Signaling pathway/molecular targets and new targeted agents under development in hepatocellular carcinoma

Table 1 Molecular targeted agents for hepatocellular carcinoma: Targets and development status

Agents	Targets (angiogenesis)			Targets (proliferation)				Positioning	Development status
	VEGFR	PDGFR	FGF	EGFR	Raf	mTOR	TRAIL-R2	DR5
Sorafenib	●	●			●			1st line	Approved
Sunitinib	●	●						1st line	PIII terminated
E7080	●	●	●					1st/2nd line	PII ongoing
Tigatuzumab (CS1008)							●	1st line (sorafenib combination)	PI/II ongoing
Linifanib (ABT-869)	●	●						1st line	PIII ongoing
Brivanib		●			●			1st line, 2nd line, TACE adjuvant	PIII ongoing
TSU-68		●	●					TACE combination	PIII ongoing
Ramucirumab		●						2nd line	PIII ongoing
Everolimus (RAD001)						●		2nd line	PIII ongoing
Axitinib		●	●					2nd line	PIII ongoing

VEGFR: Vascular endothelial growth factor receptor; PDGFR: Platelet-derived growth factor receptor; FGF: Fibroblast growth factor; EGFR: Epidermal growth factor receptor; mTOR: Mammalian target of rapamycin; TACE: Transarterial chemoembolization.

Table 2 Ongoing clinical trials (PIII)

First line

Comparison study between sorafenib and single agent (head to head):

Sunitinib → endpoint not met

Brivanib

Linifanib

Combination with sorafenib and another agent:

DXR, erlotinib (SEARCH), everolimus, CS-1008, etc.

Second line

Sorafenib failure: Brivanib, everolimus (RAD001), ramucirumab, axitinib, S-1, etc.

Combination with standard therapy

Adjuvant setting after surgery or RFA: STORM

Combination with TACE: SPACE, BRISK-TA, TACTICS, ECOG1208

Combination with HAIC: SILIUS

TACTICS: Phase II study: Transcatheter arterial chemoembolization therapy in combination with sorafenib (ClinicalTrials.gov ID: NCT01217034), SILIUS: Randomized controlled trial comparing efficacy of sorafenib vs sorafenib in combination with low dose cisplatin/fluorouracil hepatic arterial InfUSion chemotherapy in patients with advanced hepatocellular carcinoma and exploratory study of biomarker predicting its efficacy (ClinicalTrials.gov ID: NCT01214343); HAIC: Hespatic arterial infusion chemotherapy; TACE: Transarterial chemoembolization.

Table 3 Subanalysis data of the SHARP study

		Advanced HCC with vascular invasion and/or extrahepatic spread	Advanced HCC without vascular invasion and/or extrahepatic spread
Hazard ratio		0.77 (95% CI: 0.60-0.99)	0.52 (95% CI: 0.32-0.85)
Median OS (MST) (mo)	Sorafenib	8.9 (n = 209) (95% CI: 7.6-10.3)	14.5 (n = 90) (95% CI: 14.0-N/E)
	Placebo	6.7 (n = 212) (95% CI: 5.2-8.0)	10.2 (n = 91) (95% CI: 8.6-15.5)

HCC: Hepatocellular carcinoma; OS: Overall survival; MST: Median survival time.