Targeted and immune therapies for hepatocellular carcinoma: Predictions for 2019 and beyond

doi:10.3748/wjg.v25.i7.789

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World Journal of Gastroenterology

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World J Gastroenterol. Feb 21, 2019; 25(7): 789-807
Published online Feb 21, 2019. doi: 10.3748/wjg.v25.i7.789

Table 1 Phase III clinical trials of advanced stage hepatocellular carcinoma

Target population		Design	Trial name	Result	Presentation	Publication	1^st author
Advanced	First line	1 Sorafenib vs Sunitinib	SUN1170	Negative	ASCO 2011	JCO 2013[6]	Cheng AL
		2 Sorafenib +/- Erlotinib	SEARCH	Negative	ESMO 2012	JCO 2015[7]	Zhu AX
		3 Sorafenib vs Brivanib	BRISK-FL	Negative	AASLD 2012	JCO 2013[8]	Johnson PJ
		4 Sorafenib vs Linifanib	LiGHT	Negative	ASCO-GI 2013	JCO 2015[9]	Cainap C
		5 Sorafenib +/- Doxorubicin	CALGB 80802	Negative	ASCO-GI 2016
		6 Sorafenib +/- HAIC	SILIUS	Negative	EASL 2016	Lancet GH 2018[10]	Kudo M
		7 Sorafenib +/- Y90	SARAH	Negative	EASL 2017	Lancet-O 2017[11]	Vilgrain V
		8 Sorafenib +/- Y90	SIRveNIB	Negative	ASCO 2017	JCO 2018[12]	Chow P
		9 Sorafenib vs Lenvatinib	REFLECT	Positive	ASCO 2017	Lancet 2018[34]	Kudo M
		10 Sorafenib vs Nivolumab	CheckMate-459	Ongoing
		11 Sorafenib vs Durvalumab + Tremelimumab vs Durva	HIMALAYA	Ongoing
		12 Sorafenib vs Atezolizumab + Bevacizumab	Imbrave 150	Ongoing
		13 Sorafenib vs Tislelizumab		Ongoing
	Second line	1 Brivanib vs Placebo	BRISK-PS	Negative	EASL 2012	JCO 2013[13]	Llovet JM
		2 Everolimus vs Placebo	EVOLVE-1	Negative	ASCO-GI 2014	JAMA 2014[14]	Zhu AX
		3 Ramucirumab vs Placebo	REACH	Negative	ESMO 2014	Lancet-O 2015[15]	Zhu AX
		4 S-1 vs Placebo	S-CUBE	Negative	ASCO 2015	Lancet GH 2017[16]	Kudo M
		5 ADI-PEG 20 vs Placebo	NA	Negative	ASCO 2016	Ann Oncol 2018[17]	Abou-Alfa G
		6 Regorafenib vs Placebo	RESORCE	Positive	WCGC 2016	Lancet 2017[41]	Bruix J
		7 Tivantinib vs Placebo	METIV-HCC	Negative	ASCO 2017	Lancet-O 2018[18]	Rimassa L
		8 Tivantinib vs Placebo	JET-HCC	Negative	ESMO 2017
		9 DT vs Placebo	ReLive	Negative	ILCA 2017
		10 Cabozantinib vs Placebo	CELESTIAL	Positive	ASCO-GI 2018	NEJM 2018[45]	Abou-Alfe G
		11 Ramucirumab vs Placebo	REACH-2	Positive	ASCO 2018	Lancet-O 2019[30]	Zhu AX
		12 Pembrolizumab vs Placebo	KEYNOTE-240	Negative

HAIC: Hepatic arterial infusion chemotherapy; Doxorubicin-loaded nanoparticles.

