Current and novel approaches in the pharmacological treatment of 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.