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Published in: Current Treatment Options in Gastroenterology 2/2021

01-06-2021 | Systemic Therapy | Liver (J Bajaj, Section Editor)

Recent Progress in Systemic Therapy for Hepatocellular Cancer (HCC)

Authors: T. Tara Ghaziani, MD, Renumathy Dhanasekaran, MD

Published in: Current Treatment Options in Gastroenterology | Issue 2/2021

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Abstract

Purpose of review

The management of advanced hepatocellular carcinoma (HCC) has drastically changed in the past few years with approval of several first-line and second-line systemic therapies. In this review, we present an overview of the recent progress in the treatment of advanced HCC and discuss future perspectives.

Recent findings

The phase 3 clinical trial IMBRAVE150 has recently shown the combination of an immune checkpoint inhibitor, atezolizumab, with an antiangiogenic agent, bevacizumab, to be superior to sorafenib monotherapy for treatment-naive advanced HCC. Moreover, patients now have multiple options available in second-line therapy including targeted therapies like sorafenib, lenvatinib, regorafenib, cabozantinib, and ramucirumab and immunotherapies like atezolizumab and nivolumab either alone or combined with ipilimumab.

Summary

There has been tremendous recent progress in the management of advanced HCC. Combination therapy with atezolizumab–bevacizumab has recently become the standard first-line therapy for patients with advanced HCC. Additionally, immunotherapy agents are poised to play a significant role in the management of HCC either alone or in combination with molecular targeted therapies.
Literature
1.
go back to reference Ferlay J, Ervik M, Lam F, Colombet M, Mery L, Piñeros M, Znaor A, Soerjomataram I, Bray F. Cancer Today 2020. Global Cancer Observatory: International Agency for Research on Cancer. https://gco.iarc.fr/today/home. Ferlay J, Ervik M, Lam F, Colombet M, Mery L, Piñeros M, Znaor A, Soerjomataram I, Bray F. Cancer Today 2020. Global Cancer Observatory: International Agency for Research on Cancer. https://​gco.​iarc.​fr/​today/​home.​
2.
go back to reference • Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90 This trial led to the approval of sorafenib for the management of advanced HCC.PubMedCrossRef • Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90 This trial led to the approval of sorafenib for the management of advanced HCC.PubMedCrossRef
3.
go back to reference Yeo W, et al. A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst. 2005;97:1532–8.PubMedCrossRef Yeo W, et al. A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst. 2005;97:1532–8.PubMedCrossRef
4.
go back to reference Llovet JM, Sala M, Castells L, Suarez Y, Vilana R, Bianchi L, et al. Randomized controlled trial of interferon treatment for advanced hepatocellular carcinoma. Hepatology. 2000;31:54–8. Llovet JM, Sala M, Castells L, Suarez Y, Vilana R, Bianchi L, et al. Randomized controlled trial of interferon treatment for advanced hepatocellular carcinoma. Hepatology. 2000;31:54–8.
5.
go back to reference Ikeda M, Mitsunaga S, Ohno I, Hashimoto Y, Takahashi H, Watanabe K, et al. Systemic chemotherapy for advanced hepatocellular carcinoma: past, present, and future. Diseases. 2015;3:360–81. Ikeda M, Mitsunaga S, Ohno I, Hashimoto Y, Takahashi H, Watanabe K, et al. Systemic chemotherapy for advanced hepatocellular carcinoma: past, present, and future. Diseases. 2015;3:360–81.
6.
go back to reference • Cheng A-L, 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;10:25–34 This trial led to the approval of sorafenib for the management of advanced HCC.PubMedCrossRef • Cheng A-L, 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;10:25–34 This trial led to the approval of sorafenib for the management of advanced HCC.PubMedCrossRef
7.
go back to reference Cheng A-L, et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol. 2013;31:4067–75.PubMedCrossRef Cheng A-L, et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol. 2013;31:4067–75.PubMedCrossRef
8.
