Sub-analysis of OS revealed that it was significantly more favorable for patients when sorafenib was first used at a Child-Pugh score of 5 than for patients introduced to sorafenib at a score of 6; this suggests that early switching from TACE to sorafenib for patients who become refractory to TACE at a Child-Pugh score of 5, and early switching to regorafenib for patients who become refractory to sorafenib, are important for extending survival

Sub-analysis of OS revealed that it was significantly more favorable for patients when sorafenib was first used at a Child-Pugh score of 5 than for patients introduced to sorafenib at a score of 6; this suggests that early switching from TACE to sorafenib for patients who become refractory to TACE at a Child-Pugh score of 5, and early switching to regorafenib for patients who become refractory to sorafenib, are important for extending survival. of 5 clinical trials of combination therapy with transcatheter chemoembolization (TACE) plus a molecular targeted agent failed to date, however, the combination of TACE and Sdc2 sorafenib (TACTICS trials) was reported to be successful and presented at ASCO in 2018. Phase 3 clinical trials of immune checkpoint inhibitors and a combination therapy of immune checkpoint inhibitors and molecular targeted agents are also ongoing, which suggests treatment paradigm of HCC in all stages from early, intermediate and advanced stage, is SU 5205 expected to be changed drastically in the very near future. SunitinibSUN1170NegativeASCO 2011JCO 2013[6]Cheng AL2 Sorafenib +/- ErlotinibSEARCHNegativeESMO 2012JCO 2015[7]Zhu AX3 Sorafenib BrivanibBRISK-FLNegativeAASLD 2012JCO 2013[8]Johnson PJ4 Sorafenib LinifanibLiGHTNegativeASCO-GI 2013JCO 2015[9]Cainap C5 Sorafenib +/- DoxorubicinCALGB 80802NegativeASCO-GI 20166 Sorafenib +/- HAICSILIUSNegativeEASL 2016Lancet GH 2018[10]Kudo M7 Sorafenib +/- Y90SARAHNegativeEASL 2017Lancet-O 2017[11]Vilgrain V8 Sorafenib +/- Y90SIRveNIBNegativeASCO 2017JCO 2018[12]Chow P9 Sorafenib LenvatinibREFLECTPositiveASCO 2017Lancet 2018[34]Kudo M10 Sorafenib NivolumabCheckMate-459Ongoing11 Sorafenib Durvalumab + Tremelimumab DurvaHIMALAYAOngoing12 Sorafenib Atezolizumab + BevacizumabImbrave 150Ongoing13 Sorafenib TislelizumabOngoingSecond line1 Brivanib PlaceboBRISK-PSNegativeEASL 2012JCO 2013[13]Llovet JM2 Everolimus PlaceboEVOLVE-1NegativeASCO-GI 2014JAMA 2014[14]Zhu AX3 Ramucirumab PlaceboREACHNegativeESMO 2014Lancet-O 2015[15]Zhu AX4 S-1 PlaceboS-CUBENegativeASCO 2015Lancet GH 2017[16]Kudo M5 ADI-PEG 20 PlaceboNANegativeASCO 2016Ann Oncol 2018[17]Abou-Alfa G6 Regorafenib PlaceboRESORCEPositiveWCGC 2016Lancet 2017[41]Bruix J7 Tivantinib PlaceboMETIV-HCCNegativeASCO 2017Lancet-O 2018[18]Rimassa L8 Tivantinib PlaceboJET-HCCNegativeESMO 20179 DT PlaceboReLiveNegativeILCA 201710 Cabozantinib PlaceboCELESTIALPositiveASCO-GI 2018NEJM 2018[45]Abou-Alfe G11 Ramucirumab PlaceboREACH-2PositiveASCO 2018Lancet-O 2019[30]Zhu AX12 Pembrolizumab PlaceboKEYNOTE-240Negative Open in a separate window HAIC: Hepatic arterial infusion chemotherapy; Doxorubicin-loaded nanoparticles. Table 2 Randomized phase II, phase III clinical trials of early / intermediate SU 5205 stage hepatocellular carcinoma PlaceboNegativeHepatology 2011[21]Yoshida H2 Peretinoin PlaceboNIK-333NegativeASCO 2010JG 2014[22]Okita K3 Sorafenib PlaceboSTORMNegativeASCO 2014Lancet-O 2015[23]Bruix J4 Peretinoin PlaceboNIK-333/K-333OngoingImprovement of