Hepatocellular carcinoma

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 Eric I. Marks, MD
Boston University
Boston, MA

Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!.

33 regimens on this page
42 variants on this page


Guidelines

AASLD

ASCO

ESMO

Older

NCCN

SITC

TOS/ESMO

Adjuvant therapy

TACE monotherapy

TACE: Trans-Arterial Chemo-Embolization

Regimen variant #1, doxorubicin-based

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Wang et al. 2018 (LCI-125-009) 2011-2014 Phase 3 (E-esc) Observation Seems to have superior OS
OS36: 85.2% vs 77.4%
(HR 0.59, 95% CI 0.36-0.97)

Preceding treatment

Local therapy

One or more treatments


Regimen variant #2, carboplatin, epirubicin, mitomycin-based

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Wei et al. 2018 (SYSUCC-HCC-ADTACE) 2009-2012 Phase 3 (E-esc) Observation Superior DFS
Median DFS: 17.45 vs 9.27 mo
(HR 0.70, 95% CI 0.52-0.95)

Preceding treatment

Local therapy

One or two treatments

References

  1. LCI-125-009: Wang Z, Ren Z, Chen Y, Hu J, Yang G, Yu L, Yang X, Huang A, Zhang X, Zhou S, Sun H, Wang Y, Ge N, Xu X, Tang Z, Lau W, Fan J, Wang J, Zhou J. Adjuvant transarterial chemoembolization for HBV-related hepatocellular carcinoma after resection: a randomized controlled study. Clin Cancer Res. 2018 May 1;24(9):2074-2081. Epub 2018 Feb 2. link to original article PubMed Clinical Trial Registry
  2. SYSUCC-HCC-ADTACE: Wei W, Jian PE, Li SH, Guo ZX, Zhang YF, Ling YH, Lin XJ, Xu L, Shi M, Zheng L, Chen MS, Guo RP. Adjuvant transcatheter arterial chemoembolization after curative resection for hepatocellular carcinoma patients with solitary tumor and microvascular invasion: a randomized clinical trial of efficacy and safety. Cancer Commun (Lond). 2018 Oct 10;38(1):61. link to original article link to PMC article PubMed Clinical Trial Registry

Local therapy for advanced disease

Axitinib & TACE

Regimen

Study Dates of enrollment Evidence
Chan et al. 2017 (HCC028) 2011-2014 Phase 2

Targeted therapy

Local therapy

References

  1. HCC028: Chan SL, Yeo W, Mo F, Chan AWH, Koh J, Li L, Hui EP, Chong CCN, Lai PBS, Mok TSK, Yu SCH. A phase 2 study of the efficacy and biomarker on the combination of transarterial chemoembolization and axitinib in the treatment of inoperable hepatocellular carcinoma. Cancer. 2017 Oct 15;123(20):3977-3985. Epub 2017 Jun 22. link to original article PubMed Clinical Trial Registry

Lenvatinib & TACE

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Peng et al. 2022 (LAUNCH) 2019-2021 Phase 3 (E-esc) Lenvatinib Superior OS
Median OS: 17.8 vs 11.5 mo
(HR 0.45, 95% CI 0.33-0.61)

Targeted therapy

  • Lenvatinib (Lenvima) by the following weight-based criteria:
    • Less than 60 kg: 8 mg PO once per day
    • 60 kg or more: 12 mg PO once per day

Continued indefinitely

Local therapy

1 or more treatments

References

  1. LAUNCH: Peng Z, Fan W, Zhu B, Wang G, Sun J, Xiao C, Huang F, Tang R, Cheng Y, Huang Z, Liang Y, Fan H, Qiao L, Li F, Zhuang W, Peng B, Wang J, Li J, Kuang M. Lenvatinib Combined With Transarterial Chemoembolization as First-Line Treatment for Advanced Hepatocellular Carcinoma: A Phase III, Randomized Clinical Trial (LAUNCH). J Clin Oncol. 2023 Jan 1;41(1):117-127. Epub 2022 Aug 3. link to original article contains dosing details in abstract PubMed Clinical Trial Registry

DEB-TACE

DEB-TACE: Drug-Eluting Bead Trans-Arterial Chemo-Embolization

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brown et al. 2016 (MSK 07-099) 2007-2012 Randomized Phase 2 (E-esc) Bland embolization Did not meet primary endpoint of ORR
Meyer et al. 2017 (TACE2) 2010-2015 Phase 3 (C) DEB-TACE & Sorafenib Did not meet primary outcome of PFS

Note: TACE2 assessed the addition of concurrent sorafenib to DEB-TACE.

Eligibility criteria

  • TACE2: Child-Pugh A liver disease, and ECOG PS 0 or 1

Local therapy

One treatment

References

  1. MSK 07-099: Brown KT, Do RK, Gonen M, Covey AM, Getrajdman GI, Sofocleous CT, Jarnagin WR, D'Angelica MI, Allen PJ, Erinjeri JP, Brody LA, O'Neill GP, Johnson KN, Garcia AR, Beattie C, Zhao B, Solomon SB, Schwartz LH, DeMatteo R, Abou-Alfa GK. Randomized trial of hepatic artery embolization for hepatocellular carcinoma using doxorubicin-eluting microspheres compared with embolization with microspheres alone. J Clin Oncol. 2016 Jun 10;34(17):2046-53. Epub 2016 Feb 1. link to original article link to PMC article PubMed Clinical Trial Registry
  2. TACE2: Meyer T, Fox R, Ma YT, Ross PJ, James MW, Sturgess R, Stubbs C, Stocken DD, Wall L, Watkinson A, Hacking N, Evans TRJ, Collins P, Hubner RA, Cunningham D, Primrose JN, Johnson PJ, Palmer DH. Sorafenib in combination with transarterial chemoembolization in patients with unresectable hepatocellular carcimoma (TACE2): a randomized placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol. 2017 Aug;2(8):565-575. Epub 2017 Jun 23. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry

FOLFOX-HAIC

FOLFOX-HAIC: FOLinic acid, Fluorouracil, OXaliplatin Hepatic Arterial Infusion Chemotherapy

Regimen variant #1, longer duration

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Li et al. 2021 (HCC-S023) 2016-2018 Phase 3 (E-switch-ooc) TACE Superior OS (primary endpoint)
Median OS: 23.1 vs 16.1 mo
(HR 0.58, 95% CI 0.45-0.75)

Chemotherapy

  • Folinic acid (Leucovorin) 400 mg/m2 IA over 60 minutes once on day 1, given second
  • Fluorouracil 400 mg/m2 IA bolus once on day 1, given third, then 2400 mg/m2 IA continuous infusion over 24 hours (total dose per cycle: 2800 mg/m2)
  • Oxaliplatin 130 mg/m2 IA over 2 hours once on day 1, given first

21-day cycle for up to 6 cycles


Regimen variant #2, shorter duration

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Li et al. 2023 (B2017-006-01) 2016-06 to 2021-08 Phase 3 (E-esc) Observation Superior DFS (primary endpoint)
Median DFS: 20.3 vs 10 mo
(HR 0.59, 95% CI 0.43-0.81)

Preceding treatment

Chemotherapy

  • Folinic acid (Leucovorin) 400 mg/m2 IA over 90 minutes once on day 1, given second
  • Fluorouracil 400 mg/m2 IA over 2 hours once on day 1, given third, then 2400 mg/m2 IA continuous infusion over 24 hours (total dose per cycle: 2800 mg/m2)
  • Oxaliplatin 85 mg/m2 IA over 3 hours once on day 1, given first

28- to 35-day cycle for 1 to 2 cycles

References

  1. HCC-S023: Li QJ, He MK, Chen HW, Fang WQ, Zhou YM, Xu L, Wei W, Zhang YJ, Guo Y, Guo RP, Chen MS, Shi M. Hepatic Arterial Infusion of Oxaliplatin, Fluorouracil, and Leucovorin Versus Transarterial Chemoembolization for Large Hepatocellular Carcinoma: A Randomized Phase III Trial. J Clin Oncol. 2022 Jan 10;40(2):150-160. Epub 2021 Oct 14. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
  2. B2017-006-01: Li SH, Mei J, Cheng Y, Li Q, Wang QX, Fang CK, Lei QC, Huang HK, Cao MR, Luo R, Deng JD, Jiang YC, Zhao RC, Lu LH, Zou JW, Deng M, Lin WP, Guan RG, Wen YH, Li JB, Zheng L, Guo ZX, Ling YH, Chen HW, Zhong C, Wei W, Guo RP. Postoperative Adjuvant Hepatic Arterial Infusion Chemotherapy With FOLFOX in Hepatocellular Carcinoma With Microvascular Invasion: A Multicenter, Phase III, Randomized Study. J Clin Oncol. 2023 Apr 1;41(10):1898-1908. Epub 2022 Dec 16. link to original article link to PMC article contains dosing details in manuscript PubMed Clinical Trial Registry

FOFLFOX-HAIC & Sorafenib

FOLFOX-HAIC & Sorafenib: FOLinic acid, Fluorouracil, OXaliplatin Hepatic Arterial Infusion Chemotherapy & Sorafenib

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
He et al. 2019 (HCC-S021) 2016-2017 Phase 3 (E-esc) Sorafenib Superior OS
Median OS: 13.4 vs 7.1 mo
(HR 0.35, 95% CI 0.26-0.48)

Note: All patient who were hepatitis B received preemptive antiviral therapy.