Table 2 Randomized phase II, phase III clinical trials of early / intermediate stage hepatocellular carcinoma

Target population		Design	Trial name	Result	Presentation	Publication	1^st author
Early	Adjuvant (prevention of recurrence)	1 Vitamin K2 vs Placebo		Negative		Hepatology 2011[21]	Yoshida H
		2 Peretinoin vs Placebo	NIK-333	Negative	ASCO 2010	JG 2014[22]	Okita K
		3 Sorafenib vs Placebo	STORM	Negative	ASCO 2014	Lancet-O 2015[23]	Bruix J
		4 Peretinoin vs Placebo	NIK-333/K-333	Ongoing
	Improvement of RFA	1 RFA +/- LTLD	HEAT	Negative	ILCA 2013	CCR 2017[24]	Tak WY
	Improvement of RFA	2 RFA +/- LTLD	OPTIMA	Negative	ILCA 2013	CCR 2017[24]	Tak WY
Intermediate	Improvement of TACE	1 TACE +/- Sorafenib	Post-TACE	Negative	ASCO-GI 2010	EJC 2011[25]	Kudo M
		2 TACE +/- Sorafenib	SPACE (Ph II)	Negative	ASCO-GI 2012	J Hepatol 2016[26]	Lencioni R
		3 TACE +/- Brivanib	BRISK-TA	Negative	ILCA 2013	Hepatol 2014[27]	Kudo M
		4 TACE +/- Orantinib	ORIENTAL	Negative	EASL 2015	Lancet GH 2017[28]	Kudo M
		5 TACE +/- Sorafenib	TACE-2	Negative	ASCO 2016	Lancet GH 2017[29]	Meyer T
		6 TACE +/- Sorafenib	TACTICS (Ph II)	Positive	ASCO-GI 2018[30]		Kudo M

LTLD: Lyso-thermosensitive liposomal doxorubicin.

Table 3 Results of the REFLECT trial[34]

	Lenvatinib (n = 478)	Sorafenib (n = 476)	HR, P-value
OS (M, 95% CI)	13.6 (12.1-14.9)	12.3 (10.4-13.9)	HR 0.92 (0.79-1.06)
PFS (M, 95% CI)	7.3 (5.6-7.5)	3.6 (3.6-3.7)	HR 0.64 (0.55-0.75) P < 0.0001
TTP (M, 95% CI)	7.4 (7.2-9.1)	3.7 (3.6-3.9)	HR 0.60 (0.51-0.71) P < 0.0001
Objective response (independent review, mRECIST)
CR	10 (2%)	4 (1%)
PR	184 (38%)	55 (12%)
SD	159 (33%)	219 (46%)
PD	79 (17%)	152 (32%)
ORR	194 (40.6%)	59 (12.4%)	P < 0.0001
DCR	353 (73.8%)	278 (58.4%)	P < 0.0001

OS: Overall survival; PFS: Progression-free survival; TTP: Time to progression; CR: Complete response; PR: Partial response; SD: Stable disease; PD: Progressive disease; ORR: Objective response rate; DCR: Disease control rate.

Table 4 Results of the RESORCE trial[41]

	Regorafenib (n = 379)	Placebo (n = 194)	HR, P-value
OS (M, 95%CI)	10.6 (9.1-12.1)	7.8 (6.3-8.8)	HR 0.63 (95%CI 0.50-0.79) P < 0.0001
PFS (M, 95%CI)	3.1 (2.8-4.1)	10.6 (1.4-1.6)	HR 0.46 (95%CI 0.37-0.56) P < 0.0001
TTP (M, 95%CI)	3.2 (2.9-4.2)	10.6 (1.4-1.6)	HR 0.44 (95%CI 0.36-0.55) P < 0.0001
Objective response(investigator assessed, mRECIST)
CR	2 (1%)	0
PR	38 (10%)	8 (4%)
SD	206 (54%)	62 (32%)
PD	86 (23%)	108 (56%)
ORR	40 (11%)	8 (4%)	P = 0.0047
DCR	247 (65%)	70 (36%)	P < 0.0001

Table 5 Results of the CERESTIAL trial[45]

	Cabozantinib (n = 470)	Placebo (n = 237)	HR, P-value
OS (M, 95%CI)	10.2 (9.1-12.0)	8.0 (6.8-9.4)	HR 0.76 (95%CI 0.63-0.92) P = 0.0049
PFS (M, 95%CI)	5.2 (4.0-5.5)	1.9 (1.9-1.9)	HR 0.44 (95%CI 0.36-0.52) P < 0.0001
Objective response (investigator assessed, RECIST 1.1)
CR (%)	0	0
PR (%)	4	0.4
SD (%)	60	33
PD (%)	21	55
NE (%)	15	11
ORR (%, 95CI)	4 (2.3-6.0)	0.4 (0.0-2.3)	P = 0.0086
DCR (%)	64	33.4

OS: Overall survival; PFS: Progression-free survival; TTP: Time to progression; CR: Complete response; PR: Partial response; SD: Stable disease; PD: Progressive disease; NE: Not evaluable; ORR: Objective response rate; DCR: Disease control rate.

