Lenvatinib: established and promising drug for the treatment of advanced hepatocellular carcinoma

References

• Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249.
   PubMed Web of Science ®Google Scholar
• Fitzmaurice C, Akinyemiju T, Abera S, et al. The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level results from the global burden of disease study 2015. JAMA Oncol. 2017;3(12):1683–1691.
   PubMed Web of Science ®Google Scholar
• Galle PR, Forner A, Llovet JM, et al. EASL Clinical Practice Guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69:182–236.
   PubMed Web of Science ®Google Scholar
• Angulo P. Medical progress: nonalcoholic fatty liver disease. N Engl J Med. 2002;346(16):1221–1231.
   PubMed Web of Science ®Google Scholar
• Forner A, Reig M, Bruix J. Hepatocellular carcinoma. The Lancet. Lancet Publishing Group. 2018;391(10127):301–1314.
   Google Scholar
• D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. 2006;44(1):217–231.
   PubMed Web of Science ®Google Scholar
• Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018;68(2):723–750.
   PubMed Web of Science ®Google Scholar
• Vitale A, Farinati F, Pawlik TM, et al. The concept of therapeutic hierarchy for patients with hepatocellular carcinoma: a multicenter cohort study. Liver Int. 2019;39(8):1478–1489.
   PubMed Web of Science ®Google Scholar
• Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in Advanced Hepatocellular Carcinoma. N Engl J Med. 2008;359(4):378–390.
   PubMed Web of Science ®Google Scholar
• Cheng AL, Kang YK, Chen Z, et al. 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.
   PubMed Web of Science ®Google Scholar
• Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020;382(20):1894–1905.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Kudo M, Finn RS, Qin S, et al. 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.
   PubMed Web of Science ®Google Scholar
• Finn RS, Qin S, Ikeda M, et al. IMbrave150: updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC). J clin oncol. 2021;39(3_suppl):267.
   Web of Science ®Google Scholar
• 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) - Full Text View - ClinicalTrials.gov [Internet]. [cited 2021 May 3]. Available from: https://clinicaltrials.gov/ct2/show/NCT03713593.
   Google Scholar
• Matsui J, Funahashi Y, Uenaka T, et al. Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer Res. 2008;14(17):5459–5465.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMedGoogle Scholar
• Yamamoto Y, Matsui J, Matsushima T, et al. Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage. Vasc Cell. 2014;6(1):18.
   PubMedGoogle Scholar
• Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23(5):1011–1027.
   PubMed Web of Science ®Google Scholar
• Koch S, Signal C-WL Transduction by Vascular Endothelial Growth Factor Receptors.
   Google Scholar
• Takahashi H, Shibuya M. The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role under physiological and pathological conditions. Clinical Science. Clin Sci (Lond). 2005;109(3):227–241.
   Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Eswarakumar VP, Lax I, Schlessinger J. Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev. 2005;16(2):139–149.
   PubMed Web of Science ®Google Scholar
• Gotoh N. Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins. Cancer Science. 2008;99(7):1319–1325.
   PubMed Web of Science ®Google Scholar
• Ogasawara S, Yano H, Iemura A, et al. Expressions of basic fibroblast growth factor and its receptors and their relationship to proliferation of human hepatocellular carcinoma cell lines. Hepatology. 1996;24(1):198–205.
   PubMed Web of Science ®Google Scholar
• Sandhu DS, Baichoo E, Roberts LR. Fibroblast growth factor signaling in liver carcinogenesis. Hepatology. 2014;59(3):1166–1173.
   PubMed Web of Science ®Google Scholar
• Raja A, Park I, Haq F, et al. FGF19–FGFR4 Signaling in Hepatocellular Carcinoma. Cells. 2019;8(6):536.
   Web of Science ®Google Scholar
• Matsuki M, Hoshi T, Yamamoto Y, et al. Lenvatinib inhibits angiogenesis and tumor fibroblast growth factor signaling pathways in human hepatocellular carcinoma models. Cancer Med. 2018;7(6):2641–2653.
   PubMed Web of Science ®Google Scholar
• Ogasawara S, Mihara Y, Kondo R, et al. Antiproliferative Effect of Lenvatinib on Human Liver Cancer Cell Lines In Vitro and In Vivo. Anticancer Res. 2019;39(11):5943–5982.
