Current and novel approaches in the pharmacological treatment of hepatocellular carcinoma

Table 1 Barcelona Clinic Liver Cancer staging system and treatment strategy

Stage	Very early stage (0)	Early stage (A)	Intermediate stage (B)	Advanced stage (C)	Terminal stage (D)
Characteristics	Single nodule < 2 cm, preserved liver function, ECOG PS 0	Single or 2-3 nodules < 3 cm, preserved liver function, ECOG PS 0	Multinodular, unresectable, preserved liver function, ECOG PS 0	Portal invasion/extrahepatic spread, preserved liver function, ECOG PS 1-2	Not transplantable HCC, end-stage liver function, ECOG PS 3-4
Treatment	Ablation, resection, transplant		Chemoembolization	Systemic therapy	Best supportive care
Survival	> 5 yr		> 2.5 yr	> 2 yr	3 mo

ECOG PS: Eastern Cooperative Oncology Group performance status; HCC: Hepatocellular carcinoma.

Table 2 Summary of first and second-line drugs approved for the treatment of advanced hepatocellular carcinoma

Drug		Pharmacological target	Trial (NCT)	Treatment arm	Control arm
First-line
Systemic therapy
	Sorafenib	VEGF 1-3, PDGF, KIT, FLT3, BRAF, RAF	SHARP (NCT00105443)	Sorafenib (400 mg twice daily)	Placebo
	Lenvatinib	VEGFR1-3, FGFR 1-4, PDGR, RET and KIT	REFLECT (NCT01761266)	Lenvatinib (12 mg/day for bodyweight ≥ 60 kg or 8 mg/day for bodyweight < 60 kg)	Sorafenib (400 mg twice-daily in 28-d cycles)
Immunotherapy
	Atezolizumab plus bevacizumab	PD-L1, vEGF	IMbrave150 (NCT03434379)	1200 mg of atezolizumab plus 15 mg per kilogram of body weight of bevacizumab intravenously every 3 wk	Sorafenib (400 mg orally twice daily)
	Tremelimumab plus durvalumab	CTLA-4, PD-L1	HIMALAYA (NCT03298451)	STRIDE: Tremelimumab plus durvalumab or durvalumab alone (300 mg, one dose of tremelimumab plus 1500 mg every 4 wk for durvalumab)	Sorafenib (400 mg orally twice daily)
Second-line1
Systemic therapy
	Regorafenib	VEGFR 1-3, PDGFR, FGFR 1-2, RET, RAF	RESORCE (NCT01774344)	Regorafenib (160 mg once daily during weeks 1-3 of each 4-wk cycle)	Placebo
	Cabozantinib	VEGFR 1-3, MET and AXL	CELESTIAL (NCT01908426)	Cabozantinib (60 mg once daily)	Placebo
	Ramucirumab	VEGFR	REACH-2 (NCT02435433)	Ramucirumab 8 mg/kg intravenous ramucirumab every 2 wk	Placebo
Immunotherapy
	Nivolumab	PD-1	CheckMate-459 (NCT02576509)	Nivolumab (240 mg intravenously every 2 wk)	Sorafenib(400 mg orally twice daily)
	Nivolumab plus ipilimumab	PD-1, CTLA-4	CheckMate-040 (NCT01658878)	Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, administered every 3 wk (4 doses), followed by nivolumab 240 mg every 2 wk (arm A); nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, administered every 3 wk (4 doses), followed by nivolumab 240 mg every 2 wk (arm B); or nivolumab 3 mg/kg every 2 wk plus ipilimumab 1 mg/kg every 6 wk (arm C)	Placebo
	Pembrolizumab	PD-1	KEYNOTE-240 (NCT02702401)	Pembrolizumab (200 mg intravenously every 3 wk for at least 35 cycles during approximately 2 yr)	Placebo

¹Eligible patients who had received previous treatment with sorafenib.

CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; PD-1: Programmed cell death protein 1; VEGFR: Vascular endothelial growth factor receptor; FGFR: Fibroblast growth factor receptor; PDGFR: Platelet-derived growth factor receptors; OS: Overall survival; PFS: Progression-free survival; PD-L1: Programmed death ligand-1.

