Molecularly targeted therapy for advanced hepatocellular carcinoma - a drug development crisis?

Table 1 First line trials with molecular targeted therapies in advanced hepatocellular cancer

Trial	Drugs	Design	n	Median survival	HR	P value	Ref.
ASIA-PACIFIC	Sorafenib vs placebo	Superiority	150	6.5	0.68	0.01	[14]
			76	4.2
SHARP	Sorafenib vs placebo	Superiority	229	10.7	0.69	0.001	[2]
			303	7.9
SUNITINIB	Sunitinib vs sorafenib	Superiority	530	7.9	1.3	0.001	[22]
			544	10.2
BRISK-FL	Brivanib vs sorafenib	Non-inferiority	577	9.5	1.06	0.31	[28]
			578	9.9
LIGHT	Linifanib vs sorafenib	Non-inferiority	514	9.1	1.04	0.52	[24]
			521	9.8
SEARCH	Sorafenib/erlotinib vs sorafenib/placebo	Superiority	362	9.5	0.92	0.48	[29]
			358	8.5

Table 2 Second line trials with molecular targeted therapies in advanced hepatocellular cancer

Trial	Drugs	Design	n	Median survival	HR	P value
BRISK-PS	Brivanib vs placebo	Superiority	263	9.4	0.89	0.33
			132	8.2
EVOLVE-1	Everolimus vs placebo	Superiority	362	7.6	1.05	0.68
			184	7.3
REACH	Ramucirumab vs placebo	Superiority	277	9.2	0.87	0.14
			276	7.6

Table 3 Novel agents currently under evaluation in clinical trials

Drug	Phase	Target	Enriched population	Trial identifier	Study location
Tivantinib	III	MET/tubulin	High MET expression	NCT01755767	North America, Europe
Axitinib	II	VEGFR/c-KIT/PDGFR	No	NCT01334112	North America
Tivozanib	I/II	VEGFR	No	NCT01835223	North America
Nintedanib	I/II	VEGFR/FGFR/PDGFR	No	NCT00987935	Asia
Ramucirumab	III	VEGFR2	AFP > 400	NCT02435433	North America, Asia, Europe
Apatinib	III	VEGFR2	No	NCT02329860	Asia
Cabozantinib	III	MET	No	NCT01908426	North America, Asia, Europe
INC280	II	MET	MET aberration	NCT01737827	Asia
LY2875358	I/II	MET/VEGFR	No	NCT01287546	North America
Refametinib	II	MEK	RAS mutations	NCT01915602	North America, Asia, Europe
Trametinib	I/II	MEK1/2	No	NCT02292173	North America
Dovitinib	II	VEGFR, FGFR	No	NCT01232296	Asia
Temsirolimus	I, II	mTOR	No	NCT01687673	North America
Cc-223	I, II	mTOR	No	NCT01177397	North America, Europe
Galunisertib	II	TGFRβ	No	NCT02423343	North America
Mapatumumab	I/II	TRAIL-R1	No	NCT01258608	North America, Europe
Nivolumab	I	PD1	No	NCT01658878	North America, Europe, Asia
Lenvatinib	III	VEGF	No	NCT01761266	North America, Europe, Asia
Enzalutamide	II	Androgen receptors	No	NCT02528643	TBC
OMP-54F28	I	Wnt signalling	No	NCT02069145	North America