Systemic Therapy for Hepatocellular Carcinoma: Advances and Hopes

Author(s): Chen-Hao Zhang, Ming Li, You-Pei Lin, Qiang Gao*

Journal Name: Current Gene Therapy

Volume 20 , Issue 2 , 2020

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Graphical Abstract:


Abstract:

The majority of patients with hepatocellular carcinoma (HCC) are diagnosed at an advanced stage that can only benefit from systemic treatments. Although HCC is highly treatmentresistant, significant achievements have been made in the molecular targeted therapy and immunotherapy of HCC. In addition to regorafenib, cabozantinib and ramucirumab were approved for the second- line targeted treatment by the FDA after disease progression on sorafenib. Nivolumab failed to demonstrate remarkable benefit in overall survival (OS) as first-line therapy, while pembrolizumab did not achieve pre-specified statistical significance in both OS and progression-free survival (PFS) as second-line treatment. Combinations of targeted agents, immune checkpoint inhibitors and other interventions showed favorable results. In this review, we summarized the progress of systemic therapy in HCC and discussed the future directions of the treatment of HCC.

Keywords: Hepatocellular carcinoma, clinical trials, targeted therapy, immunotherapy, liver cancer, hepatitis B virus, hepatitis C virus.

[1]
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(6): 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
Villanueva A. Hepatocellular Carcinoma. N Engl J Med 2019; 380(15): 1450-62.
[http://dx.doi.org/10.1056/NEJMra1713263] [PMID: 30970190]
[3]
Zehir A, Benayed R, Shah RH, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med 2017; 23(6): 703-13.
[http://dx.doi.org/10.1038/nm.4333] [PMID: 28481359]
[4]
Cancer Genome Atlas Research Network. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell 2017; 169(7): 1327-41.
[http://dx.doi.org/10.1016/j.cell.2017.05.046] [PMID: 28622513]
[5]
Gao Q, Zhu H, Dong L, et al. Integrated Proteogenomic Characterization of HBV-Related Hepatocellular Carcinoma. Cell 2019; 179(2): 561-577.e22.
[http://dx.doi.org/10.1016/j.cell.2019.08.052] [PMID: 31585088]
[6]
Jiang Y, Sun A, Zhao Y, et al. Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma. Nature 2019; 567(7747): 257-61.
[http://dx.doi.org/10.1038/s41586-019-0987-8] [PMID: 30814741]
[7]
Zhu X-D, Sun H-C. Emerging agents and regimens for hepatocellular carcinoma. J Hematol Oncol 2019; 12(1): 110.
[http://dx.doi.org/10.1186/s13045-019-0794-6] [PMID: 31655607]
[8]
Cheng 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(1): 25-34.
[http://dx.doi.org/10.1016/S1470-2045(08)70285-7] [PMID: 19095497]
[9]
Goyal L, Zheng H, Abrams TA, et al. A Phase II and biomarker study of sorafenib combined with modified FOLFOX in patients with advanced hepatocellular carcinoma. Clin Cancer Res 2019; 25(1): 80-9.
[http://dx.doi.org/10.1158/1078-0432.CCR-18-0847] [PMID: 30190369]
[10]
Assenat E, Pageaux G-P, Thézenas S, et al. Sorafenib alone vs. sorafenib plus GEMOX as 1st-line treatment for advanced HCC: the phase II randomised PRODIGE 10 trial. Br J Cancer 2019; 120(9): 896-902.
[http://dx.doi.org/10.1038/s41416-019-0443-4] [PMID: 30944458]
[11]
Yau TC, Tang V, Leung RC-Y, et al. Randomized phase II trial of sorafenib, capecitabine and oxaliplatin (SECOX) versus single agent sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2019; 37(Suppl. 4): 365.
[http://dx.doi.org/10.1200/JCO.2019.37.4_suppl.365]
[12]
Abou-Alfa GK, Shi Q, Knox JJ, et al. Assessment of treatment with sorafenib plus doxorubicin vs sorafenib alone in patients with advanced hepatocellular carcinoma: Phase 3 CALGB 80802 Randomized Clinical Trial. JAMA Oncol 2019; 5(11): 1582-8.
