Targeted and Immune-Based Therapies for Hepatocellular Carcinoma

Treatment options for patients with hepatocellular carcinoma are rapidly changing based on positive results from phase 3 trials of targeted and immune-based therapies. More agents designed to target specific pathways and immune checkpoints are in clinical development. Some agents have already been shown to improve outcomes of patients with hepatocellular carcinoma, as first- and second-line therapies, and are awaiting approval by the Food and Drug Administration or have been recently approved. We summarize the targeted and immune-based agents in trials of patients with advanced hepatocellular carcinoma and discuss the future of these strategies for liver cancer. Treatment options for patients with hepatocellular carcinoma are rapidly changing based on positive results from phase 3 trials of targeted and immune-based therapies. More agents designed to target specific pathways and immune checkpoints are in clinical development. Some agents have already been shown to improve outcomes of patients with hepatocellular carcinoma, as first- and second-line therapies, and are awaiting approval by the Food and Drug Administration or have been recently approved. We summarize the targeted and immune-based agents in trials of patients with advanced hepatocellular carcinoma and discuss the future of these strategies for liver cancer. Chunwei Walter LaiView Large Image Figure ViewerDownload Hi-res image Download (PPT)Guangfu LiView Large Image Figure ViewerDownload Hi-res image Download (PPT)Kevin F. Staveley-O’CarrollView Large Image Figure ViewerDownload Hi-res image Download (PPT) Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide, with approximately 800,000 cases per year.1Ferlay J. Soerjomataram I. Dikshit R. et al.Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.Int J Cancer. 2015; 136: E359-E386Crossref PubMed Scopus (14492) Google Scholar More than 80% of all HCCs occur in patients with liver diseases and cirrhosis. Most patients receive a diagnosis when their tumors are already too advanced for curative approaches such as surgical resection, orthotopic liver transplantation, or local percutaneous tumor ablation.2Clavien P.A. Lesurtel M. Bossuyt P.M. et al.Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report.Lancet Oncol. 2012; 13: e11-e22Abstract Full Text Full Text PDF PubMed Scopus (539) Google Scholar, 3Vitale A. Peck-Radosavljevic M. Giannini E.G. et al.Personalized treatment of patients with very early hepatocellular carcinoma.J Hepatol. 2017; 66: 412-423Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar Therefore, palliative treatment options are important in management of patients with HCC. First-line treatment options include transarterial approaches such as transarterial chemoembolization (TACE) or transarterial radio-embolization (TARE) and systemic therapies. We review the accepted treatment options for HCC, based on recently updated American Association for the Study of Liver Diseases and European Association for the Study of Liver Diseases guidelines.4European Association for the Study of the LiverElectronic address: [email protected]; European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma.J Hepatol. 2018; 69: 154-181Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 5Heimbach J.K. Kulik L.M. Finn R.S. et al.AASLD guidelines for the treatment of hepatocellular carcinoma.Hepatology. 2018; 67: 358-380Crossref PubMed Scopus (601) Google Scholar We discuss standard of care options for patients with unresectable HCC, results from recent phase 3 trials, and their effects on treatment algorithms. We provide an overview of new targeted and immune-based treatment options and challenges to upcoming trials, with a focus on combination therapies. Locoregional therapies include percutaneous local ablation, chemoembolization, radio-embolization, and external radiation therapy; they are the most common first-line treatments, although 50% of patients receive systemic therapies at some point during disease progression.4European Association for the Study of the LiverElectronic address: [email protected]; European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma.J Hepatol. 