   PubMed Web of Science ®Google Scholar
• Arighi E, Borrello MG, Sariola H. RET tyrosine kinase signaling in development and cancer. Cytokine and Growth Factor Reviews. Cytokine Growth Factor Rev. 2005;16(4-5):441–467.
   Google Scholar
• Romei C, Ciampi R, Elisei R. A comprehensive overview of the role of the RET proto-oncogene in thyroid carcinoma. Nature Reviews Endocrinology. Nature Publishing Group. 2016;12(4):192–202.
   Google Scholar
• Okamoto K, Kodama K, Takase K, et al. Antitumor activities of the targeted multi-tyrosine kinase inhibitor lenvatinib (E7080) against RET gene fusion-driven tumor models. Cancer Lett. 2013;340(1):97–103.
   PubMed Web of Science ®Google Scholar
• Kato Y, Bao X, Macgrath S, et al. Lenvatinib mesilate (LEN) enhanced antitumor activity of a PD-1 blockade agent by potentiating Th1 immune response. Ann Oncol. 2016;27:vi1.
   Web of Science ®Google Scholar
• Voron T, Marcheteau E, Pernot S, et al. Control of the immune response by pro-angiogenic factors. Frontiers in Oncology. Frontiers Research Foundation; 2014.
   Google Scholar
• Hansen W, Hutzler M, Abel S, et al. Neuropilin 1 deficiency on CD4+Foxp3+ regulatory T cells impairs mouse melanoma growth. J Exp Med. 2012;209(11):2001–2016.
   PubMed Web of Science ®Google Scholar
• Gabrilovich D, Ishida T, Oyama T, et al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood. 1998;92(11):4150–4166.
   PubMed Web of Science ®Google Scholar
• Voron T, Colussi O, Marcheteau E, et al. VEGF-A modulates expression of inhibitory checkpoints on CD8++ T cells in tumors. J Exp Med. 2015;212(2):139–148.
   PubMed Web of Science ®Google Scholar
• Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331(6024):1565–1570.
   Google Scholar
• Kato Y, Tabata K, Kimura T, et al. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway. PLoS ONE. 2019;14(2):e0212513.
   Google Scholar
• Kimura T, Kato Y, Ozawa Y, et al. Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model. Cancer Sci. 2018;109(12):3993–4002.
   PubMed Web of Science ®Google Scholar
• Nakamichi S, Nokihara H, Yamamoto N, et al. 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.
   PubMed Web of Science ®Google Scholar
• Shumaker R, Aluri J, Fan J, et al. Evaluation of the effects of formulation and food on the pharmacokinetics of lenvatinib (E7080) in healthy volunteers. Int Journal of Clinical Pharmacology and Therapeutics. 2014;52(04):284–291.
   PubMedGoogle Scholar
• Gupta A, Jarzab B, Capdevila J, et al. Population pharmacokinetic analysis of lenvatinib in healthy subjects and patients with cancer. Br J Clin Pharmacol. 2016;81(6):1124–1133.
   PubMed Web of Science ®Google Scholar
• Tamai T, Hayato S, Hojo S, et al. Dose Finding of Lenvatinib in Subjects With Advanced Hepatocellular Carcinoma Based on Population Pharmacokinetic and Exposure–Response Analyses. The Journal of Clinical Pharmacology. 2017;57(9):1138–1147.
   PubMed Web of Science ®Google Scholar
• Dubbelman A-C, Rosing H, Nijenhuis C, Dubbelman AC, Rosing H, Nijenhuis C, et al. Pharmacokinetics and excretion of 14C-lenvatinib in patients with advanced solid tumors or lymphomas. Invest New Drugs. 2015;33(1):233–240.
   PubMed Web of Science ®Google Scholar
• Hao Z, Wang P. Lenvatinib in Management of Solid Tumors. The Oncologist. 2020;25(2):e302-e310.
   Google Scholar
• Nair A, Lemery SJ, Yang J, et al. CCR Perspectives in Drug Approval FDA Approval Summary. Lenvatinib for Progressive, Radio-iodine-Refractory Differentiated Thyroid Cancer; 2015;21(23):2505-8.