[http://dx.doi.org/10.1001/jamaoncol.2019.2792] [PMID: 31486832]
[13]
Merle P, Blanc J-F, Phelip J-M, et al. RELIVE Investigators. Doxorubicin-loaded nanoparticles for patients with advanced hepatocellular carcinoma after sorafenib treatment failure (RELIVE): a phase 3 randomised controlled trial. Lancet Gastroenterol Hepatol 2019; 4(6): 454-65.
[http://dx.doi.org/10.1016/S2468-1253(19)30040-8] [PMID: 30954567]
[14]
Kondo M, Morimoto M, Kobayashi S, et al. Randomized, phase II trial of sequential hepatic arterial infusion chemotherapy and sorafenib versus sorafenib alone as initial therapy for advanced hepatocellular carcinoma: SCOOP-2 trial. BMC Cancer 2019; 19(1): 954.
[http://dx.doi.org/10.1186/s12885-019-6198-8] [PMID: 31615466]
[15]
He M, Li Q, Zou R, et al. Sorafenib plus hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin vs sorafenib alone for hepatocellular carcinoma with portal vein invasion: a randomized clinical trial. JAMA Oncol 2019; 5(7): 953-60.
[http://dx.doi.org/10.1001/jamaoncol.2019.0250] [PMID: 31070690]
[16]
Kudo M, Ueshima K, Ikeda M, et al. Randomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial. Gut 2019; 69(8): 1492-501.
[PMID: 31801872]
[17]
Park J-W, Kim YJ, Kim DY, et al. Sorafenib with or without concurrent transarterial chemoembolization in patients with advanced hepatocellular carcinoma: The phase III STAH trial. J Hepatol 2019; 70(4): 684-91.
[http://dx.doi.org/10.1016/j.jhep.2018.11.029] [PMID: 30529387]
[18]
Huang C-C, Chen H-Y, Chang R-H, et al. A real-life experience of sorafenib treatment for patients with advanced hepatocellular carcinoma: a retrospective analysis at Cathay General Hospital, 2007-2015. Drug Des Devel Ther 2019; 13: 397-404.
[http://dx.doi.org/10.2147/DDDT.S191334] [PMID: 30774305]
[19]
Jouve J-L, Lecomte T, Bouché O, et al. PRODIGE-11 investigators/collaborators. Pravastatin combination with sorafenib does not improve survival in advanced hepatocellular carcinoma. J Hepatol 2019; 71(3): 516-22.
[http://dx.doi.org/10.1016/j.jhep.2019.04.021] [PMID: 31125576]
[20]
Ikeda K, Kudo M, Kawazoe S, et al. Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma. J Gastroenterol 2017; 52(4): 512-9.
[http://dx.doi.org/10.1007/s00535-016-1263-4] [PMID: 27704266]
[21]
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): 1163-73.
[http://dx.doi.org/10.1016/S0140-6736(18)30207-1] [PMID: 29433850]
[22]
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): 113-22.
[http://dx.doi.org/10.1007/s00535-019-01642-1] [PMID: 31720835]
[23]
Kudo M, Finn RS, Qin S, et al. Analysis of survival and objective response (OR) in patients with hepatocellular carcinoma in a phase III study of lenvatinib (REFLECT). J Clin Oncol 2019; 37(Suppl. 4): 186.
[http://dx.doi.org/10.1200/JCO.2019.37.4_suppl.186]
[24]
Kudo M, Ueshima K, Chiba Y, et al. Objective response by mrecist is an independent prognostic factor for overall survival in hepatocellular carcinoma treated with sorafenib in the SILIUS trial. Liver Cancer 2019; 8(6): 505-19.
[http://dx.doi.org/10.1159/000503032] [PMID: 31799207]
[25]
Kobayashi M, Kudo M, Izumi N, et al. Cost-effectiveness analysis of lenvatinib treatment for patients with unresectable hepatocellular carcinoma (uHCC) compared with sorafenib in Japan. J Gastroenterol 2019; 54(6): 558-70.
[http://dx.doi.org/10.1007/s00535-019-01554-0] [PMID: 30788569]
[26]
Kim JJ, McFarlane T, Tully S, et al. Lenvatinib versus sorafenib as first-line treatment of unresectable hepatocellular carcinoma: a cost-utility analysis Oncologist 2019; 0501.
