Molecular targeted therapy for hepatocellular carcinoma: Current and future

Table 1 Molecular targets and therapeutic agents

Molecular targets	Therapeutic agents
VEGF/VEGFR	Sorafenib
	Bevacizumab
	Vatalanib (PTK787)
	Cediranib (AZD2171)
	Brivanib
	Sunitinib
	Linifanib (ABT869)
EGF/EGFR	Cetuximab
	Erlotinib
	Lapatinib
IGF/IGFR	OSI-906
	IMC-A12
	AVE1642
	BIIB022
Ras/Raf/MEK/ERK	Sorafenib
	Selumetinib (AZD6244)
PI3K/Akt/mTOR	AZD8055
	Everolimus
	Sirolimus
	Temsirolimus
Wnt-β-catenin	PFK118-310
	PFK115-584
	CGP049090
MET	Tivanitib

EGF: Epidermal growth factor; EGFR: EGF receptor; ERK: Extracellular signal-regulated kinase; FGFR: Fibroblast growth factor receptor; IGFR: Insulin-like growth factor (IGF) receptor; VEGF: Vascular endothelial growth factor; VEGFR: VEGF receptor; mTOR: Mammalian target of rapamycin; MET: Met proto-oncogene.

Table 2 Efficacy results of targeted therapies for advanced hepatocellular carcinoma

Molecular targets/agents	Phase	Efficacy	Ref.
VEGF/VEGFR
Sorafenib	Phase III SHARP	Median OS: 10.7 mo vs 7.9 mo	[58]
	Sorafenib vs placebo
	Phase III (Asian)	Median OS:6.5 mo vs 4.2 mo	[59]
Sunitinib	Phase II	Median PFS: 3.9 mo	[65]
		Median OS: 9.8 mo
	Phase III	Median OS: 7.9 mo vs 10.2 mo
	Sunitinib vs sorafenib
Brivanib	Phase II, first-line	Median PFS: 2.8 mo	[68]
		Median OS: 10 mo
	Phase II, second-line	Median PFS: 2.7 mo	[69]
		Median OS: 9.8 mo
	Phase III (BRISK-PS)	Median OS: 9.4 mo vs 8.3 mo	[70]
	Brivanib vs placebo	TTP: 4.2 mo vs 2.7 mo
		RR: 12% vs 2%
	Phase III (BRISK-FL)	Median OS: 9.5 mo vs 9.9 mo	[71]
	Brivanib vs placebo	TTP: 4.2 mo vs 4.1 mo
		RR: 12% vs 8%
Vatalanib (PTK787)	Phase I/II, combined with doxorubicin	OS: 7.3 mo	[73]
		PFS: 5. 4 mo
Inifanib (ABT-869)	Phase II	TTP: 3.7 mo	[75]
		Median OS: 9.7 mo
Cediranib (AZD2171)	Phase II	Median OS: 5.8 mo	[78]
		TTP: 2.8 mo
EGF/EGFR
Cetuximab	Phase II	Median OS: 9.6 mo	[81]
		Median PFS: 1.4 mo
Erlotinib	Phase III (SEARCH)	Median OS: 9.5 mo vs 8.5 mo	[83]
	Sorafenib/erlotinib vs orafenib/placebo	TTP: 3.2 mo vs 4.0 mo
Lapatinib	Phase II	Median PFS: 2.3 mo	[85]
		Median OS: 6.2 mo
	Phase III	Median OS: 9.1 mo vs 9.8 mo
	Lipatinib vs sorafenib
IGF/IGFR
Cituxumumab (IMC-A12)	Phase II	Median OS: 8 mo	[93]
Ras/Raf/MEK/ERK
Selumetinib (AZD6244)	Phase I/II	11 patients enrolled	[31]
		PR in 3, SD in 6, PD in 2 patients
PI3K/Akt/mTOR
Everolimus	Phase I/II	Median PFS: 3.8 mo	[37]
		Median OS: 8.4 mo
Sirolimus	Phase II	Median PFS: 15.3 wk	[38]
		Median OS: 26.4 wk
MET
Tivantinib	Randomized Phase II		[100]
	Tivantinib vs placebo
	ITT population	Median TTP: 6.9 wk vs 6.0 wk
		Median OS: 6.6 mo vs 6.2 wk
	c-Met high	Median TTP: 11.7 wk vs 6.1 wk
		Median OS: 7.2 mo vs 3.8 wk

ITT: Intent to treat; OS: Overall survival; PD: Progressive disease; PFS: Progression-free survival; PR: Partial response; RR: Response rate; SD: Stable disease; TTP: Time to progression; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor; mTOR: Mammalian target of rapamycin; PI3K: Phosphatidylinositol-3-kinase; Met: Met proto-oncogene; EGFR: Epidermal growth factor (EGF) receptor.