Eligibility criteria

  • HCC with portal vein invasion confirmed by 2 imaging techniques, Child-Pugh A class liver function, and an ECOG PS of 0 to 2
  • Excluded: Patients with esophageal or gastric variceal bleeding and hepatic encephalopathy

Chemotherapy

Targeted therapy

21-day cycles

References

  1. HCC-S021: He M, Li Q, Zou R, Shen J, Fang W, Tan G, Zhou Y, Wu X, Xu L, Wei W, Le Y, Zhou Z, Zhao M, Guo Y, Guo R, Chen M, Shi M. 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 Jul 1;5(7):953-960. link to original article contains dosing details in abstract link to PMC article PubMed Clinical Trial Registry

Radioembolization

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Chow et al. 2018 (SIRveNIB) 2010-2016 Phase 3 (E-switch-ooc) Sorafenib Did not meet primary outcome of OS
Vilgrain et al. 2017 (SARAH) 2011-2015 Phase 3 (E-switch-ooc) Sorafenib Did not meet primary outcome of OS

Synopsis

  • SARAH was a multicenter European study that also included patients without two unsuccessful rounds of TACE. Primary endpoint of improved OS was not met; Y90 was associated with higher ORR, lower DCR, fewer AE, and similar survival. Additional post-hoc analysis showed patients who received Y90 at > or equal to 100 Gy may derive a meaningful response as compared to sorafenib.
  • SIRveNIB was a multicenter Asian study randomized newly diagnosed patients with locally advanced inoperable HCC to a single injection of Y90 or sorafenib until progressive disease or unacceptable toxicity. Primary endpoint of improved OS was not met; Y90 was associated with higher ORR, few SAE, and similar OS, similar OS and DCR.

Radiotherapy

References

  1. SARAH: Vilgrain V, Pereira H, Assenat E, Guiu B, Ilonca AD, Pageaux GP, Sibert A, Bouattour M, Lebtahi R, Allaham W, Barraud H, Laurent V, Mathias E, Bronowicki JP, Tasu JP, Perdrisot R, Silvain C, Gerolami R, Mundler O, Seitz JF, Vidal V, Aubé C, Oberti F, Couturier O, Brenot-Rossi I, Raoul JL, Sarran A, Costentin C, Itti E, Luciani A, Adam R, Lewin M, Samuel D, Ronot M, Dinut A, Castera L, Chatellier G; SARAH Trial Group. 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 Dec;18(12):1624-1636. Epub 2017 Oct 26. link to original article PubMed Clinical Trial Registry
    1. Update: Abstract: Hawkins NS, Ross PJ, Palmer DH, Chatellier G, Pereira H, Vilgrain V. Overall survival of patients with hepatocellular carcinoma receiving sorafenib versus selective internal radiation therapy with predicted osimetry in the SARAH trial. Annals of Oncology. 2019 Sept; 30 (suppl_5): v253-v324. Epub 2019 Sept 29. link to original article
  2. SIRveNIB: Chow PKH, Gandhi M, Tan SB, Khin MW, Khasbazar A, Ong J, Choo SP, Cheow PC, Chotipanich C, Lim K, Lesmana LA, Manuaba TW, Yoong BK, Raj A, Law CS, Cua IHY, Lobo RR, Teh CSC, Kim YH, Jong YW, Han HS, Bae SH, Yoon HK, Lee RC, Hung CF, Peng CY, Liang PC, Bartlett A, Kok KYY, Thng CH, Low AS, Goh ASW, Tay KH, Lo RHG, Goh BKP, Ng DCE, Lekurwale G, Liew WM, Gebski V, Mak KSW, Soo KC; Asia-Pacific Hepatocellular Carcinoma Trials Group. SIRveNIB: selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma. J Clin Oncol. 2018 Jul 1;36(19):1913-1921. Epub 2018 Mar 2. link to original article PubMed Clinical Trial Registry

TACE monotherapy

TACE: Trans-Arterial Chemo-Embolization

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Trinchet et al. 1995 1990-1992 Phase 3 (E-esc) Best supportive care Did not meet primary endpoint of OS
Llovet et al. 2002 1996-2000 Phase 3 (E-esc) Best supportive care Seems to have superior OS
Okusaka et al. 2009 1999-2003 Phase 3 (E-esc) TAI Did not meet primary endpoint of OS
Kudo et al. 2011 (Bayer 11721) 2006-2009 Non-randomized part of RCT
Ikeda et al. 2017 2008-2010 Phase 3 (C) TACE with Miriplatin Did not meet primary endpoint of OS
Kudo et al. 2014 (BRISK TA) 2009-2012 Phase 3 (C) TACE & Brivanib Did not meet primary endpoint of OS
Kudo et al. 2017 (ORIENTAL) 2010-2013 Phase 3 (C) TACE & Orantinib Did not meet primary endpoint of OS

Synopsis

  • Bayer 11721 was a Japanese and Korean study including patients with Child-Pugh A cirrhosis with a primary endpoint of TTP, and secondary endpoint of OS. More than 50% of patients started sorafenib after 9 weeks post TACE. 73% of patients had dose reductions, and 91% of patients had dose interruptions.

Local therapy

1 or more treatments

Subsequent treatment

  • Bayer 11721: Placebo versus sorafenib

References

  1. Trinchet JC, Abou Rached A, Beaugrand M, Mathieu D, Chevret S, Chastang C; Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire. A comparison of lipiodol chemoembolization and conservative treatment for unresectable hepatocellular carcinoma. N Engl J Med. 1995 May 11;332(19):1256-61. link to original article PubMed
  2. Llovet JM, Real MI, Montaña X, Planas R, Coll S, Aponte J, Ayuso C, Sala M, Muchart J, Solà R, Rodés J, Bruix J; Barcelona Liver Cancer Group. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002 May 18;359(9319):1734-9. link to original article PubMed
  3. Okusaka T, Kasugai H, Shioyama Y, Tanaka K, Kudo M, Saisho H, Osaki Y, Sata M, Fujiyama S, Kumada T, Sato K, Yamamoto S, Hinotsu S, Sato T. Transarterial chemotherapy alone versus transarterial chemoembolization for hepatocellular carcinoma: a randomized phase III trial. J Hepatol. 2009 Dec;51(6):1030-6. Epub 2009 Oct 1. link to original article PubMed
  4. Bayer 11721: Kudo M, Imanaka K, Chida N, Nakachi K, Tak WY, Takayama T, Yoon JH, Hori T, Kumada H, Hayashi N, Kaneko S, Tsubouchi H, Suh DJ, Furuse J, Okusaka T, Tanaka K, Matsui O, Wada M, Yamaguchi I, Ohya T, Meinhardt G, Okita K. Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma. Eur J Cancer. 2011 Sep;47(14):2117-27. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
  5. BRISK TA: Kudo M, Han G, Finn RS, Poon RT, Blanc JF, Yan L, Yang J, Lu L, Tak WY, Yu X, Lee JH, Lin SM, Wu C, Tanwandee T, Shao G, Walters IB, Dela Cruz C, Poulart V, Wang JH. Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: A randomized phase III trial. Hepatology. 2014 Nov;60(5):1697-707. Epub 2014 Sep 29. link to original article PubMed Clinical Trial Registry
  6. Ikeda M, Kudo M, Aikata H, Nagamatsu H, Ishii H, Yokosuka O, Torimura T, Morimoto M, Ikeda K, Kumada H, Sato T, Kawai I, Yamashita T, Horio H, Okusaka T; Miriplatin TACE Study Group. Transarterial chemoembolization with miriplatin vs epirubicin for unresectable hepatocellular carcinoma: a phase III randomized trial. J Gastroenterol. 2018 Feb;53(2):281-290. Epub 2017 Aug 1. link to original article link to PMC article PubMed JapicCTI-080632
  7. ORIENTAL: Kudo M, Cheng AL, Park JW, Park JH, Liang PC, Hidaka H, Izumi N, Heo J, Lee YJ, Sheen IS, Chiu CF, Arioka H, Morita S, Arai Y. 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 Jan;3(1):37-46. Epub 2017 Oct 4. link to original article PubMed Clinical Trial Registry

