Selection of first-line systemic therapies for advanced hepatocellular carcinoma: A network meta-analysis of randomized controlled trials

Table 1 Details of included studies

Ref.	Year	Experimental arm(s)	Comparator arm	Primary endpoint	Analysis timing	Survival outcomes, mo
Yen et al[47]	2018	Nintedanib	Sorafenib	TTP	PFS: Final; OS: Final	PFS: 2.7 vs 3.7; OS: 10.2 vs 1.1
Ciuleanu et al[48]	2016	Mapatumumab + sorafenib	Placebo + sorafenib	TTP	PFS: Final; OS: Final	PFS: 3.2 vs 4.3; OS: 10.0 vs 10.1
Finn et al[11]	2020	Atezolizumab + bevacizumab	Sorafenib	OS and PFS	PFS: Final; OS: Final	PFS: 6.8 vs 4.3; OS: NE vs 13.2
Abou-Alfa et al[49]	2010	Doxorubicin + sorafenib	Doxorubicin + placebo	TTP	PFS: Final; OS: Final	PFS: 6.0 vs 2.7; OS: 13.7 vs 6.5
Cheng et al[50]	2016	Dovitinib	Sorafenib	OS and TTP	TTP: Final; OS: Final	TTP: 4.1 vs 4.1; OS: 8.0 vs 8.4
Cheng et al[28]	2015	Tigatuzumab (6 + 2) + sorafenib; Tigatuzumab (6 + 6) + sorafenib	Sorafenib	TTP	TTP: Final; OS: Final	TTP: 3.0 vs 3.9 vs 2.8; OS: 8.2 vs 12.2 vs 8.2
Hsu et al[51]	2012	Vandetanib 300 mg/d; Vandetanib 100 mg/d	Placebo	Tumor stabilization rate	PFS: Final; OS: Final	PFS: 1.1 vs 0.7 vs 1.0; OS: 6.0 vs 5.8 vs 4.3
Johnson et al[22]	2013	Sorafenib	Brivanib	OS	PFS: No; OS: Final	PFS: 4.1 vs 4.2; OS: 9.9 vs 9.5
Cainap et al[24]	2015	Linifanib	Sorafenib	OS	PFS: Final; OS: Final	PFS: 4.2 vs 2.9; OS: 9.1 vs 9.8
Kudo et al[10]	2018	Lenvatinib	Sorafenib	OS	PFS: No; OS: Final	PFS: 7.4 vs 3.7; OS: 13.6 vs 12.3
Yau et al[23]	2019	Nivolumab	Sorafenib	OS	PFS: Final; OS: Final	PFS: 3.7 vs 3.8; OS: 16.4 vs 14.7
Cheng et al[29]	2013	Sunitinib	Sorafenib	OS	PFS: Final;OS: Final	PFS: 3.6 vs 3.0; OS: 7.9 vs 10.2
Zhu et al[26]	2015	Sorafenib + erlotinib	Sorafenib + placebo	OS	TTP: Final; OS: Final	TTP: 3.2 vs 4.0; OS: 9.5 vs 8.5
Llovet et al[52]	2008	Sorafenib	Placebo	OS and TTP	TTP: Final; OS: Final	TSP: 5.5 vs 2.8; OS: 10.7 vs 7.9
Cheng et al[25]	2009	Sorafenib	Placebo	-	TTP: Final; OS: Final	TTP: 2.8 vs 1.4; OS: 6.5 vs 4.2
Palmer et al[53]	2018	Nintedanib	Sorafenib	TTP	PFS: Final; OS: Final	PFS: 5.3 vs 3.9; OS: 11.9 vs 11.4
Thomas et al[54]	2018	Bevacizumab + erlotinib	Sorafenib	OS	PFS: No; OS: Final	PFS: 4.4 vs 2.8; OS: 8.6 vs 8.6
Abou-Alfa et al[55]	2019	Sorafenib + doxorubicin	Sorafenib	OS	PFS: Final; OS: Final	PFS: 4.0 vs 3.7; OS: 9.3 vs. 9.4
Tak et al[27]	2018	Sorafenib	Sorafenib + resminostat	TTP	TTP: Final; OS: Final	TTP: 2.8 vs 2.8; OS: 14.1 vs 11.8
Jouve et al[56]	2019	Sorafenib + pravastatin	Sorafenib	OS	PFS: Final; OS: Final	PFS: 5.0 vs 5.4; OS: 10.7 vs 10.5
Lee et al[57]	2016	AEG35156 + sorafenib	Sorafenib	PFS	PFS: Final; OS: Final	PFS: 4.0 vs 2.6; OS: 6.5 vs 5.4
Assenat et al[58]	2019	Sorafenib + GEMOX	Sorafenib	PFS	PFS: Final; OS: Final	PFS: 6.2 vs 4.6; OS:13.5 vs 14.8
Azim et al[59]	2018	Sorafenib + tegafur–uracil	Sorafenib	TTP	PFS: Final; OS: Final	PFS: 6.0 vs 6.0; OS: 8.2 vs 10.5
Koeberle et al[60]	2016	Sorafenib	Sorafenib + everolimus	PFS	PFS: Final; OS: Final	PFS: 6.6 vs 5.7; OS: 10.0 vs 12
Bi et al[17]	2020	Donafinib	Sorafenib	OS	PFS: Final; OS: Final	PFS: 3.7 vs 3.6; OS: 21.1 vs 10.3
Qin et al[61]	2013	FOLFOX4	Doxorubicin	OS	PFS: Final; OS: Final	PFS: 2.9 vs 1.8; OS: 6.4 vs 5.0
Yeo et al[62]	2005	Doxorubicin	PIAF	OS	PFS: No; OS: Final	OS: 6.8 vs 8.7

FOLFOX4: Oxaliplatin/folinic acid/5-fluorouracil; GEMOX: Gemcitabine and oxaliplatin; NE, Not reported; OS, Overall survival; PFS, Progression-free survival; PIAF, Cisplatin/interferon α-2b/doxorubicin/5-fluorouracil; TTP, Time to progression.

