Efficacy and Safety of TACE Combined with Regorafenib Plus PD-1 Inhibitor in the Treatment of Hepatocellular Carcinoma After Sorafenib Resistance

Figures & data

Figure 1 Flow diagram showed selection criteria.

Abbreviations: HCC, hepatocellular carcinoma; TACE-R-P, transarterial chemoembolization combined with regorafenib plus PD-1 inhibitor; TACE-R, transarterial chemoembolization combined with regorafenib.

Table 1 Baseline Demographic and Clinical Characteristics of Patients Enrolled in This Study

Characteristics		Group		P
		TACE-R-P (n=35)	TACE-R (n=41)
Sex (n/%)	Male	30 (85.71)	34 (82.93)	0.496
	Female	5 (14.29)	7 (17.07)
Age (mean±SD)	Years	49.52±7.93	51.46±8.34	0.603
ECOG-PS (n/%)	0	29 (82.86)	36 (87.80)	0.762
	1	6 (17.14)	5 (12.20)
Child–Pugh (n/%)	A	21 (60.00)	25 (60.98)	0.931
	B	14 (40.00)	16 (39.02)
BCLC (n/%)	A	1 (2.86)	1 (2.44)	0.939
	B	9 (25.71)	12 (29.27)
	C	25 (71.43)	28 (68.29)
Viral hepatitis (n/%)	HBV	33 (94.29)	38 (92.68)	0.779
	None	2 (5.71)	3 (7.32)
AFP (n/%)	AFP>400ng/mL	20 (57.14)	29 (70.73)	0.217
	AFP≤400ng/mL	15 (42.86)	12 (29.27)
Number of tumors (n/%)	>3	23 (65.71)	31 (75.61)	0.343
	≤3	12 (34.29)	10 (24.39)
Largest diameter of liver tumor (n/%)	>5cm	25 (71.43)	28 (68.29)	0.767
	≤5cm	10 (28.57)	13 (31.71)
PVTT (n/%)	Yes	16 (45.71)	20 (48.78)	0.790
	No	19 (54.29)	21 (51.22)
Hepatic vein invasion (n/%)	Yes	11 (31.43)	13 (31.71)	0.979
	No	24 (68.57)	28 (68.29)
Extrahepatic metastasis (n/%)	Yes	9 (25.71)	12 (29.27)	0.730
	No	26 (74.29)	29 (70.73)
Regorafenib dose	40mg	3 (8.57)	3 (7.32)	0.930
	80mg	13 (37.14)	15 (36.59)
	120mg	17 (48.57)	19 (46.34)
	160mg	2 (5.71)	4 (9.76)

Note: Results are presented as n (%) unless otherwise indicated.

Abbreviations: TACE-R-P, transarterial chemoembolization combined with regorafenib plus PD-1 inhibitor; TACE-R, transarterial chemoembolization combined with regorafenib; SD, standard deviation; ECOG, Eastern Cooperative Oncology Group; BCLC, Barcelona Clinic Liver Cancer; HBV, hepatitis B virus; AFP, alpha-fetoprotein; PVTT, portal vein tumor thrombus.

Table 2 Tumor Response in Patients to TACE-R-P Group and TACE-R Group

Tumor Response	TACE-R-P (n=35)	TACE-R (n=41)	χ^2	P
CR	2 (5.71)	0 (0.00)	20.104	0.001
PR	11 (31.43)	8 (19.51)
SD	12 (34.29)	12 (29.27)
PD	10 (28.57)	21 (51.22)
ORR (CR+PR)	13 (37.14)	8 (19.51)
DCR (CR+PR+SD)	25 (71.43)	20 (48.78)

Note: Results are presented as n (%) unless otherwise indicated.

Abbreviations: TACE-R-P, transarterial chemoembolization combined with regorafenib plus PD-1 inhibitor; TACE-R, transarterial chemoembolization combined with regorafenib; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR (CR+PR), objective response rate; DCR (CR+PR+SD), disease control rate.

Figure 2 Kaplan–Meier curves of OS (A) and PFS (B) according to TACE-R-P and TACE-R groups.

Abbreviations: OS, overall survival; PFS, progression-free survival; TACE-R-P, transarterial chemoembolization combined with regorafenib plus PD-1 inhibitor; TACE-R, transarterial chemoembolization combined with regorafenib.

Figure 3 (A) Contrast-enhanced MRI showed HCC progression after sorafenib resistance; (B) In patients undergoing TACE, the staining of HCC was obvious; (C) The staining of HCC disappeared after TACE treatment; (D) Eight months after TACE-R-P treatment, contrast-enhanced MRI showed necrosis in most lesions, and tumor response was assessed as PR.

