Tyrosine Kinase Inhibitors Plus Anti-PD-1 Antibodies with Hepatic Arterial Infusion Chemotherapy or Transarterial Chemoembolization for Unresectable Hepatocellular Carcinoma

Figures & data

Table 1 Clinicopathological Characteristics Before and After PSM

	Before PSM			After PSM
	HAIC-TP (n = 302)	TACE-TP (n = 446)	P value	HAIC-TP (n = 232)	TACE-TP (n = 232)	P value
Age, years			<0.001			0.987
<50	105 (34.8)	105 (23.5)		72 (31.0)	73 (31.5)
≥50	197 (65.2)	341 (76.5)		160 (69.0)	159 (68.5)
Sex			0.445			1.000
Male	266 (88.1)	383 (85.9)		202 (87.1)	202 (87.1)
Female	36 (11.9)	63 (14.1)		30 (12.9)	30 (12.9)
ECOG PS			<0.001			1.000
0	102 (33.8)	95 (21.3)		69 (29.7)	69 (29.7)
1	200 (66.2)	351 (78.7)		163 (70.3)	163 (70.3)
HBV			0.014			0.650
Positive	248 (82.1)	331 (74.2)		185 (79.7)	180 (77.6)
Negative	54 (17.9)	115 (25.8)		47 (20.3)	52 (22.4)
HCV			0.057			0.416
Positive	5 (1.7)	20 (4.5)		5 (2.2)	9 (3.9)
Negative	297 (98.3)	426 (95.5)		227 (97.8)	223 (96.1)
AFP, ng/mL			0.002			0.642
≤400	146 (48.3)	267 (59.9)		123 (53.0)	117 (50.4)
>400	156 (51.7)	179 (40.1)		109 (47.0)	115 (49.6)
ALBI grade			0.087			0.960
1	177 (58.6)	289 (64.8)		142 (61.2)	139 (59.9)
2/3	125 (41.4)	157 (35.2)		90 (38.8)	93 (40.1)
Albumin, g/l			0.950			0.487
<36	57 (18.9)	85 (19.1)		43 (18.5)	50 (21.6)
≥36	245 (81.1)	361 (80.9)		189 (81.5)	182 (78.4)
T-BIL, μmol/L			0.003			1.000
≤17	185 (61.3)	320 (71.7)		154 (66.4)	154 (66.4)
>17	117 (38.7)	126 (28.3)		78 (33.6)	78 (33.6)
ALT, U/L			0.525			1.000
≤50	226 (74.8)	344 (77.1)		173 (74.6)	172 (74.1)
>50	76 (25.2)	102 (22.9)		59 (25.4)	60 (25.9)
AST, U/L			<0.001			0.924
≤40	104 (34.4)	228 (51.1)		92 (39.7)	90 (38.8)
>40	198 (65.6)	218 (48.9)		140 (60.3)	142 (61.2)
Child-Pugh class			0.133			1.000
A	298 (98.7)	431 (96.6)		229 (98.7)	230 (99.1)
B	4 (1.3)	15 (3.4)		3 (1.3)	2 (0.9)
Tumor number			<0.001			0.786
Single	9 (3.0)	57 (12.8)		8 (3.4)	6 (2.6)
Multiple	293 (97.0)	389 (87.2)		224 (96.6)	226 (97.4)
Maximum tumor diameter, cm			<0.001			1.000
≤10	150 (49.7)	316 (70.9)		136 (58.6)	136 (58.6)
>10	152 (50.3)	130 (29.1)		96 (41.4)	96 (41.4)
PVTT			<0.001			1.000
Presence	126 (41.7)	90 (20.2)		70 (30.2)	69 (29.7)
Absence	176 (58.3)	356 (79.8)		162 (69.8)	163 (70.3)
Extrahepatic metastases			0.378			0.707
Presence	44 (14.6)	77 (17.3)		36 (15.5)	40 (17.2)
Absence	258 (85.4)	369 (82.7)		196 (84.5)	192 (82.8)
BCLC stage			<0.001			0.820
A/B	152 (50.3)	312 (70.0)		143 (61.7)	140 (60.3)
C	150 (49.7)	134 (30.0)		89 (38.4)	92 (39.7)