[http://dx.doi.org/10.1634/theoncologist.2019-0501] [PMID: 31748341]
[27]
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.
[http://dx.doi.org/10.1016/S0140-6736(16)32453-9] [PMID: 27932229]
[28]
Yoo C, Park J-W, Kim YJ, et al. Multicenter retrospective analysis of the safety and efficacy of regorafenib after progression on sorafenib in Korean patients with hepatocellular carcinoma. Invest New Drugs 2019; 37(3): 567-72.
[http://dx.doi.org/10.1007/s10637-018-0707-5] [PMID: 30523474]
[29]
Ogasawara S, Ooka Y, Itokawa N, et al. Sequential therapy with sorafenib and regorafenib for advanced hepatocellular carcinoma: a multicenter retrospective study in Japan. Invest New Drugs 2020; 38(1): 172-80.
[http://dx.doi.org/10.1007/s10637-019-00801-8] [PMID: 31172442]
[30]
Facciorusso A, Abd El Aziz MA, Sacco R. Efficacy of regorafenib in hepatocellular carcinoma patients: A systematic review and meta-analysis. Cancers (Basel) 2019; 12(1) E36
[http://dx.doi.org/10.3390/cancers12010036] [PMID: 31877664]
[31]
Bruix J, Reig M, Merle P, et al. Alpha-fetoprotein (AFP) response in patients with unresectable hepatocellular carcinoma (HCC) in the phase III RESORCE trial. Ann Oncol 2019; 30: 291.
[http://dx.doi.org/10.1093/annonc/mdz247.081]
[32]
Teufel M, Seidel H, Köchert K, et al. Biomarkers associated with response to regorafenib in patients with hepatocellular carcinoma. Gastroenterology 2019; 156(6): 1731-41.
[http://dx.doi.org/10.1053/j.gastro.2019.01.261] [PMID: 30738047]
[33]
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.
[http://dx.doi.org/10.1056/NEJMoa1717002] [PMID: 29972759]
[34]
Abou-Alfa GK, Meyer T, Cheng A-L, et al. Association of adverse events (AEs) with efficacy outcomes for cabozantinib (C) in patients (pts) with advanced hepatocellular carcinoma (aHCC) in the phase III CELESTIAL trial. J Clin Oncol 2019; 37(Suppl. 15): 4088.
[http://dx.doi.org/10.1200/JCO.2019.37.15_suppl.4088]
[35]
Rimassa L, Kelley RK, Meyer T, et al. Outcomes based on plasma biomarkers for the phase III CELESTIAL trial of cabozantinib (C) versus placebo (P) in advanced hepatocellular carcinoma (aHCC). Ann Oncol 2019; 30: v257-8.
[http://dx.doi.org/10.1093/annonc/mdz247.006]
[36]
Liao W, Huang J, Hutton D, et al. Cost-effectiveness analysis of cabozantinib as second-line therapy in advanced hepatocellular carcinoma. Liver Int 2019; 39(12): 2408-16.
[http://dx.doi.org/10.1111/liv.14257] [PMID: 31544330]
[37]
Shlomai A, Leshno M, Goldstein DA. Cabozantinib for patients with advanced hepatocellular carcinoma: a cost-effectiveness analysis. Therap Adv Gastroenterol 2019; 12, 1756284819878304
[http://dx.doi.org/10.1177/1756284819878304] [PMID: 31579104]
[38]
Soto-Perez-de-Celis E, Aguiar PN, Cordón ML, Chavarri-Guerra Y, Lopes GL. Cost-effectiveness of cabozantinib in the second-line treatment of advanced hepatocellular carcinoma. J Natl Compr Canc Netw 2019; 17(6): 669-75.
[http://dx.doi.org/10.6004/jnccn.2018.7275] [PMID: 31200357]
[39]
Kudo M, Cheng A-L, Park J-W, et al. Orantinib versus placebo combined with transcatheter arterial chemoembolisation in patients with unresectable hepatocellular carcinoma (ORIENTAL): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study. Lancet Gastroenterol Hepatol 2018; 3(1): 37-46.