   Google Scholar
• Motzer RJ, Hutson TE, Glen H, et al. 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.
   PubMed Web of Science ®Google Scholar
• Approves Drug FDA. Combo for Kidney Cancer. In: Cancer discovery. American Association for Cancer Research. 2016;6(7):687–688.
   Google Scholar
• Sasaki R, Fukushima M, Haraguchi M, et al. Response to lenvatinib is associated with optimal relativedose intensity in hepatocellular carcinoma: experience in clinical settings. Cancers (Basel). 2019;11(11):1769.
   Web of Science ®Google Scholar
• Maruta S, Ogasawara S, Ooka Y, et al. Potential of Lenvatinib for an Expanded Indication from the REFLECT Trial in Patients with Advanced Hepatocellular Carcinoma. Liver Cancer. 2020;9(4):382–396.
   PubMed Web of Science ®Google Scholar
• Wang DX, Yang X, Lin JZ, et al. Efficacy and safety of lenvatinib for patients with advanced hepatocellular carcinoma: a retrospective, real-world study conducted in China. World J Gastroenterol. 2020;26(30):4465–4478.
   PubMed Web of Science ®Google Scholar
• Cheon J, Chon HJ, Bang Y, et al. Real-World Efficacy and Safety of Lenvatinib in Korean Patients with Advanced Hepatocellular Carcinoma: a Multicenter Retrospective Analysis. Liver Cancer. 2020;9(5):613–624.
   PubMed Web of Science ®Google Scholar
• Ohki T, Sato K, Kondo M, et al. Impact of Adverse Events on the Progression-Free Survival of Patients with Advanced Hepatocellular Carcinoma Treated with Lenvatinib: a Multicenter Retrospective Study. Drugs Real World Outcomes. 2020;7(2):141–149.
   PubMedGoogle Scholar
• Ueshima K, Nishida N, Hagiwara S, et al. Impact of baseline ALBI grade on the outcomes of hepatocellular carcinoma patients treated with lenvatinib: a multicenter study. Cancers. 2019;11(7):952.
   Google Scholar
• Ogushi K, Chuma M, Uojima H, et al. Safety and efficacy of lenvatinib treatment in child–pugh a and b patients with unresectable hepatocellular carcinoma in clinical practice: a multicenter analysis. Clin Exp Gastroenterol. 2020;13:385–396.
   PubMed Web of Science ®Google Scholar
• Hatanaka T, Kakizaki S, Nagashima T, et al. Liver function changes in patients with hepatocellular carcinoma treated with lenvatinib: predictive factors of progression to child-pugh class b, the formation of ascites and the candidates for the post-progression treatment. Cancers (Basel). 2020;12(10):1–19.
   Web of Science ®Google Scholar
• Sho T, Suda G, Ogawa K, et al. Lenvatinib in patients with unresectable hepatocellular carcinoma who do not meet the REFLECT trial eligibility criteria. Hepatol Res. 2020;50:966–977.
   PubMed Web of Science ®Google Scholar
• Ono A, Aikata H, Yamauchi M, et al. Circulating cytokines and angiogenic factors based signature associated with the relative dose intensity during treatment in patients with advanced hepatocellular carcinoma receiving lenvatinib. Therapeutic Advances in Medical Oncology. 2020;12:1758835920922051.
   Google Scholar
• Kirino S, Tsuchiya K, Kurosaki M, et al. Relative dose intensity over the first four weeks of lenvatinib therapy is a factor of favorable response and overall survival in patients with unresectable hepatocellular carcinoma. PLoS ONE. 2020;15(4):e0231828.
   Google Scholar
• Eso Y, Nakano S, Mishima M, et al. Dose intensity/body surface area ratio is a novel marker useful for predicting response to lenvatinib against hepatocellular carcinoma. Cancers. 2020;12(1):49.
   Google Scholar
• Takahashi A, Moriguchi M, Seko Y, et al. Impact of Relative Dose Intensity of Early-phase Lenvatinib Treatment on Therapeutic Response in Hepatocellular Carcinoma. Anticancer Res. 2019;39(9):5149–5156.
