Efficacy and Safety of Tyrosine Kinase Inhibitors Alone or Combination with Programmed Death-1 Inhibitors in Treating of Hepatitis C-Related Hepatocellular Carcinoma

Figures & data

Table 1 Baseline Patient Characteristics

	TKI Group (n=43), n (%)	Combination Group (n=24), n (%)	P value
Sex (male)	35(81.3)	21(87.5)	0.762
Age (≥60), years	32(74.4)	16(66.7)	0.500
Hypertension	17(39.5)	11(45.8)	0.616
Diabetes	10(23.3)	10(41.6)	0.114
Drinking history	21(48.8)	11(45.8)	0.813
Liver cirrhosis	35(81.3)	18(75.0)	0.537
Extrahepatic metastasis			0.913
No	31(72.1)	17(70.8)
Yes	12(27.9)	7(29.2)
Vascular invasion			0.358
No	19(44.2)	8(33.3)
Yes	24(55.8)	16(66.7)
Ascites			0.521
No	18(41.9)	12(50.0)
Yes	25(58.1)	12(50.0)
AFP			0.567
≤400 ng/mL	33(76.7)	14(58.3)
>400 ng/mL	10(23.3)	10(41.7)
HCV RNA			0.920
Undetectable	34(79.1)	20(83.3)
Detectable	9(20.9)	4(16.7)
Child-Pugh score class			0.898
A	28(65.1)	16(66.7)
B	15(34.9)	8(33.3)
BCLC stage			0.595
B	19(44.2)	9(25.0)
C	24(55.8)	15(75.0)
Treatment modality
Sorafenib	24(55.8)	0
Lenvatinib	19(44.2)	0
Lenvatinib + sintilimab	0	16(66.7)
Lenvatinib + camrelizumab	0	3(12.5)
Lenvatinib + toripalimab	0	3(12.5)
Sorafenib + toripalimab	0	1(4.2)
Sorafenib +camrelizumab	0	1(4.2)

Abbreviations: AFP, alpha fetoprotein; BCLC, Barcelona Clinic Liver Cancer; TKI group, tyrosine kinase inhibitors; combination group, TKI combined with PD-1 inhibitors.

Table 2 Tumor Response

	TKI Group (n=43), n (%)	Combination Group (n=24), n (%)	P value	HCV RNA (-) (n=54), n (%)	HBV RNA (+) (n=13), n (%)	P value
CR	0	1(4.2)		1(1.9)	0
PR	6(13.9)	5(20.8)		7(13.0)	3(23.1)
SD	19(44.1)	13(54.2)		29(3.7)	4(30.8)
PD	18(41.9)	5(20.8)		17(31.5)	6(46.2)
ORR	6(13.9)	6(25.0)	0.425	8(14.8)	3(23.1)	0.760
DCR	25(58.1)	19(79.2)	0.080	37(68.5)	7(53.8)	0.500
mPFS(months)	5	8	0.005	6	4	0.238
mOS(months)	13	21	0.043	19	14	0.578

Abbreviations: CR, complet eresponse; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; DCR, disease control rate; mPFS, median progression free survival; mOS, median overall survival; TKI group, tyrosine kinase inhibitors; combination group, TKI combined with PD-1 inhibitors; HCV RNA (-), HCV RNA baseline undetectable; HCV RNA (+), HCV RNA baseline detectable.

Figure 1 Kaplan-Meier survival curves of treatment outcome including (A) progression-free survival (PFS) and (B) overall survival (OS) betweenTKI group and combination group, (C) PFS and (D) OS between lenvatinib group and lenvatinib plus sintilimab group.

Figure 2 Kaplan-Meier survival curves of treatment outcome including (A) progression-free survival (PFS) and (B) overall survival (OS) between HCV RNA-positive group and HCV RNA-negative group; Comparison of (C) PFS and (D) OS in patients with baseline undetectable HCV RNA who received lenvatinib or lenvatinib plus sintilimab for HCC; (E), Changes in HCV RNA levels after antiviral therapy in 13 HCC patients with detectable baseline HCV RNA, genotype tested at baseline and type of antiviral drug used.

Table 3 Adverse Event

Adverse Event	TKI Group (n=43), n (%)			Combination Group (n=24), n (%)
	All Grade	Grade 1–2	Grade 3–4	All Grade	Grade 1–2	Grade 3–4
Hand and foot syndrome	13(32.6)	10(23.3)	3(7.0)	8(33.3)	6(25.0)	2(8.3)
Platelet count decreased	12(27.9)	8(18.6)	4(9.3)	4(16.7)	3(12.5)	1(4.2)
Lymphocyte count decreased	11(25.6)	9(20.9)	2(4.7)	7(25.9)	4(16.7)	3(12.5)
Diarrhea	9(20.9)	6(14.0)	0	4(16.7)	4(16.7)	0
White blood cell decreased	9(20.9)	6(14.0)	3(7.0)	7(25.9)	5(20.8)	2(8.3)
Neutrophil count decreased	9(20.9)	7(16.3)	2(4.7)	4(16.7)	2(8.3)	2(8.3)
Fatigue	8(18.6)	8(18.6)	0	3(12.5)	3(12.5)	0
Hypoalbuminemia	7(16.3)	7(16.3)	0	3(12.5)	3(12.5)	0
Hypertension	6(14.0)	4(9.3)	2(4.7)	3(12.5)	2(8.3)	1(4.2)
Increased AST	5(11.6)	5(11.6)	0	3(12.5)	3(12.5)	0
Fibrinogen decreased	4(9.3)	4(9.3)	0	1(4.2)	0	1(4.2)
Increased ALT	3(7.0)	3(7.0)	0	2(8.3)	2(8.3)	0
Anemia	3(7.0)	3(7.0)	0	1(4.2)	1(4.2)	0
Loss of appetite	1(2.3)	1(2.3)	0	3(12.5)	3(12.5)	0
Abdominal distention	1(2.3)	1(2.3)	0	2(8.3)	2(8.3)	0
Proteinuria	1(2.3)	1(2.3)	0	1(4.2)	1(4.2)	0
Fever	1(2.3)	1(2.3)	0	1(4.2)	0	1(4.2)
Immune-related pneumonia	0	0	0	1(4.2)	0	1(4.2)

Abbreviations: AST, aspartate aminotransferase; ALT, alanine transaminase; TKI group, tyrosine kinase inhibitors; combination group, TKI combined with PD-1 inhibitors.

Table 4 Clinical Characteristics of Patients with HCV Reactivation

Patients Characteristics			Baseline							At Reactivation
Patient	Age/Sex	Anti-Tumor Therapy	Antiviral Therapy	Genotype	HCV RNA (IU/mL)	AFP (ng/mL)	ALT (U/L)	Child-Pugh	BCLC	Onset (Weeks)	HCV RNA (IU/mL)	AFP (ng/mL)	ALT (U/L)	Child-Pugh	BCLC	Antiviral Therapy
1	51/M	L+S		1b	0	1210	29	A6	C	15	3.914×10^3	17,608	19	B8	C	S+V
2	56/M	Sorafenib	Sofosbuvir	3b	7.446×10^5	9	32	A5	B	13	4.59×10^7	35	142	A5	B	S+D
3	64/F	Sorafenib		2a	0	90	42	A6	B	16	1.491×10^2	17	26	A6	B	S+V

Abbreviations: M, male; F, female; AFP, Alpha fetoprotein; BCLC, Barcelona Clinic Liver Cancer; L+S, lenvatinib +sintilimab; S+V, Sofosbuvir-velpatasvir; S+D, Sofosbuvir + daclatasvir; NA, not applicable.