[http://dx.doi.org/10.1016/S2468-1253(17)30290-X] [PMID: 28988687]
[40]
Hidaka H, Izumi N, Aramaki T, et al. Subgroup analysis of efficacy and safety of orantinib in combination with TACE in Japanese HCC patients in a randomized phase III trial (ORIENTAL). Med Oncol 2019; 36(6): 52.
[http://dx.doi.org/10.1007/s12032-019-1272-2] [PMID: 31053989]
[41]
Shen G, Zheng F, Ren D, et al. Anlotinib: a novel multi-targeting tyrosine kinase inhibitor in clinical development. J Hematol Oncol 2018; 11(1): 120.
[http://dx.doi.org/10.1186/s13045-018-0664-7] [PMID: 30231931]
[42]
Zhou A, Sun Y, Zhang W, et al. Anlotinib for advanced hepatocellular carcinoma: Interim results from the phase II ALTER0802 study. Ann Oncol 2019; 30: v288-9.
[http://dx.doi.org/10.1093/annonc/mdz247.077]
[43]
Qin S. Apatinib in Chinese patients with advanced hepatocellular carcinoma: A phase II randomized, open-label trial. J Clin Oncol 2014; 32(Suppl. 15): 4019-20.
[http://dx.doi.org/10.1200/jco.2014.32.15_suppl.4019]
[44]
Yang Z, Chen G, Cui Y, et al. The safety and efficacy of TACE combined with apatinib on patients with advanced hepatocellular carcinoma: a retrospective study. Cancer Biol Ther 2019; 20(3): 321-7.
[http://dx.doi.org/10.1080/15384047.2018.1529099] [PMID: 30332553]
[45]
Wei L, Lee D, Law C-T, et al. Genome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC. Nat Commun 2019; 10(1): 4681.
[http://dx.doi.org/10.1038/s41467-019-12606-7] [PMID: 31615983]
[46]
El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 2017; 389(10088): 2492-502.
[http://dx.doi.org/10.1016/S0140-6736(17)31046-2] [PMID: 28434648]
[47]
Yau T, Park J, Finn R, et al. CheckMate 459: A randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann Oncol 2019; 30: v874-5.
[http://dx.doi.org/10.1093/annonc/mdz394.029]
[48]
Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013; 369(2): 122-33.
[http://dx.doi.org/10.1056/NEJMoa1302369] [PMID: 23724867]
[49]
Hellmann MD, Ciuleanu T-E, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 2018; 378(22): 2093-104.
[http://dx.doi.org/10.1056/NEJMoa1801946] [PMID: 29658845]
[50]
Hammers HJ, Plimack ER, Infante JR, et al. Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: The CheckMate 016 study. J Clin Oncol 2017; 35(34): 3851-8.
[http://dx.doi.org/10.1200/JCO.2016.72.1985] [PMID: 28678668]
[51]
He AR, Yau T, Hsu C, et al. Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): Results from CheckMate 040. J Clin Oncol 2020; 38(Suppl. 4): 512.
[http://dx.doi.org/10.1200/JCO.2020.38.4_suppl.512]
[52]
Doi T, Muro K, Ishii H, et al. A phase I study of the anti-CC chemokine receptor 4 antibody, mogamulizumab, in combination with nivolumab in patients with advanced or metastatic solid tumors. Clin Cancer Res 2019; 25(22): 6614-22.
[http://dx.doi.org/10.1158/1078-0432.CCR-19-1090] [PMID: 31455681]
[53]
Kudo M, Ikeda M, Motomura K, et al. A phase Ib study of lenvatinib (LEN) plus nivolumab (NIV) in patients (pts) with unresectable hepatocellular carcinoma (uHCC): Study 117. J Clin Oncol 2020; 38(4_suppl): 513.
[http://dx.doi.org/10.1200/JCO.2020.38.4_suppl.513]
[54]
Zhu AX, Finn RS, Edeline J, et al. KEYNOTE-224 investigators. 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): 940-52.
[http://dx.doi.org/10.1016/S1470-2045(18)30351-6] [PMID: 29875066]
[55]
National Comprehensive Cancer Network; NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary Cancers 2019. Available at: https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf.
[56]
Finn RS, Ryoo B-Y, Merle P, et al. Pembrolizumab As second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: A randomized, double-blind, phase III trial. J Clin Oncol 2020; 38(3): 193-202.
