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Review

Hepatocellular carcinoma: an update on investigational drugs in phase I and II clinical trials

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Pages 941-949 | Received 02 Aug 2019, Accepted 04 Oct 2019, Published online: 12 Oct 2019

References

  • Akinyemiju T, Abera S, Ahmed M, et al.; Global Burden of Disease Liver Cancer C. 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 Dec 1;3(12):1683–1691.
  • Ma J, Siegel RL, Islami F, et al. Temporal trends in liver cancer mortality by educational attainment in the United States, 2000–2015. Cancer. 2019 Jun 15;125(12):2089–2098.
  • Johnson PJ, Qin S, Park JW, 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 Oct 1;31(28):3517–3524.
  • Llovet JM, 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(28):3509–3516.
  • Rimassa 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(5):682–693.
  • Cheng AL, Kang YK, Lin DY, et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol. 2013 Nov 10;31(32):4067–4075.
  • 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.
  • 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.
  • Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018 Jul 5;379(1):54–63.
  • 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):2492–2502.
  • 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.
  • Zhu AX, Kang Y-K, Yen C-J, 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.
  • Cancer Genome Atlas Research Network. Electronic address wbe, Cancer Genome Atlas Research N. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell. 2017 Jun 15;169(7):1327–41e23.
  • Harding JJ, Nandakumar S, Armenia J, et al. Prospective genotyping of hepatocellular carcinoma: clinical implications of next-generation sequencing for matching patients to targeted and immune therapies. Clin Cancer Res. 2019 Apr 1;25(7):2116–2126.
  • Rawal P, Siddiqui H, Hassan M, et al. Endothelial cell-derived TGF-beta promotes epithelial-mesenchymal transition via CD133 in HBx-infected hepatoma cells. Front Oncol. 2019;9:308.
  • Hoshida Y, Nijman SM, Kobayashi M, et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res. 2009 Sep 15;69(18):7385–7392.
  • Giannelli G, Fransvea E, Marinosci F, et al. Transforming growth factor-beta1 triggers hepatocellular carcinoma invasiveness via alpha3beta1 integrin. Am J Pathol. 2002 Jul;161(1):183–193.
  • 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 Apr 8.
  • 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 Feb;37(1):118–126.
  • Wang W, Smits R, Hao H, et al. Wnt/β-catenin signaling in liver cancers. Cancers (Basel). 2019;11(7):926.
  • Nhieu JT, Renard CA, Wei Y, et al. Nuclear accumulation of mutated beta-catenin in hepatocellular carcinoma is associated with increased cell proliferation. Am J Pathol. 1999 Sep;155(3):703–710.
  • Jimeno A, Gordon M, Chugh R, et al. A first-in-human phase I study of the anticancer stem cell agent ipafricept (OMP-54F28), a decoy receptor for Wnt ligands, in patients with advanced solid tumors. Clin Cancer Res. 2017 Dec 15;23(24):7490–7497.
  • Wu J, Contratto M, Shanbhogue KP, et al. Evaluation of a locked nucleic acid form of antisense oligo targeting HIF-1alpha in advanced hepatocellular carcinoma. World J Clin Oncol. 2019 Mar 24;10(3):149–160.
  • Peters S, Adjei AA. MET: a promising anticancer therapeutic target. Nat Rev Clin Oncol. 2012 May 8;9(6):314–326.
  • Venepalli NK, Goff L. Targeting the HGF-cMET axis in hepatocellular carcinoma. Int J Hepatol. 2013;2013:341636.
  • Kiss A, Wang NJ, Xie JP, et al. Analysis of transforming growth factor (TGF)-alpha/epidermal growth factor receptor, hepatocyte growth Factor/c-met,TGF-beta receptor type II, and p53 expression in human hepatocellular carcinomas. Clin Cancer Res. 1997 Jul;3(7):1059–1066.
  • Xiang QF, Zhan MX, Li Y, et al. Activation of MET promotes resistance to sorafenib in hepatocellular carcinoma cells via the AKT/ERK1/2-EGR1 pathway. Artif Cells Nanomed Biotechnol. 2019 Dec;47(1):83–89.
  • Bladt F, Friese-Hamim M, Ihling C, et al. The c-Met inhibitor MSC2156119J effectively inhibits tumor growth in liver cancer models. Cancers (Basel). 2014 Aug 19;6(3):1736–1752.
  • Faivre SJ, Blanc JF, Merle P, et al. Final phase Ib data for the oral c-Met inhibitor tepotinib in patients with previously treated advanced hepatocellular carcinoma. J Clin Oncol. 2017;35(Suppl):e15676-e15676.
  • Shih J, Zhong B, Shi H, et al. Bozitinib, a highly selective inhibitor of c-MET, demonstrates robust activity in gastric, lung, hepatic and pancreatic in vivo models. American Association for Cancer Research Annual Meeting; 2017 Apr 1–5; Washington DC, USA.