   PubMed Web of Science ®Google Scholar
• Hiraoka A, Kumada T, Atsukawa M, et al. Prognostic factor of lenvatinib for unresectable hepatocellular carcinoma in real-world conditions—Multicenter analysis. Cancer Med. 2019;8(8):3719–3728.
   PubMed Web of Science ®Google Scholar
• Hayashi T, Shibata M, Oe S, et al. C-reactive protein can predict dose intensity, time to treatment failure and overall survival in HCC treated with lenvatinib. PLoS ONE. 2020;15(12):e0244370
   Google Scholar
• Yamashita T, Kudo M, Ikeda K, et al. REFLECT—a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset. J Gastroenterol. 2020;55(1):113–122.
   PubMed Web of Science ®Google Scholar
• Facciorusso A, Tartaglia N, Villani R, et al. Lenvatinib versus sorafenib as first-line therapy of advanced hepatocellular carcinoma: a systematic review and meta-analysis. Am J Transl Res. 2021;13:2379–2387.
   PubMed Web of Science ®Google Scholar
• Facciorusso A, Ma AEA, Cincione I, et al. Angiotensin receptor 1 blockers prolong time to recurrence after radiofrequency ablation in hepatocellular carcinoma patients: a retrospective study. Biomedicines. 2020;8(10):1–13.
   Web of Science ®Google Scholar
• Facciorusso A, Del Prete V, Antonino M, et al. Conditional survival analysis of hepatocellular carcinoma patients treated with radiofrequency ablation. Hepatol Res. 2015;45(10):E62–E72.
   PubMed Web of Science ®Google Scholar
• Facciorusso A, Del Prete V, Antonino M, et al. Post-recurrence survival in hepatocellular carcinoma after percutaneous radiofrequency ablation. Digestive Liver Dis. 2014;46(11):1014–1019.
   Web of Science ®Google Scholar
• Casadei‐Gardini A, Scartozzi M, Tada T, et al. Lenvatinib versus sorafenib in first‐line treatment of unresectable hepatocellular carcinoma: an inverse probability of treatment weighting analysis. Liver Int. 2021;41(6):1389–1397.
   PubMed Web of Science ®Google Scholar
• Komatsu S, Yano Y, Sofue K, et al. Assessment of lenvatinib treatment for unresectable hepatocellular carcinoma with liver cirrhosis. HPB. 2020;22(10):1450–1456.
   PubMed Web of Science ®Google Scholar
• Kudo M, Ueshima K, Chan S, et al. Lenvatinib as an initial treatment in patients with intermediate-stage hepatocellular carcinoma beyond up-to-seven criteria and child–pugh a liver function: a proof-of-concept study. Cancers. 2019;11(8):1084.
   Google Scholar
• Kudo M, Arizumi T, Ueshima K, et al. Subclassification of BCLC B Stage Hepatocellular Carcinoma and Treatment Strategies: proposal of Modified Bolondi’s Subclassification (Kinki Criteria). Digestive Diseases. S. Karger AG. 2015;33(6):751–758.
   Google Scholar
• Shimose S, Kawaguchi T, Tanaka M, et al. Lenvatinib prolongs the progression.free survival time of patients with intermediate.stage hepatocellular carcinoma refractory to transarterial chemoembolization: a multicenter cohort study using data mining analysis. Oncology Letters. 2020;20:2257–2265.
   Google Scholar
• Lenvatinib May KM. Drastically Change the Treatment Landscape of Hepatocellular Carcinoma. Liver Cancer. S. Karger AG. 2018;7(1):1–19.
   Google Scholar
• Shimose S, Iwamoto H, Niizeki T, et al. Clinical significance of adverse events for patients with unresectable hepatocellular carcinoma treated with lenvatinib: a multicenter retrospective study. Cancers (Basel). 2020;12(7):1–15.
   Web of Science ®Google Scholar
• Sueta D, Suyama K, Sueta A, et al. Lenvatinib, an oral multi-kinases inhibitor, -associated hypertension: potential role of vascular endothelial dysfunction. Atherosclerosis. 2017;260:116–120.
   PubMed Web of Science ®Google Scholar
• Takahashi S, Kiyota N, Tahara M. Optimal use of lenvatinib in the treatment of advanced thyroid cancer. Cancers of the Head & Neck. 2017;2(1):7.
