Table 5.

Agents targeting the intracellular space.

Drug	Trial	Comparison	Setting	Enrolled Patients (%)	OS	PFS/TTRP *	ORR/DCR **	Grade 3–4 AEs
Everolimus (Afinitor)	VOLVE-1 (Phase III) [148]	Placebo	Second-line	- Child–Pugh Stage A (100%) - Orientals (60%) - HBV (26%), HCV (25%) - Extrahepatic disease (74%) - Macrovascular invasion (33%)	7.6 vs. 7.3 months (HR 1.05; p  = 0.68)	3.0 vs. 2.6 months (HR 0.93) *	56.1% vs. 45.1% (p = 0.01)	70.9% vs. 52.2%
Selumetinib	Phase I/II [149]	/	First-line	- Child–Pugh Stage A (96.3%) - Orientals (60%) - HBV (59.3%), HCV (7.4%) - Extrahepatic disease (48%) - Macrovascular invasion (26%)	/	/	15%	Diarrhea, rash, hypertension
Refametinib Refametinib + Sorafenib	Phase II [150]	/	First-line	- Child–Pugh Stage A (100%) - Orientals (56%) - HBV (12%), HCV (6%) - Extrahepatic disease (50%) - Macrovascular invasion (35%)	5.8 months 12.7 months	1.9 months 1.5 months	0% 56.3% ** 6.3% 43.8% **	Fatigue, hypertension, and acneiform rash
Resminostat Resminostat + Sorafenib	SHELTER (Phase I/II)	/	Second-line	- Child–Pugh Stage A (100%) - Westerns (100%) - HBV (32%), HCV (15%). - Extrahepatic disease (60%)	4.1 months 8 months	1.8 months * 6.5 months *	/	Nausea (11%), asthenia (11%) Thrombocytopenia(12%), diarrhea (8%), hypertension (8%)

Abbreviations: Progression free-Survival (PFS); Overall Survival (OS); Objective Response Rate (ORR); Time to Radiological Progression (TTRP) *; Disease Control Rate (DCR) **.