go back to reference Johnson PJ, 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;31:3517–24.PubMedCrossRef Johnson PJ, 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;31:3517–24.PubMedCrossRef
9.
go back to reference Cainap C, Qin S, Huang WT, Chung IJ, Pan H, Cheng Y, et al. Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol. 2015;33:172–9. Cainap C, Qin S, Huang WT, Chung IJ, Pan H, Cheng Y, et al. Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol. 2015;33:172–9.
10.
go back to reference Kudo M, et al. A randomized, double-blind, placebo-controlled phase III study of S-1 in patients with sorafenib-refractory advanced hepatocellular carcinoma (S-CUBE). J Clin Oncol. 2015;33:4018.CrossRef Kudo M, et al. A randomized, double-blind, placebo-controlled phase III study of S-1 in patients with sorafenib-refractory advanced hepatocellular carcinoma (S-CUBE). J Clin Oncol. 2015;33:4018.CrossRef
11.
go back to reference • Bruix J, 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;389:56–66 This trial led to the approval of regorafenib as second-line therapy for advanced HCC.PubMedCrossRef • Bruix J, 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;389:56–66 This trial led to the approval of regorafenib as second-line therapy for advanced HCC.PubMedCrossRef
12.
go back to reference El-Khoueiry AB, 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;389:2492–502.PubMedPubMedCentralCrossRef El-Khoueiry AB, 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;389:2492–502.PubMedPubMedCentralCrossRef
13.
go back to reference • Kudo M, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391:1163–73 The results of this trial led to the approval of lenvatinib as first-line therapy for advanced HCC.PubMedCrossRef • Kudo M, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391:1163–73 The results of this trial led to the approval of lenvatinib as first-line therapy for advanced HCC.PubMedCrossRef
14.
go back to reference •• Finn RS, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894–905 Results of this early phase trial revealed that immunotherapy can be safe for patients with HCC and can potentially lead to durable responses, leading to its accelerate approval for advanced HCC.PubMedCrossRef •• Finn RS, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894–905 Results of this early phase trial revealed that immunotherapy can be safe for patients with HCC and can potentially lead to durable responses, leading to its accelerate approval for advanced HCC.PubMedCrossRef
15.
go back to reference Hegde PS, Wallin JJ, Mancao C. Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics. Semin Cancer Biol. 2018;52:117–24.PubMedCrossRef Hegde PS, Wallin JJ, Mancao C. Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics. Semin Cancer Biol. 2018;52:117–24.PubMedCrossRef
16.
go back to reference Wallin JJ, Bendell JC, Funke R, Sznol M, Korski K, Jones S, et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun. 2016;7:12624. Wallin JJ, Bendell JC, Funke R, Sznol M, Korski K, Jones S, et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun. 2016;7:12624.
17.
go back to reference 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:ix187.CrossRef 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:ix187.CrossRef
18.
go back to reference Finn RS, 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 Orthod. 2021;39:267. Finn RS, 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 Orthod. 2021;39:267.
19.
go back to reference Bruix J, Raoul JL, Sherman M, Mazzaferro V, Bolondi L, Craxi A, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol. 2012;57:821–9. Bruix J, Raoul JL, Sherman M, Mazzaferro V, Bolondi L, Craxi A, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol. 2012;57:821–9.
20.
go back to reference Jackson R, Psarelli E-E, Berhane S, Khan H, Johnson P. Impact of viral status on survival in patients receiving sorafenib for advanced hepatocellular cancer: a meta-analysis of randomized phase III trials. J Clin Oncol. 2017;35:622–8.PubMedCrossRef Jackson R, Psarelli E-E, Berhane S, Khan H, Johnson P. Impact of viral status on survival in patients receiving sorafenib for advanced hepatocellular cancer: a meta-analysis of randomized phase III trials. J Clin Oncol. 2017;35:622–8.PubMedCrossRef