TACE, then 5-FU

TACE, then 5-FU: Trans-Arterial ChemoEmbolization followed by 5-FluoroUracil

Protocol

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kawata et al. 2001 1990-1993 Phase 3 (C) TACE, then 5-FU & Pravastatin Inferior OS

Chemotherapy, TACE portion

  • Doxorubicin (Adriamycin) 30 mg IA once on day 1, given first
  • Gelatin-sponge particles and ethyl ester of poppyseed oil fatty acids containing 38% iodine by weight (Lipiodol; AndreGelbe Laboratories, Paris, France)

One treatment, followed in 2 weeks by:

Chemotherapy

2-month course

References

  1. Kawata S, Yamasaki E, Nagase T, Inui Y, Ito N, Matsuda Y, Inada M, Tamura S, Noda S, Imai Y, Matsuzawa Y. Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma: a randomized controlled trial. Br J Cancer. 2001 Apr 6;84(7):886-91. link to original article contains dosing details in manuscript link to PMC article PubMed

First-line therapy for advanced or metastatic disease

Note: in this setting, first-line refers to first-line systemic therapy; many patients had resection, ablation, and/or TACE prior to systemic therapy. See individual trials for details.

Atezolizumab & Bevacizumab

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Finn et al. 2020 (IMbrave150)
ESMO-MCBS (5)
2018-03-15 to 2019-01-30 Phase 3 (E-RT-esc) Sorafenib Superior OS1 (co-primary endpoint)
Median OS: 19.2 vs 13.4 mo
(HR 0.66, 95% CI 0.52-0.85)

1Reported efficacy is based on the 2021 update.

Eligibility criteria

  • Excluded: Child-Pugh class B and C, coinfection with hepatitis B or C virus, and untreated or incompletely treated esophageal or gastric varices

Immunotherapy

Targeted therapy

21-day cycles

References

  1. IMbrave150: Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Xu DZ, Hernandez S, Liu J, Huang C, Mulla S, Wang Y, Lim HY, Zhu AX, Cheng AL; IMbrave150 Investigators. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020 May 14;382(20):1894-1905. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
    1. Update: Cheng AL, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Lim HY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Ma N, Nicholas A, Wang Y, Li L, Zhu AX, Finn RS. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022 Apr;76(4):862-873. Epub 2021 Dec 11. link to original article PubMed

Bevacizumab monotherapy

Regimen

Study Dates of enrollment Evidence Efficacy
Siegel et al. 2008 2003-2006 Phase 2 ORR: 13% (95% CI, 3-23)

Note: The dose here was a pre-planned escalation dose with initial dose of 5mg/kg. The study met and exceeded primary endpoint of determining whether bevacizumab improved 6 month PFS from 40-60% (observed 6 months PFS was 65%).

Targeted therapy

14-day cycles

References

  1. Siegel AB, Cohen EI, Ocean A, Lehrer D, Goldenberg A, Knox JJ, Chen H, Clark-Garvey S, Weinberg A, Mandeli J, Christos P, Mazumdar M, Popa E, Brown RS Jr, Rafii S, Schwartz JD. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol. 2008 Jun 20;26(18):2992-8. link to original article contains dosing details in manuscript link to PMC article PubMed

Capecitabine & Bevacizumab

Regimen

Study Dates of enrollment Evidence Efficacy
Hsu et al. 2010 2005-2006 Phase 2 ORR: 9%

Chemotherapy

Targeted therapy

21-day cycle for 6 or more cycles depending on response

References

  1. Hsu CH, Yang TS, Hsu C, Toh HC, Epstein RJ, Hsiao LT, Chen PJ, Lin ZZ, Chao TY, Cheng AL. Efficacy and tolerability of bevacizumab plus capecitabine as first-line therapy in patients with advanced hepatocellular carcinoma. Br J Cancer. 2010 Mar 16;102(6):981-6. Epub 2010 Feb 16. link to original article contains dosing details in manuscript link to PMC article PubMed

CapeOx

CapeOX: Capecitabine, OXaliplatin
XELOX: XELoda (Capecitabine), OXaliplatin

Regimen

Study Dates of enrollment Evidence Efficacy
Boige et al. 2007 (FFCD 03-03) 2003-2004 Phase 2 DCR: 72% (95% CI, 57-83)

Chemotherapy

21-day cycles

References

  1. FFCD 03-03: Boige V, Raoul JL, Pignon JP, Bouché O, Blanc JF, Dahan L, Jouve JL, Dupouy N, Ducreux M; Fédération Francophone de Cancérologie Digestive. Multicentre phase II trial of capecitabine plus oxaliplatin (XELOX) in patients with advanced hepatocellular carcinoma: FFCD 03-03 trial. Br J Cancer. 2007 Oct 8;97(7):862-7. Epub 2007 Sep 18. link to original article contains dosing details in manuscript link to PMC article PubMed

CapeOx & Bevacizumab

CapeOX & Bevacizumab: Capecitabine, OXaliplatin, Bevacizumab

Regimen

Study Dates of enrollment Evidence Efficacy
Sun et al. 2011 2004-2007 Phase 2 DCR: 77.5%

Chemotherapy

Targeted therapy

  • Bevacizumab (Avastin) 5 mg/kg IV once on day 1
    • Infusion times are 75 to 105 minutes for the first dose, which if tolerated could be decreased to 50 to 70 minutes for the second dose, then 20 to 40 minutes for dose 3 and later

21-day cycles

References

  1. Sun W, Sohal D, Haller DG, Mykulowycz K, Rosen M, Soulen MC, Caparro M, Teitelbaum UR, Giantonio B, O'Dwyer PJ, Shaked A, Reddy R, Olthoff K. Phase 2 trial of bevacizumab, capecitabine, and oxaliplatin in treatment of advanced hepatocellular carcinoma. Cancer. 2011 Jul 15;117(14):3187-92. Epub 2011 Jan 24. link to original article contains dosing details in manuscript PubMed

Doxorubicin monotherapy

Regimen variant #1, 50 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Qin et al. 2013 (EACH) 2007-2009 Phase 3 (C) FOLFOX4 Trend towards inferior OS

Note: EACH included patients with both Child-Pugh stage A and B disease (AST or ALT less than 2.5x ULN, T bil less than 1.5x ULN, INR less than 1.5).

Chemotherapy

21-day cycles


Regimen variant #2, 60 mg/m2 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yeo et al. 2005 1999-2003 Phase 3 (C) PIAF Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 6 cycles


Regimen variant #3, 60 mg/m2 x 9

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Johnson et al. 1978 1976-1977 Non-randomized
Abou-Alfa et al. 2010 (Study 11546) 2005-2006 Phase 3 (C) Doxorubicin & Sorafenib Inferior OS

Chemotherapy

21-day cycle for up to 9 cycles


Regimen variant #4, 60 mg/m2, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lai et al. 1988 NR Randomized (E-esc) Best supportive care Seems to have superior OS
Gish et al. 2007 (ZARIX-ZX101-301) 2000-2005 Phase 3 (C) Nolatrexed Superior OS

Note: this was the lower bound of the dosing range provided by Lai et al. 1988.

Chemotherapy

  • Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
    • ZARIX-ZX101-301: Initial dose reduction to 30 mg/m2 IV for patients with T bili greater than 1.2 mg/dL

21-day cycles


Regimen variant #5, 75 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yeo et al. 2005 1999-2003 Phase 3 (C) PIAF Did not meet primary endpoint of OS

Chemotherapy

  • Doxorubicin (Adriamycin) as follows:
    • Cycle 1: 60 mg/m2 IV once on day 1
    • Cycle 2 onwards, if "well tolerated": 75 mg/m2 IV once on day 1