2018; 69: 154-181Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Their efficacy is limited by tumor size and location. Percutaneous local ablation is the only curative locoregional therapy—subtypes include percutaneous ethanol injection, radiofrequency ablation (RFA), microwave ablation, cryoablation, and irreversible electroporation (reviewed by Nault et al6Nault J.-C. Sutter O. Nahon P. et al.Percutaneous treatment of hepatocellular carcinoma: state of the art and innovations.J Hepatol. 2018; 68: 783-797Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). RFA is the most commonly used and studied percutaneous ablation technique; rates of 3-year overall survival range from 67% to 84%, rates of 3-year local recurrence range from 3.2% to 28.5%, and rates of complete response range from 90% to 98.5% (for tumors <3 cm).6Nault J.-C. Sutter O. Nahon P. et al.Percutaneous treatment of hepatocellular carcinoma: state of the art and innovations.J Hepatol. 2018; 68: 783-797Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar RFA is sometimes used in combination with TACE for tumors larger than 3 cm.7Peng Z.W. Chen M.S. Liang H.H. et al.A case-control study comparing percutaneous radiofrequency ablation alone or combined with transcatheter arterial chemoembolization for hepatocellular carcinoma.Eur J Surg Oncol. 2010; 36: 257-263Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Studies comparing RFA with liver resection for tumors of 2–3 cm are often underpowered, but findings generally support the concept that rates of recurrence are similar for patients treated with RFA vs liver resection. Arterial embolization is recommended for patients with tumors not amenable to curative resection or ablation, without extrahepatic spread, and with preserved liver function.4European Association for the Study of the LiverElectronic address: [email protected]; European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma.J Hepatol. 2018; 69: 154-181Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 5Heimbach J.K. Kulik L.M. Finn R.S. et al.AASLD guidelines for the treatment of hepatocellular carcinoma.Hepatology. 2018; 67: 358-380Crossref PubMed Scopus (601) Google Scholar Vascular invasion could be an exclusion criterion for TACE depending on tumor location. It is contraindicated for patients with decompensated cirrhosis owing to the risk of fulminant liver failure from low liver reserve. Arterial embolization techniques include conventional TACE, drug-eluting bead TACE, and transarterial embolization. Conventional TACE involves an intrahepatic injection of a chemotherapy lipiodol emulsion into the tumor vasculature followed by particle embolization. This is the most commonly used TACE technique worldwide.8Habib A. Desai K. Hickey R. et al.Transarterial approaches to primary and secondary hepatic malignancies.Nat Rev Clin Oncol. 2015; 12: 481Crossref PubMed Scopus (17) Google Scholar Drug-eluting bead TACE uses drug-eluting beads to deliver a high dose of doxorubicin locally, to minimize systemic toxicity. Transarterial embolization uses Gelfoam to obstruct arterial perfusion, thereby causing local ischemia near the tumor without application of any cytotoxic reagents. TARE typically involves intra-arterial infusion of yttrium-90, an element that emits beta radiation, has a half-live of 2.5 days, and affects only the local tumor region (reviewed by Sacco et al9Sacco R. Mismas V. Marceglia S. et al.Transarterial radioembolization for hepatocellular carcinoma: An update and perspectives.World J Gastroenterol. 