Sequencing of systemic treatment for hepatocellular carcinoma: Second line competitors

Table 1 First line agents failed for the treatment of advanced hepatocellular carcinoma

Study drug	Population	Design-intervention	Results
Sunitinib (EGFR), Cheng et al[24], 2013	n = 1074, BCLC B-C, ECOG 0-1, Child Pugh A/B	RCT Fase III. Non-inferiority. Sunitinib vs Sorafenib	Failed to reach its primary end-point. Higher rate of EAs
Brivanib (VEGF, FGF), Johnson et al[25], 2013	n = 1150, BCLC B-C, ECOG 0-1, Child Pugh A/B	RCT Fase III. Non-inferiority. Brivanib vs Sorafenib (Bristol)	Failed to reach its primary end-point. Higher rate of EAs
Erlotinib (EGFR), Zhu et al[14], 2006	n = 720, BCLC B-C, ECOG 0-1, Child Pugh A/B	RCT Fase III. Superiority, Erlotinib + Sorafenib vs Placebo + Sorafenib	OS similar, TTP similar, Similar EAs
Linifanib (VEGF, PDGF), Cainap et al[27], 2015	n = 1035, BCLC B-C, ECOG 0-1, Child Pugh A/B	RCT Fase III. Superiority, Linifanib vs Sorafenib	Failed to reach its primary end-point. TTP better for linifanib, Similar EAs
Tigatuzumab, Bruix et al[30], 2017	n = 162, BCLC B-C, ECOG 0-1, Child Pugh A/B	RCT Fase II, Tigatuzumab + Sorafenib vs Placebo + Soraf	Safety profile adequate but no better TTP and OS
Dovitinib (VEGF, FGF, PDGF), Cheng et al[28], 2016	n = 165, BCLC B-C, ECOG 0-1, Child Pugh A/B	RCT Fase II. Dovitinib vs Sorafenib	OS non superior, TTP similar, Higher rate of EAs
Bevacizumab (Ab VEGF), Hubbard et al[29], 2016	n = 17, BCLC B-C, ECOG 0-1, Child Pugh A/B	RCT Fase I/II, Bevacizumab + Sorafenib	Higher rate of EAs, Excessive toxicity

BCLC: Barcelona Clinic Liver Cancer; ECOG: Eastern Cooperative Oncology Group; EGFR: Endothelial growth factor; FGF: Fibroblast growth factor; OS: Overall survival; PDGF: Platelet-derived growth factor inhibitor; TTP: Time to progression; VEGF: Vascular-endothelial growth factor; RCT: Randomized clinical trials.

Table 2 Second line tyrosine kinase inhibitors approved for the treatment of advanced hepatocellular carcinoma

Study drug	Population	Design-intervention	Results
Regorafenib, Bruix et al[34], 2017, resorce	n = 553, BCLC B-C, ECOG 0-1, Child Pugh A, SOR-Tolerant	RCT phase III. Superiority. Regorafenib vs placebo	OS HR 0.63 (CI: 0.50-0.79), ORR 11%, DCR 65% (mRECIST)
Cabozantinib, Abou-Alfa et al[47], Celestial	n = 707, BCLC B-C, ECOG 0-1, Child Pugh A, 1-2 prior systemic treatment, SOR-Tolerant/intolerant	RCT phase III. Superiority. Cabozantinib vs placebo	OS HR 0.76 (CI: 0.63-0.93), ORR 4%, DCR 64% (RECIST 1.1)
Ramucirumab, Zhu et al[48], reach I-II	n = 542, BCLC B-C, ECOG 0-1, Child Pugh A, AFP ≥ 400 ng/mL, SOR-Tolerant/intolerant	RCT phase III. Superiority. Ramucirumab vs placebo	OS HR 0.69 (CI: 0.57-0.84), ORR 5%, DCR 60%, (RECIST 1.1)

Comparison across studies should cautiously analyzed. BCLC: Barcelona Clinic Liver Cancer; ECOG: Eastern Cooperative Oncology Group; OS: Overall survival; HR: Hazard ratio; SOR: Sorafenib; ORR: Objective response rate; RCT: Randomized clinical trials; DCR: Disease control rate; AFP: Alpha-fetoprotein.

Table 3 Scheme dose, adverse events and discontinuation rate of first and second line tyrosine kinase inhibitors and anti-vascular-endothelial growth factor agents approved for the treatment of advanced hepatocellular carcinoma

Study drug	Dose reduction - interruption	Discontinuation rate
Sorafenib	26% dose reduction (any AE), 44% drug interruption (any AE), most frequent AE leading to dose reductions: diarrhea, hand-foot skin reaction and rash	11%
Lenvatinib	37% dose reduction (related-AE), 40% drug interruption (related-AE), Most frequent AE leading to dose reductions: not reported	9%
Regorafenib	68% dose reduction or drug interruption (any AE), most frequent AE leading to dose reductions: diarrhea, hand-foot skin reaction	10%
Cabozantinib	62% dose reduction or drug interruption (any AE), most frequent AE leading to dose reductions: diarrhea, hand-foot skin reaction	16%
Ramucirumab	34% dose reduction or drug interruption (any AE), most frequent AE leading to dose reductions: fatigue, peripheral edema, hypertension and anorexia	11%

Comparison across studies should cautiously analyzed. AE: Adverse event.