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.