Abbreviations: PSM, propensity score matching; HAIC-TP, hepatic artery infusion chemotherapy combined with tyrosine kinase inhibitors and anti-PD-1 antibodies; TACE-TP, transarterial chemoembolization combined with tyrosine kinase inhibitor and anti-PD-1 antibodies; ECOG PS, Eastern Cooperative Oncology Group performance status; HBV, hepatitis B virus; HCV, hepatitis C virus; AFP, ⍺-fetoprotein; ALBI, albumin-bilirubin; T-BIL, total bilirubin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; PVTT, portal vein tumor thrombus; BCLC stage, Barcelona Clinic Liver Cancer stage.

Figure 1 Flow diagram of the study.

Abbreviations: HCC, hepatocellular carcinoma; TKIs, tyrosine kinase inhibitor; HAIC, hepatic arterial infusion chemotherapy; TACE, transarterial chemoembolization; PSM, propensity score matching.

Table 2 Summary of Response Before and After PSM

	Before PSM			After PSM
	HAIC-TP (%)	TACE-TP (%)	P value	HAIC-TP (%)	TACE-TP (%)	P value
RECIST	n = 302	n = 446		n = 232	n = 232
CR	0 (0.0)	0 (0.0)	-	0 (0)	0 (0)	-
PR	100 (33.1)	35 (7.8)	<0.001	80 (34.5)	20 (8.6)	<0.001
SD	135 (44.7)	175 (39.2)	0.154	105 (45.3)	74 (31.5)	0.002
PD	67 (22.2)	236 (52.9)	<0.001	47 (20.3)	138 (59.9)	<0.001
ORR	33.1%	7.8%	<0.001	34.5%	8.6%	<0.001
DCR	77.8%	47.1%	<0.001	79.7%	40.1%	<0.001
mRECIST	n = 302	n = 446		n = 232	n = 232
CR	9 (3.0)	0 (0.0)	<0.001	8 (3.4)	0 (0.0)	0.004
PR	143 (47.4)	78 (17.5)	<0.001	114 (49.1)	37 (15.9)	<0.001
SD	83 (27.5)	132 (29.6)	0.531	63 (27.2)	56 (24.1)	0.457
PD	67 (22.2)	236 (52.9)	<0.001	47 (20.3)	139 (59.9)	<0.001
ORR	51.4%	17.5%	<0.001	52.5%	15.9%	<0.001
DCR	77.8%	47.1%	<0.001	79.7%	40.1%	<0.001

Abbreviations: PSM, propensity score matching; RECIST, Response Evaluation Criteria in Solid Tumors; HAIC-TP, hepatic artery infusion chemotherapy combined with tyrosine kinase inhibitors and anti-PD-1 antibodies; TACE-TP, transarterial chemoembolization combined with tyrosine kinase inhibitors and anti-PD-1 antibodies; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, overall response rate; DCR, disease control rate.

Figure 2 Kaplan-Meier curves for survival outcomes before and after PSM.

Notes: (A) Kaplan-Meier curves of PFS between HAIC-TP group and TACE-TP group before PSM. (B) Kaplan-Meier curves of OS between HAIC-TP group and TACE-TP group before PSM. (C) Kaplan-Meier curves of PFS between HAIC-TP group and TACE-TP group after PSM. (D) Kaplan-Meier curves of OS between HAIC-TP group and TACE-TP group after PSM.

Abbreviations: PSM, propensity score matching; PFS, progression-free survival; HAIC-TP, hepatic artery infusion chemotherapy combined with tyrosine kinase inhibitors and anti-PD-1 antibodies; TACE-TP, transarterial chemoembolization combined with tyrosine kinase inhibitor and anti-PD-1 antibodies; OS, overall survival.

Figure 3 Subgroup analyses of survival outcomes before PSM.

Notes: (A) Forest plots for subgroup analyses of PFS between HAIC-TP group and TACE-TP group. (B) Forest plots for subgroup analyses of OS between HAIC-TP group and TACE-TP group.