RFA1 RFA +/- LTLDHEATNegativeILCA 2013CCR 2017[24]Tak WY2 RFA +/- LTLDOPTIMAIntermediateImprovement of TACE1 TACE +/- SorafenibPost-TACENegativeASCO-GI 2010EJC 2011[25]Kudo M2 TACE +/- SorafenibSPACE (Ph II)NegativeASCO-GI 2012J Hepatol 2016[26]Lencioni R3 TACE +/- BrivanibBRISK-TANegativeILCA 2013Hepatol 2014[27]Kudo M4 TACE +/- OrantinibORIENTALNegativeEASL 2015Lancet GH 2017[28]Kudo M5 TACE +/- SorafenibTACE-2NegativeASCO 2016Lancet GH 2017[29]Meyer T6 TACE +/- SorafenibTACTICS (Ph II)PositiveASCO-GI 2018[30]Kudo M Open in a separate window LTLD: Lyso-thermosensitive liposomal doxorubicin. MOLECULAR TARGETED AGENTS: FIRST-LINE AGENTS Sorafenib Sorafenib is an oral drug that suppresses tumor growth by inhibiting the serine-threonine kinases C-Raf, wild-type B-Raf, and mutant (V600E) B-Raf, all of which are components of the Raf/MEK/ERK pathway (mitogen-activated proteins kinase pathway). This pathway acts SU 5205 downstream of the vascular endothelial growth factor receptor (VEGFR), the platelet-derived growth factor receptor (PDGFR), and the epidermal growth factor receptor. It also exerts anti-tumor effects by SU 5205 suppressing neovascularization. It achieves tumor neovascularization by inhibiting the tyrosine kinases VEGFR1, VEGFR2, VEGFR3, PDGFR, RET, and fms-related tyrosine kinase 3 (FLT-3). Two large-scale pivotal trials (the SHARP and Asia-Pacific trials) of sorafenib reported significant prolongation of overall survival (OS) compared with placebo[31,32]; indeed, sorafenib is now the standard therapeutic agent for advanced HCC. However, its ability to shrink tumors is weak and its systemic toxicity is relatively high. Therefore, novel molecular targeted agents with more potency or similar effects, but less toxicity, have been unmet need. Lenvatinib: Overview of the results of the REFLECT trial Although eight clinical trials with various agents/modalities comparing with sorafenib conducted in the last decade has shown negative outcomes, the results of the REFLECT trial with use of lenvatinib met its primary endpoint of non-inferiority of prolonging OS compared with sorafenib. Lenvatinib is an oral kinase inhibitor that selectively inhibits receptor tyrosine kinases involved in neovascularization and progression to high malignancy grade tumors and a poor prognosis; targeted kinases include VEGFR1, VEGFR2, VEGFR3, fibroblast growth factor receptor (FGFR) 1, FGFR2, FGFR3, FGFR4, PDGFR, KIT, and RET. In particular, strong inhibition of FGFR4 is considered important for preventing aggressive growth or progression to a higher malignancy grade of HCC. The drug also suppresses invasion and metastasis. A single-arm phase II study of lenvatinib SU 5205 as a treatment for advanced HCC reported a time to progression (TTP) of 7.4 mo and an OS of 18.7 mo, which are very favorable[33]. Subsequently, a phase III study comparing sorafenib with lenvatinib, the REFLECT trial, was conducted[34]. The REFLECT trial was a global phase III study to show the non-inferiority of lenvatinib to sorafenib, in which patients with unresectable HCC, not previously treated with systemic chemotherapy, were allocated randomly to the lenvatinib or sorafenib arms at a 1:1 ratio. Stratification factors were Asian/non-Asian, vascular invasion and/or extrahepatic spread (presence or absence), Eastern Cooperative Oncology Group performance status 0 or 1, and body weight < 60 kg or 60 kg. Administration was continued.