21.
go back to reference Bruix J, et al. Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: analysis of two phase III studies. J Hepatol. 2017;67:999–1008.PubMedCrossRef Bruix J, et al. Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: analysis of two phase III studies. J Hepatol. 2017;67:999–1008.PubMedCrossRef
22.
go back to reference Reig M, Torres F, Rodriguez-Lope C, Forner A, LLarch N, Rimola J, et al. Early dermatologic adverse events predict better outcome in HCC patients treated with sorafenib. J Hepatol. 2014;61:318–24. Reig M, Torres F, Rodriguez-Lope C, Forner A, LLarch N, Rimola J, et al. Early dermatologic adverse events predict better outcome in HCC patients treated with sorafenib. J Hepatol. 2014;61:318–24.
23.
go back to reference Estfan B, Byrne M, Kim R. Sorafenib in advanced hepatocellular carcinoma: hypertension as a potential surrogate marker for efficacy. Am J Clin Oncol. 2013;36:319–24.PubMedCrossRef Estfan B, Byrne M, Kim R. Sorafenib in advanced hepatocellular carcinoma: hypertension as a potential surrogate marker for efficacy. Am J Clin Oncol. 2013;36:319–24.PubMedCrossRef
24.
go back to reference Bettinger D, Schultheiβ M, Knüppel E, Thimme R, Blum HE, Spangenberg HC. Diarrhea predicts a positive response to sorafenib in patients with advanced hepatocellular carcinoma. Hepatology. 2012;56:789–90.PubMedCrossRef Bettinger D, Schultheiβ M, Knüppel E, Thimme R, Blum HE, Spangenberg HC. Diarrhea predicts a positive response to sorafenib in patients with advanced hepatocellular carcinoma. Hepatology. 2012;56:789–90.PubMedCrossRef
25.
go back to reference Arao T, et al. FGF3/FGF4 amplification and multiple lung metastases in responders to sorafenib in hepatocellular carcinoma. Hepatology. 2013;57:1407–15.PubMedCrossRef Arao T, et al. FGF3/FGF4 amplification and multiple lung metastases in responders to sorafenib in hepatocellular carcinoma. Hepatology. 2013;57:1407–15.PubMedCrossRef
26.
go back to reference Personeni N, et al. Molecular determinants of outcome in sorafenib-treated patients with hepatocellular carcinoma. J Cancer Res Clin Oncol. 2013;139:1179–87.PubMedCrossRef Personeni N, et al. Molecular determinants of outcome in sorafenib-treated patients with hepatocellular carcinoma. J Cancer Res Clin Oncol. 2013;139:1179–87.PubMedCrossRef
27.
go back to reference Marrero JA, et al. Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: the GIDEON study. J Hepatol. 2016;65:1140–7.PubMedCrossRef Marrero JA, et al. Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: the GIDEON study. J Hepatol. 2016;65:1140–7.PubMedCrossRef
28.
go back to reference McNamara MG, Slagter AE, Nuttall C, Frizziero M, Pihlak R, Lamarca A, et al. Sorafenib as first-line therapy in patients with advanced Child-Pugh B hepatocellular carcinoma-a meta-analysis. Eur J Cancer. 2018;105:1–9. McNamara MG, Slagter AE, Nuttall C, Frizziero M, Pihlak R, Lamarca A, et al. Sorafenib as first-line therapy in patients with advanced Child-Pugh B hepatocellular carcinoma-a meta-analysis. Eur J Cancer. 2018;105:1–9.
29.
go back to reference Abou-Alfa GK, Shi Q, Knox JJ, Kaubisch A, Niedzwiecki D, Posey J, 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;5:1582. https://doi.org/10.1001/jamaoncol.2019.2792. Abou-Alfa GK, Shi Q, Knox JJ, Kaubisch A, Niedzwiecki D, Posey J, 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;5:1582. https://​doi.​org/​10.​1001/​jamaoncol.​2019.​2792.
30.
go back to reference Assenat E, et al. Sorafenib alone vs. sorafenib plus GEMOX as 1-line treatment for advanced HCC: the phase II randomised PRODIGE 10 trial. Br J Cancer. 2019;120:896–902.PubMedPubMedCentralCrossRef Assenat E, et al. Sorafenib alone vs. sorafenib plus GEMOX as 1-line treatment for advanced HCC: the phase II randomised PRODIGE 10 trial. Br J Cancer. 2019;120:896–902.PubMedPubMedCentralCrossRef
31.
