PD-1 Inhibitors Combined with Tyrosine Kinase Inhibitors with or without Hepatic Artery Infusion Chemotherapy for the First-Line Treatment of HBV-Related Advanced Hepatocellular Carcinoma: A Retrospective Study

Figures & data

Table 1 Baseline Clinical Characteristics

Variables	HPT (n=99)	PT (n=95)	p-value
Combined with HAIC	Yes	No	< 0.001
Age, years	56.40 ± 8.70	57.11 ± 8.60	0.573
Sex			0.959
Male	81	78
Female	18	17
BMI, kg/m^2	22.42 ± 3.37	21.66 ± 2.75	0.860
Child-Pugh			0.424
A	70	72
B	29	23
ECOG			0.161
0	26	17
1	73	78
ALBI			0.514
< −2.59	41	35
≥ −2.59	58	60
Maximum tumor size, cm			0.101
≤ 10	51	60
> 10	48	35
Tumor number			0.375
Solitary	17	12
Multiple	82	83
Macrovascular invasion			0.005
Absent	40	38
PVTT	33	49
HVTT	8	3
Both PVTT and HVTT	18	5
Intrahepatic metastasis			0.748
Absent	17	18
Present	82	77
Extrahepatic metastasis			0.408
Absent	34	24
Lung	30	33
Bone	4	9
Celiac lymph nodes	26	23
Others	5	6
Differentiation degree			0.080
Well	13	5
Moderately	17	22
Poorly	27	36
Unknown	42	32
Types of PD-1 inhibitors			0.945
Camrelizumab	80	75
Sintilimab	14	15
Others	5	5
Types of TKIs			0.975
Lenvatinib	83	80
Sorafenib	7	6
Others	9	9
Surgery			0.168
Yes	21	13
No	78	82
AFP, ng/mL			0.252
≤ 400	45	51
> 400	54	44
NLR			0.322
< 3	56	47
≥ 3	43	48
PLR			0.244
< 108.47	37	28
≥ 108.47	62	67
MLR			0.185
< 0.31	37	27
≥ 0.31	62	68
SII			0.862
< 532.22	54	53
≥ 532.22	45	42
SIRI			0.181
< 1.33	48	37
≥ 1.33	51	58

Notes: HPT, hepatic artery infusion chemotherapy combined with programmed cell death protein-1 inhibitors plus tyrosine kinase inhibitors; PT, programmed cell death protein-1 inhibitors plus tyrosine kinase inhibitors; SII, multiplying the platelet count by the neutrophil count divided by the lymphocyte count; SIRI, multiplying the monocyte count by the neutrophil count divided by the lymphocyte count.

Abbreviations: HAIC, hepatic artery infusion chemotherapy; BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; ALBI, albumin-bilirubin; PVTT, portal vein tumor thrombus; HVTT, hepatic vein tumor thrombus; PD-1, programmed cell death protein-1; TKIs, tyrosine kinase inhibitors; AFP, α-fetoprotein; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; MLR, monocyte-to-lymphocyte ratio; SII, systemic immune inflammation index; SIRI, systemic inflammatory response index.

Figure 1 Patient screening flowchart.

Abbreviations: HCC, hepatocellular carcinoma; HPT, hepatic artery infusion chemotherapy combined with programmed cell death protein-1 inhibitors plus tyrosine kinase inhibitors; PT, programmed cell death protein-1 inhibitors plus tyrosine kinase inhibitors.

Figure 2 Kaplan–Meier curves for progression-free survival (A) and overall survival (B).

Abbreviations: HPT, hepatic artery infusion chemotherapy combined with programmed cell death protein-1 inhibitors plus tyrosine kinase inhibitors; PT, programmed cell death protein-1 inhibitors plus tyrosine kinase inhibitors.