Abbreviations: PSM, propensity score matching; PFS, progression-free survival; HAIC-TP, hepatic arterial infusion chemotherapy combined with tyrosine kinase inhibitors and anti-PD-1 antibodies; TACE-TP, transarterial chemoembolization combined with tyrosine kinase inhibitors and anti-PD-1 antibodies; OS, overall survival; ECOG PS, Eastern Cooperative Oncology Group performance status; HBV, hepatitis B virus; AFP, alpha-fetoprotein; ALBI, albumin-bilirubin; T-BIL, total bilirubin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; PVTT, portal vein tumor thrombus; BCLC stage, Barcelona Clinic Liver Cancer stage.

Figure 4 Subgroup analyses of survival outcomes after PSM.

Notes: (A) Forest plots for subgroup analyses of PFS between HAIC-TP group and TACE-TP group. (B) Forest plots for subgroup analyses of OS between HAIC-TP group and TACE-TP group.

Abbreviations: PSM, propensity score matching; PFS, progression-free survival; HAIC-TP, hepatic arterial infusion chemotherapy combined with tyrosine kinase inhibitors and anti-PD-1 antibodies; TACE-TP, transarterial chemoembolization combined with tyrosine kinase inhibitors and anti-PD-1 antibodies; OS, overall survival; ECOG PS, Eastern Cooperative Oncology Group performance status; HBV, hepatitis B virus; AFP, alpha-fetoprotein; ALBI, albumin-bilirubin; T-BIL, total bilirubin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; PVTT, portal vein tumor thrombus; BCLC stage, Barcelona Clinic Liver Cancer stage.

Table 3 Univariate and Multivariate Analysis of Progression-Free Survival in All Patients

Variables	Median PFS (months)	Univariate	Multivariate	P value
		P value	HR (95% CI)
Group		<0.001		<0.001
HAIC-TP	12.4		Reference
TACE-TP	8.2		2.173 (1.720–2.744)
Age		0.011		NS
<50	7.5
≥50	11.6
Sex		0.334
Male	10.0
Female	8.2
ECOG PS		0.019		NS
0	7.6
1	11.4
HBV		0.034		NS
Positive	9.4
Negative	14.2
AFP, ng/mL		<0.001		0.001
≤400	13.5		Reference
>400	10.8		1.480 (1.181–1.856)
ALBI grade		0.022		NS
1	12.6
2/3	10.9
Tumor number		0.488		NS
Single	10.7
Multiple	9.7
Maximum tumor diameter, cm		0.005		NS
≤10	11.7
>10	8.1
PVTT		0.003		0.015
Presence	8.7		Reference
Absence	11.7		0.740 (0.581–0.942)
Extrahepatic metastases		<0.001		0.001
Presence	6.5		Reference
Absence	11.4		0.653 (0.507–0.842)

Abbreviations: PFS, progression-free survival; HR, hazard ratio; CI, confidence interval; HAIC-TP, hepatic artery infusion chemotherapy combined with tyrosine kinase inhibitors and anti-PD-1 antibodies; TACE-TP, transarterial chemoembolization combined with tyrosine kinase inhibitors and anti-PD-1 antibodies; ECOG PS, Eastern Cooperative Oncology Group performance status; HBV, hepatitis B virus; AFP, ⍺-fetoprotein; ALBI, albumin-bilirubin; PVTT, portal vein tumor thrombus; NS, not significant.

Table 4 Univariate and Multivariate Analysis of Overall Survival in All Patients

Variables	Median OS (months)	Univariate	Multivariate	P value
		P value	HR (95% CI)
Group		<0.001		<0.001
HAIC-TP	Not reached		Reference
TACE-TP	13.8		3.333 (2.391–4.645)
Age		0.064
<50	14.3
≥50	18.2
Sex		0.077
Male	16.7
Female	16.0
ECOG PS		0.052
0	14.0
1	18.4
HBV		0.641
Positive	16.0
Negative	Not reached
AFP, ng/mL		<0.001		0.012
≤400	Not reached		Reference
>400	15.0		1.457 (1.088–1.951)
ALBI grade		0.006		0.023
1	19.3		Reference
2/3	13.2		1.387 (1.045–1.839)
Tumor number		0.955
Single	16.7
Multiple	16.3
Maximum tumor diameter, cm		0.031		NS
≤10	Not reached			NS
>10	15.2			NS
PVTT		0.014		0.001
Presence	14.0		Reference
Absence	18.4		0.593 (0.431–0.816)
Extrahepatic metastases		0.001		0.027
Presence	12.5		Reference
Absence	19.3		0.693 (0.502–0.958)

Abbreviations: OS, overall survival; HR, hazard ratio; CI, confidence interval; HAIC-TP, hepatic artery infusion chemotherapy combined with tyrosine kinase inhibitors and anti-PD-1 antibodies; TACE-TP, transarterial chemotherapy combined with tyrosine kinase inhibitors and anti-PD-1 antibodies; ECOG PS, Eastern Cooperative Oncology Group performance status; HBV, hepatitis B virus; AFP, ⍺-fetoprotein; ALBI, albumin-bilirubin; PVTT, portal vein tumor thrombus; NS, not significant.

Table 5 Treatment-Related Adverse Events in All Patients

	HAIC-TP (n = 302), No. (%)		TACE-TP (n = 446), No. (%)		P value
	Any Grade	Grade 3/4	Any Grade	Grade 3/4	Any Grade	Grade 3/4
Neutropenia	94 (31.1)	18 (6.0)	153 (34.3)	19 (4.3)	0.408	0.379
Thrombocytopenia	101 (33.4)	13 (4.3)	132 (29.6)	13 (2.9)	0.301	0.415
Fatigue	172 (57.0)	7 (2.3)	272 (61.0)	7 (1.6)	0.305	0.641
Hypertension	100 (33.1)	10 (3.3)	132 (29.6)	15 (3.4)	0.347	1.000
Weight loss	78 (25.8)	8 (2.6)	124 (27.8)	5 (1.1)	0.608	0.199
Hand foot skin reaction	100 (33.1)	16 (5.3)	135 (30.3)	24 (5.4)	0.458	1.000
Rash	34 (11.3)	4 (1.3)	45 (10.1)	7 (1.6)	0.697	1.000
Nausea	140 (46.4)	20 (6.6)	153 (34.3)	23 (5.2)	0.001	0.493
Vomiting	85 (28.1)	11 (3.6)	96 (21.5)	13 (2.9)	0.047	0.732
Diarrhea	76 (25.2)	13 (4.3)	59 (13.2)	5 (1.1)	<0.001	0.011
Abdominal pain	100 (33.1)	17 (5.6)	106 (23.8)	11 (2.5)	0.006	0.041
Sensory neuropathy	43 (14.2)	3 (1.0)	70 (15.7)	7 (1.6)	0.659	0.727
Proteinuria	73 (24.2)	4 (1.3)	81 (18.2)	5 (1.1)	0.057	1.000
Elevated ALT	140 (46.4)	26 (8.6)	268 (60.1)	78 (17.5)	<0.001	0.001
Elevated AST	130 (43.0)	52 (17.2)	285 (63.9)	113 (25.3)	<0.001	0.011
Hyperbilirubinemia	106 (35.1)	7 (2.3)	232 (52.0)	25 (5.6)	<0.001	0.046
Hypoalbuminemia	136 (45.0)	11 (3.6)	253 (56.7)	39 (8.7)	0.002	0.010
Fever	46 (15.2)	5 (1.7)	155 (34.8)	6 (1.3)	<0.001	0.971
Anemia	97 (32.1)	6 (2.0)	148 (33.2)	5 (1.1)	0.822	0.512
Elevated creatinine	15 (5.0)	3 (1.0)	19 (4.3)	5 (1.1)	0.782	1.000

Abbreviations: PSM, propensity score matching; HAIC-TP, hepatic artery infusion chemotherapy combined with tyrosine kinase inhibitors and anti-PD-1 antibodies; TACE-TP, transarterial chemotherapy combined with tyrosine kinase inhibitors and anti-PD-1 antibodies; ALT, alanine aminotransferase; AST, aspartate aminotransferase.