[http://dx.doi.org/10.1200/JCO.19.01307] [PMID: 31790344]
[57]
Qin S, Ren Z, Meng Z, et al. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial. Lancet Oncol 2020; 21(4): 571-80.
[http://dx.doi.org/10.1016/S1470-2045(20)30011-5] [PMID: 32112738]
[58]
Xu J, Zhang Y, Jia R, et al. Anti-PD-1 antibody SHR-1210 combined with apatinib for advanced hepatocellular carcinoma, gastric, or esophagogastric junction cancer: an open-label, dose escalation and expansion study. Clin Cancer Res 2019; 25(2): 515-23.
[http://dx.doi.org/10.1158/1078-0432.CCR-18-2484] [PMID: 30348638]
[59]
Floudas CS, Xie C, Brar G, et al. Combined immune checkpoint inhibition (ICI) with tremelimumab and durvalumab in patients with advanced hepatocellular carcinoma (HCC) or biliary tract carcinomas (BTC). J Clin Oncol 2019; 37(4_suppl): 336.
[http://dx.doi.org/10.1200/JCO.2019.37.4_suppl.336]
[60]
Gao Q, Wang X-Y, Qiu S-J, et al. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res 2009; 15(3): 971-9.
[http://dx.doi.org/10.1158/1078-0432.CCR-08-1608] [PMID: 19188168]
[61]
Gong J, Chehrazi-Raffle A, Reddi S, Salgia R. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trials and future considerations. J Immunother Cancer 2018; 6(1): 8.
[http://dx.doi.org/10.1186/s40425-018-0316-z] [PMID: 29357948]
[62]
Cheng A-L, Qin S, Ikeda M, et al. IMbrave150: efficacy and safety results from a ph III study evaluating atezolizumab (atezo)+ bevacizumab (bev) vs sorafenib (Sor) as first treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma (HCC). Ann Oncol 2019; 30: 186-7.
[http://dx.doi.org/10.1093/annonc/mdz446.002]
[63]
Barlesi F, Vansteenkiste J, Spigel D, et al. Avelumab versus docetaxel in patients with platinum-treated advanced non-small-cell lung cancer (JAVELIN Lung 200): an open-label, randomised, phase 3 study. Lancet Oncol 2018; 19(11): 1468-79.
[http://dx.doi.org/10.1016/S1470-2045(18)30673-9] [PMID: 30262187]
[64]
Shirley M. Avelumab: A review in metastatic merkel cell carcinoma. Target Oncol 2018; 13(3): 409-16.
[http://dx.doi.org/10.1007/s11523-018-0571-4] [PMID: 29799096]
[65]
Kudo M, Motomura K, Wada Y, et al. First-line avelumab + axitinib in patients with advanced hepatocellular carcinoma: Results from a phase 1b trial (VEGF Liver 100). J Clin Oncol 2019; 37(15)(Suppl.): 4072.
[http://dx.doi.org/10.1200/JCO.2019.37.15_suppl.4072]
[66]
Zhang N, Tu J, Wang X, Chu Q. Programmed cell death-1/programmed cell death ligand-1 checkpoint inhibitors: differences in mechanism of action. Immunotherapy 2019; 11(5): 429-41.
[http://dx.doi.org/10.2217/imt-2018-0110] [PMID: 30698054]
[67]
Li S, Han X, Lyu N, et al. Mechanism and prognostic value of indoleamine 2,3-dioxygenase 1 expressed in hepatocellular carcinoma. Cancer Sci 2018; 109(12): 3726-36.
[http://dx.doi.org/10.1111/cas.13811] [PMID: 30264546]
[68]
Wang J, Sun J, Liu LN, et al. Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy. Nat Med 2019; 25(4): 656-66.
[http://dx.doi.org/10.1038/s41591-019-0374-x] [PMID: 30833750]
[69]
Moehler M, Heo J, Lee HC, et al. Vaccinia-based oncolytic immunotherapy Pexastimogene Devacirepvec in patients with advanced hepatocellular carcinoma after sorafenib failure: a randomized multicenter Phase IIb trial (TRAVERSE). OncoImmunology 2019; 8(8) 1615817
[http://dx.doi.org/10.1080/2162402X.2019.1615817] [PMID: 31413923]
[70]
Fuchs CS, Tomasek J, Yong CJ, et al. REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2014; 383(9911): 31-9.