Table 3 Identified drugs and their targets for drug repurposing in hepatocellular carcinoma

Drug	Original therapeutic indication	Molecular targets in HCC	Ref.
Antihistamines	Allergy	H1R-H4R, Eag1, CYP2J2, TRPV2, AP-1, NF-B	[88,91,96,98,102,103,105,109,111,113,115,116]
Raloxifene, bazedoxifene	Breast cancer (raloxifene), osteoporosis	ER-, ER-, GPER, IL-6R, aHR, NF-B, STAT3, PI3K/AKT, MAPK	[135-137,141,142]
Disulfiram	Alcoholism	NF-B, TGF-β, ROS-JNK	[149-151,157]
Clofazimine	Antimycobacterial used to treat leprosy	Wnt/-catenin pathway	[166-178]
Albendazole	Anthelmintic	Tubulin, ERK1/2-HIF-1α-p300/CREB	[175]
Pimozide	Antipsychotic used to manage Tourette's Disorder	STAT3, Wnt/-catenin	[185,188]
Natamycin	Macrolide antifungal	PRDX1	[191]
Metformin	Glycemic control in type 2 diabetes mellitus	PI3K-mTOR pathway, AMPK	[200-202,206,207]
Valproate	Anticonvulsant	HDAC, Notch-1, MAPK pathway, -catenin pathway	[220,221,223]
Atorvastatin	Lower lipid levels and reduce the risk of cardiovascular disease	Mevalonate pathway	[231]
Celebrex	NSAID	COX-2, PNO1	[237,243]
Hydroxychloroquine	Antimalarial	Autophagy inhibition, TLR9 pathway	[247]

NSAID: Non-steroidal anti-inflammatory drug; mTOR: Mechanistic target of rapamycin; HCC: Hepatocellular carcinoma; NF-kB: Nuclear factor kB; AP-1: Activating protein-1; CYP2J2: Cytochrome P450 2J2; ER: Oestrogen receptor; IL-6R: Interleukin-6R; STAT3: Signal transducer and activator of transcription 3; PI3K: Phosphoinositide 3-kinase; TGF-β: Transforming growth factor-β; PRDX1: Peroxiredoxin 1; HDAC: Histone deacetylase; aHR: Adjusted hazard ratio.

Table 4 Ongoing clinical trials involving monotherapy, drug combination and non-oncology drugs