Table 6 Results of the REACH-2 trial[49]

	Ramucirumab (n = 197)	Placebo (n = 95)	HR, P-value
OS (M, 95%CI)	8.5	7.3	HR 0.710 (95%CI 0.531-0.949) P = 0.0199
PFS (M, 95%CI)	2.8	1.6	HR 0.452 (95%CI 0.339-0.603) P < 0.0001
Objective response (RECIST 1.1)
CR (n, %)	0 (0.0)	0 (0.0)
PR (n, %)	9 (4.6)	1 (1.1)
SD (n, %)	109 (55.3)	36 (37.9)
PD (n,%)	66 (33.5)	48 (50.5)
NE (n, %)	13 (6.6)	10 (10.5)
ORR (%, 95CI)	9 (4.6)	1 (1.1)	P = 0.1697
DCR (%)	118 (59.9)	37 (38.9)	P = 0.0006

Table 7 Results of TACTICS trial[30]

	TACE with sorafenib median (M)	TACE alone median (M)	HR (95% CI)	P value
PFS	25.2	13.5	0.59 (0.41-0.87)	0.006
TTUP	26.7	20.6	0.57 (0.36-0.92)	0.02
TTP	26.7	16.4	0.54 (0.35-0.83)	0.005
TTVI	31.3	4.0	0.26 (0.09-0.75)	0.005
TTEHS	15.7	6.9	0.21 (0.06-0.70)	0.006
TTSP	22.5	6.3	0.31 (0.15-0.63)	0.001

TACE: Transcatheter arterial chemoembolization; HR: Hazard ratio; PFS: Progression free survival; TTUP: Time to untreatable or unTACEable progression; TTP: Time to progression; TTVI: Time to vascular invasion; TTEHS: Time to extrahepatic spread; TTSP: Time to stage progression.

Table 8 Results of immune checkpoint inhibitors and combination therapy

	Nivolumab[58]	Pembrolizumab[59]	Pembrolizumab plus Lenvatinib[67]	Atezolizumab plus Bevacizumab¹[62]	SHR-1210 plus Apatinib[64]	Durvalumab plus Tremelimumab[65]
	(n = 214)	(n = 104)	(n = 26)	(n = 73)	(n = 18)	(n = 40)
ORR (%, 95%CI)	20 (15-26)²	17 (11-26)²	42.3 (23.4-63.1)³	34³	38.9 ³	25²
DCR (%, 95%CI)	64 (58-71)	62 (52-71)	100	75	83.3	57.5 (> 16 wk)
PFS (M, 95%CI)	4.0 (2.9-5.4)	4.9 (3.4-7.2)	9.7 (5.6-NE)	7.5 (0.4-23.9)	7.2 (2.6-NE)	NA
OS (M, 95%CI)	NR (9M, 74%)	12.9 (9.7-15.5)	NR	NR	NR	NA
DOR (M)	9.9 (8.3-NE)	≤ 9 (77%)	NE	NR	NE	NA

¹Independent Review Facility assessment;

²RECIST 1.1; ³modified RECIST; ORR: Objective response rate; DCR: Disease control rate; PFS: Progression free survival; OS: Overall survival; DOR: Duration of response; NR: Not reached; NE: Not estimable; NA: Not available.

Citation: Kudo M. Targeted and immune therapies for hepatocellular carcinoma: Predictions for 2019 and beyond. World J Gastroenterol 2019; 25(7): 789-807
URL: https://www.wjgnet.com/1007-9327/full/v25/i7/789.htm
DOI: https://dx.doi.org/10.3748/wjg.v25.i7.789