Lenvatinib and other tyrosine kinase inhibitors for the treatment of radioiodine refractory, advanced, and progressive thyroid cancer

Loredana Lorusso, Letizia Pieruzzi, Agnese Biagini, Elena Sabini, Laura Valerio, Carlotta Giani, Paolo Passannanti, Benedetta Pontillo-Contillo, Valentina Battaglia, Salvatore Mazzeo, Eleonora Molinaro, Rossella Elisei, Loredana Lorusso, Letizia Pieruzzi, Agnese Biagini, Elena Sabini, Laura Valerio, Carlotta Giani, Paolo Passannanti, Benedetta Pontillo-Contillo, Valentina Battaglia, Salvatore Mazzeo, Eleonora Molinaro, Rossella Elisei

Abstract

Lenvatinib is a small oral molecule able to inhibit three of the extracellular and intracellular molecules involved in the modulation of angiogenesis and lymphangiogenesis: vascular endothelial growth factor receptor 1-3, fibroblast growth factor receptor 1-4, and platelet-derived growth factor receptor alpha. Since it is also able to inhibit the REarranged during Transfection oncogene and the protooncogene c-KIT, this drug can also be used to control tumor cell proliferation. The maximum tolerated dose, as demonstrated in Phase I studies, is 25 mg daily. The drug is rapidly absorbed with maximum concentrations achieved within 3 and 5 hours after administration in fasting and nonfasting treated patients, respectively. The most common adverse events, reported in Phase I study and confirmed in the subsequent Phase II and III studies, are hypertension, proteinuria, and gastrointestinal symptoms such as nausea, diarrhea, and stomatitis. In Phase I studies, efficacy of lenvatinib in solid tumors was demonstrated, and these encouraging results have led to the development of a Phase II study using lenvatinib in advance radioiodine-refractory differentiated thyroid cancer (DTCs) patients. Since an overall response rate of 50% was reported, this study also confirmed the efficacy of lenvatinib in DTCs patients with an acceptable toxicity profile. Recently, a Phase III study in patients with DTCs (SELECT study) demonstrated the lenvatinib efficacy in prolonging progression-free survival with respect to the placebo (18.3 vs 3.6 months; P<0.001). Although there was no statistically significant difference in the overall survival of the entire group, this result was observed when the analysis was restricted to both the follicular histotype and the group of senior patients (>65 years). The study confirmed that the most common side effects of this drug are hypertension, diarrhea, decreased appetite, weight loss, nausea, and proteinuria. In this review, we report the results of the main studies on lenvatinib efficacy in patients with advanced and progressive thyroid cancer, mainly in DTCs but also in medullary and anaplastic thyroid cancer. We also compared the efficacy of lenvatinib with that of other tyrosine kinase inhibitors, mainly sorafenib, already tested in the same type of patient population.

Keywords: E7080; lenvatinib; radioiodine refractory thyroid cancer; tyrosine kinase inhibitor.

Conflict of interest statement

Rossella Elisei is a consultant and a speaker for Genzyme, Eisai, Exelixis, Bayer. The authors declare that this review is an independent work and expression of personal experience and knowledge. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
MAPK and PI3K-AKT-mTOR signaling cascades involved in the development and progression of thyroid cancer after TKI receptor(s) activation.