2015; 21: 6518-6525Crossref PubMed Scopus (22) Google Scholar). Retrospective studies have found yttrium-90 therapy to be superior to TACE in downsizing tumors and as a bridge to transplantation. However, no randomized trials have directly compared the treatments. Therefore, it is difficult to clearly define the role of TARE in the management of HCC. TARE failed to increase overall survival compared with sorafenib, the first-line systemic treatment for HCC, in patients with locally advanced HCC in 2 phase 3 trials (Sorafenib Versus Radioembolization in Advanced Hepatocellular Carcinoma [SARAH] and Selective Internal Radiation Therapy Versus Sorafenib in Locally Advanced Hepatocellular Carcinoma [SIRveNIB]).10Vilgrain V. Pereira H. Assenat E. et al.Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial.Lancet Oncol. 2017; 18: 1624-1636Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar, 11Chow P.K.H. Gandhi M. Tan S.B. et al.SIRveNIB: selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma.J Clin Oncol. 2018; 36: 1913-1921Crossref PubMed Scopus (101) Google Scholar Locoregional therapies are important in management of patients with HCC. The SARAH and SIRveNIB trials did not find TARE to increase survival times of patients compared with systemic therapy.10Vilgrain V. Pereira H. Assenat E. et al.Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial.Lancet Oncol. 2017; 18: 1624-1636Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar, 11Chow P.K.H. Gandhi M. Tan S.B. et al.SIRveNIB: selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma.J Clin Oncol. 2018; 36: 1913-1921Crossref PubMed Scopus (101) Google Scholar In contrast, a recent study reported an overall survival time of 26 months for patients treated consecutively with the tyrosine kinase inhibitors sorafenib and then regorafenib.12Finn R.S. Merle P. Granito A. et al.Outcomes with sorafenib (SOR) followed by regorafenib (REG) or placebo (PBO) for hepatocellular carcinoma (HCC): results of the international, randomized phase 3 RESORCE trial.J Clin Oncol. 2017; 35 (344–344)Crossref Google Scholar These findings indicate that targeted therapies could be as effective as locoregional therapies. There have been attempts to improve outcomes of patients by adding targeted therapies to locoregional therapy. However, adding sorafenib to TACE failed to improve time to progression (Strategies for Prescribing Analgesics Comparative Effectiveness [SPACE] trial).13Lencioni R. Llovet J.M. Han G. et al.Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: The SPACE trial.J Hepatol. 2016; 64: 1090-1098Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar The combination of TACE (or RFA) and an immune checkpoint inhibitor was tested in a small pilot study,14Duffy A.G. Ulahannan S.V. Makorova-Rusher O. et al.Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma.J Hepatol. 2017; 66: 545-551Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar which demonstrated safety and early signs of efficacy. However, larger studies are needed to compare the effectiveness of combined locoregional therapies and immune-based therapies with only locoregional therapy. Sorafenib was the only drug approved for the systemic treatment of patients with HCC until 2017. It is a tyrosine kinase inhibitor that blocks the activities of vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors, and Raf family kinases. It extends the mean overall survival time of patients with advanced HCC by 2.8 months.15Llovet J.M. Ricci S. Mazzaferro V. et al.Sorafenib in advanced hepatocellular carcinoma.N Engl J Med. 2008; 359: 378-390Crossref PubMed Scopus (6394) Google Scholar Similar results have been reported in an Asian patient population.16Cheng A.L. Kang Y.K. 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: 25-34Abstract Full Text Full Text PDF PubMed Scopus (3221) Google Scholar After positive results from a pivotal phase 3 trial (Study of Heart and Renal Protection [SHARP]15Llovet J.M. Ricci S. Mazzaferro V. et al.Sorafenib in advanced hepatocellular carcinoma.N Engl J Med. 2008; 359: 378-390Crossref PubMed Scopus (6394) Google Scholar) and Food and Drug Administration (FDA) approval of sorafenib for treatment of patients with HCC, several promising targeted agents were tested in phase 3 trials, from 2008 through 2017. However, these were not found to improve patient outcomes (Table 1).10Vilgrain V. Pereira H. Assenat E. et al.Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial.Lancet Oncol. 2017; 18: 1624-1636Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar, 11Chow P.K.H. Gandhi M. Tan S.B. et al.SIRveNIB: selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma.J Clin Oncol. 2018; 36: 1913-1921Crossref PubMed Scopus (101) Google Scholar, 13Lencioni R. Llovet J.M. Han G. et al.Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: The SPACE trial.J Hepatol. 2016; 64: 1090-1098Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar, 15Llovet J.M. Ricci S. Mazzaferro V. et al.Sorafenib in advanced hepatocellular carcinoma.N Engl J Med. 2008; 359: 378-390Crossref PubMed Scopus (6394) Google Scholar, 16Cheng A.L. Kang Y.K. 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: 25-34Abstract Full Text Full Text PDF PubMed Scopus (3221) Google Scholar, 17Kudo M. Finn R.S. 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: 1163-1173Abstract Full Text Full Text PDF PubMed Scopus (503) Google Scholar, 18Bruix 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: 56-66Abstract Full Text Full Text PDF PubMed Scopus (859) Google Scholar, 19Abou-Alfa G.K. Meyer T. Cheng A.L. et al.Cabozantinib in patients with advanced and progressing hepatocellular carcinoma.N Engl J Med. 2018; 379: 54-63Crossref PubMed Scopus (245) Google Scholar, 20Zhu A.X. Park J.O. Ryoo B.Y. et al.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: 859-870Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar, 21Zhu A.X. Kang Y.-K. Yen C.-J. et al.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 (abstract 4003)Google Scholar, 22Lee J.H. Lee J.H. Lim Y.S. et al.Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma.Gastroenterology. 2015; 148: 1383-1391 e6Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar, 23Cheng A.L. Kang Y.K. Lin D.Y. et al.Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial.J Clin Oncol. 2013; 31: 4067-4075Crossref PubMed Google Scholar, 24Cainap C. Qin S. Huang W.T. et al.Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial.J Clin Oncol. 2015; 33: 172-179Crossref PubMed Scopus (269) Google Scholar, 25Johnson P.J. Qin S. Park J.W. et al.Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study.J Clin Oncol. 2013; 31: 3517-3524Crossref PubMed Google Scholar, 26Zhu A.X. Rosmorduc O. Evans T.R.J. et al.SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma.J Clin Oncol. 2015; 33: 559-566Crossref PubMed Scopus (239) Google Scholar, 27Abou-Alfa G.K. Niedzwieski D. Knox J.J. et al.Phase III randomized study of sorafenib plus doxorubicin versus sorafenib in patients with advanced hepatocellular carcinoma (HCC): CALGB 80802 (Alliance).J Clin Oncol. 2016; 34: 192Crossref Google Scholar, 28Kudo M. Ueshima K. Yokosuka O. et al.Sorafenib plus low-dose cisplatin and fluorouracil hepatic arterial infusion chemotherapy versus sorafenib alone in patients with advanced hepatocellular carcinoma (SILIUS): a randomised, open label, phase 3 trial.Lancet Gastroenterol Hepatol. 2018; 3: 424-432Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 29Abou-Alfa G.K. Qin S. Ryoo B.Y. et al.Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular carcinoma.Ann Oncol. 2018; 29: 1402-1408Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 30Llovet J.M. Decaens T. Raoul J.L. et al.Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study.J Clin Oncol. 2013; 31: 3509-3516Crossref PubMed Google Scholar, 31Zhu A.X. Kudo M. Assenat E. et al.Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial.JAMA. 2014; 312: 57-67Crossref PubMed Scopus (321) Google Scholar, 32Rimassa L. Assenat E. Peck-Radosavljevic M. et al.Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study.Lancet Oncol. 2018; 19: 682-693Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 33Kudo M. Moriguchi M. Numata K. et al.S-1 versus placebo in patients with sorafenib-refractory advanced hepatocellular carcinoma (S-CUBE): a randomised, double-blind, multicentre, phase 3 trial.Lancet Gastroenterol Hepatol. 