Study title	NTC number	Study design	Drugs	Status
Monotherapy
Study of Pembrolizumab (MK-3475) as Monotherapy in Participants With Advanced Hepatocellular Carcinoma (MK-3475-224/KEYNOTE-224)	NCT02702414	Phase II, non-randomized, parallel assignment, open label	Pembrolizumab	Active, not recruiting
An Investigational Immuno-therapy Study of Nivolumab Compared to Sorafenib as a First Treatment in Patients With Advanced Hepatocellular Carcinoma	NCT02576509	Phase III, randomized, parallel assignment, open label	Nivolumab. Sorafenib	Active, not recruiting
Exploratory Study on Combined Conversion Immunotherapy for Liver Metastasis of MSS Type Initial Unresectable Colorectal Cancer Based on Gene Status	NCT05409417	Phase II, III, single group assignment, open label	Experimental drug	Recruiting
First-in-Human Safety, Tolerability and Antitumour Activity Study of MTL-CEBPA in Patients With Advanced Liver Cancer	NCT02716012	Phase I, non-randomized, parallel assignment, open label	MLT-CEBPA. Sorafenib (200 mg)	Active, not recruiting
Drug combination
A Phase III, Open-Label, Randomized Study of Atezolizumab in Combination With Bevacizumab Compared With Sorafenib in Patients With Untreated Locally Advanced or Metastatic Hepatocellular Carcinoma (IMbrave150)	NCT03434379	Phase III, randomized, parallel assignment, open label	Atezolizumab. Bevacizumab. Sorafenib	Active, not recruiting
A Trial of Lenvatinib Plus Pembrolizumab in Participants With Hepatocellular Carcinoma	NCT03006926	Phase I, single group, open label	Lenvatinib. Pembrolizumab (200 mg)	Active, not recruiting
A Study of Durvalumab or Tremelimumab Monotherapy, or Durvalumab in Combination With Tremelimumab or Bevacizumab in Advanced Hepatocellular Carcinoma	NCT02519348	Phase II, randomized, parallel assignment, open label	Tremelimumab. Durvalumab. Bevacizumab	Active, not recruiting
Pembrolizumab With or Without Elbasvir/Grazoprevir and Ribavirin in Treating Patients With Advanced Refractory Liver Cancer	NCT02940496	Phase II, non-randomized, parallel assignment, open label	Elbasvir/Grazoprevir. Pembrolizumab. Ribavirin	Active, not recruiting
Clinical Recruitment of Patients With First-line Targeted Drug Resistance or Intolerance to Hepatocellular Cancer With PD-1 Inhibitor (Toripalimab, JS001) Detected on the NGS Platform Combined With Anlotinib	NCT05453383	Phase II, single group assignment, open label	Anlotinib. Toripalimab	Recruiting
TACE Combined With Camrelizumab and Apatinib in the Treatment of Advanced Liver Cancer	NCT05550025	Phase II, single group assignment, open label	Camrelizumab. Apatinib	Recruiting
IBR900 Cell Injection Combined With Lenvatinib or Bevacizumab in the Treatment of Advanced Primary Liver Cancer	NCT05411757	Phase I, single group assignment, open label	IBR900. Lenvatinib. Bevacizumab	Not recruiting yet
Trial to Evaluate the Safety of Talimogene Laherparepvec Injected Into Tumors Alone and in Combination With Systemic Pembrolizumab MK-3475-611/Keynote-611	NCT02509507	Phase I, II, non-randomized, sequential assignment, open label	Talimogene. Laherparepvec. Pembrolizumab	Active, not recruiting
HAIC Sequential TAE Combined With Lenvatinib and Tislelizumab in Unresectable HCC	NCT05532319	Phase II, single group assignment, open label	HAIC sequential TAE. Lenvatinib. Tislelizumab	Not recruiting yet
A Study of E7386 in Combination With Other Anticancer Drug in Participants With Solid Tumor	NCT04008797	Phase I, non-randomized, sequential assignment, open label	E7386. Lenvatinib	Recruiting
An Immuno-therapy Study to Evaluate the Effectiveness, Safety and Tolerability of Nivolumab or Nivolumab in Combination With Other Agents in Patients With Advanced Liver Cancer	NCT01658878	Phase I, II, parallel assignment, open label	Nivolumab. Sorafenib. Ipilimumab. Cabozantinib	Active, not recruiting
A Phase I Clinical Study of Recombinant Humanized Anti-BTLA Monoclonal Antibody (JS004) Injection Combined With Toripalimab Injection in Patients With Advanced Solid Tumors	NCT05427396	Phase I, single group assignment, open label	JS004. Toripalimab	Recruiting
mFOLFOX7 Plus Camrelizumab and Apatinib for Advanced HCC	NCT05412589	Phase II, single group assignment, open label	mFOLFOX7. Camrelizumab. Apatinib	Recruiting
Trial of PXS-5505 Combined With First Line Atezolizumab Plus Bevacizumab For Treating Patients With Unresectable Hepatocellular Carcinoma	NCT05109052	Phase II, III, single group assignment, open label	PXS-5505. Atezolizumab. Bevacizumab	Not recruiting yet
Combination of Regorafenib and Nivolumab in Unresectable Hepatocellular Carcinoma	NCT04310709	Phase II, single group assignment, open label	Regorafenib. Nivolumab	Recruiting
Phase Ib Trial of Infigratinib In Combination With Atezolizumab And Bevacizumab for The Second-Line Treatment of Advanced Cholangiocarcinoma With FGFR2 Fusion/Amplification	NCT05510427	Phase I, randomized, single group assignment, open label	Infigratinib. Atezolizumab. Bevacizumab	Recruiting
A Study of TAK-500 With or Without Pembrolizumab in Adults With Select Locally Advanced or Metastatic Solid Tumors	NCT05070247	Phase I, non-randomized, parallel assignment, open label	TAK-500. Pembrolizumab	Recruiting
A Study of Nivolumab and Relatlimab in Combination With Bevacizumab in Advanced Liver Cancer	NCT05337137	Phase I, II, randomized, parallel assignment, quadruple (participant care, provider, investigator, outcomes assessor)	Relatlimab. Nivolumab. Bevacizumab	Recruiting
Drug repurposing
High Dose Vitamin C Combined With Metformin in the Treatment of Malignant Tumors	NCT04033107	Phase II, single group assignment, open label	Vitamin C. Metformin	Recruiting
Statin Combination Therapy in Patients Receiving Sorafenib for Advanced Hepatocellular Carcinoma	NCT03275376	Phase II, randomized, parallel assignment, Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)	Atorvastatin	Terminated
The Combination Effect of Statin Plus Metformin on Relapse-free	NCT02819869	Phase II, randomized, parallel assignment	Statin. Metfotmin	Terminated
Statin for Preventing Hepatocellular Carcinoma Recurrence After Curative Treatment	NCT03024684	Phase IV, randomized, parallel assignment, triple masking (Participant, Care Provider, Investigator)	Atorvastatin	Recruiting
Meclizine for Hepatocellular Carcinoma	NCT03253289	Phase I, single group assignment, open label	Meclizine	Recruiting
Celebrex and Metformin for Postoperative Hepatocellular Carcinoma	NCT03184493	Phase III, non- randomized, parallel assignment	Celebrex plus metformin	Recruiting
Sorafenib Induced Autophagy Using Hydroxychloroquine in Hepatocellular Cancer	NCT03037437	Phase II, non-randomized, parallel assignment, open label	Sorafenib. Hydroxychloroquine	Recruiting

PD-1: Programmed cell death protein 1; HCC: Hepatocellular carcinoma.