References

    1. National Cancer Institute Surveillance epidemiology and end results program: seer stat facts: thyroid cancer. [Accessed August 1, 2015]. Available from: . (cited 2015 December 29)
    1. Schlumberger MJ. Papillary and follicular thyroid carcinoma. N Engl J Med. 1998;338(5):297–306.
    1. Biondi B, Cooper DS. Benefits of thyrotropin suppression versus the risks of adverse effects in differentiated thyroid cancer. Thyroid. 2010;20(2):135–146.
    1. Elisei R, Pinchera A, Chiovato L, et al. Transfection with the cDNA of the human thyrotropin receptor of a poorly differentiated rat thyroid cell line (FRT) J Endocrinol Invest. 1996;19(4):230–235.
    1. Elisei R, Molinaro E, Agate L, et al. Are the clinical and pathological features of differentiated thyroid carcinoma really changed over the last 35 years? Study on 4187 patients from a single Italian institution to answer this question. J Clin Endocrinol Metab. 2010;95(4):1516–1527.
    1. Eustatia-Rutten CF, Corssmit EP, Biermasz NR, Pereira AM, Romijn JA, Smit JW. Survival and death causes in differentiated thyroid carcinoma. J Clin Endocrinol Metab. 2006;91(1):313–319.
    1. Durante C, Haddy N, Baudin E, et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab. 2006;91(8):2892–2899.
    1. Haugen BRM, Alexander EK, Bible KC, et al. 2015 American Thyroid Association Management Guidelines for adult patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2016;26(1):1–33.
    1. Kim BM, Kim MJ, Kim EK, Park SI, Park CS, Chung WY. Controlling recurrent papillary thyroid carcinoma in the neck by ultrasonography-guided percutaneous ethanol injection. Eur Radiol. 2008;18(4):835–842.
    1. Baek JH, Kim YS, Lee D, Huh JY, Lee JH. Benign predominantly solid thyroid nodules: prospective study of efficacy of sonographically guided radiofrequency ablation versus control condition. AJR Am J Roentgenol. 2010;194(4):1137–1142.
    1. Papini E, Bizzarri G, Bianchini A, et al. Percutaneous ultrasound-guided laser ablation is effective for treating selected nodal metastases in papillary thyroid cancer. J Clin Endocrinol Metab. 2013;98(1):E92–E97.
    1. Park KW, Shin JH, Han BK, Ko EY, Chung JH. Inoperable symptomatic recurrent thyroid cancers: preliminary result of radiofrequency ablation. Ann Surg Oncol. 2011;18(9):2564–2568.
    1. Sherman SI, Wirth LJ, Droz JP, et al. Motesanib diphosphate in progressive differentiated thyroid cancer. N Engl J Med. 2008;359(1):31–42.
    1. Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med. 2005;353(2):172–187.
    1. Antonelli A, Fallahi P, Ferrari SM, et al. Dedifferentiated thyroid cancer: a therapeutic challenge. Biomed Pharmacother. 2008;62(8):559–563.
    1. Nikiforova MN, Nikiforov YE. Molecular genetics of thyroid cancer: implications for diagnosis, treatment and prognosis. Expert Rev Mol Diagn. 2008;8(1):83–95.
    1. Kroll TG, Sarraf P, Pecciarini L, et al. PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected] Science. 2000;289(5483):1357–1360.
    1. Soh EY, Duh QY, Sobhi SA, et al. Vascular endothelial growth factor expression is higher in differentiated thyroid cancer than in normal or benign thyroid. J Clin Endocrinol Metab. 1997;82(11):3741–3747.
    1. Zhang J, Wang P, Dykstra M, et al. Platelet-derived growth factor receptor-alpha promotes lymphatic metastases in papillary thyroid cancer. J Pathol. 2012;228(2):241–250.
    1. Matsui J, Yamamoto Y, Funahashi Y, et al. E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition. Int J Cancer. 2008;122(3):664–671.
    1. Bruheim S, Kristian A, Uenaka T, et al. Antitumour activity of oral E7080, a novel inhibitor of multiple tyrosine kinases, in human sarcoma xenografts. Int J Cancer. 2011;129(3):742–750.
    1. Ikuta K, Yano S, Trung VT, et al. E7080, a multi-tyrosine kinase inhibitor, suppresses the progression of malignant pleural mesothelioma with different proangiogenic cytokine production profiles. Clin Cancer Res. 2009;15(23):7229–7237.
    1. Glen H, Mason S, Patel H, Macleod K, Brunton VG. E7080, a multitargeted tyrosine kinase inhibitor suppresses tumor cell migration and invasion. BMC Cancer. 2011;11:309.
    1. Ezzat S, Asa SL. FGF receptor signaling at the crossroads of endocrine homeostasis and tumorigenesis. Horm Metab Res. 2005;37(6):355–360.
    1. Grose R, Dickson C. Fibroblast growth factor signaling in tumorigenesis. Cytokine Growth Factor Rev. 2005;16(2):179–186.