21-day cycles

References

  1. Johnson PJ, Williams R, Thomas H, Sherlock S, Murray-Lyon IM. Induction of remission in hepatocellular carcinoma with doxorubicin. Lancet. 1978 May 13;1(8072):1006-9. link to original article contains dosing details in abstract PubMed
  2. Lai CL, Wu PC, Chan GC, Lok AS, Lin HJ. Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma: a prospective randomized trial. Cancer. 1988 Aug 1;62(3):479-83. link to original article contains dosing details in abstract PubMed
  3. Yeo W, Mok TS, Zee B, Leung TW, Lai PB, Lau WY, Koh J, Mo FK, Yu SC, Chan AT, Hui P, Ma B, Lam KC, Ho WM, Wong HT, Tang A, Johnson PJ. 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 Oct 19;97(20):1532-8. link to original article contains dosing details in manuscript PubMed
  4. ZARIX-ZX101-301: Gish RG, Porta C, Lazar L, Ruff P, Feld R, Croitoru A, Feun L, Jeziorski K, Leighton J, Gallo J, Kennealey GT. Phase III randomized controlled trial comparing the survival of patients with unresectable hepatocellular carcinoma treated with nolatrexed or doxorubicin. J Clin Oncol. 2007 Jul 20;25(21):3069-75. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
  5. Study 11546: Abou-Alfa GK, Johnson P, Knox JJ, Capanu M, Davidenko I, Lacava J, Leung T, Gansukh B, Saltz LB. Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA. 2010 Nov 17;304(19):2154-60. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
  6. EACH: Qin S, Bai Y, Lim HY, Thongprasert S, Chao Y, Fan J, Yang TS, Bhudhisawasdi V, Kang WK, Zhou Y, Lee JH, Sun Y. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J Clin Oncol. 2013 Oct 1;31(28):3501-8. Epub 2013 Aug 26. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry

Durvalumab & Tremelimumab

STRIDE: Single Tremelimumab Regular Interval Durvalumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Abou-Alfa et al. 2022 (HIMALAYA)
ESMO-MCBS (5)
2017-2019 Phase 3 (E-RT-switch-ooc) 1. Sorafenib Superior OS1
Median OS: 16.4 vs 13.8 mo
(HR 0.78, 96.02% CI 0.65-0.93)
2. Durvalumab Not reported

1Reported efficacy and treatment details are based on the FDA approval summary. Note: full reference details for HIMALAYA will be added once NEJM Evidence is MEDLINE-indexed.

Immunotherapy

28-day cycles

References

  1. HIMALAYA: link to original article contains dosing details in manuscript Clinical Trial Registry

Durvalumab monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Abou-Alfa et al. 2022 (HIMALAYA) 2017-2019 Phase 3 (E-switch-ooc) 1. Sorafenib Non-inferior OS
Median OS: 16.6 vs 13.8 mo
(HR 0.86, 95% CI 0.73-1.03)
2. Durvalumab & Tremelimumab Not reported

Note: full reference details for HIMALAYA will be added once NEJM Evidence is MEDLINE-indexed.

Immunotherapy

28-day cycles

References

  1. HIMALAYA: link to original article contains dosing details in manuscript Clinical Trial Registry

Erlotinib & Bevacizumab

Regimen

Study Dates of enrollment Evidence Efficacy
Thomas et al. 2009 NR Phase 2 PFS16: 62.5%
Philip et al. 2011 2006-2008 Phase 2 ORR: 5% (95% CI, 0-23)

Note: Patients in Thomas et al. 2009 could have up to one prior systemic treatment.

Targeted therapy

28-day cycles

References

  1. Thomas MB, Morris JS, Chadha R, Iwasaki M, Kaur H, Lin E, Kaseb A, Glover K, Davila M, Abbruzzese J. Phase II trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma. J Clin Oncol. 2009 Feb 20;27(6):843-50. Epub 2009 Jan 12. link to original article contains dosing details in manuscript PubMed
  2. Philip PA, Mahoney MR, Holen KD, Northfelt DW, Pitot HC, Picus J, Flynn PJ, Erlichman C. Phase 2 study of bevacizumab plus erlotinib in patients with advanced hepatocellular cancer. Cancer. 2012 May 1;118(9):2424-30. Epub 2011 Sep 27. link to original article link to PMC article PubMed

FULV

FULV: 5-FU & LeucoVorin (Folinic acid)

Regimen

Study Dates of enrollment Evidence Efficacy
Porta et al. 1995 NR in abstract Phase 2 ORR: 28% (95% CI, 10-46)

Chemotherapy

28-day cycles

References

  1. Porta C, Moroni M, Nastasi G, Arcangeli G. 5-Fluorouracil and d,l-leucovorin calcium are active to treat unresectable hepatocellular carcinoma patients: preliminary results of a phase II study. Oncology. 1995 Nov-Dec;52(6):487-91. link to original article PubMed

FOLFOX4

FOLFOX4: FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Qin et al. 2013 (EACH) 2007-2009 Phase 3 (E-switch-ic) Doxorubicin Might have superior OS
Median OS: 6.4 vs 5.0 mo
(HR 0.80, 95% CI 0.63-1.02)

Note: This study included patients with both Child-Pugh stage A and B disease (AST or ALT less than 2.5x ULN, T bil less than 1.5x ULN, INR less than 1.5).

Chemotherapy

14-day cycles

References

  1. EACH: Qin S, Bai Y, Lim HY, Thongprasert S, Chao Y, Fan J, Yang TS, Bhudhisawasdi V, Kang WK, Zhou Y, Lee JH, Sun Y. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J Clin Oncol. 2013 Oct 1;31(28):3501-8. Epub 2013 Aug 26. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
  2. SHR-1210-III-305-HCC: Clinical Trial Registry

mFOLFOX & Sorafenib

mFOLFOX & Sorafenib: modified FOLinic acid, Fluorouracil, OXaliplatin, Sorafenib

Regimen

Study Dates of enrollment Evidence Efficacy
Goyal et al. 2019 (MGH 12-218) 2013-2017 Phase 2 mTTP: 7.7 mo (95% CI, 4.4-8.9)

Note: Patients had improved mTTP, but increased incidence of hepatotoxicity. Note that the regimen specifies that 5-FU be given at 1200 mg/m2/day over 46 hours; the total dose is therefore unclear.

Eligibility criteria

  • Child Pugh A with advanced HCC with no prior systemic therapy

Chemotherapy

Targeted therapy

14-day cycles

References

  1. MGH 12-218: Goyal L, Zheng H, Abrams TA, Miksad R, Bullock AJ, Allen JN, Yurgelun MB, Clark JW, Kambadakone A, Muzikansky A, Knowles M, Galway A, Afflitto AJ, Dinicola CF, Regan E, Hato T, Mamessier E, Shigeta K, Jain RK, Duda DG, Zhu AX. A Phase II and Biomarker Study of Sorafenib Combined with Modified FOLFOX in Patients with Advanced Hepatocellular Carcinoma. Clin Cancer Res. 2019 Jan 1;25(1):80-89. Epub 2018 Sep 6. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry

GemOx

GemOx: Gemcitabine, Oxaliplatin

Regimen

Study Dates of enrollment Evidence Efficacy
Louafi et al. 2007 2002-2004 Phase 2 ORR: 18% (95% CI, 8–34)

Chemotherapy

14-day cycles

References

  1. Louafi S, Boige V, Ducreux M, Bonyhay L, Mansourbakht T, de Baere T, Asnacios A, Hannoun L, Poynard T, Taïeb J. Gemcitabine plus oxaliplatin (GEMOX) in patients with advanced hepatocellular carcinoma (HCC): results of a phase II study. Cancer. 2007 Apr 1;109(7):1384-90. link to original article contains dosing details in manuscript PubMed
  2. Retrospective: Zaanan A, Williet N, Hebbar M, Dabakuyo TS, Fartoux L, Mansourbakht T, Dubreuil O, Rosmorduc O, Cattan S, Bonnetain F, Boige V, Taïeb J. Gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma: A large multicenter AGEO study. J Hepatol. 2013 Jan;58(1):81-8. Epub 2012 Sep 16. link to original article PubMed

GemOx & Sorafenib

GemOx & Sorafenib: Gemcitabine, Oxaliplatin , Sorafenib

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Assenat et al. 2019 (PRODIGE 10) 2008-2011 Randomized Phase 2 (E-esc) Sorafenib Did not meet primary endpoint of PFS4

Chemotherapy

Targeted therapy

14-day cycles

References

  1. PRODIGE 10: Assenat E, Pageaux GP, Thézenas S, Peron JM, Bécouarn Y, Seitz JF, Merle P, Blanc JF, Bouché O, Ramdani M, Poujol S, de Forges H, Ychou M, Boige V. Sorafenib alone vs sorafenib plus GEMOX as 1st-line treatment for advanced HCC: the phase II randomised PRODIGE 10 trial. Br J Cancer. 2019 Apr;120(9):896-902. Epub 2019 Apr 4. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry

Lenvatinib monotherapy

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kudo et al. 2018 (REFLECT) 2013-2015 Phase 3 (E-RT-switch-ic) Sorafenib Non-inferior OS
Median OS: 13 vs 12.3 mo
(HR 0.92, 95% CI 0.79-1.06)
Peng et al. 2022 (LAUNCH) 2019-2021 Phase 3 (C) Lenvatinib & TACE Inferior OS

Targeted therapy

  • Lenvatinib (Lenvima) by the following weight-based criteria:
    • Less than 60 kg: 8 mg PO once per day
    • 60 kg or more: 12 mg PO once per day