   PubMedGoogle Scholar
• Aoki T, Kokudo N, Matsuyama Y, et al. Prognostic impact of spontaneous tumor rupture in patients with hepatocellular carcinoma: an analysis of 1160 cases from a nationwide survey. Ann Surg. 2014;259(3):532–542.
   PubMed Web of Science ®Google Scholar
• Evans TRJ, Kudo M, Finn RS, et al. Urine protein: creatinineratio vs 24-hour urine protein for proteinuria management: analysis from the phase 3 REFLECT study of lenvatinib vs sorafenib in hepatocellular carcinoma. Br J Cancer. 2019;121(3):218–221.
   PubMed Web of Science ®Google Scholar
• Brose MS, Frenette CT, Keefe SM, et al. Management of Sorafenib-related adverse events: a clinician’s perspective. Seminars in Oncology. 2014;41 Suppl 2: S1-S16.
   Google Scholar
• Je Y, Schutz FA, Choueiri TK. Risk of bleeding with vascular endothelial growth factor receptor tyrosine-kinase inhibitors sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. Lancet Oncol. 2009;10(10):967–974.
   PubMed Web of Science ®Google Scholar
• Schutz FAB, Je Y, Richards CJ, et al. Meta-analysis of randomized controlled trials for the incidence and risk of treatment-related mortality in patients with cancer treated with vascular endothelial growth factor tyrosine kinase inhibitors. J clin oncol. 2012;30(8):871–877.
   PubMed Web of Science ®Google Scholar
• Li X, Wan J, Wu Z, et al. Fatal adverse events with molecular targeted agents in the treatment of advanced hepatocellular carcinoma: a meta-analysis of randomized controlled trials. Drug Des Devel Ther. 2018;12:3043–3049.
   PubMed Web of Science ®Google Scholar
• Uchida-Kobayashi S, Kageyama K, Yamamoto A, et al. Lenvatinib-Induced Tumor-Related Hemorrhages in Patients with Large Hepatocellular Carcinomas. Oncology. 2020;99:1–6.
   PubMed Web of Science ®Google Scholar
• Hirooka M, Ochi H, Hiraoka A, et al. Destructive Thyroiditis Induced by Lenvatinib in Three Patients with Hepatocellular Carcinoma. Int Med. 2019;58(6):791–795.
   PubMed Web of Science ®Google Scholar
• Torino F, Corsello SM, Longo R, et al. Hypothyroidism related to tyrosine kinase inhibitors: an emerging toxic effect of targeted therapy. Nature Reviews Clinical Oncology. Nat Rev Clin Oncol. 2009;6(4):219–228.
   Google Scholar
• Shomura M, Okabe H, Sato E, et al. Hypothyroidism is a predictive factor for better clinical outcomes in patients with advanced hepatocellular carcinoma undergoing lenvatinib therapy. Cancers (Basel). 2020;12(11):1–14.
   Web of Science ®Google Scholar
• Ikeda M, Okusaka T, Mitsunaga S, et al. Safety and pharmacokinetics of lenvatinib in patients with advanced hepatocellular carcinoma. Clin Cancer Res. 2016;22(6):1385–1394.
   PubMed Web of Science ®Google Scholar
• Inoue K, Asai N, Mizuo H, et al. Unique Metabolic Pathway of [14C]Lenvatinib after Oral Administration to Male Cynomolgus Monkey. Drug Metab Dispos. 2012;40(4):662–670.
   PubMed Web of Science ®Google Scholar
• Iwamoto H, Suzuki H, Shimose S, et al. Weekends-off lenvatinib for unresectable hepatocellular carcinoma improves therapeutic response and tolerability toward adverse events. Cancers. 2020;12(4):1010.
   Google Scholar
• Fisher R, Pusztai L, Swanton C. Cancer heterogeneity: implications for targeted therapeutics. Br J Cancer. 2013;108(3):479–485.
   PubMed Web of Science ®Google Scholar
• McGranahan N, Clonal Heterogeneity SC. Tumor Evolution: past, Present, and the Future. Cell Press. 2017;168(4):613–628.