[http://dx.doi.org/10.1016/S0140-6736(13)61719-5] [PMID: 24094768]
[71]
Garon EB, Ciuleanu T-E, Arrieta O, 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(9944): 665-73.
[http://dx.doi.org/10.1016/S0140-6736(14)60845-X] [PMID: 24933332]
[72]
Zhu AX, Kang Y-K, Yen C-J, et al. REACH-2 study investigators. 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): 282-96.
[http://dx.doi.org/10.1016/S1470-2045(18)30937-9] [PMID: 30665869]
[73]
Keating GM. Bevacizumab: a review of its use in advanced cancer. Drugs 2014; 74(16): 1891-925.
[http://dx.doi.org/10.1007/s40265-014-0302-9] [PMID: 25315029]
[74]
Siegel AB, Cohen EI, Ocean A, et al. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol 2008; 26(18): 2992-8.
[http://dx.doi.org/10.1200/JCO.2007.15.9947] [PMID: 18565886]
[75]
He L, Deng H, Lei J, et al. Efficacy of bevacizumab combined with erlotinib for advanced hepatocellular carcinoma: a single-arm meta-analysis based on prospective studies. BMC Cancer 2019; 19(1): 276.
[http://dx.doi.org/10.1186/s12885-019-5487-6] [PMID: 30922256]
[76]
Lee M, Ryoo B-Y, Hsu C-H, et al. Randomised efficacy and safety results for Atezolizumab (Atezo)+ bevacizumab (Bev) in patients (PTS) with previously untreated, unresectable hepatocellular carcinoma (HCC). Ann Oncol 2019; 30: v875.
[http://dx.doi.org/10.1093/annonc/mdz394.030]
[77]
Hong DS, DuBois SG, Kummar S, et al. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol 2020; 21(4): 531-40.
[http://dx.doi.org/10.1016/S1470-2045(19)30856-3] [PMID: 32105622]
[78]
Hoadley KA, Yau C, Hinoue T, et al. Cancer genome atlas network. Cell-of-origin patterns dominate the molecular classification of 10,000 tumors from 33 types of cancer. Cell 2018; 173(2): 291-304.
[http://dx.doi.org/10.1016/j.cell.2018.03.022] [PMID: 29625048]
[79]
Hong DS, Bauer TM, Lee JJ, et al. Larotrectinib in adult patients with solid tumours: a multi-centre, open-label, phase I dose-escalation study. Ann Oncol 2019; 30(2): 325-31.
[http://dx.doi.org/10.1093/annonc/mdy539] [PMID: 30624546]
[80]
Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol 2020; 21(2): 271-82.
[http://dx.doi.org/10.1016/S1470-2045(19)30691-6] [PMID: 31838007]
[81]
Ungerleider N, Han C, Zhang J, Yao L, Wu T. TGFβ signaling confers sorafenib resistance via induction of multiple RTKs in hepatocellular carcinoma cells. Mol Carcinog 2017; 56(4): 1302-11.
[http://dx.doi.org/10.1002/mc.22592] [PMID: 27862334]
[82]
Ikeda M, Morimoto M, Tajimi M, et al. A phase 1b study of transforming growth factor-beta receptor I inhibitor galunisertib in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma. Invest New Drugs 2019; 37(1): 118-26.
[http://dx.doi.org/10.1007/s10637-018-0636-3] [PMID: 29995286]
[83]
Faivre S, Santoro A, Kelley RK, et al. Novel transforming growth factor beta receptor I kinase inhibitor galunisertib (LY2157299) in advanced hepatocellular carcinoma. Liver Int 2019; 39(8): 1468-77.
[http://dx.doi.org/10.1111/liv.14113] [PMID: 30963691]
[84]
Kelley RK, Gane E, Assenat E, et al. A phase 2 study of galunisertib (TGF-β1 receptor type I inhibitor) and sorafenib in patients with advanced hepatocellular carcinoma. Clin Transl Gastroenterol 2019; 10(7) e00056
[http://dx.doi.org/10.14309/ctg.0000000000000056] [PMID: 31295152]
[85]
Bang Y-J, Su W-C, Schuler M, et al. Phase 1 study of capmatinib in MET-positive solid tumor patients: Dose escalation and expansion of selected cohorts. Cancer Sci 2020; 111(2): 536-47.