28-day cycles

References

  1. REFLECT: Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng AL. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018 Mar 24;391(10126):1163-1173. Epub 2018 Feb 9. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
  2. LAUNCH: Peng Z, Fan W, Zhu B, Wang G, Sun J, Xiao C, Huang F, Tang R, Cheng Y, Huang Z, Liang Y, Fan H, Qiao L, Li F, Zhuang W, Peng B, Wang J, Li J, Kuang M. Lenvatinib Combined With Transarterial Chemoembolization as First-Line Treatment for Advanced Hepatocellular Carcinoma: A Phase III, Randomized Clinical Trial (LAUNCH). J Clin Oncol. 2023 Jan 1;41(1):117-127. Epub 2022 Aug 3. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
  3. CheckMate 9DW: Clinical Trial Registry
  4. LEAP-002: Clinical Trial Registry

Sorafenib monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Abou-Alfa et al. 2006b 2002-2003 Phase 2
Llovet et al. 2008 (SHARP)
ESMO-MCBS (3)
2005-03-10 to 2006-04-11 Phase 3 (E-RT-esc) Placebo Superior OS (co-primary endpoint)
Median OS: 10.7 vs 7.9 mo
(HR 0.69, 95% CI 0.55-0.87)
Cheng et al. 2008 (Sorafenib AP) 2005-2007 Phase 3 (E-esc) Placebo Seems to have superior OS
Median OS: 6.5 vs 4.2 mo
(HR 0.68, 95% CI 0.50-0.93)
Pinter et al. 2009 2006-2007 Retrospective
Cheng et al. 2013 (SUN 1170) 2008-2010 Phase 3 (C) Sunitinib Superior OS
Median OS: 10.2 vs 7.9 mo
(HR 0.77, 95% CI 0.67-0.88)
Johnson et al. 2013 (BRISK-FL) 2009-2011 Phase 3 (C) Brivanib Inconclusive whether non-inferior OS
Cainap et al. 2014 (LIGHT) NR Phase 3 (C) Linifanib Did not meet primary endpoint of OS
Zhu et al. 2014 (SEARCH) 2009-2011 Phase 3 (C) Erlotinib & Sorafenib Did not meet primary endpoint of OS
Koeberle et al. 2016 (SAKK 77/08; SASL 29) 2009-2013 Randomized Phase 2 (C) Everolimus & Sorafenib Did not meet primary endpoint of PFS3
Abdel-Rahman et al. 2013 2010-2011 Randomized Phase 2 (C) Capecitabine Superior OS
Median OS: 7.1 vs 5.1 mo
(HR 0.42, 95% CI 0.21-0.85)
Kudo et al. 2018 (SILIUS) 2010-2014 Phase 3 (C) HAI CF & Sorafenib Did not meet primary endpoint of OS
Abou-Alfa et al. 2019 (CALGB 80802) 2010-2015 Phase 3 (C) Doxorubicin & Sorafenib Did not meet primary endpoint of OS
Chow et al. 2018 (SIRveNIB) 2010-2016 Phase 3 (C) SIRT Did not meet primary endpoint of OS
Jouve et al. 2019 (PRODIGE-11) 2010-NR in abstract Phase 3 (C) Pravastatin & Sorafenib Did not meet primary endpoint of OS
Vilgrain et al. 2017 (SARAH) 2011-2015 Phase 3 (C) SIRT Did not meet primary endpoint of OS
Park et al. 2018 (STAH) 2013-2015 Phase 3 (C) Sorafenib & TACE Did not meet primary endpoint of OS
Kudo et al. 2018 (REFLECT) 2013-2015 Phase 3 (C) Lenvatinib Non-inferior OS
He et al. 2019 (HCC-S021) 2016-2017 Phase 3 (C) SoraHAIC Inferior OS
Yau et al. 2021 (CheckMate 459) 2016-2017 Phase 3 (C) Nivolumab Might have inferior OS
Qin et al. 2021 2016-2018 Phase 3 (C) Donafenib Inferior OS
Lyu et al. 2021 (FOHAIC-1) 2017-2020 Phase 3 (C) HAI FOLFOX Inferior OS
Abou-Alfa et al. 2022 (HIMALAYA) 2017-2019 Phase 3 (C) 1. Durvalumab & Tremelimumab Inferior OS
2. Durvalumab Non-inferior OS
Finn et al. 2020 (IMbrave150) 2018-03-15 to 2019-01-30 Phase 3 (C) Atezolizumab & Bevacizumab Inferior OS
Kelley et al. 2022 (COSMIC-312) 2018-2020 Phase 3 (C) 1. Cabozantinib & Atezolizumab Inferior PFS1
2. Cabozantinib Not reported
Ren et al. 2021 (ORIENT-32) 2019-02-11 to 2020-01-15 Phase 3 (C) IBI305 & Sintilimab Inferior OS

1The co-primary endpoint of OS was not met at the interim analysis.
Note: full reference details for HIMALAYA will be added once NEJM Evidence is MEDLINE-indexed.

Targeted therapy

  • Sorafenib (Nexavar) 400 mg PO twice per day
    • Dose/schedule changes due to toxicity include 400 mg PO once per day, 400 mg PO every other day, 200 mg PO twice per day, 200 mg PO once per day

