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Guidelines

AASLD

• 2018: Marrero et al. Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases

ASCO

• 2020: Gordan et al. Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline

ESMO

• 2018: Vogel et al. Hepatocellular Carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Older

• 2012: Verslype et al. Hepatocellular carcinoma: ESMO-ESDO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PubMed

NCCN

• NCCN Guidelines - Hepatobiliary Cancers

TOS/ESMO

• 2020: Chen et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with intermediate and advanced/relapsed hepatocellular carcinoma: a TOS–ESMO initiative endorsed by CSCO, ISMPO, JSMO, KSMO, MOS and SSO

Local therapy

Axitinib & TACE

Regimen

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

Targeted therapy

• Axitinib (Inlyta) 5 mg PO twice per day, held before and after TACE

Chemotherapy

• TACE

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 NCT01352728

DEB-TACE

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

Regimen

Study	Years 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

Chemotherapy

• TACE with drug-eluting beads loaded with Doxorubicin (Adriamycin) 150 mg

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 NCT00539643
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 NCT01324076

Radioembolization

Regimen

Study	Years 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

• Selective internal radiotherapy (SIRT) with yttrium-90 resin microspheres

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 randomized controlled phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1624-1636. Epub 2017 Oct 26. link to original article PubMed NCT01482442
   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 NCT01135056

TACE monotherapy

TACE: Trans-Arterial Chemo-Embolization

Regimen

Study	Years 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 portion 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.

Chemotherapy

• TACE

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 NCT00494299
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 NCT00908752
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 NCT01465464

Adjuvant therapy

TACE monotherapy

TACE: Trans-Arterial Chemo-Embolization

Regimen variant #1, doxorubicin-based

Study	Years 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

• Curative surgical resection

Chemotherapy

• TACE consisting of:
  • Doxorubicin (Adriamycin) 20 to 30 mg/m²
  • Lipiodol 3 to 5 mL

One or more treatments

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

Study	Years 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

• Curative surgical resection

Chemotherapy

• TACE consisting of:
  • Carboplatin (Paraplatin) 200 mg/m²
  • Mitomycin (Mutamycin) 6 mg/m²
  • Epirubicin (Ellence) 40 mg/m²
  • Lipiodol 4 to 5 mL

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 NCT01966133
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 NCT02788526

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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Finn et al. 2020 (IMbrave150)	2018-2019	Phase 3 (E-RT-esc)	Sorafenib	Superior OS1 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

• Atezolizumab (Tecentriq) 1200 mg IV once on day 1, given first

Targeted therapy

• Bevacizumab (Avastin) 15 mg/kg IV once on day 1, given second

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 NCT03434379
   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	Years of enrollment	Evidence	Efficacy
Siegel et al. 2008	2003-2006	Phase 2	ORR: 13% (95% CI, 3-23)

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

• Bevacizumab (Avastin) 10 mg/kg IV once on day 1

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 monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Abdel-Rahman et al. 2013	2010-2011	Randomized Phase 2 (E-switch-ooc)	Sorafenib	Inferior OS

Neither the primary outcome (progression-free survival) or secondary outcome (overall survival) were met.

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14

21-day cycles

References

1. Retrospective: Patt YZ, Hassan MM, Aguayo A, Nooka AK, Lozano RD, Curley SA, Vauthey JN, Ellis LM, Schnirer II, Wolff RA, Charnsangavej C, Brown TD. Oral capecitabine for the treatment of hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma. Cancer. 2004 Aug 1;101(3):578-86. link to original article PubMed
2. 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

Capecitabine & Bevacizumab

Regimen

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

Chemotherapy

• Capecitabine (Xeloda) 800 mg/m² PO twice per day on days 1 to 14

Targeted therapy

• Bevacizumab (Avastin) 7.5 mg/kg IV once on day 1

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

Chemotherapy

• Capecitabine (Xeloda) 1000 mg/m² PO twice per day on days 1 to 14
• Oxaliplatin (Eloxatin) 130 mg/m² IV over 2 hours once on day 1

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

Chemotherapy

• Capecitabine (Xeloda) 825 mg/m² PO twice per day on days 1 to 14
• Oxaliplatin (Eloxatin) 130 mg/m² IV over 2 hours once on day 1

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

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

• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1

21-day cycles

Regimen variant #2, 60 mg/m² x 6

Study	Years 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) 60 mg/m² IV once on day 1