go back to reference Meyer T, Fox R, Ma YT, Ross PJ, James MW, Sturgess R, et al. Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol. 2017;2:565–75. Meyer T, Fox R, Ma YT, Ross PJ, James MW, Sturgess R, et al. Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol. 2017;2:565–75.
32.
go back to reference Lencioni R, et al. Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: the SPACE trial. J Hepatol. 2016;64:1090–8.PubMedCrossRef Lencioni R, et al. Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: the SPACE trial. J Hepatol. 2016;64:1090–8.PubMedCrossRef
33.
go back to reference Shimose S, 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. Oncol Lett. 2020;20:2257–65.PubMedPubMedCentralCrossRef Shimose S, 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. Oncol Lett. 2020;20:2257–65.PubMedPubMedCentralCrossRef
34.
go back to reference Cheon J, Chon HJ, Bang Y, Park NH, Shin JW, Kim KM, et al. Real-world efficacy and safety of lenvatinib in Korean patients with advanced hepatocellular carcinoma: a multicenter retrospective analysis. Liver Cancer. 2020;9:613–24. Cheon J, Chon HJ, Bang Y, Park NH, Shin JW, Kim KM, et al. Real-world efficacy and safety of lenvatinib in Korean patients with advanced hepatocellular carcinoma: a multicenter retrospective analysis. Liver Cancer. 2020;9:613–24.
35.
go back to reference Amaro CP, Allen MJ, Knox JJ, Tsang ES, Lim HJ, Lee-Ying RM, et al. Efficacy and safety of lenvatinib in the real-world treatment of hepatocellular carcinoma: results from a Canadian multicenter database (HCC CHORD). J Clin Oncol. 2021;39:275. Amaro CP, Allen MJ, Knox JJ, Tsang ES, Lim HJ, Lee-Ying RM, et al. Efficacy and safety of lenvatinib in the real-world treatment of hepatocellular carcinoma: results from a Canadian multicenter database (HCC CHORD). J Clin Oncol. 2021;39:275.
36.
go back to reference Lee J, Sung PS, Yang H, Lee SK, Nam HC, Yoo SH, Lee HL, Kim HY, Lee SW, Kwon JH, Jang JW, Kim CW, Nam SW, Bae SH, Choi JY, Yoon SK. A Real-World Comparative Analysis of Lenvatinib and Sorafenib as a Salvage Therapy for Transarterial Treatments in Unresectable HCC. J Clin Med. 2020 Dec 21;9(12):4121. https://doi.org/10.3390/jcm9124121. Lee J, Sung PS, Yang H, Lee SK, Nam HC, Yoo SH, Lee HL, Kim HY, Lee SW, Kwon JH, Jang JW, Kim CW, Nam SW, Bae SH, Choi JY, Yoon SK. A Real-World Comparative Analysis of Lenvatinib and Sorafenib as a Salvage Therapy for Transarterial Treatments in Unresectable HCC. J Clin Med. 2020 Dec 21;9(12):4121. https://​doi.​org/​10.​3390/​jcm9124121.
37.
go back to reference National Comprehensive Cancer Network® (NCCN®). NCCN Guidelines for Patients® Liver Cancer. 2020. National Comprehensive Cancer Network® (NCCN®). NCCN Guidelines for Patients® Liver Cancer. 2020.
38.
go back to reference Crocenzi TS, et al. Nivolumab (nivo) in sorafenib (sor)-naive and -experienced pts with advanced hepatocellular carcinoma (HCC): CheckMate 040 study. J Clin Oncol. 2017;35:4013.CrossRef Crocenzi TS, et al. Nivolumab (nivo) in sorafenib (sor)-naive and -experienced pts with advanced hepatocellular carcinoma (HCC): CheckMate 040 study. J Clin Oncol. 2017;35:4013.CrossRef
39.
go back to reference Yau T, Park JW, Finn RS, Cheng AL, Mathurin P, Edeline J, 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. Yau T, Park JW, Finn RS, Cheng AL, Mathurin P, Edeline J, 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.
40.
go back to reference Larkin J, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381:1535–46.PubMedCrossRef Larkin J, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381:1535–46.PubMedCrossRef
41.
go back to reference Hellmann MD, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med. 2019;381:2020–31.PubMedCrossRef Hellmann MD, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med. 2019;381:2020–31.PubMedCrossRef
42.
go back to reference El-Khoueiry AB, et al. Nivolumab (NIVO) plus ipilimumab (IPI) combination therapy in patients (Pts) with advanced hepatocellular carcinoma (aHCC): long-term results from CheckMate 040. J Clin Orthod. 2021;39:269. El-Khoueiry AB, et al. Nivolumab (NIVO) plus ipilimumab (IPI) combination therapy in patients (Pts) with advanced hepatocellular carcinoma (aHCC): long-term results from CheckMate 040. J Clin Orthod. 2021;39:269.