   Google Scholar
• Zheng A, Chevalier N, Calderoni M, et al. CRISPR/Cas9 genome-wide screening identifies KEAP1 as a sorafenib, lenvatinib, and regorafenib sensitivity gene in hepatocellular carcinoma. Oncotarget. 2019;10(66):7058–7070.
   PubMedGoogle Scholar
• Göbel T, Graf D, Hosnowsky C, et al. Multimodal and sequential treatment improves survival in patients with hepatocellular carcinoma. Z Gastroenterol. 2017;55:251–259.
   PubMed Web of Science ®Google Scholar
• Finn RS, Merle P, Granito A, et al. 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.
   PubMed Web of Science ®Google Scholar
• Heo J, Breitbach CJ, Moon A, et al. Sequential therapy with JX-594, a targeted oncolytic poxvirus, followed by sorafenib in hepatocellular carcinoma: preclinical and clinical demonstration of combination efficacy. Mol Ther. 2011;19(6):1170–1179.
   PubMed Web of Science ®Google Scholar
• Bruix J, Qin S, Merle P, et al. 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.
   PubMed Web of Science ®Google Scholar
• Abou-Alfa GK, Meyer T, Cheng A-L, et al. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. N Engl J Med. 2018;379(1):54–63.
   PubMed Web of Science ®Google Scholar
• Zhu AX, Kang YK, Yen CJ, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(2):282–296.
   PubMed Web of Science ®Google Scholar
• Kasuya K, Kawamura Y, Kobayashi M, et al. Efficacy and Safety of Ramucirumab in Patients with Unresectable Hepatocellular Carcinoma with Progression after Treatment with Lenvatinib. Int Med. 2021;60(3):345–351.
   PubMed Web of Science ®Google Scholar
• Kuzuya T, Ishigami M, Ito T, et al. Initial experience of ramucirumab treatment after lenvatinib failure for patients with advanced hepatocellular carcinoma. Anticancer Res. 2020;40:2089–2093.
   PubMed Web of Science ®Google Scholar
• Terashima T, Yamashita T, Takata N, et al. Comparative analysis of liver functional reserve during lenvatinib and sorafenib for advanced hepatocellular carcinoma. Hepatol Res. 2020;50(7):871–884.
   PubMed Web of Science ®Google Scholar
• Alsina A, Kudo M, Vogel A, et al. Effects of Subsequent Systemic Anticancer Medication Following First-Line Lenvatinib: a Post Hoc Responder Analysis from the Phase 3 REFLECT Study in Unresectable Hepatocellular Carcinoma. Liver Cancer. 2020;9(1):93–104.
   PubMed Web of Science ®Google Scholar
• Nakano M, Kuromatsu R, Niizeki T, et al. Primary Treatment with Molecular‐Targeted Agents for Hepatocellular Carcinoma: a Propensity Score‐matching Analysis. Hepatol Commun. 2020;4(8):1218–1228.
   PubMed Web of Science ®Google Scholar
• Lemmon C, Sadek I, Hao Z. Angiogenesis and Anti-tumor Immunity in the Tumor Microenvironment: opportunities for Synergism in Intervention. undefined. 2017;3(10):1-8.
   Google Scholar
• Huang Y, Yuan J, Righi E, et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci USA. 2012;109(43):17561–17566.
   PubMed Web of Science ®Google Scholar
• Bose A, Taylor JL, Alber S, et al. Sunitinib facilitates the activation and recruitment of therapeutic anti-tumor immunity in concert with specific vaccination. Int J Cancer. 2011;129(9):2158–2170.
   PubMed Web of Science ®Google Scholar
• Casadei-Gardini A, Tada T, Shimose S, et al. Is Atezolizumab Plus Bevacizumab for Unresectable Hepatocellular Carcinoma Superior Even to Lenvatinib? A Matching-Adjusted Indirect Comparison. Target Oncol. 2021;16(2):249–254.
   PubMed Web of Science ®Google Scholar
• Zhu AX, Finn RS, Ikeda M, et al. A phase Ib study of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC). J clin oncol. 2020;38:4519.
   Web of Science ®Google Scholar
• Zhu AX, Finn RS, Edeline J, et al. 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.