21-day cycle for up to 6 cycles

Regimen variant #3, 60 mg/m² x 9

Study	Years 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

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1

21-day cycle for up to 9 cycles

Regimen variant #4, 60 mg/m², indefinite

Study	Years 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	Years 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 NCT00012324
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 NCT00108953
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 NCT00471965

Erlotinib & Bevacizumab

Regimen

Study	Years 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)

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

Targeted therapy

• Erlotinib (Tarceva) 150 mg PO once per day
• Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15

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

Chemotherapy

• Fluorouracil (5-FU) 370 mg/m² IV once per day on days 1 to 5
• Folinic acid (Leucovorin) 200 mg/m² IV once per day on days 1 to 5

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	Years 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)

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

• Fluorouracil (5-FU) 400 mg/m² IV bolus once per day on days 1 & 2, given second, then 600 mg/m² IV continuous infusion over 22 hours after each bolus (total dose per cycle: 2000 mg/m²)
• Folinic acid (Leucovorin) 200 mg/m² IV over 2 hours once per day on days 1 & 2, given first
• Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1

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 NCT00471965
2. SHR-1210-III-305-HCC: NCT03605706

mFOLFOX & Sorafenib

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

Regimen

Study	Years 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)

Inclusion criteria: Child Pugh A with advanced HCC with no prior systemic therapy. 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.

Chemotherapy

• Fluorouracil 1200 mg/m²/day IV continuous infusion over 46 hours, started on day 1
• Leucovorin 200 mg/m² IV once on day 1
• Oxaliplatin 85 mg/m² IV once on day 1

Targeted therapy

• Sorafenib 400 mg twice per day

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 NCT01775501

FOFLFOX-HAIC

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

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Li et al. 2021 (HCC-S023)	2016-2018	Phase 3 (E-switch-ooc)	TACE	Superior OS 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

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 NCT02973685

FOFLFOX-HAIC & Sorafenib

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

Regimen

Study	Years 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

• Folinic acid (Leucovorin) 400 mg/m² IA once on day 1
• Fluorouracil 400 mg/m² IA bolus once on day 1, then 2400 mg/m² IA continuous infusion over 46 hours (total dose per cycle: 2800 mg/m²)
• Oxaliplatin 85 mg/m² IA once on day 1

Targeted therapy

• Sorafenib 400 mg twice per day

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 NCT02774187

GemOx

GemOx: Gemcitabine, Oxaliplatin

Regimen

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

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² IV once on day 1
• Oxaliplatin (Eloxatin) 100 mg/m² IV over 2 hours once on day 2

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	Years 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

• Gemcitabine 1000 mg/m² IV once on day 1
• Oxaliplatin 100 mg/m² IV once on day 1

Targeted therapy

• Sorafenib 400 mg twice per day

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 NCT00941967

Lenvatinib monotherapy

Regimen

FDA-recommended dose

Study	Years 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)

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 NCT01761266
2. CheckMate 9DW: NCT04039607
3. LEAP-002: NCT03713593

Sorafenib monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Abou-Alfa et al. 2006b	2002-2003	Phase 2
Llovet et al. 2008 (SHARP)	2005-2006	Phase 3 (E-RT-esc)	Placebo	Superior OS 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
Finn et al. 2020 (IMbrave150)	2018-2019	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)	2019-2020	Phase 3 (C)	IBI305 & Sintilimab	Inferior OS

¹The co-primary endpoint of OS was not met at the interim analysis.

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 NCT00105443
   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 NCT00492752
   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 NCT00858871
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 NCT00699374
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 NCT01009593
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 NCT01005199
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 NCT01482442
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 NCT01761266
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 NCT01135056
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 NCT01214343
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 NCT01829035
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 NCT01075555
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 NCT02774187
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 NCT01015833
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 NCT03434379
    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 NCT03794440
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 NCT02576509
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 NCT03164382
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 NCT03755791
25. CheckMate 9DW: NCT04039607
26. HIMALAYA: NCT03298451
27. RATIONALE 301: NCT03412773
28. SHR-1210-III-310: NCT03764293

TACE, then 5-FU

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

Protocol

Study	Years 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

• Fluorouracil (5-FU) 200 mg PO once per day

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

Subsequent lines of therapy

Apatinib monotherapy

Regimen

Study	Years 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

• Apatinib (Aitan) 750 mg once per day

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 May 7:S2468-1253(21)00109-6. Epub ahead of print. link to original article contains dosing details in abstract PubMed NCT02329860

Cabozantinib monotherapy

Regimen

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

Retrospective analysis demonstrated Cabozantinib is safe and effective in patients with patients with Child Pugh class A and patients who progressed to Child Pugh class B patients.

