Table 2. Second-line (after sorafenib) phase 3 trials on advanced HCC.

Year of publication	Trial name	Study design	Number of patients	Reason for sorafenib discontinuation	Drug	Main target of experimental drug	Main inclusion criterion	Primary endpoints	Secondary endpoints	Status	Outcome
2013	Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase 3 BRISK-PS Study)	Phase 3, randomized, placebo-controlled, double-blind, multicenter	395 (263 vs 132)	Progression or intolerance	Brivanib vs placebo	FGFR, VEGFR		OS	TTP, ORR, DCR and safety	Completed	Failed
2014	Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib, the EVOLVE-1 randomized clinical trial	Phase 3, randomized, placebo-controlled, double-blind, multicenter	546 (362 vs 184)	Progression or intolerance	Everolimus vs placebo	mTOR		OS	TTP, QoL and safety	Completed	Failed
2015	Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomized, double-blind, multicenter, phase 3 trial	Phase 3, randomized, placebo-controlled, double-blind, multicenter	565 (283 vs 282)	Progression or intolerance	Ramucirumab vs placebo	VEGFR 2		OS	PFS, TTP, ORR, DCR and safety	Completed	Failed
2016	Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomized, double-blind, placebo-controlled, phase 3 trial	Phase 3, randomized, placebo-controlled, double-blind, multicenter	573 (379 vs 194)	Progression	Regorafenib vs placebo	VEGFR, PDGFR, BRAF, FGFR, KIT, RET		OS	TTP, ORR, QoL and safety	Completed	Reached
Not yet published	A phase 3, randomized, double-blind study of tivantinib (ARQ 197) in subjects with MET diagnostic-high inoperable hepatocellular carcinoma treated with one prior systemic therapy (METIV-HCC; NCT01755767)	Phase 3, randomized, placebo-controlled, double-blind, multicenter	368	Progression or intolerance	Tivantinib (ARQ 197) vs placebo	c-MET	High MET on IHC	OS	PFS and safety	Ongoing, not recruiting
Not yet published	Randomized, double-blind, placebo-controlled, phase 3 study of ramucirumab and best supportive care (BSC) versus placebo and BSC as second-line treatment in patients with hepatocellular carcinoma and elevated baseline alpha-fetoprotein (AFP) following first-line therapy with sorafenib (REACH-2; NCT02435433)	Phase 3, randomized, placebo-controlled, double-blind, multicenter	399 (estimated)	Progression or intolerance	Ramucirumab vs placebo	VEGFR 2	α-FP > 400 ng/mL	OS	PFS, TTP, CR, PR, ORR, QoL and safety	Ongoing, recruiting
Not yet published	Phase 3 randomized, double-blind, controlled study of cabozantinib (XL184) versus placebo in subjects with hepatocellular carcinoma who have received prior sorafenib (CELESTIAL; NCT01908426)	Phase 3, randomized, placebo-controlled, double-blind, multicenter	760 (estimated)	Progression or intolerance	Cabozantinib vs placebo	c-MET, VEGFR, RET		OS	PFS	Ongoing, recruiting

Abbreviations: FGFR, fibroblast growth factor receptor; VEGFR, vascular endothelial growth factor receptor; mTOR, mammalian target of rapamycin; PDGFR, platelet-derived growth factor receptor; OS, overall survival; TTP, time to (radiologic) progression; ORR, objective response rate; DCR, disease control rate; PFS, progression-free survival; IHC, immunohistochemistry.