Continued indefinitely

References

  1. Abou-Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A, De Greve J, Douillard JY, Lathia C, Schwartz B, Taylor I, Moscovici M, Saltz LB. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006 Sep 10;24(26):4293-300. Epub 2006 Aug 14. link to original article contains dosing details in manuscript PubMed
  2. SHARP: Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, Cosme de Oliveira A, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008 Jul 24;359(4):378-90. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
    1. Subgroup analysis: Bruix J, Raoul JL, Sherman M, Mazzaferro V, Bolondi L, Craxi A, Galle PR, Santoro A, Beaugrand M, Sangiovanni A, Porta C, Gerken G, Marrero JA, Nadel A, Shan M, Moscovici M, Voliotis D, Llovet JM. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol. 2012 Oct;57(4):821-9. Epub 2012 Jun 19. link to original article PubMed
  3. Sorafenib AP: Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z. 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 Jan;10(1):25-34. Epub 2008 Dec 16. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
    1. Subgroup analysis: Cheng AL, Guan Z, Chen Z, Tsao CJ, Qin S, Kim JS, Yang TS, Tak WY, Pan H, Yu S, Xu J, Fang F, Zou J, Lentini G, Voliotis D, Kang YK. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: Subset analyses of the phase III Sorafenib Asia-Pacific trial. Eur J Cancer. 2012 Jul;48(10):1452-65. Epub 2012 Jan 10. link to original article contains dosing details in manuscript PubMed
  4. Retrospective: Pinter M, Sieghart W, Graziadei I, Vogel W, Maieron A, Königsberg R, Weissmann A, Kornek G, Plank C, Peck-Radosavljevic M. Sorafenib in unresectable hepatocellular carcinoma from mild to advanced stage liver cirrhosis. Oncologist. 2009 Jan;14(1):70-6. Epub 2009 Jan 14. link to original article PubMed
  5. Abdel-Rahman O, Abdel-Wahab M, Shaker M, Abdel-Wahab S, Elbassiony M, Ellithy M. Sorafenib versus capecitabine in the management of advanced hepatocellular carcinoma. Med Oncol. 2013 Sep;30(3):655. Epub 2013 Jul 4. link to original article PubMed
  6. BRISK-FL: Johnson PJ, Qin S, Park JW, Poon RT, Raoul JL, Philip PA, Hsu CH, Hu TH, Heo J, Xu J, Lu L, Chao Y, Boucher E, Han KH, Paik SW, Robles-Aviña J, Kudo M, Yan L, Sobhonslidsuk A, Komov D, Decaens T, Tak WY, Jeng LB, Liu D, Ezzeddine R, Walters I, Cheng 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):3517-24. Epub 2013 Aug 26. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
  7. SUN 1170: Cheng AL, Kang YK, Lin DY, Park JW, Kudo M, Qin S, Chung HC, Song X, Xu J, Poggi G, Omata M, Pitman Lowenthal S, Lanzalone S, Yang L, Lechuga MJ, Raymond E. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol. 2013 Nov 10;31(32):4067-75. Epub 2013 Sep 30. link to original article PubMed Clinical Trial Registry
  8. LIGHT: Cainap C, Qin S, Huang WT, Chung IJ, Pan H, Cheng Y, Kudo M, Kang YK, Chen PJ, Toh HC, Gorbunova V, Eskens FA, Qian J, McKee MD, Ricker JL, Carlson DM, El-Nowiem S. Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol. 2015 Jan 10;33(2):172-9. Epub 2014 Dec 8. link to original article contains dosing details in abstract link to PMC article PubMed Clinical Trial Registry
  9. SEARCH: Zhu AX, Rosmorduc O, Evans TR, Ross PJ, Santoro A, Carrilho FJ, Bruix J, Qin S, Thuluvath PJ, Llovet JM, Leberre MA, Jensen M, Meinhardt G, Kang YK. SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2015 Feb 20;33(6):559-66. Epub 2014 Dec 29. link to original article contains dosing details in manuscript PubMed NCT0901901
  10. SAKK 77/08; SASL 29: Koeberle D, Dufour JF, Demeter G, Li Q, Ribi K, Samaras P, Saletti P, Roth AD, Horber D, Buehlmann M, Wagner AD, Montemurro M, Lakatos G, Feilchenfeldt J, Peck-Radosavljevic M, Rauch D, Tschanz B, Bodoky G; Swiss Group for Clinical Cancer Research; SASL. Sorafenib with or without everolimus in patients with advanced hepatocellular carcinoma (HCC): a randomized multicenter, multinational phase II trial (SAKK 77/08 and SASL 29). Ann Oncol. 2016 May;27(5):856-61. Epub 2016 Feb 15. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
  11. SARAH: Vilgrain V, Pereira H, Assenat E, Guiu B, Ilonca AD, Pageaux GP, Sibert A, Bouattour M, Lebtahi R, Allaham W, Barraud H, Laurent V, Mathias E, Bronowicki JP, Tasu JP, Perdrisot R, Silvain C, Gerolami R, Mundler O, Seitz JF, Vidal V, Aubé C, Oberti F, Couturier O, Brenot-Rossi I, Raoul JL, Sarran A, Costentin C, Itti E, Luciani A, Adam R, Lewin M, Samuel D, Ronot M, Dinut A, Castera L, Chatellier G; SARAH Trial Group. 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 Dec;18(12):1624-1636. Epub 2017 Oct 26. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
  12. REFLECT: Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng AL. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018 Mar 24;391(10126):1163-1173. Epub 2018 Feb 9. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
  13. SIRveNIB: Chow PKH, Gandhi M, Tan SB, Khin MW, Khasbazar A, Ong J, Choo SP, Cheow PC, Chotipanich C, Lim K, Lesmana LA, Manuaba TW, Yoong BK, Raj A, Law CS, Cua IHY, Lobo RR, Teh CSC, Kim YH, Jong YW, Han HS, Bae SH, Yoon HK, Lee RC, Hung CF, Peng CY, Liang PC, Bartlett A, Kok KYY, Thng CH, Low AS, Goh ASW, Tay KH, Lo RHG, Goh BKP, Ng DCE, Lekurwale G, Liew WM, Gebski V, Mak KSW, Soo KC; Asia-Pacific Hepatocellular Carcinoma Trials Group. SIRveNIB: selective internal radiation therapy versus sorafenib in Asia-Pacific patients with hepatocellular carcinoma. J Clin Oncol. 2018 Jul 1;36(19):1913-1921. Epub 2018 Mar 2. link to original article PubMed Clinical Trial Registry
  14. SILIUS: Kudo M, Ueshima K, Yokosuka O, Ogasawara S, Obi S, Izumi N, Aikata H, Nagano H, Hatano E, Sasaki Y, Hino K, Kumada T, Yamamoto K, Imai Y, Iwadou S, Ogawa C, Okusaka T, Kanai F, Akazawa K, Yoshimura KI, Johnson P, Arai Y; SILIUS study group. 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 Jun;3(6):424-432. Epub 2018 Apr 7. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
  15. STAH: Park JW, Kim YJ, Kim DY, Bae SH, Paik SW, Lee YJ, Kim HY, Lee HC, Han SY, Cheong JY, Kwon OS, Yeon JE, Kim BH, Hwang J. Sorafenib with or without concurrent transarterial chemoembolization in patients with advanced hepatocellular carcinoma: the phase III STAH trial. J Hepatol. 2019 Apr;70(4):684-691. Epub 2018 Dec 6. link to original article PubMed Clinical Trial Registry
  16. PRODIGE-11: Jouve JL, Lecomte T, Bouché O, Barbier E, Khemissa Akouz F, Riachi G, Nguyen Khac E, Ollivier-Hourmand I, Debette-Gratien M, Faroux R, Villing AL, Vergniol J, Ramee JF, Bronowicki JP, Seitz JF, Legoux JL, Denis J, Manfredi S, Phelip JM; FFCD. Pravastatin combination with sorafenib does not improve survival in advanced hepatocellular carcinoma. J Hepatol. 2019 Sep;71(3):516-522. Epub 2019 May 22. link to original article PubMed Clinical Trial Registry
  17. HCC-S021: He M, Li Q, Zou R, Shen J, Fang W, Tan G, Zhou Y, Wu X, Xu L, Wei W, Le Y, Zhou Z, Zhao M, Guo Y, Guo R, Chen M, Shi M. 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 Jul 1;5(7):953-960. link to original article link to PMC article contains dosing details in abstract PubMed Clinical Trial Registry
  18. CALGB 80802: Abou-Alfa GK, Shi Q, Knox JJ, Kaubisch A, Niedzwiecki D, Posey J, Tan BR Jr, Kavan P, Goel R, Lammers PE, Bekaii-Saab TS, Tam VC, Rajdev L, Kelley RK, El Dika I, Zemla T, Potaracke RI, Balletti J, El-Khoueiry AB, Harding JH, Suga JM, Schwartz LH, Goldberg RM, Bertagnolli MM, Meyerhardt J, O'Reilly EM, Venook AP. 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 Nov 1;5(11):1582-1588. Epub 2019 Sep 5. link to original article link to PMC article PubMed Clinical Trial Registry
  19. IMbrave150: Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Xu DZ, Hernandez S, Liu J, Huang C, Mulla S, Wang Y, Lim HY, Zhu AX, Cheng AL; IMbrave150 Investigators. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020 May 14;382(20):1894-1905. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
    1. Update: Cheng AL, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Lim HY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Ma N, Nicholas A, Wang Y, Li L, Zhu AX, Finn RS. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022 Apr;76(4):862-873. Epub 2021 Dec 11. link to original article PubMed
  20. ORIENT-32: Ren Z, Xu J, Bai Y, Xu A, Cang S, Du C, Li Q, Lu Y, Chen Y, Guo Y, Chen Z, Liu B, Jia W, Wu J, Wang J, Shao G, Zhang B, Shan Y, Meng Z, Wu J, Gu S, Yang W, Liu C, Shi X, Gao Z, Yin T, Cui J, Huang M, Xing B, Mao Y, Teng G, Qin Y, Wang J, Xia F, Yin G, Yang Y, Chen M, Wang Y, Zhou H, Fan J; ORIENT-32 study group. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study. Lancet Oncol. 2021 Jul;22(7):977-990. Epub 2021 Jun 15. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
  21. Qin S, Bi F, Gu S, Bai Y, Chen Z, Wang Z, Ying J, Lu Y, Meng Z, Pan H, Yang P, Zhang H, Chen X, Xu A, Cui C, Zhu B, Wu J, Xin X, Wang J, Shan J, Chen J, Zheng Z, Xu L, Wen X, You Z, Ren Z, Liu X, Qiu M, Wu L, Chen F. Donafenib Versus Sorafenib in First-Line Treatment of Unresectable or Metastatic Hepatocellular Carcinoma: A Randomized, Open-Label, Parallel-Controlled Phase II-III Trial. J Clin Oncol. 2021 Sep 20;39(27):3002-3011. Epub 2021 Jun 29. link to original article contains dosing details in manuscript link to PMC article PubMed
  22. CheckMate 459: Yau T, Park JW, Finn RS, Cheng AL, Mathurin P, Edeline J, Kudo M, Harding JJ, Merle P, Rosmorduc O, Wyrwicz L, Schott E, Choo SP, Kelley RK, Sieghart W, Assenat E, Zaucha R, Furuse J, Abou-Alfa GK, El-Khoueiry AB, Melero I, Begic D, Chen G, Neely J, Wisniewski T, Tschaika M, Sangro B. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2022 Jan;23(1):77-90. Epub 2021 Dec 13. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
  23. FOHAIC-1: Lyu N, Wang X, Li JB, Lai JF, Chen QF, Li SL, Deng HJ, He M, Mu LW, Zhao M. Arterial Chemotherapy of Oxaliplatin Plus Fluorouracil Versus Sorafenib in Advanced Hepatocellular Carcinoma: A Biomolecular Exploratory, Randomized, Phase III Trial (FOHAIC-1). J Clin Oncol. 2022 Feb 10;40(5):468-480. Epub 2021 Dec 14. link to original article PubMed Clinical Trial Registry
  24. COSMIC-312: Kelley RK, Rimassa L, Cheng AL, Kaseb A, Qin S, Zhu AX, Chan SL, Melkadze T, Sukeepaisarnjaroen W, Breder V, Verset G, Gane E, Borbath I, Rangel JDG, Ryoo BY, Makharadze T, Merle P, Benzaghou F, Banerjee K, Hazra S, Fawcett J, Yau T. Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2022 Aug;23(8):995-1008. Epub 2022 Jul 4. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
  25. HIMALAYA: link to original article contains dosing details in manuscript Clinical Trial Registry
  26. CheckMate 9DW: Clinical Trial Registry
  27. RATIONALE 301: Clinical Trial Registry
  28. SHR-1210-III-310: Clinical Trial Registry