43.
go back to reference Zhu AX, et al. Pembrolizumab (pembro) in patients with advanced hepatocellular carcinoma (HCC): KEYNOTE-224 update. J Clin Orthod. 2018;36:4020. Zhu AX, et al. Pembrolizumab (pembro) in patients with advanced hepatocellular carcinoma (HCC): KEYNOTE-224 update. J Clin Orthod. 2018;36:4020.
44.
go back to reference Finn RS, et al. KEYNOTE investigators. Results of KEYNOTE-240: phase 3 study of pembrolizumab (Pembro) vs. best supportive care (BSC) for second line therapy in advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2019;37:4004.CrossRef Finn RS, et al. KEYNOTE investigators. Results of KEYNOTE-240: phase 3 study of pembrolizumab (Pembro) vs. best supportive care (BSC) for second line therapy in advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2019;37:4004.CrossRef
45.
go back to reference Merle P, et al. Pembrolizumab (pembro) vs placebo (pbo) in patients (pts) with advanced hepatocellular carcinoma (aHCC) previously treated with sorafenib: updated data from the randomized, phase III KEYNOTE-240 study. J Clin Orthod. 2021;39:268. Merle P, et al. Pembrolizumab (pembro) vs placebo (pbo) in patients (pts) with advanced hepatocellular carcinoma (aHCC) previously treated with sorafenib: updated data from the randomized, phase III KEYNOTE-240 study. J Clin Orthod. 2021;39:268.
46.
go back to reference Merle P, et al. Sequential treatment with sorafenib (SOR) followed by regorafenib (REG) in patients (pts) with unresectable hepatocellular carcinoma (HCC): interim analysis of the observational REFINE study. J Clin Orthod. 2020;38:e16680. Merle P, et al. Sequential treatment with sorafenib (SOR) followed by regorafenib (REG) in patients (pts) with unresectable hepatocellular carcinoma (HCC): interim analysis of the observational REFINE study. J Clin Orthod. 2020;38:e16680.
47.
go back to reference Abou-Alfa GK, Meyer T, Cheng AL, el-Khoueiry AB, Rimassa L, Ryoo BY, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379:54–63. Abou-Alfa GK, Meyer T, Cheng AL, el-Khoueiry AB, Rimassa L, Ryoo BY, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379:54–63.
48.
go back to reference Rimassa L, et al. Outcomes based on age in the phase 3 CELESTIAL trial of cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2018;36:4090.CrossRef Rimassa L, et al. Outcomes based on age in the phase 3 CELESTIAL trial of cabozantinib (C) versus placebo (P) in patients (pts) with advanced hepatocellular carcinoma (HCC). J Clin Oncol. 2018;36:4090.CrossRef
50.
go back to reference Zhu AX, Park JO, Ryoo BY, Yen CJ, Poon R, Pastorelli D, 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;16:859–70. Zhu AX, Park JO, Ryoo BY, Yen CJ, Poon R, Pastorelli D, 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;16:859–70.
51.
go back to reference • Zhu AX, 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;20:282–96 The results of this trial led to the approval of ramucirumab for advanced sorafenib experienced HCC in patients with AFP > 400 ng/ml, the first biomarker stratified treatment strategy.PubMedCrossRef • Zhu AX, 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;20:282–96 The results of this trial led to the approval of ramucirumab for advanced sorafenib experienced HCC in patients with AFP > 400 ng/ml, the first biomarker stratified treatment strategy.PubMedCrossRef
52.
go back to reference Schutz FAB, Je Y, Richards CJ, Choueiri TK. 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;30:871–7.PubMedCrossRef Schutz FAB, Je Y, Richards CJ, Choueiri TK. 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;30:871–7.PubMedCrossRef
53.
go back to reference Sivendran S, Liu Z, Portas LJ Jr, Yu M, Hahn N, Sonpavde G, et al. Treatment-related mortality with vascular endothelial growth factor receptor tyrosine kinase inhibitor therapy in patients with advanced solid tumors: a meta-analysis. Cancer Treat Rev. 2012;38:919–25. Sivendran S, Liu Z, Portas LJ Jr, Yu M, Hahn N, Sonpavde G, et al. Treatment-related mortality with vascular endothelial growth factor receptor tyrosine kinase inhibitor therapy in patients with advanced solid tumors: a meta-analysis. Cancer Treat Rev. 2012;38:919–25.