[PMID: 31778267]
[86]
Qin S, Chan SL, Sukeepaisarnjaroen W, et al. A phase II study of the efficacy and safety of the MET inhibitor capmatinib (INC280) in patients with advanced hepatocellular carcinoma. Ther Adv Med Oncol 2019; 11, 1758835919889001
[http://dx.doi.org/10.1177/1758835919889001] [PMID: 31853265]
[87]
Yu H, Lee H, Herrmann A, Buettner R, Jove R. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer 2014; 14(11): 736-46.
[http://dx.doi.org/10.1038/nrc3818] [PMID: 25342631]
[88]
Oh D-Y, Lee S-H, Han S-W, et al. Phase I study of OPB-31121, an oral STAT3 inhibitor, in patients with advanced solid tumors. Cancer Res Treat 2015; 47(4): 607-15.
[http://dx.doi.org/10.4143/crt.2014.249] [PMID: 25715763]
[89]
Okusaka T, Ueno H, Ikeda M, et al. Phase 1 and pharmacological trial of OPB-31121, a signal transducer and activator of transcription-3 inhibitor, in patients with advanced hepatocellular carcinoma. Hepatol Res 2015; 45(13): 1283-91.
[http://dx.doi.org/10.1111/hepr.12504] [PMID: 25676869]
[90]
Christian S, Ahorn H, Koehler A, et al. Molecular cloning and characterization of endosialin, a C-type lectin-like cell surface receptor of tumor endothelium. J Biol Chem 2001; 276(10): 7408-14.
[http://dx.doi.org/10.1074/jbc.M009604200] [PMID: 11084048]
[91]
Leonardi GC, Candido S, Cervello M, et al. The tumor microenvironment in hepatocellular carcinoma. (review) Int J Oncol 2012; 40(6): 1733-47.
[PMID: 22447316]
[92]
Doi T, Aramaki T, Yasui H, et al. A phase I study of ontuxizumab, a humanized monoclonal antibody targeting endosialin, in Japanese patients with solid tumors. Invest New Drugs 2019; 37(5): 1061-74.
[http://dx.doi.org/10.1007/s10637-018-0713-7] [PMID: 30623276]
[93]
Hahn AW, Pal SK, Agarwal N. Targeting endoglin to treat metastatic renal cell carcinoma: lessons from osler-weber-rendu syndrome. Oncologist 2019; 24(2): 143-5.
[http://dx.doi.org/10.1634/theoncologist.2018-0443] [PMID: 30139834]
[94]
Raghav KPS, Lee RT, Paluri RK, et al. An open-label phase Ib/2 trial of TRC105 plus sorafenib in patients with advanced/metastatic hepatocellular carcinoma (HCC) (NCT01806064). J Clin Oncol 2019; 37(4)(Suppl.): 268.
[http://dx.doi.org/10.1200/JCO.2019.37.4_suppl.268]
[95]
Abou-Alfa GK, Puig O, Daniele B, et al. Randomized phase II placebo controlled study of codrituzumab in previously treated patients with advanced hepatocellular carcinoma. J Hepatol 2016; 65(2): 289-95.
[http://dx.doi.org/10.1016/j.jhep.2016.04.004] [PMID: 27085251]
[96]
Zhai B, Shi D, Gao H, et al. A phase I study of anti-GPC3 chimeric antigen receptor modified T cells (GPC3 CAR-T) in Chinese patients with refractory or relapsed GPC3+ hepatocellular carcinoma (r/r GPC3+ HCC). J Clin Oncol 2017; 35(15)(Suppl.): 3049.
[http://dx.doi.org/10.1200/JCO.2017.35.15_suppl.3049]
[97]
Gao Q, Wang Z-C, Duan M, et al. Cell culture system for analysis of genetic heterogeneity within hepatocellular carcinomas and response to pharmacologic agents. Gastroenterology 2017; 152(1): 232-42.