Advanced or metastatic disease, second-line

Pembrolizumab monotherapy

Regimen variant #1, q3wk

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Zhu et al. 2018 (KEYNOTE-224) 2016-06-07 to 2017-02-09 Phase 2 (RT) ORR: 17% (95% CI, 11–26)
Finn et al. 2020 (KEYNOTE-240) 2016-05-31 to 2017-11-23 Phase 3 (E-esc) Placebo Seems to have superior OS (co-primary endpoint)
Median OS: 13.9 vs 10.6 mo
(HR 0.78, 95% CI 0.61-0.998)
Qin et al. 2023 (KEYNOTE-394) 2017-05-31 to 2019-12-11 Phase 3 (E-esc) Placebo Seems to have superior OS (primary endpoint)
Median OS: 14.6 vs 13 mo
(HR 0.79, 95% CI 0.63-0.99)

Note: All patients in KEYNOTE-240 were Child-Pugh class A. 21.5-25.9% had hepatitis B infection and 15.5-15.6% of patients had hepatitic C infection.

Prior treatment criteria

  • Sorafenib

Immunotherapy

21-day cycle for up to 35 cycles (2 years)


Regimen variant #2, q6wk

FDA-recommended dose

Immunotherapy

6-week cycles

References

  1. Abstract: Lala  M, Li  M, Sinha  V, de Alwis  D, Chartash  E, Jain  L.  A six-weekly (Q6W) dosing schedule for pembrolizumab based on an exposure-response (E-R) evaluation using modeling and simulation. J Clin Oncol. 2018;36(15, supp):3062. link to original article FDA approval
  2. KEYNOTE-224: Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, Verslype C, Zagonel V, Fartoux L, Vogel A, Sarker D, Verset G, Chan SL, Knox J, Daniele B, Webber AL, Ebbinghaus SW, Ma J, Siegel AB, Cheng AL, Kudo M; 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 Jul;19(7):940-952. Epub 2018 Jun 3. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
    1. Update: Kudo M, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer DH, Verslype C, Zagonel V, Fartoux L, Vogel A, Sarker D, Verset G, Chan SL, Knox J, Daniele B, Yau T, Gurary EB, Siegel AB, Wang A, Cheng AL, Zhu AX; KEYNOTE-224 Investigators. Updated efficacy and safety of KEYNOTE-224: a phase II study of pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib. Eur J Cancer. 2022 May;167:1-12. Epub 2022 Mar 29. link to original article PubMed
  3. KEYNOTE-240: Finn RS, Ryoo BY, Merle P, Kudo M, Bouattour M, Lim HY, Breder V, Edeline J, Chao Y, Ogasawara S, Yau T, Garrido M, Chan SL, Knox J, Daniele B, Ebbinghaus SW, Chen E, Siegel AB, Zhu AX, Cheng AL; KEYNOTE-240 investigators. 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 Jan 20;38(3):193-202. Epub 2019 Dec 2. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
  4. KEYNOTE-394: Qin S, Chen Z, Fang W, Ren Z, Xu R, Ryoo BY, Meng Z, Bai Y, Chen X, Liu X, Xiao J, Ho GF, Mao Y, Wang X, Ying J, Li J, Zhong W, Zhou Y, Siegel AB, Hao C. Pembrolizumab Versus Placebo as Second-Line Therapy in Patients From Asia With Advanced Hepatocellular Carcinoma: A Randomized, Double-Blind, Phase III Trial. J Clin Oncol. 2023 Mar 1;41(7):1434-1443. Epub 2022 Dec 1. link to original article link to PMC article contais dosing details in abstract PubMed Clinical Trial Registry

Ramucirumab monotherapy

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Zhu et al. 2015 (REACH-HCC) 2010-2013 Phase 3 (E-esc) Placebo Did not meet primary outcome of OS
Zhu et al. 2019 (REACH-2)
ESMO-MCBS (1)
2015-2017 Phase 3 (E-RT-esc) Placebo Superior OS
Median OS: 8.5 vs 7.3 mo
(HR 0.71, 95% CI 0.53-0.95)

Note: REACH should not be confused for the trial of the same name in CLL.

Targeted therapy

14-day cycles

References

  1. REACH-HCC: Zhu AX, Park JO, Ryoo BY, Yen CJ, Poon R, Pastorelli D, Blanc JF, Chung HC, Baron AD, Pfiffer TE, Okusaka T, Kubackova K, Trojan J, Sastre J, Chau I, Chang SC, Abada PB, Yang L, Schwartz JD, Kudo M; REACH Trial Investigators. 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 Jul;16(7):859-70. Epub 2015 Jun 18. link to original article PubMed Clinical Trial Registry
    1. Pooled PRO analysis: Zhu AX, Nipp RD, Finn RS, Galle PR, Llovet JM, Blanc JF, Okusaka T, Chau I, Cella D, Girvan A, Gable J, Bowman L, Wang C, Hsu Y, Abada PB, Kudo M. Ramucirumab in the second-line for patients with hepatocellular carcinoma and elevated alpha-fetoprotein: patient-reported outcomes across two randomised clinical trials. ESMO Open. 2020 Aug;5(4):e000797. link to original article link to PMC article PubMed
  2. REACH-2: Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, Assenat E, Brandi G, Pracht M, Lim HY, Rau KM, Motomura K, Ohno I, Merle P, Daniele B, Shin DB, Gerken G, Borg C, Hiriart JB, Okusaka T, Morimoto M, Hsu Y, Abada PB, Kudo M; 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 Feb;20(2):282-296. Epub 2019 Jan 18. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
    1. Pooled PRO analysis: Zhu AX, Nipp RD, Finn RS, Galle PR, Llovet JM, Blanc JF, Okusaka T, Chau I, Cella D, Girvan A, Gable J, Bowman L, Wang C, Hsu Y, Abada PB, Kudo M. Ramucirumab in the second-line for patients with hepatocellular carcinoma and elevated alpha-fetoprotein: patient-reported outcomes across two randomised clinical trials. ESMO Open. 2020 Aug;5(4):e000797. link to original article link to PMC article PubMed

Regorafenib monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bruix et al. 2016 (RESORCE)
ESMO-MCBS (4)
2013-05-14 to 2015-12-31 Phase 3 (E-RT-esc) Placebo Superior OS (primary endpoint)
Median OS: 10.6 vs 7.8 mo
(HR 0.63, 95% CI 0.50-0.79)

Note: The RESORCE study required patients with sorafenib tolerance of at least 400 mg/day for at least 20 days of the last 28 days of treatment, and who were ECOS PG 0-1, and with Child-Pugh A status.

Prior treatment criteria

  • Sorafenib

Targeted therapy

28-day cycles

References

  1. RESORCE: Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, Pracht M, Yokosuka O, Rosmorduc O, Breder V, Gerolami R, Masi G, Ross PJ, Song T, Bronowicki JP, Ollivier-Hourmand I, Kudo M, Cheng AL, Llovet JM, Finn RS, LeBerre MA, Baumhauer A, Meinhardt G, Han G; RESORCE Investigators. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Jan 7;389(10064):56-66. Epub 2016 Dec 6. Erratum in: Lancet. 2017 Jan 7;389(10064):36. link to original article contains dosing details in abstract PubMed Clinical Trial Registry

Subsequent lines of therapy

Apatinib monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Qin et al. 2021 (AHELP) 2014-2017 Phase 3 (E-esc) Placebo Seems to have superior OS
Median OS: 8.7 vs 6.8 mo
(HR 0.79, 95% CI 0.62-0.998)

Targeted therapy

28-day cycles

References

  1. AHELP: Qin S, Li Q, Gu S, Chen X, Lin L, Wang Z, Xu A, Chen X, Zhou C, Ren Z, Yang L, Xu L, Bai Y, Chen L, Li J, Pan H, Cao B, Fang W, Wu W, Wang G, Cheng Y, Yu Z, Zhu X, Jiang D, Lu Y, Wang H, Xu J, Bai L, Liu Y, Lin H, Wu C, Zhang Y, Yan P, Jin C, Zou J. Apatinib as second-line or later therapy in patients with advanced hepatocellular carcinoma (AHELP): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol. 2021 Jul;6(7):559-568. Epub 2021 May 7. link to original article contains dosing details in abstract PubMed Clinical Trial Registry

Cabozantinib monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Abou-Alfa et al. 2018 (CELESTIAL)
ESMO-MCBS (3)
2013-2017 Phase 3 (E-RT-esc) Placebo Superior OS (primary endpoint)
Median OS: 10.2 vs 8 mo
(HR 0.76, 95% CI 0.63-0.92)

Note: Retrospective analysis demonstrated cabozantinib was safe and effective in patients with patients with Child Pugh class A and patients who progressed to Child Pugh class B.