Targeted therapy

• Cabozantinib (Cometriq) 60 mg PO once per day

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 PubMed NCT01908426
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	Years of enrollment	Evidence
Qin et al. 2020 (SHR-1210-II/III-HCC)	2016-2017	Phase 2

Immunotherapy

• Camrelizumab (AiRuiKa) 3 mg/kg IV once on day 1

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 NCT02989922

Doxorubicin monotherapy

Regimen

Study	Years 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

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

• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1

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 NCT00471965
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 NCT01655693

FOLFOX4

FOLFOX4: FOLinic acid, Fluorouracil, OXaliplatin

Regimen

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

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

• Fluorouracil (5-FU) 400 mg/m² IV bolus once per day on days 1 & 2, given second, then 600 mg/m² IV continuous infusion over 22 hours after each bolus (total dose per cycle: 2000 mg/m²)
• Folinic acid (Leucovorin) 200 mg/m² IV over 2 hours once per day on days 1 & 2, given first
• Oxaliplatin (Eloxatin) 85 mg/m² IV once on day 1

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 NCT00471965

Ipilimumab & Nivolumab

Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence
Yau et al. 2020 (CheckMate 040)	2012-2016	Phase 1/2 (RT)

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

Immunotherapy

• Ipilimumab (Yervoy) as follows:
  • Cycles 1 to 4: 3 mg/kg IV once on day 1
• Nivolumab (Opdivo) as follows:
  • Cycles 1 to 4: 1 mg/kg IV once on day 1
  • Cycle 5 onwards: 240 mg IV once on day 1

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 NCT01658878

Lenvatinib monotherapy

Regimen

Study	Years 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

• Exposure to Atezolizumab & Bevacizumab, with progression

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 NCT04770896

Nivolumab monotherapy

Regimen variant #1, 3 mg/kg

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

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

• Nivolumab (Opdivo) 3 mg/kg IV once on day 1

14-day cycles

Regimen variant #2, 240 mg

FDA-recommended dose

This is the FDA-recommended dose. See first line therapy above.

Immunotherapy

• Nivolumab (Opdivo) 240 mg IV once on day 1

14-day cycles

Regimen variant #3, 480 mg

FDA-recommended dose

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

Immunotherapy

• Nivolumab (Opdivo) 480 mg IV once on day 1

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 PubMed NCT01658878

Pembrolizumab monotherapy

Regimen variant #1, q3wk

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Zhu et al. 2018 (KEYNOTE-224)	2016-2017	Phase 2 (RT)		ORR: 17% (95% CI, 11–26)
Finn et al. 2020 (KEYNOTE-240)	2016-2017	Phase 3 (E-esc)	Placebo	Seems to have superior OS Median OS: 13.9 vs 10.6 mo (HR 0.78, 95% CI 0.61-0.998)

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

Immunotherapy

• Pembrolizumab (Keytruda) 200 mg IV once on day 1

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

Regimen variant #2, q6wk

FDA-recommended dose

Immunotherapy

• Pembrolizumab (Keytruda) 400 mg IV once on day 1

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 NCT02702414
   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 NCT02702401

Ramucirumab monotherapy

Regimen

FDA-recommended dose

Study	Years 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)	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 that REACH should not be confused for the trial of the same name in CLL.

Targeted therapy

• Ramucirumab (Cyramza) 8 mg/kg IV once on day 1

14-day cycles

References

1. REACH: 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 NCT01140347
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 NCT02435433

Regorafenib monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Bruix et al. 2016 (RESORCE)	2013-2015	Phase 3 (E-RT-esc)	Placebo	Superior OS Median OS: 10.6 vs 7.8 mo (HR 0.63, 95% CI 0.50-0.79)

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.

Targeted therapy

• Regorafenib (Stivarga) 160 mg PO once per day on days 1 to 21

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 NCT01774344

Sorafenib monotherapy

Regimen

Study	Years 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

• Exposure to Atezolizumab & Bevacizumab, with progression

Targeted therapy

• Sorafenib (Nexavar) 400 mg PO twice per day

21-day cycles

References

1. IMbrave251: contains dosing details on CT.gov NCT04770896

Investigational agents

• Refametinib (BAY 869766)