  • Liu X, Ling ZQ. Role of isocitrate dehydrogenase 1/2 (IDH 1/2) gene mutations in human tumors. Histol Histopathol. 2015 Oct;30(10):1155–1160.
  • Cortes JE, Watts J, Prebet T, et al. FT-2102, an IDH1m inhibitor, in combination with azacitidine in patients with acute myeloid leukemia (AML) or myelodysplastic ayndrome (MDS): results from a phase 1 study. Blood. 2018;132(Suppl 1):1452.
  • Reference NGH. FGFR4 Gene. NIH Genetics Home Reference Accessed July 2019.
  • Raja A, Park I, Haq F, et al. FGF19-FGFR4 signaling in hepatocellular carcinoma. Cells. 2019. 4. 8(6):Jun.
  • Huynh H, Lee LY, Goh KY, et al. Infigratinib mediates vascular normalization, impairs metastasis, and improves chemotherapy in hepatocellular carcinoma. Hepatology. 2019 Mar;69(3):943–958.
  • Joshi JJ, Coffey H, Corcoran E, et al. H3B-6527 is a potent and selective inhibitor of FGFR4 in FGF19-driven hepatocellular carcinoma. Cancer Res. 2017 Dec 15;77(24):6999–7013.
  • Duffy AG, Ma C, Ulahannan SV, et al. Phase I and preliminary phase II study of TRC105 in combination with sorafenib in hepatocellular carcinoma. Clin Cancer Res. 2017 Aug 15;23(16):4633–4641.
  • Shimizu Y, Suzuki T, Yoshikawa T, et al. Next-generation cancer immunotherapy targeting glypican-3. Front Oncol. 2019;9:248.
  • 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 Aug;65(2):289–295.
  • Greten TF, Duffy AG, Korangy F. Hepatocellular carcinoma from an immunologic perspective. Clin Cancer Res. 2013 Dec 15;19(24):6678–6685.
  • Finn RS, Ryoo BY, Merle P, et al. Results of KEYNOTE-240: phase 3 study of pembrolizumab (Pembro) vs best supportive care (BSC) for second line therapy in advanced hepatocellular carcinoma (HCC). ASCO Annual Meeting 2019; 2019; Chicago, IL, USA: Journal of Clinical Oncology; 2019.
  • Yau T, Park JW, Finn RS, et al. Checkmate 459: a randomized, multi-center phase 3 study of nivolumab (nivo) vs sorafenib (sor) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (AHCC). ESMO 2019; 2019 Oct; Barcelona, Spain: Annals of Oncology; 2019.
  • Masafumi Ikeda MWS, Kudo M, Kobayashi M, et al. A Phase Ib trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC): updated results. AACR Annual Meeting; 2019: Proceedings of the 110th Annual Meeting of the American Association for Cancer Research, Chicago, IL; 2019.
  • Lee M, Ryoo BY, Hsu CH, et al. Randomised efficacy and safety results for atezolizumab (Atezo) + Bevacizumab (Bev) in Patients (pts) with previously untreated, unresectable hepatocellular carcinoma. ESMO Annual Meeting; 2019: Annals of Oncology, Barcelona, Spain; 2019.
  • Sawada Y, Yoshikawa T, Nobuoka D, et al. Phase I trial of a glypican-3-derived peptide vaccine for advanced hepatocellular carcinoma: immunologic evidence and potential for improving overall survival. Clin Cancer Res. 2012 Jul 1;18(13):3686–3696.
  • Jiang Z, Jiang X, Chen S, et al. Anti-GPC3-CAR T cells suppress the growth of tumor cells in patient-derived xenografts of hepatocellular carcinoma. Front Immunol. 2016;7:690.
  • Wu X, Luo H, Shi B, et al. Combined antitumor effects of sorafenib and GPC3-CAR T cells in mouse models of hepatocellular carcinoma. Mol Ther. 2019 Apr 29;27:1483–1494.
  • Tchou J, Zhao Y, Levine BL, et al. Safety and efficacy of intratumoral injections of chimeric antigen receptor (CAR) T cells in metastatic breast cancer. Cancer Immunol Res. 2017 Dec;5(12):1152–1161.
  • Zhou J, Wu J, Chen X, et al. Icariin and its derivative, ICT, exert anti-inflammatory, anti-tumor effects, and modulate myeloid derived suppressive cells (MDSCs) functions. Int Immunopharmacol. 2011 Jul;11(7):890–898.
  • Zhao H, Guo Y, Li S, et al. A novel anti-cancer agent Icaritin suppresses hepatocellular carcinoma initiation and malignant growth through the IL-6/Jak2/Stat3 pathway. Oncotarget. 2015 Oct 13;6(31):31927–31943.
  • Fan Y, Li S, Ding X, et al. First-in-class immune-modulating small molecule Icaritin in advanced hepatocellular carcinoma: preliminary results of safety, durable survival and immune biomarkers. BMC Cancer. 2019 Mar 28;19(1):279.
  • Ma C, Han M, Heinrich B, et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science. 2018 May 25;360(6391).
  • Ghamande S, Lin CC, Cho DC, et al. A phase 1 open-label, sequential dose-escalation study investigating the safety, tolerability, and pharmacokinetics of intravenous TLC388 administered to patients with advanced solid tumors. Invest New Drugs. 2014 Jun;32(3):445–451.
  • Duan J, Wang Z, Li Q, et al. Abstract 1369: in vitro and in vivo antitumor activity of TH3424: preclinical rationale for a highly selective AKR1C3 prodrug for treating hepatocellular carcinomas. Cancer Res. 2016;76:1369.

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