Targeted therapy

Continued indefinitely

References

  1. CELESTIAL: Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, Cicin I, Merle P, Chen Y, Park JW, Blanc JF, Bolondi L, Klümpen HJ, Chan SL, Zagonel V, Pressiani T, Ryu MH, Venook AP, Hessel C, Borgman-Hagey AE, Schwab G, Kelley RK. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018 Jul 5;379(1):54-63. link to original article contains dosing details in abstract link to PMC article PubMed Clinical Trial Registry
  2. Retrospective: El-Khoueiry A, Meyer T, Cheng A, Rimassa L, Sen S, Milwee S , Kelley R, Abou-Alfa G. Outcomes for patients with advanced hepatocellular carcinoma and Child-Pugh B liver function in the phase 3 CELESTIAL study of cabozantinib vs placebo. Annals of Oncology. 2020 Jul 1-4;31(3):S220. link to original article

Camrelizumab monotherapy

Regimen

Study Dates of enrollment Evidence
Qin et al. 2020 (SHR-1210-II/III-HCC) 2016-2017 Phase 2

Immunotherapy

14- to 21-day cycles

References

  1. SHR-1210-II/III-HCC: Qin S, Ren Z, Meng Z, Chen Z, Chai X, Xiong J, Bai Y, Yang L, Zhu H, Fang W, Lin X, Chen X, Li E, Wang L, Chen C, Zou J. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial. Lancet. 2020 Apr;21(4):571-580. Epub 2020 Feb 26. link to original article PubMed Clinical Trial Registry

Doxorubicin monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Qin et al. 2013 (EACH) 2007-2009 Phase 3 (C) FOLFOX4 Trend toward inferior OS
Merle et al. 2019 (RELIVE) 2012-2017 Phase 3 (C) Doxorubicin-loaded nanoparticles Did not meet primary endpoint of OS

Note: The EACH study required evidence of HBV or HCV with cirrhosis, and included patients with both Child-Pugh stage A and B disease (AST or ALT less than 2.5x ULN, T bili less than 1.5x ULN, INR less than 1.5x ULN; patients with AST and ALT less than 5x ULN were included if T bili was within normal limits). RELIVE did not specify control regimens in the abstract but stated "any systemic anticancer therapy (except sorafenib) as per investigator decision."

Chemotherapy

21-day cycles

References

  1. EACH: Qin S, Bai Y, Lim HY, Thongprasert S, Chao Y, Fan J, Yang TS, Bhudhisawasdi V, Kang WK, Zhou Y, Lee JH, Sun Y. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J Clin Oncol. 2013 Oct 1;31(28):3501-8. Epub 2013 Aug 26. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
  2. RELIVE: Merle P, Blanc JF, Phelip JM, Pelletier G, Bronowicki JP, Touchefeu Y, Pageaux G, Gerolami R, Habersetzer F, Nguyen-Khac E, Casadei-Gardini A, Borbath I, Tran A, Wege H, Saad AS, Colombo M, Abergel A, Richou C, Waked I, Yee NS, Molé A, Attali P, Le Boulicaut J, Vasseur B; 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 Jun;4(6):454-465. Epub 2019 Apr 4. link to original article PubMed Clinical Trial Registry

FOLFOX4

FOLFOX4: FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Qin et al. 2013 (EACH) 2007-2009 Phase 3 (E-switch-ic) Doxorubicin Trend towards superior OS

Note: The EACH study required evidence of HBV or HCV with cirrhosis, and included patients with both Child-Pugh stage A and B disease (AST or ALT < 2.5x ULN, T bil < than 1.5x ULN, INR < 1.5 ULN; patients with AST and ALT < 5x ULN were included if T bili was within normal limits).

Chemotherapy

14-day cycles

References

  1. EACH: Qin S, Bai Y, Lim HY, Thongprasert S, Chao Y, Fan J, Yang TS, Bhudhisawasdi V, Kang WK, Zhou Y, Lee JH, Sun Y. Randomized, multicenter, open-label study of oxaliplatin plus fluorouracil/leucovorin versus doxorubicin as palliative chemotherapy in patients with advanced hepatocellular carcinoma from Asia. J Clin Oncol. 2013 Oct 1;31(28):3501-8. Epub 2013 Aug 26. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry

Ipilimumab & Nivolumab

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence
Yau et al. 2020 (CheckMate 040)
ESMO-MCBS (3)
2012-2016 Phase 1/2 (RT)

Note: this is Arm A of this trial, which compared three variants of ipi/nivo dosing.

Immunotherapy

21-day cycle for 4 cycles, then 14-day cycles

References

  1. CheckMate 040: Yau T, Kang YK, Kim TY, El-Khoueiry AB, Santoro A, Sangro B, Melero I, Kudo M, Hou MM, Matilla A, Tovoli F, Knox JJ, Ruth He A, El-Rayes BF, Acosta-Rivera M, Lim HY, Neely J, Shen Y, Wisniewski T, Anderson J, Hsu C. Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial. JAMA Oncol. 2020 Nov 1;6(11):e204564. Epub 2020 Oct 1. link to original article link to PMC article contains dosing details in abstract PubMed Clinical Trial Registry

Lenvatinib monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Awaiting publication (IMbrave251) 2021-ongoing Phase 3 (C) 1. Atezolizumab & Lenvatinib
2. Atezolizumab & Sorafenib 		TBD

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Prior treatment criteria

Targeted therapy

  • Lenvatinib (Lenvima) by the following weight-based criteria:
    • Less than 60 kg: 8 mg PO once per day
    • 60 kg or more: 12 mg PO once per day

21-day cycles

References

  1. IMbrave251: contains dosing details on CT.gov Clinical Trial Registry

Nivolumab monotherapy

Regimen variant #1, 3 mg/kg

Study Dates of enrollment Evidence Efficacy
El-Khoueiry et al. 2017 (CheckMate 040) 2012-2016 Phase 1/2 (RT) ORR (dose-expansion phase): 20% (95% CI, 15–26)

Note: This is the dose used in the expansion cohort of this study; patients were required to have ECOG PS 1 or less, and Child-Pugh scores of 6 or less (Child-Pugh A) for the dose expansion; Child-Pugh B7 patients were eligible for the dose-escalation phase. Patients with HBV infection were required to be receiving effective antiviral therapy (viral load < 100 IU/mL). 68% of patients in the dose expansion phase received prior sorafenib therapy.

Immunotherapy

14-day cycles


Regimen variant #2, 240 mg

FDA-recommended dose

Note: This is the FDA-recommended dose; we are not aware of a published trial using this dose in this context.

Immunotherapy

14-day cycles


Regimen variant #3, 480 mg

FDA-recommended dose

Note: This is the FDA-recommended dose; we are not aware of a published trial using this dose in this context.

Immunotherapy

28-day cycles

References

  1. CheckMate 040: El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, Choo SP, Trojan J, Welling TH 3rd, Meyer T, Kang YK, Yeo W, Chopra A, Anderson J, Dela Cruz C, Lang L, Neely J, Tang H, Dastani HB, Melero I. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017 Jun 24;389(10088):2492-2502. Epub 2017 Apr 20. link to original article contains dosing details in abstract link to PMC article PubMed Clinical Trial Registry

Sorafenib monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Awaiting publication (IMbrave251) 2021-ongoing Phase 3 (C) 1. Atezolizumab & Lenvatinib
2. Atezolizumab & Sorafenib 		TBD

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Prior treatment criteria

Targeted therapy

21-day cycles

References

  1. IMbrave251: contains dosing details on CT.gov Clinical Trial Registry

Tislelizumab monotherapy

Regimen

Study Dates of enrollment Evidence
Awaiting publication (RATIONALE-208) 2018-NR Phase 2

1Reported efficacy is based on the 2022 update.

Immunotherapy

21-day cycles

References

  1. RATIONALE-208: contains dosing details on CT.gov Clinical Trial Registry

Investigational agents

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