Table 2 Summary of Best Response

	RECIST version 1.1			mRECIST
	HPT (%)	PT (%)	p-value	HPT (%)	PT (%)	p-value
CR	0(0)	0(0)	-	0(0)	0(0)	-
PR	43 (43.4)	21 (22.1)	0.002	53 (53.5)	30 (31.6)	0.002
SD	51 (51.5)	58 (61.1)	0.181	41 (41.4)	49 (51.6)	0.156
PD	5(5.1)	16 (16.8)	0.008	5(5.1)	16 (16.8)	0.008
ORR	43 (43.4)	21 (22.1)	0.002	53 (53.5)	30 (31.6)	0.002
DCR	94 (94.9)	79 (83.2)	0.008	94 (94.9)	79 (83.2)	0.008

Abbreviations: HPT, hepatic artery infusion chemotherapy combined with programmed cell death protein-1 inhibitors plus tyrosine kinase inhibitors; PT, programmed cell death protein-1 inhibitors plus tyrosine kinase inhibitors; RECIST version 1.1, Response Evaluation Criteria in Solid Tumors version 1.1; mRECIST, modified Response Evaluation Criteria in Solid Tumors; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; DCR, disease control rate.

Figure 3 Best assessment of intrahepatic target lesions in both groups.

Notes: (A) Evaluated according to RECIST 1.1 criteria. (B) Evaluated according to mRECIST criteria.

Abbreviations: HPT, hepatic artery infusion chemotherapy combined with programmed cell death protein-1 inhibitors plus tyrosine kinase inhibitors; PT, programmed cell death protein-1 inhibitors plus tyrosine kinase inhibitors; RECIST1.1, Response Evaluation Criteria in Solid Tumors version 1.1; mRECIST, modified Response Evaluation Criteria in Solid Tumors; PR, partial response; SD, stable disease; PD, progressive disease.

Table 3 Univariate and Multivariate Analysis of Risk Factors for Overall Survival in Combined HAIC Group

Variables	Univariate analysis			Multivariate analysis
	HR	95% CI	p-value	HR	95% CI	p-value
Age (years)	0.997	0.971–1.024	0.834
Sex, (female/male)	0.922	0.506–1.682	0.792
AFP (ng/mL), (≤/>400)	1.545	0.965–2.476	0.070
Extrahepatic metastasis, (no/yes)	1.122	0.687–1.832	0.645
Child-Pugh, (A/B)	3.153	1.922–5.174	<0.001*	3.121	1.811–5.378	<0.001*
Largest liver tumor size (cm)	1.057	1.008–1.109	0.023*	1.017	0.960–1.078	0.567
Tumor number, (1/>1)	1.373	0.717–2.627	0.339
Macrovascular invasion, (no/yes)	1.489	0.943–2.354	0.088
Differentiation degree
Well
Moderately	1.470	0.609–3.550	0.391
Poorly	3.465	1.530–7.846	0.003*	3.981	1.699–9.330	0.001*
Types of PD-1 inhibitors(camrelizumab/sintilimab)	0.982	0.674–1.430	0.923
Types of TKIs (lenvatinib/sorafenib)	0.852	0.583–1.244	0.406
Surgery, (no/yes)	0.591	0.329–1.063	0.079
ALBI, (<-2.59/≥-2.59)	1.827	1.160–2.878	0.009*	2.220	1.306–3.776	0.003*
MLR, (<0.31/≥0.31)	1.232	0.786–1.931	0.363
NLR, (<3/≥3)	1.812	1.158–2.834	0.009*	1.016	0.578–1.785	0.956
PLR, (<108.47/≥108.47)	1.564	0.981–2.495	0.060
SIRI, (<1.33/≥1.33)	2.061	1.306–3.253	0.002*	1.925	1.132–3.275	0.016*
SII, (<532.22/≥532.22)	1.292	0.828–2.015	0.259

Note: *Referred to p<0.05 in univariate and multivariate analysis.

Abbreviations: HAIC, hepatic artery infusion chemotherapy; AFP, α-fetoprotein; PD-1, programmed cell death protein-1; TKIs, tyrosine kinase inhibitors; ALBI, albumin-bilirubin; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; MLR, monocyte-to-lymphocyte ratio; SII, systemic immune inflammation index (multiplying the platelet count by the neutrophil count divided by the lymphocyte count); SIRI, systemic inflammatory response index (multiplying the monocyte count by the neutrophil count divided by the lymphocyte count).