Table 2 Patient characteristics in the included studies

Ref.	Year	Treatments	n	Age, median	Males, %	ECOG 0/1–2, %	Extrahepatic disease, %
Yen et al[47]	2018	Nintedanib	63	58	91	55.6/44.5	68.3
		Sorafenib	32	62	81	56.3/43.8	68.3
Ciuleanu et al[48]	2016	Mapatumumab + sorafenib	50	60	52	36.0/64.0	66.0
		Placebo + sorafenib	51	61	77	33.3/66.6	49.0
Finn et al[11]	2020	Atezolizumab + bevacizumab	336	64	82	62.0/38.0	63.0
		Sorafenib	165	66	83	62.0/38.0	56.0
Abou-Alfa et al[49]	2010	Doxorubicin + sorafenib	47	66	66	-	51.1
		Doxorubicin + placebo	49	65	86	-	79.6
Cheng et al[50]	2016	Dovitinib	82	56	89	63.0/37.0	-
		Sorafenib	83	56	81	64.0/35.0	-
Cheng et al[28]	2015	Tigatuzumab (6 + 2) + sorafenib	53	63	85	60.4/39.6	-
		Tigatuzumab (6 + 6) + sorafenib	54	63	83	57.4/42.6	-
		Sorafenib	55	66	80	54.5/45.5	-
Hsu et al[51]	2012	Vandetanib 300 mg/d	19	55	95	-	-
		Vandetanib 100 mg/d	25	61	68	-	-
		Placebo	23	56	87	-	-
Johnson et al[22]	2013	Sorafenib	578	60	84	61.0/39.0	62.0
		Brivanib	577	61	84	64.0/36.0	63.0
Cainap et al[24]	2015	Linifanib	514	59	86	62.8/37.2	59.7
		Sorafenib	521	60	84	66.2/33.8	56.8
Kudo et al[10]	2018	Lenvatinib	478	63	85	-	-
		Sorafenib	476	62	84	-	-
Yau et al[23]	2019	Nivolumab	371	65	85	-	-
		Sorafenib	372	65	85	-	-
Cheng et al[29]	2013	Sunitinib	530	59	82	52.5/46.8	78.9
		Sorafenib	544	59	84	52.9/46.7	76.3
Zhu et al[26]	2015	Sorafenib + erlotinib	362	60	82	61.3/38.7	56.6
		Sorafenib + placebo	358	61	80	60.3/39.7	61.2
Llovet et al[52]	2008	Sorafenib	299	65	87	54.0/46.0	53.0
		Placebo	303	66	87	54.0/46.0	50.0
Cheng et al[25]	2009	Sorafenib	150	51	85	25.3/74.6	68.7
		Placebo	76	52	87	27.6/72.4	68.4
Palmer et al[53]	2018	Nintedanib	62	66	77	51.6/48.4	64.5
		Sorafenib	31	64	84	58.1/33.0	67.7
Thomas et al[54]	2018	Bevacizumab + erlotinib	47	61	NR	32.0/68.0	40.0
		Sorafenib	43	61	NR	40.0/60.0	25.0
Abou-Alfa et al[55]	2019	Sorafenib + doxorubicin	180	62	85	36.1/63.9	-
		Sorafenib	176	62	87	39.8/60.2	-
Tak et al[27]	2018	Sorafenib	84	62	87	-	56.0
		Sorafenib + resminostat	86	65	80	-	51.8
Jouve et al[56]	2019	Sorafenib + pravastatin	162	68	96	-	29.0
		Sorafenib	161	68	88	-	30.4
Lee et al[57]	2016	AEG35156 + sorafenib	31	61	87	3.2/96.8	-
		Sorafenib	17	54	88	11.8/88.3	-
Assenat et al[58]	2019	Sorafenib + GEMOX	39	62	86	-	77.0
		Sorafenib	44	65	92	-	61.0
Azim et al[59]	2018	Sorafenib + tegafur–uracil	36	59	86	69.4/30.6	52.8
		Sorafenib	38	59	90	65.8/34.2	47.4
Koeberle et al[60]	2016	Sorafenib	46	65	87	72.0/28.0	57.0
		Sorafenib + everolimus	59	66	81	59.0/41.0	54.0
Bi et al[17]	2020	Donafinib	328	53	86	61.3/38.7	-
		Sorafenib	331	53	88	66.8/33.2	-
Qin et al[61]	2013	FOLFOX4	184	50	90	-	-
		Doxorubicin	187	49	87	-	-
Yeo et al[62]	2005	Doxorubicin	94	54	90	87.2/12.8	-
		PIAF	94	49	93	92.6/7.4	-

ECOG: Eastern Co-operative Oncology Group; FOLFOX4: Oxaliplatin/folinic acid/5-fluorouracil; GEMOX: Gemcitabine and oxaliplatin; NR: Not reported; PIAF: Cisplatin/interferon α-2b/doxorubicin/5-fluorouracil.