54.
go back to reference • Rimassa L, Danesi R, Pressiani T, Merle P. Management of adverse events associated with tyrosine kinase inhibitors: improving outcomes for patients with hepatocellular carcinoma. Cancer Treat Rev. 2019;77:20–8 This paper describes the management of adverse events from systemic therapy for HCC.PubMedCrossRef • Rimassa L, Danesi R, Pressiani T, Merle P. Management of adverse events associated with tyrosine kinase inhibitors: improving outcomes for patients with hepatocellular carcinoma. Cancer Treat Rev. 2019;77:20–8 This paper describes the management of adverse events from systemic therapy for HCC.PubMedCrossRef
55.
go back to reference Tridente G. Adverse Events and oncotargeted kinase Inhibitors: Academic Press; 2017. Tridente G. Adverse Events and oncotargeted kinase Inhibitors: Academic Press; 2017.
56.
go back to reference Kim S, Abou-Alfa GK. The role of tyrosine kinase inhibitors in hepatocellular carcinoma. Clin Adv Hematol Oncol. 2014;12:36–41. Kim S, Abou-Alfa GK. The role of tyrosine kinase inhibitors in hepatocellular carcinoma. Clin Adv Hematol Oncol. 2014;12:36–41.
57.
go back to reference Hang XF, Xu WS, Wang JX, Wang L, Xin HG, Zhang RQ, et al. Risk of high-grade bleeding in patients with cancer treated with bevacizumab: a meta-analysis of randomized controlled trials. Eur J Clin Pharmacol. 2011;67:613–23. Hang XF, Xu WS, Wang JX, Wang L, Xin HG, Zhang RQ, et al. Risk of high-grade bleeding in patients with cancer treated with bevacizumab: a meta-analysis of randomized controlled trials. Eur J Clin Pharmacol. 2011;67:613–23.
58.
go back to reference Hapani S, Sher A, Chu D, Wu S. Increased risk of serious hemorrhage with bevacizumab in cancer patients: a meta-analysis. Oncology. 2010;79:27–38.PubMedCrossRef Hapani S, Sher A, Chu D, Wu S. Increased risk of serious hemorrhage with bevacizumab in cancer patients: a meta-analysis. Oncology. 2010;79:27–38.PubMedCrossRef
60.
go back to reference Postow MA, Hellmann MD. Adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378:1165.PubMedCrossRef Postow MA, Hellmann MD. Adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378:1165.PubMedCrossRef
61.
go back to reference Brahmer JR, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36:1714–68.PubMedCrossRef Brahmer JR, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36:1714–68.PubMedCrossRef
62.
go back to reference Naing A, Hajjar J, Gulley JL, Atkins MB, Ciliberto G, Meric-Bernstam F, et al. Strategies for improving the management of immune-related adverse events. J Immunother Cancer. 2020;8:e001754. Naing A, Hajjar J, Gulley JL, Atkins MB, Ciliberto G, Meric-Bernstam F, et al. Strategies for improving the management of immune-related adverse events. J Immunother Cancer. 2020;8:e001754.
63.
go back to reference Jeung H-C, Oh SE, Kim JH. Immune-related adverse events: overview and management strategies for the use of immune checkpoint inhibitors. Journal of Rheumatic Diseases. 2019;26:221.CrossRef Jeung H-C, Oh SE, Kim JH. Immune-related adverse events: overview and management strategies for the use of immune checkpoint inhibitors. Journal of Rheumatic Diseases. 2019;26:221.CrossRef
64.
go back to reference Kelley RK, et al. Efficacy, tolerability, and biologic activity of a novel regimen of tremelimumab (T) in combination with durvalumab (D) for patients (pts) with advanced hepatocellular carcinoma (aHCC). J Clin Orthod. 2020;38:4508. Kelley RK, et al. Efficacy, tolerability, and biologic activity of a novel regimen of tremelimumab (T) in combination with durvalumab (D) for patients (pts) with advanced hepatocellular carcinoma (aHCC). J Clin Orthod. 2020;38:4508.
Metadata
Title
Recent Progress in Systemic Therapy for Hepatocellular Cancer (HCC)
Authors
T. Tara Ghaziani, MD
Renumathy Dhanasekaran, MD
Publication date
01-06-2021

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