Figure 4 (A) Contrast-enhanced MRI showed HCC progression after sorafenib resistance; (B) In patients undergoing TACE, the staining of HCC was obvious; (C) The staining of HCC disappeared after TACE treatment; (D) Two months after TACE-R treatment, contrast-enhanced MRI showed HCC progression, and tumor response was assessed as PD.

Table 3 Univariate and Multivariate Analyses of Risk Factors for OS in HCC Cases After Sorafenib Resistance

Factors	Univariate Analysis			Multivariate Analysis
	HR	95% CI	P	HR	95% CI	P
Sex
Female/Male	0.812	0.418–1.573	0.810
Age (years)
≤60/>60	0.855	0.393–1.406	0.362
ECOG-PS
0/1	0.537	0.302–1.218	0.216
Child–Pugh grade
B/A	1.523	0.756–1.822	0.002	1.283	0.623–1.707	0.014
Viral hepatitis
HBV/None	0.836	0.419–1.201	0.517
AFP (µg/L)
>400/≤400	1.149	0.590–1.603	0.009	0.779	0.405–1.187	0.094
Number of tumors
>3/≤3	0.717	0.297–1.258	0.061
Tumor size (cm)
>5/≤5	1.446	0.801–1.885	0.006	0.933	0.379–1.296	0.228
Hepatic vein invasion
Yes/No	0.909	0.537–1.416	0.108
PVTT
Yes/No	1.759	1.206–2.115	0.001	1.455	0.977–2.038	0.018
Extrahepatic metastasis
Yes/No	1.815	1.106–3.058	0.003	1.766	1.135–2.302	0.022
Treatment option
TACE-R/TACE-R-P	1.634	1.203–2.627	0.001	1.930	1.461–2.850	0.017

Abbreviations: HR, hazard ratio; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HBV, hepatitis B virus; AFP, alpha-fetoprotein; PVTT, portal vein tumor thrombus.

Table 4 Treatment-Related Adverse Events in Two Groups

Adverse Events	TACE-R-P (n=35)		TACE-R (n=41)		χ^2	P
	Grade 1–2	Grade 3–4	Grade 1–2	Grade 3–4
Hand-foot syndrome	8 (22.86)	5 (14.29)	10 (24.39)	4 (9.76)	0.297	0.586
Hypertension	6 (17.14)	4 (11.43)	7 (17.07)	5 (12.20)	0.006	0.937
Diarrhea	6 (17.14)	0 (0.00)	8 (19.51)	0 (0.00)	-	-
Hyperbilirubinemia	5 (14.29)	2 (5.71)	5 (12.20)	1 (2.44)	0.258	0.612
Anorexia and nausea	9 (25.71)	3 (8.57)	9 (21.95)	4 (9.76)	0.103	0.748
Fatigue	9 (25.71)	2 (5.71)	9 (21.95)	3 (7.32)	0.157	0.692
Rash	7 (20.00)	1 (2.86)	8 (19.51)	2 (4.88)	0.180	0.671
Thyroid dysfunction	4 (11.43)	0 (0.00)	6 (14.63)	0 (0.00)	-	-
Lymphopenia	5 (14.29)	1 (2.86)	7 (17.07)	1 (2.44)	0.049	0.825
Abdominal pain	10 (28.57)	2 (5.71)	12 (29.27)	4 (9.76)	0.283	0.595
Trachyphonia	3 (8.57)	0 (0.00)	4 (9.76)	1 (2.44)	0.686	0.408
Thrombocytopenia	9 (25.71)	5 (14.29)	11 (26.83)	6 (14.63)	0.001	0.981
Fever	4 (11.43)	1 (2.86)	6 (14.63)	0 (0.00)	1.320	0.251
Oral ulcer	5 (14.29)	1 (2.86)	7 (17.07)	2 (4.88)	0.069	0.792
Pruritus	7 (20.00)	2 (5.71)	8 (19.51)	3 (7.32)	0.067	0.795
Pneumonitis	3 (8.57)	1 (2.86)	5 (12.20)	1 (2.44)	0.104	0.747
Proteinuria	5 (14.29)	0 (0.00)	6 (14.63)	1 (2.44)	0.779	0.377

Note: Results are presented as n (%) unless otherwise indicated.

Abbreviations: TACE-R-P, transarterial chemoembolization combined with regorafenib plus PD-1 inhibitor; TACE-R, transarterial chemoembolization combined with regorafenib.