tyrosine kinase inhibitors: an up-to-date meta-analysis. Crit Rev Oncol Hematol. 2014;92:71–82. doi: 10.1016/j.critrevonc.2014.04.004.
    1. Liu Z, Wang J, Meng Z, Wang X, Zhang C, Chen J, et al. Analysis on ALTER0303 trial: aCECs level may correlate with metastases burden and predict PFS of Anlotinib in advanced NSCLC. J Thorac Oncol. 2017;12:S2234–S2235. doi: 10.1016/j.jtho.2017.09.1525.
    1. Han B, Zhao Y, Li K, Wang J, Wang Q, Zhang L, et al. P3. Blood samples NGS for baseline molecular signature of anotinib treated advanced NSCLC patients in ALTER0303 trial. J Thorac Oncol. 2017;12:S2279. doi: 10.1016/j.jtho.2017.09.1643.
    1. Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15:1224–1235. doi: 10.1016/S1470-2045(14)70420-6.
    1. Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384:665–673. doi: 10.1016/S0140-6736(14)60845-X.
    1. Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012;12:237–251. doi: 10.1038/nrc3237.
    1. Hughes Paul E., Caenepeel Sean, Wu Lawren C. Targeted Therapy and Checkpoint Immunotherapy Combinations for the Treatment of Cancer. Trends in Immunology. 2016;37(7):462–476. doi: 10.1016/j.it.2016.04.010.

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