Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma

Table 1 Completed clinical trials for overcoming sorafenib resistance

Therapeutic strategies	Phases	Cases	Efficacy
Combinational therapy
5-fluorouracil plus sorafenib[46]	Phase II	39	SD: 46.2%; median TTP: 8 mo; OS: 13.7 mo
Tegafur/uracil plus sorafenib[47]	Phase II	53	Median PFS: 3.7 mo; median OS: 7.4 mo
Octreotide plus sorafenib[48]	Phase II (So.LAR.)	50	SD: 66%; median TTP: 7.0 mo; median OS: 12 mo
Doxorubicin plus sorafenib vs doxorubicin plus placebo[50]	Phase III	47 vs 49	Median TTP: 6.4 mo vs 2.8 mo; OS: 13.7 mo vs 6.5 mo; PFS: 6.0 mo vs 2.7 mo
Erlotinib plus sorafenib vs erlotinib plus placebo[53,54]	Phase III (SEARCH)	362	Median TTP: 3.2 mo vs 4.0 mo; OS: 9.5 mo vs 8.5 mo
Second-line treatments
Sunitinib[55]	Retrospective analysis	11	SD: 40%; median TTP: 3.2 mo
Brivanib[56]	Phase II	46	SD: 41.3%; RR: 4.3%; DCR: 45.7%; median OS: 9.79 mo
Tivantinib vs placebo[6]	Phase II	71 vs 36	Progressive disease: 65% vs 72%; TTP: 1.6 mo vs 1.4 mo
Gemcitabine plus oxaliplatin[59]	Retrospective analysis	18	Overall RR: 18.8%; SD: 18.8%; median PFS: 3.2 mo; OS: 4.7 mo
Erlotinib plus bevacizumab[61]	Phase II	10	No response or SD; median TTP: 1.81 mo; OS: 4.37 mo

SD: Stable disease; TTP: Time to progression; OS: Overall survival; PFS: Progression-free survival; DCS: Disease control rate; RR: Response rate.

Table 2 Ongoing clinical trials for overcoming sorafenib resistance

Studies	Therapeutic strategies	Phases	Primary outcomes
Combinational therapy
NCT01271504	E7050 plus sorafenib vs sorafenib	Phase II	Adverse event
NCT01033240	CS-1008 plus sorafenib vs sorafenib	Phase II	TTP
NCT01539018	Tegafur-uracil plus sorafenib vs sorafenib	Phase II	TTP
NCT01272557	Doxorubicin plus sorafenib vs sorafenib	Phase II	TTP
NCT01015833	Doxorubicin plus sorafenib vs sorafenib	Phase III	OS
NCT01214343	Cisplatin/fluorouracil plus sorafenib vs sorafenib	Phase III	OS
Second-line treatments
NCT01507168	GC33 vs placebo	Phase II	PFS
NCT01273662	Axitinib	Phase II	SD
NCT00717756	Lenalidomide	Phase II	RR
NCT01545804	Lenalidomide	Phase II	SD
NCT01567930	Temsirolimus	Phase II	Disease progression
NCT01180959	Erlotinib plus bevacizumab	Phase II	PFS
NCT01140347	Ramucirumabplus BSC vs placebo plus BSC	Phase III	PFS
NCT01108705	Brivanib plus BSC vs placebo plus BSC	Phase III	OS
NCT00825955	Brivanib plus BSC vs placebo plus BSC	Phase III	OS
NCT01035229	Everolimus plus BSC vs placebo plus BSC	Phase III	OS

TTP: Time to progression; OS: Overall survival; SD: Stable disease; PFS: Progression-free survival; RR: Response rate; BSC: Best supportive care.