    1. Santoro M, Carlomagno F, Melillo RM, Billaud M, Vecchio G, Fusco A. Molecular mechanisms of RET activation in human neoplasia. J Endocrinol Invest. 1999;22(10):811–819.
    1. Castellone MD, Santoro M. Dysregulated RET signaling in thyroid cancer. Endocrinol Metab Clin North Am. 2008;37(2):363–374. viii.
    1. Tallini G, Asa SL. RET oncogene activation in papillary thyroid carcinoma. Adv Anat Pathol. 2001;8(6):345–354.
    1. Salvatore G, Chiappetta G, Nikiforov YE, et al. Molecular profile of hyalinizing trabecular tumours of the thyroid: high prevalence of RET/PTC rearrangements and absence of B-raf and N-ras point mutations. Eur J Cancer. 2005;41(5):816–821.
    1. Freche B, Guillaumot P, Charmetant J, et al. Inducible dimerization of RET reveals a specific AKT deregulation in oncogenic signaling. J Biol Chem. 2005;280(44):36584–36591.
    1. Favus MJ, Schneider AB, Stachura ME, et al. Thyroid cancer occurring as a late consequence of head-and-neck irradiation. Evaluation of 1056 patients. N Engl J Med. 1976;294(19):1019–1025.
    1. Schneider AB, Ron E, Lubin J, Stovall M, Gierlowski TC. Dose-response relationships for radiation-induced thyroid cancer and thyroid nodules: evidence for the prolonged effects of radiation on the thyroid. J Clin Endocrinol Metab. 1993;77(2):362–369.
    1. Fenton CL, Lukes Y, Nicholson D, Dinauer CA, Francis GL, Tuttle RM. The ret/PTC mutations are common in sporadic papillary thyroid carcinoma of children and young adults. J Clin Endocrinol Metab. 2000;85(3):1170–1175.
    1. Romei C, Ciampi R, Elisei R. A comprehensive overview of the role of the RET proto-oncogene in thyroid carcinoma. Nat Rev Endocrinol. 2016;12(4):192–202.
    1. Mazeh H, Mizrahi I, Halle D, et al. Development of a microRNA-based molecular assay for the detection of papillary thyroid carcinoma in aspiration biopsy samples. Thyroid. 2011;21(2):111–118.
    1. Boss DS, Glen H, Beijnen JH, et al. 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.
    1. Yamada K, Yamamoto N, Yamada Y, et al. Phase I dose-escalation study and biomarker analysis of E7080 in patients with advanced solid tumors. Clin Cancer Res. 2011;17(8):2528–2537.
    1. Hong DS, Koetz BS, Kurzrock R, et al. Phase I dose-escalation study of E7080, a selective tyrosine kinase inhibitor, administered orally to patients with solid tumours. Poster presented at: 2010 ASCO Annual Meeting; 2010.
    1. Cabanillas ME, Schlumberger M, Jarzab B, et al. A phase 2 trial of lenvatinib (E7080) in advanced, progressive, radioiodine-refractory, differentiated thyroid cancer: a clinical outcomes and biomarker assessment. Cancer. 2015;121(16):2749–2756.
    1. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372(7):621–630.
    1. Brose MS, Tahara M, Wirth LJ, et al. Effect of age and lenvatinib treatment on overall survival for patients with 131I-refractory differentiated thyroid cancer in SELECT Poster Session 2015 ASCO Annual Meeting; 2015
    1. Elisei R, Schlumberger MJ, Tahara M, et al. Subgroup analysis according to differentiated thyroid cancer histology in phase 3 (SELECT) trial of lenvatinib. Oncol Res Treat 2015. 2015;38(suppl 5):1–270. abstract 91.
    1. Schlumberger M, Carlomagno F, Baudin E, Bidart JM, Santoro M. New therapeutic approaches to treat medullary thyroid carcinoma. Nat Clin Pract Endocrinol Metab. 2008;4(1):22–32.
    1. Tohyama O, Matsui J, Kodama K, et al. Antitumor activity of lenvatinib (e7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models. J Thyroid Res. 2014;2014:638747.
    1. Brose MS, Nutting CM, Jarzab B, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. 2014;384(9940):319–328.
    1. Wells SA, Jr, Robinson BG, Gagel RF, 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(2):134–141.
    1. Leboulleux S, Bastholt L, Krause T, et al. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial. Lancet Oncol. 2012;13(9):897–905.
    1. Bergers G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008;8(8):592–603.
    1. Miller KD, Sweeney CJ, Sledge GW., Jr Can tumor angiogenesis be inhibited without resistance? EXS. 2005;(94):95–112.
    1. Kerbel RS, Yu J, Tran J, et al. Possible mechanisms of acquired resistance to anti-angiogenic drugs: implications for the use of combination therapy approaches. Cancer Metastasis Rev. 2001;20(1–2):79–86.