2017; 2: 407-417Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 34Bruix J. Takayama T. Mazzaferro V. et al.Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial.Lancet Oncol. 2015; 16: 1344-1354Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar, 35Kudo M. Han G. Finn R.S. et al.Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: a randomized phase III trial.Hepatology. 2014; 60: 1697-1707Crossref PubMed Scopus (126) Google ScholarTable 1Phase 3 StudiesTrialDrugsnMedian time of overall survival (mo)Hazard ratio (95% CI)P valuePositive resultReferenceFirst line SHARPYes15Llovet J.M. Ricci S. Mazzaferro V. et al.Sorafenib in advanced hepatocellular carcinoma.N Engl J Med. 2008; 359: 378-390Crossref PubMed Scopus (6394) Google ScholarSorafenib29910.70.69 (0.55–0.87)<.001Placebo3037.9 Asian-PacificYes16Cheng A.L. Kang Y.K. 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: 25-34Abstract Full Text Full Text PDF PubMed Scopus (3221) Google ScholarSorafenib1506.50.68 (0.5–0.93).01Placebo764.2 SUN1170No23Cheng A.L. Kang Y.K. Lin D.Y. et al.Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial.J Clin Oncol. 2013; 31: 4067-4075Crossref PubMed Google ScholarSunitinib5307.91.3 (1.13–1.5).001Sorafenib54410.2 LiGHTNo24Cainap C. Qin S. Huang W.T. et al.Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial.J Clin Oncol. 2015; 33: 172-179Crossref PubMed Scopus (269) Google ScholarLinifanib5149.11.046 (0.896–1.221)NSSorafenib5219.8 BRISK-FLNo25Johnson P.J. Qin S. Park J.W. et al.Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study.J Clin Oncol. 2013; 31: 3517-3524Crossref PubMed Google ScholarBrivanib5779.51.07 (0.94–1.23).31Sorafenib5789.9 SEARCHNo26Zhu A.X. Rosmorduc O. Evans T.R.J. et al.SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma.J Clin Oncol. 2015; 33: 559-566Crossref PubMed Scopus (239) Google ScholarSorafenib + Everolimus3629.50.92 (0.781–1.106).2Sorafenib3588.5 REFLECT/Study 304Yes17Kudo M. Finn R.S. 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: 1163-1173Abstract Full Text Full Text PDF PubMed Scopus (503) Google ScholarLenvatinib47813.60.92 (0.79–1.06)<.05Sorafenib47612.3 CALGB 80802No27Abou-Alfa G.K. Niedzwieski D. Knox J.J. et al.Phase III randomized study of sorafenib plus doxorubicin versus sorafenib in patients with advanced hepatocellular carcinoma (HCC): CALGB 80802 (Alliance).J Clin Oncol. 2016; 34: 192Crossref Google ScholarSorafenib + doxo1739.31.06 (0.8–1.4)NSSorafenib17310.5 SILIUSNo28Kudo M. Ueshima K. Yokosuka O. et al.Sorafenib plus low-dose cisplatin and fluorouracil hepatic arterial infusion chemotherapy versus sorafenib alone in patients with advanced hepatocellular carcinoma (SILIUS): a randomised, open label, phase 3 trial.Lancet Gastroenterol Hepatol. 2018; 3: 424-432Abstract Full Text Full Text PDF PubMed Scopus (39) Google ScholarSorafenib + HIAC8816.91.2 (0.8–1.6)NSSorafenib10216.1 SARAHNo10Vilgrain V. Pereira H. Assenat E. et al.Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial.Lancet Oncol. 2017; 18: 1624-1636Abstract Full Text Full Text PDF PubMed Scopus (143) Google ScholarSIRT (Y-90)23781.15 (0.94–1.41)NSSorafenib2229.9 NCT 01287585No29Abou-Alfa G.K. Qin S. Ryoo B.Y. et al.Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular carcinoma.Ann Oncol. 2018; 29: 1402-1408Abstract Full Text Full Text PDF PubMed Scopus (31) Google ScholarADI-PEG204247.81.17Placebo2117.4 SIRveNIBNo11Chow P.K.H. Gandhi M. Tan S.B. et al.SIRveNIB: selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma.J Clin Oncol. 2018; 36: 1913-1921Crossref PubMed Scopus (101) Google ScholarSIRT (Y-90)1828.81.12 (0.88–1.42)Sorafenib17810NSSecond line BRISK-PSNo30Llovet J.M. Decaens T. Raoul J.L. et al.Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISK-PS study.J Clin Oncol. 2013; 31: 3509-3516Crossref PubMed Google ScholarBrivanib2639.40.89 (0.69–1.15).33Placebo1328.2 EVOLVE-1No31Zhu A.X. Kudo M. Assenat E. et al.Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial.JAMA. 2014; 312: 57-67Crossref PubMed Scopus (321) Google ScholarEverolimus3627.61.05 (0.86–1.27).68Placebo1847.3 REACHNo20Zhu A.X. Park J.O. Ryoo B.Y. et al.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: 859-870Abstract Full Text Full Text PDF PubMed Scopus (283) Google ScholarRamucirumab2839.20.86 (0.72–1.05).13Placebo2827.6 RESORCEYes18Bruix 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: 56-66Abstract Full Text Full Text PDF PubMed Scopus (859) Google ScholarRegorafenib37910.60.63 (0.50–0.79)<.001Placebo1947.8 METIV-HCCNo32Rimassa L. Assenat E. Peck-Radosavljevic M. et al.Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study.Lancet Oncol. 2018; 19: 682-693Abstract Full Text Full Text PDF PubMed Scopus (91) Google ScholarTivantinib2268.40.97 (0.75–1.25)NSPlacebo1149.1 S-CUBE33Kudo M. Moriguchi M. Numata K. et al.S-1 versus placebo in patients with sorafenib-refractory advanced hepatocellular carcinoma (S-CUBE): a randomised, double-blind, multicentre, phase 3 trial.Lancet Gastroenterol Hepatol. 2017; 2: 407-417Abstract Full Text Full Text PDF PubMed Scopus (11) Google ScholarS-122311.10.86 (0.67–1.10).220Placebo11111.2 CELESTIALYes19Abou-Alfa G.K. Meyer T. Cheng A.L. et al.Cabozantinib in patients with advanced and progressing hepatocellular carcinoma.N Engl J Med. 2018; 379: 54-63Crossref PubMed Scopus (245) Google ScholarCabozantinib46710.20.76 (0.63–0.92).0049Placebo2378.0 REACH IIYes21Zhu A.X. Kang Y.-K. Yen C.-J. et al.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 (abstract 4003)Google ScholarRamucirumab1978.50.71 (0.531–0.949).0199Placebo957.3Adjuvant Surgery or RFA STORMNo34Bruix J. Takayama T. Mazzaferro V. et al.Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial.Lancet Oncol. 2015; 16: 1344-1354Abstract Full Text Full Text PDF PubMed Scopus (326) Google ScholarSorafenib556RFS 33.3 mo0.891 (0.735–1.081).12Placebo558RFS 33.7 mo Adjuvant CIKNo22Lee J.H. Lee J.H. Lim Y.S. et al.Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma.Gastroenterology. 2015; 148: 1383-1391 e6Abstract Full Text Full Text PDF PubMed Scopus (157) Google ScholarCIK115RFS 44.0 mo.010No treatment114RFS 30.0 mo TACE SPACENo13Lencioni R. Llovet J.M. Han G. et al.Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: The SPACE trial.J Hepatol. 2016; 64: 1090-1098Abstract Full Text Full Text PDF PubMed Scopus (220) Google ScholarSorafenib154TP 169 d0.797 (0.588–1.08).072Placebo153TP 166 d35Kudo M. Han G. Finn R.S. et al.Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: a randomized phase III trial.Hepatology. 2014; 60: 1697-1707Crossref PubMed Scopus (126) Google Scholar BRISK-TAaEarly termination.Brivanib24926.40.9 (0.66–0.23)NSNoPlacebo25326.1CI, confidence interval; BRISK-FL, Brivanib Studied in First- and Second-Line Therapy for Hepatocellular Carcinoma; BRISK-PS, Brivanib Study in HCC Patients at Risk Post Sorafenib; BRISK-TA, Phase III Trans-arterial Chemo-embolization Adjuvant HCC; EVOLVE-1, Evaluation of Galcanezumab in the Prevention of Episodic Migraine; LiGHT, Linifanib Versus Sorafenib in Patients With Advanced Hepatocellular Carcinoma; METIV-HCC, Tivantinib in Subjects With Inoperable Hepatocellular Carcinoma Who Have Been Treated With One Prior Therapy; NS, not significant; REACH, Study of Ramucirumab (LY3009806) Versus Placebo in Participants With Hepatocellular Carcinoma and Elevated Baseline Alpha-Fetoprotein; RESORCE, Regorafenib After Sorafenib in Patients With Hepatocellular Carcinoma; RFS, recurrence-free survival; S-CUBE, S-1 Versus Placebo in Patients With Sorafenib-Refractory Advanced Hepatocellular Carcinoma; SILIUS, Sorafenib in Combination With Low-dose 5-Fluorouracil/Cisplatin Intraarterial Infusion Chemotherapy; SPACE, Strategies for Prescribing Analgesics Comparative Effectiveness; STORM, Selinexor Treatment of Refractory Myeloma; TP, time to progression; Y-90, yttrium-90.a Early termination. 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