   PubMed Web of Science ®Google Scholar
• Pishvaian MJ, Lee MS, Ryoo B-Y, et al. Updated safety and clinical activity results from a phase Ib study of atezolizumab + bevacizumab in hepatocellular carcinoma (HCC). Ann Oncol. 2018;29:viii718–viii719.
   Web of Science ®Google Scholar
• Jasim S, Iniguez-Ariza NM, Hilger CR, et al. OPTIMIZING LENVATINIB THERAPY in PATIENTS with METASTATIC RADIOACTIVE IODINE-RESISTANT DIFFERENTIATED THYROID CANCERS. Endocr Pract. 2017;23(10):1254–1261.
   PubMed Web of Science ®Google Scholar
• Yamazaki H, Iwasaki H, Takasaki H, et al. Efficacy and tolerability of initial low-dose lenvatinib to treat differentiated thyroid cancer. Medicine (Baltimore). 2019;98(10):e14774.
   PubMed Web of Science ®Google Scholar
• Arai N, Sasaki H, Tamura R, et al. Unusual Magnetic Resonance Imaging Findings of a Glioblastoma Arising During Treatment with Lenvatinib for Thyroid Cancer. World Neurosurg. 2017;107:1047.e9–1047.e15.
   Web of Science ®Google Scholar
• Wang R, Yamada T, Arai S, et al. Distribution and activity of lenvatinib in brain tumor models of human anaplastic thyroid cancer cells in severe combined immune deficient mice. Mol Cancer Ther. 2019;18(5):947–956.
   PubMed Web of Science ®Google Scholar
• Kuorda H, Abe T, Fujiwara Y, et al. Change in arterial tumor perfusion is an early biomarker of lenvatinib efficacy in patients with unresectable hepatocellular carcinoma. World J Gastroenterol. 2019;25(19):2365–2372.
   PubMed Web of Science ®Google Scholar
• Saeki I, Yamasaki T, Yamashita S, et al. Early predictors of objective response in patients with hepatocellular carcinoma undergoing lenvatinib treatment. Cancers. 2020;12(4):779.
   Google Scholar
• Chuma M, Uojima H, Numata K, et al. Early changes in circulating FGF19 and ang-2 levels as possible predictive biomarkers of clinical response to lenvatinib therapy in hepatocellular carcinoma. I Cancers. 2020;12(2):293.
   Google Scholar
• Xue R, Li R, Guo H, et al. Variable Intra-Tumor Genomic Heterogeneity of Multiple Lesions in Patients with Hepatocellular Carcinoma. Gastroenterology. 2016;150(4):998–1008.
   PubMed Web of Science ®Google Scholar
• Reig M, Torres F, Rodriguez-Lope C, et al. Early dermatologic adverse events predict better outcome in HCC patients treated with sorafenib. J Hepatol. 2014;61(2):318–324.
   PubMed Web of Science ®Google Scholar
• Bruix J, Cheng AL, Meinhardt G, et al. Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: analysis of two phase III studies. J Hepatol. 2017;67(5):999–1008.
   PubMed Web of Science ®Google Scholar
• Kato Y, Tabata K, Kimura T, et al. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8 + T cells through reduction of tumor-associated macrophage and activation of the interferon pathway. PLoS ONE. 2019;14(2):e0212513.
   Google Scholar
• Takase N, Koma YI, Urakawa N, et al. NCAM- and FGF-2-mediated FGFR1 signaling in the tumor microenvironment of esophageal cancer regulates the survival and migration of tumor-associated macrophages and cancer cells. Cancer Lett. 2016;380:47–58.
   PubMed Web of Science ®Google Scholar
• Kelley RK, Oliver J W, Hazra S, et al. Cabozantinib in combination with atezolizumab versus sorafenib in treatment-naive advanced hepatocellular carcinoma: COSMIC-312 Phase III study design. Future Oncol. 2020;16(21):1525–1536.
   PubMed Web of Science ®Google Scholar
• Mazzaferro V, Citterio D, Bhoori S, et al. Liver transplantation in hepatocellular carcinoma after tumour downstaging (XXL): a randomised, controlled, phase 2b/3 trial. Lancet Oncol. 2020;21(7):947–956.
   PubMed Web of Science ®Google Scholar