    1. Carbognin L, Pilotto S, Milella M, et al. Differential activity of nivolumab, pembrolizumab and MPDL3280A according to the tumor expression of programmed death-ligand-1 (PD-L1): sensitivity analysis of trials in melanoma, lung and genitourinary cancers. PLoS One. 2015;10(6):e0130142.
    1. Keizer RJ, Gupta A, Shumaker R, Beijnen JH, Schellens JH, Huitema AD. Model-based treatment optimization of a novel VEGFR inhibitor. Br J Clin Pharmacol. 2012;74(2):315–326.
    1. Keizer RJ, Gupta A, Mac Gillavry MR, et al. A model of hypertension and proteinuria in cancer patients treated with the anti-angiogenic drug E7080. J Pharmacokinet Pharmacodyn. 2010;37(4):347–363.
    1. Rugo HS, Herbst RS, Liu G, et al. Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J Clin Oncol. 2005;23(24):5474–5483.
    1. Cohen EE, Rosen LS, Vokes EE, et al. Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study. J Clin Oncol. 2008;26(29):4708–4713.
    1. Locati LD, Licitra L, Agate L, et al. Treatment of advanced thyroid cancer with axitinib: Phase 2 study with pharmacokinetic/pharmacodynamic and quality-of-life assessments. Cancer. 2014;120(17):2694–2703.
    1. Kurzrock R, Sherman SI, Ball DW, et al. Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol. 2011;29(19):2660–2666.
    1. Cabanillas ME, Brose MS, Holland J, Ferguson KC, Sherman SI. A phase I study of cabozantinib (XL184) in patients with differentiated thyroid cancer. Thyroid. 2014;24(10):1508–1514.
    1. Elisei R, Schlumberger MJ, Muller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31(29):3639–3646.
    1. Lim SM, Chung WY, Nam KH, et al. An open label, multicenter, phase II study of dovitinib in advanced thyroid cancer. Eur J Cancer. 2015;51(12):1588–1595.
    1. de Groot JW, Zonnenberg BA, van Ufford-Mannesse PQ, et al. A phase II trial of imatinib therapy for metastatic medullary thyroid carcinoma. J Clin Endocrinol Metab. 2007;92(9):3466–3469.
    1. Ha HT, Lee JS, Urba S, et al. A phase II study of imatinib in patients with advanced anaplastic thyroid cancer. Thyroid. 2010;20(9):975–980.
    1. Rosen LS, Kurzrock R, Mulay M, et al. Safety, pharmacokinetics, and efficacy of AMG 706, an oral multikinase inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2007;25(17):2369–2376.
    1. Sherman SI, Wirth LJ, Droz JP, et al. Motesanib diphosphate in progressive differentiated thyroid cancer. N Engl J Med. 2008;359(1):31–42.
    1. Schlumberger MJ, Elisei R, Bastholt L, et al. Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer. J Clin Oncol. 2009;27(23):3794–3801.
    1. Bible KC, Suman VJ, Molina JR, et al. Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study. Lancet Oncol. 2010;11(10):962–972.
    1. Bible KC, Suman VJ, Menefee ME, et al. A multiinstitutional phase 2 trial of pazopanib monotherapy in advanced anaplastic thyroid cancer. J Clin Endocrinol Metab. 2012;97(9):3179–3184.
    1. Hayes DN, Lucas AS, Tanvetyanon T, et al. Phase II efficacy and pharmacogenomic study of Selumetinib (AZD6244; ARRY-142886) in iodine-131 refractory papillary thyroid carcinoma with or without follicular elements. Clin Cancer Res. 2012;18(7):2056–2065.
    1. Lam ET, Ringel MD, Kloos RT, et al. Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer. J Clin Oncol. 2010;28(14):2323–2330.
    1. Schneider TC, Abdulrahman RM, Corssmit EP, Morreau H, Smit JW, Kapiteijn E. Long-term analysis of the efficacy and tolerability of sorafenib in advanced radio-iodine refractory differentiated thyroid carcinoma: final results of a phase II trial. Eur J Endocrinol. 2012;167(5):643–650.
    1. Savvides P, Nagaiah G, Lavertu P, et al. Phase II trial of sorafenib in patients with advanced anaplastic carcinoma of the thyroid. Thyroid. 2013;23(5):600–604.
    1. Brose MS, Nutting CM, Jarzab B, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. 2014;384(9940):319–328.
    1. Carr LL, Mankoff DA, Goulart BH, 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(21):5260–5268.
    1. Ravaud A, Wallerand H, Culine S, et al. Update on the medical treatment of metastatic renal cell carcinoma. Eur Urol. 2008;54(2):315–325.
    1. Wells SA, Jr, Gosnell JE, Gagel RF, et al. Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Oncol. 2010;28(5):767–772.
    1. Wells SA, Jr, Robinson BG, Gagel RF, 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(2):134–141.
    1. Leboulleux S, Bastholt L, Krause T, et al. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial. Lancet Oncol. 2012;13(9):897–905.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir