Efficacy and Safety of Transarterial Chemoembolization Plus Donafenib with or without Immune Checkpoint Inhibitors as the First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Propensity Score Matching Analysis

Figures & data

Table 1 Baseline Characteristics of Patients in the Two Groups Before and After PSM

Characteristics	Before PSM			After PSM
	T+D (n=41)	T+D+I (n=28)	P value	T+D (n=26)	T+D+I (n=26)	P value
Age (years)	57.6 ± 9.1	55.4 ± 11.7	0.385	56.8 ± 9.8	54.8 ± 11.1	0.503
< 55	15 (36.6)	15 (53.6)		12 (46.2)	14 (53.8)
≥ 55	26 (63.4)	13 (46.4)		14 (53.8)	12 (46.2)
Sex			0.228			>0.999
Male	35 (85.4)	27 (96.4)		25 (96.2)	25 (96.2)
Female	6 (14.6)	1 (3.6)		1 (3.8)	1 (3.8)
ECOG PS			0.344			0.188
0	9 (22.0)	9 (32.1)		4 (15.4)	8 (30.8)
1	32 (78.0)	19 (67.9)		22 (84.6)	18 (69.2)
BCLC stage			0.729			0.768
B	13 (31.7)	10 (35.7)		8 (30.8)	9 (34.6)
C	28 (68.3)	18 (64.3)		18 (69.2)	17 (65.4)
HBsAg			0.386			0.720
Positive	30 (73.2)	23 (82.1)		22 (84.7)	21 (80.8)
Negative	11 (26.8)	5 (17.9)		4 (15.3)	5 (19.2)
Child-Pugh class			0.424			>0.999
A	32 (78.0)	24 (85.7)		23 (88.5)	23 (88.5)
B	9 (22.0)	4 (14.3)		3 (11.5)	3 (11.5)
ALBI grade			0.682			>0.999
1	6 (14.6)	6 (21.4)		5 (19.2)	5 (19.2)
2	33 (80.5)	20 (71.4)		20 (76.9)	20 (76.9)
3	2 (4.9)	2 (7.1)		1 (3.8)	1 (3.8)
AFP(ng/mL)			0.683			0.780
< 400	24 (58.5)	15 (53.6)		15 (57.7)	14 (53.8)
≥ 400	17 (41.5)	13 (46.4)		11 (42.3)	12 (46.2)
TBil (μmol/L)	18.0 ± 10.1	17.7 ± 8.9	0.899	16.1 ± 6.5	17.4 ± 8.9	0.539
Albumin (g/dL)	35.0 ± 3.8	36.2 ± 4.5	0.275	35.7 ± 3.5	36.3 ± 3.9	0.594
ALT (U/L)	61.4 ± 45.5	70.6 ± 70.8	0.510	61.8 ± 38.7	64.2 ± 58.3	0.863
AST (U/L)	90.7 ± 68.2	73.4 ± 55.9	0.271	78.4 ± 45.4	67.6 ± 41.9	0.376
Tumor size (cm)	8.7 ± 4.4	9.6 ± 3.5	0.379	8.1 ± 3.9	9.8 ± 3.5	0.397
< 10	25 (61.0)	16 (57.1)		17 (65.4)	14 (53.8)
≥ 10	16 (39.0)	12 (42.9)		9 (34.6)	12 (46.2)
Tumor distribution			0.187			0.375
Single lobe	10 (24.4)	11 (39.3)		7 (26.9)	10 (38.5)
Multiple lobes	31 (75.6)	17 (60.7)		19 (73.1)	16 (61.5)
Tumor number			0.380			0.397
≤ 3	19 (46.3)	10 (35.7)		12 (46.2)	9 (34.6)
> 3	22 (53.7)	18 (64.3)		14 (53.8)	17 (65.4)
Vascular invasion			0.921			>0.999
Yes	21 (51.2)	14 (50.0)		13 (50.0)	13 (50.0)
No	20 (48.8)	14 (50.0)		13 (50.0)	13 (50.0)
EHS			0.559			0.773
Yes	16 (39.0)	9 (32.1)		10 (38.5)	9 (34.6)
No	25 (61.0)	19 (67.9)		16 (61.5)	17 (65.4)\
TACE type			0.698			0.337
cTACE	31 (75.6)	20 (71.4)		21 (80.8)	18 (69.2)
DEB-TACE	10 (24.4)	8 (28.6)		5 (19.2)	8 (30.8)
Number of TACE			0.683			0.402
≤ 2	24 (58.5)	15 (53.6)		16 (61.5)	13 (50.0)
>2	17 (41.5)	13 (46.4)		10 (38.5)	13 (50.0)

Note: Data were mean ± standard deviation or number (percent).

Abbreviations: PSM, propensity score matching; T+D, transarterial chemoembolization plus donafenib; T+D+I, transarterial chemoembolization plus donafenib with immune checkpoint inhibitors; ECOG PS, Eastern Cooperative Oncology Group performance status; BCLC, Barcelona Clinic Liver Cancer; HBsAg, hepatitis B surface antigen; ALBI, albumin-bilirubin; AFP, alpha-fetoprotein; ALT, alanine transaminase; TBil, total bilirubin; AST, aspartate aminotransferase; EHS, extrahepatic metastasis; TACE, transarterial chemoembolization.

Figure 1 Patient flow chart.

Abbreviations: HCC, hepatocellular carcinoma; TACE, transarterial chemoembolization; ICIs, immune checkpoint inhibitors; BCLC, Barcelona Clinic Liver Cancer.

Table 2 Summary of Response Rates Before and After PSM

All Response, n(%)	Before PSM			After PSM
	T+D (n=41)	T+D+I (n=28)	P value	T+D (n=26)	T+D+I (n=26)	P value
CR	0 (0)	0 (0)	>0.999	0 (0)	0 (0)	>0.999
PR	18 (43.9)	15 (53.6)	0.430	13 (50.0)	14 (53.8)	0.781
SD	13 (31.70)	12 (42.9)	0.344	6 (23.1)	11 (42.3)	0.139
PD	10 (24.4)	1 (3.6)	0.020	7 (26.9)	1 (3.8)	0.021
ORR	18 (43.9)	15 (53.6)	0.430	13 (50.0)	14 (53.8)	0.781
DCR	31 (75.6)	27 (96.4)	0.020	19 (73.1)	25 (96.2)	0.021

Abbreviations: PSM, propensity score matching; T+D, transarterial chemoembolization plus donafenib; T+D+I, transarterial chemoembolization plus donafenib with immune checkpoint inhibitors; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; DCR, disease control rate.

Figure 2 Kaplan-Meier analyses of progression-free survival (A) and overall survival (B) according to two groups before PSM.

Abbreviations: T+D, transarterial chemoembolization plus donafenib; T+D+I, transarterial chemoembolization plus donafenib with immune checkpoint inhibitors; PSM, propensity score matching.

Figure 3 Kaplan-Meier analyses of progression-free survival (A) and overall survival (B) according to two groups after PSM.

Abbreviations: T+D, transarterial chemoembolization plus donafenib; T+D+I, transarterial chemoembolization plus donafenib with immune checkpoint inhibitors; PSM, propensity score matching.

Table 3 Univariate and Multivariate Predictors of Progression-Free Survival and Overall Survival After PSM

Variables	PFS						OS
	Univariate Analysis			Multivariate Analysis			Univariate Analysis			Multivariate Analysis
	HR	95% CI	P	HR	95% CI	P	HR	95% CI	P	HR	95% CI	P
Age (years)
≥55/ <55	1.20	0.56–2.57	0.641				1.23	0.47–3.26	0.671
Sex
Female/Male	1.34	0.18–10.13	0.776				2.93	0.36–23.54	0.312
ECOG PS
1/0	1.02	0.43–2.42	0.967				3.29	0.75–14.49	0.115
BCLC stage
C/B	1.09	0.49–2.43	0.836				1.95	0.64–5.94	0.242.
HBsAg
Yes/No	2.09	0.71–6.18	0.181				2.01	0.56–7.13	0.282
Child-Pugh class
B/A	1.66	0.57–4.87	0.352				4.20	1.34–13.15	0.014	4.95	1.25–19.63	0.023
AFP (ng/mL)
≥400/<400	1.09	0.50–2.37	0.835				1.56	0.61–3.96	0.352
TBil (μmol/L)
≥20/<20	2.18	0.99–4.79	0.052	2.73	1.20–6.20	0.017	2.16	0.82–5.67	0.118
Albumin (g/dL)
≥35/<35	0.74	0.34–1.59	0.437				0.65	0.25–1.71	0.384
ALT (U/L)
≥35/<35	0.79	0.36–1.73	0.552				0.70	0.27–1.86	0.478
AST (U/L)
≥40/<40	1.67	0.67–4.17	0.268				1.89	0.62–5.81	0.265
Tumor size (cm)
≥10/< 10	1.50	0.70–3.22	0.297				1.64	0.63–4.29	0.311
Tumor distribution
Single lobe/Multiple lobes	0.69	0.31–1.55	0.368				0.14	0.03–0.60	0.008	0.15	0.03–0.66	0.012
Tumor number
>3/≤ 3	1.42	0.63–3.20	0.395				1.68	0.59–4.79	0.331
Vascular invasion
Yes/No	1.25	0.59–2.68	0.563				1.15	0.45–2.91	0.774
EHS
Yes/No	1.42	0.66–3.07	0.372				2.35	0.90–6.17	0.082	1.13	0.41–3.06	0.816
TACE type
DEB-TACE/cTACE	1.08	0.43–3.70	0.866				1.38	0.40–4.84	0.611
Number of TACE
>2/≤ 2	0.64	0.30–1.39	0.261				0.44	0.16–1.16	0.097	0.59	0.20–1.79	0.351
Treatment
T+D+I/T+D	0.39	0.18–0.87	0.021	0.32	0.14–0.74	0.008	0.32	0.11–0.89	0.029	0.32	0.11–0.93	0.037

Abbreviations: PSM, propensity score matching; PFS, Progression-Free Survival; OS, overall Survival; ECOG PS, Eastern Cooperative Oncology Group performance status; BCLC, Barcelona Clinic Liver Cancer; HBsAg, hepatitis B surface antigen; AFP, alpha-fetoprotein; TBil, total bilirubin; ALT, alanine transaminase; AST, aspartate aminotransferase; EHS, extrahepatic metastasis; TACE, transarterial chemoembolization; DEB-TACE, drug-eluting beads transarterial chemoembolization; cTACE, conventional transarterial chemoembolization; T+D, transarterial chemoembolization plus donafenib; T+D+I, transarterial chemoembolization plus donafenib with immune checkpoint inhibitors.

Table 4 Treatment-Related Adverse Events

Events, n(%)	T+D (N=41)			T+D+I (N=28)			P value
	Any Grade	Grade 1/2	Grade 3/4	Any Grade	Grade 1/2	Grade 3/4	Any Grade	Grade 1/2	Grade 3/4
Any TRAE	36 (87.8)	34 (82.9)	3 (7.3)	25 (89.3)	24 (85.7)	3 (10.7)	0.850	0.756	0.623
Pain	6 (14.6)	6 (14.6)	0 (0.0)	5 (17.9)	4 (14.3)	1 (3.6)	0.720	0.968	0.223
Diarrhea	5 (12.2)	5 (12.2)	0 (0.0)	4 (14.3)	4 (14.3)	0 (0.0)	0.800	0.800	–
Fever	4 (9.8)	4 (9.8)	0 (0.0)	3 (10.7)	3 (10.7)	0 (0.0)	0.897	0.897	–
Increased ALT	5 (12.2)	3 (7.3)	2 (4.9)	4 (14.3)	3 (10.7)	1 (3.6)	0.800	0.623	0.794
Increased AST	6 (14.6)	5 (12.2)	1 (2.4)	5 (17.9)	5 (17.9)	0 (0.0)	0.720	0.512	0.405
Increased blood bilirubin	4 (9.8)	4 (9.8)	0 (0.0)	3 (10.7)	2 (7.1)	1 (3.6)	0.705	0.623	0.783
Leukopenia	4 (9.8)	4 (9.8)	0 (0.0)	3 (10.7)	3 (10.7)	0 (0.0)	0.897	0.897	–
Hypothyroidism	0 (0.0)	0 (0.0)	0 (0.0)	4 (14.3)	4 (14.3)	0 (0.0)	0.013	0.013	–
Gastrointestinal hemorrhage	1 (2.4)	1 (2.4)	0 (0.0)	1 (3.6)	1 (3.6)	0 (0.0)	0.783	0.783	–
Nausea	3 (7.3)	3 (7.3)	0 (0.0)	4 (14.3)	4 (14.3)	0 (0.0)	0.346	0.346	–
Fatigue	5 (12.2)	5 (12.2)	0 (0.0)	2 (7.1)	2 (7.1)	0 (0.0)	0.495	0.340	–
Hypertension	6 (14.6)	5 (12.2)	1 (2.4)	5 (17.9)	5 (17.9)	0 (0.0)	0.720	0.512	0.405
Proteinuria	1 (2.4)	1 (2.4)	0 (0.0)	1 (3.6)	1 (3.6)	0 (0.0)	0.783	0.783	–
Hand and foot syndrome	3 (7.3)	3 (7.3)	0 (0.0)	3 (10.7)	3 (10.7)	0 (0.0)	0.623	0.623	–
RCCEP	0 (0.0)	0 (0.0)	0 (0.0)	3 (10.7)	3 (10.7)	0 (0.0)	0.032	0.032	–

Note: Data were presented as number (percent).

Abbreviations: TRAEs, Treatment-Related Adverse Events; T+D, transarterial chemoembolization plus donafenib; T+D+I, transarterial chemoembolization plus donafenib with immune checkpoint inhibitors; ALT, alanine transaminase; AST, aspartate aminotransferase; RCCEP, reactive cutaneous capillary endothelial proliferation.