Figure 4 Time-dependent ROC curve of overall survival at 1 year for SIRI (A) and ALBI (B).

Abbreviations: AUC, area under the curve; ROC, receiver operating characteristic; SIRI, systemic inflammatory response index; ALBI, albumin-bilirubin.

Figure 5 The OS of patients with HBV-related advanced HCC treated with HAIC combined with PD-1 inhibitors plus TKIs. Notes: (A) OS according to the SIRI. (B) OS according to the ALBI value.

Abbreviations: OS, overall survival; PD-1, programmed cell death protein-1; TKIs, tyrosine kinase inhibitors; HAIC, hepatic artery infusion chemotherapy; HCC, hepatocellular carcinoma; SIRI, systemic inflammatory response index; ALBI, albumin-bilirubin.

Table 4 Treatment-Related Adverse Events

Adverse events	HPT (n=99)		PT (n=95)		p-value
	Any grade (%)	Grade 3–4(%)	Any grade (%)	Grade 3-4(%)	Any grade (%)	Grade 3-4(%)
Laboratory-related AEs, n (%)
Leukopenia/neutropenia	40 (40.4)	7(7.1)	29 (30.5)	3(3.2)	0.151	0.364
Thrombocytopenia	45 (45.5)	10 (10.1)	41 (43.2)	6(6.3)	0.748	0.338
Hemoglobin decreased	15 (15.2)	4(4.0)	8(8.4)	2(2.1)	0.147	0.716
Elevated ALT	63 (63.6)	7(7.1)	54 (56.8)	2(2.1)	0.334	0.193
Elevated AST	77 (77.8)	7(7.1)	67 (70.5)	6(6.3)	0.248	0.833
Hyperbilirubinemia	69 (69.7)	3(3.0)	67 (70.5)	5(5.3)	0.900	0.674
Hypoalbuminemia	70 (70.7)	7(7.1)	64 (67.4)	6(6.3)	0.615	0.833
Hematuria/proteinuria	7(7.1)	1(1.0)	2(2.1)	0(0)	0.193	1.000
Creatinine increased	3(3.0)	0(0)	1(1.1)	0(0)	0.643	1.000
Other-related AEs, n (%)
Fatigue	58 (58.6)	1(1.0)	49 (51.6)	3(3.2)	0.327	0.584
Pain	31 (31.3)	4(4.0)	29 (30.5)	2(2.1)	0.906	0.716
Hypertension	24 (24.2)	2(2.0)	23 (24.2)	0(0)	0.996	0.498
Rash	6(6.1)	1(1.0)	3(3.2)	1(1.1)	0.536	1.000
Pruritus	3(3.0)	0(0)	5(5.3)	2(2.1)	0.674	0.239
Fever	14 (14.1)	0(0)	15 (15.8)	0(0)	0.748	1.000
Nausea/vomiting	38 (38.4)	7(7.1)	30 (31.6)	2(2.1)	0.321	0.193
Diarrhea	15 (15.2)	0(0)	11 (11.6)	1(1.1)	0.456	0.490
Decreased appetite	31 (31.3)	0(0)	36 (37.9)	1(1.1)	0.335	0.490
Dental ulcer	21 (21.2)	1(1.0)	18 (18.9)	1(1.1)	0.694	1.000
Hypothyroidism	11 (11.1)	0(0)	16 (16.8)	0(0)	0.249	1.000
Peripheral neurotoxicity	14 (14.1)	0(0)	1(1.1)	0(0)	<0.001	1.000

Abbreviations: AEs, adverse events; HPT, hepatic artery infusion chemotherapy combined with programmed cell death protein-1 inhibitors plus tyrosine kinase inhibitors; PT, programmed cell death protein-1 inhibitors plus tyrosine kinase inhibitors; ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Data Sharing Statement

The datasets generated during the current study are available from the corresponding author on reasonable request.