[http://dx.doi.org/10.1053/j.gastro.2016.09.008] [PMID: 27639803]
[98]
Duan M, Hao J, Cui S, et al. Diverse modes of clonal evolution in HBV-related hepatocellular carcinoma revealed by single-cell genome sequencing. Cell Res 2018; 28(3): 359-73.
[http://dx.doi.org/10.1038/cr.2018.11] [PMID: 29327728]
[99]
Dong L, Peng L, Ma L, et al. Heterogeneous immunogenomic features and distinct escape mechanisms in multifocal hepatocellular carcinoma. J Hepatol 2020; 72(5): 896-908.
[http://dx.doi.org/10.1016/j.jhep.2019.12.014] [PMID: 31887370]
[100]
Eilard MS, Andersson M, Naredi P, et al. A prospective clinical trial on sorafenib treatment of hepatocellular carcinoma before liver transplantation. BMC Cancer 2019; 19(1): 568.
[http://dx.doi.org/10.1186/s12885-019-5760-8] [PMID: 31185950]
[101]
Rizell M, Sternby Eilard M, Andersson M, Andersson B, Karlsson-Parra A, Suenaert P. Phase 1 trial with the cell-based immune primer ilixadencel, alone, and combined with sorafenib, in advanced hepatocellular carcinoma. Front Oncol 2019; 9: 19.
[http://dx.doi.org/10.3389/fonc.2019.00019] [PMID: 30719425]
[102]
Labeur TA, Achterbergh R, Takkenberg B, Van Delden O, Mathôt R, Klümpen HJ. Sorafenib for patients with hepatocellular carcinoma and child-pugh b liver cirrhosis: lessons learned from a terminated study. Oncologist 2019.
[http://dx.doi.org/10.1634/theoncologist.2019-0718] [PMID: 31645371]
[103]
Mokdad AA, Zhu H, Beg MS, et al. Efficacy and safety of bavituximab in combination with sorafenib in advanced hepatocellular carcinoma: a single-arm, open-label, Phase II clinical trial. Target Oncol 2019; 14(5): 541-50.
[http://dx.doi.org/10.1007/s11523-019-00663-3] [PMID: 31429027]
[104]
Kambhampati S, Bauer KE, Bracci PM, et al. Nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh class B cirrhosis: Safety and clinical outcomes in a retrospective case series. Cancer 2019; 125(18): 3234-41.
[http://dx.doi.org/10.1002/cncr.32206] [PMID: 31154669]
[105]
Feun LG, Li Y-Y, Wu C, et al. Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced, unresectable hepatocellular carcinoma. Cancer 2019; 125(20): 3603-14.
[http://dx.doi.org/10.1002/cncr.32339] [PMID: 31251403]
[106]
Llovet J, Shepard K, Finn R, et al. A phase Ib trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC): Updated results. Ann Oncol 2019; 30: v286-7.
[http://dx.doi.org/10.1093/annonc/mdz247.073]
[107]
Weekes C, Lockhart AC, Lee JJ, et al. A phase 1b study evaluating the safety and pharmacokinetics of regorafenib in combination with cetuximab in patients with advanced solid tumors. Int J Cancer 2019; 145(9): 2450-8.
[http://dx.doi.org/10.1002/ijc.32317] [PMID: 30958892]
[108]
Yoo C, Kang J, Lim HY, et al. Phase I dose-finding study of OPB-111077, a novel STAT3 inhibitor, in patients with advanced hepatocellular carcinoma. Cancer Res Treat 2019; 51(2): 510-8.
[http://dx.doi.org/10.4143/crt.2018.226] [PMID: 29898591]
[109]
Yamazaki K, Doi T, Ikeda M, et al. Phase I trial of pimasertib monotherapy in Japanese patients with solid tumors and those with hepatocellular carcinoma. Cancer Chemother Pharmacol 2019; 84(5): 1027-37.
[http://dx.doi.org/10.1007/s00280-019-03924-0] [PMID: 31482223]
[110]
Qin S, Finn RS, Kudo M, et al. RATIONALE 301 study: tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. Future Oncol 2019; 15(16): 1811-22.
[http://dx.doi.org/10.2217/fon-2019-0097] [PMID: 30969136]


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VOLUME: 20
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Year: 2020
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DOI: 10.2174/1566523220666200628014530
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