The Safety and Efficacy of Hepatic Arterial Infusion Chemotherapy Combined with PD-(L)1 Inhibitors and Molecular Targeted Therapies for the Treatment of Intermediate and Advanced Hepatocellular Carcinoma Unsuitable for Transarterial Chemoembolization

Figures & data

Figure 1 Study flow diagram.

Figure 2 NLR cutoff value calculation.

Table 1 Baseline Characteristics of Patients

Characteristics	No. (%)
Age (years)	60.2±12.5
Sex (male), n (%)	44 (80.0%)
Hepatitis B virus infection	47 (85.5%)
Liver cirrhosis	42 (76.4%)
Ascites (present), n (%)	14 (25.5%)
Total bilirubin (umol/L)	18.0±7.3
Albumin (g/L)	36.4±6.4
AFP > 400 (ng/mL)	29 (52.7%)
NLR > 3.82	20 (36.4%)
ECOG
0	33 (60.0%)
1	22 (40.0%)
Child-Pugh score (points)	6.0 (5.0–6.0)
Child-Pugh grade, n (%)
A	45 (81.8%)
B	10 (18.2%)
ALBI grade
1	17 (30.9%)
2	38 (69.1%)
BCLC stage
B	18 (32.7%)
C	37 (67.3%)
Size of largest nodule (cm)
<10	31 (56.4%)
≥10	24 (43.6%)
Tumor distribution
Uni-lobar	19 (34.5%)
Bi-lobar	36 (65.5%)
Infiltrative type	10 (18.2%)
Main portal vein invasion	33 (60.0%)
Extrahepatic metastasis	10 (18.2%)

Note: Data are expressed as n (%) or mean ± standard deviation.

Abbreviations: AFP, alpha-fetoprotein; NLR, neutrophil-to-lymphocyte ratio; ECOG, Eastern Cooperative Oncology Group; ALBI, albumin-bilirubin; BCLC, Barcelona Clinic Liver Cancer.

Table 2 Regimens of the Triple Combination Therapy

Treatment		No. (%)
PD-(L)1 inhibitors and MTT
	Atezolizumab + Bevacizumab	3 (5.5%)
	Donafenib + Tislelizumab	7 (12.7%)
	Lenvatinib + Tislelizumab	5 (9.1%)
	Lenvatinib + Stintilimab	8 (14.5%)
	Bevacizumab + Stintilimab	9 (16.4%)
	Lenvatinib + Camrelizumab	7 (12.7%)
	Sorafenib + Camrelizumab	8 (14.5%)
	Apatinib + Camrelizumab	8 (14.5%)
HAIC treatment cycle
	Median (IQR)	4 (2–4)
PD-(L)1 treatment cycle
	Median (IQR)	6 (4–11)

Note: Data are expressed as median (IQR) or n (%).

Abbreviations: MTT, molecular targeted therapies; HAIC, hepatic arterial infusion chemotherapy.

Table 3 Summary of Best Response

Best Response	All Patients (n = 55)
CR	8 (14.5%)
PR	16 (29.1%)
SD	10 (18.2%)
PD	21 (38.2%)
ORR	24 (43.6%)
DCR	34 (61.8%)

Note: Data are expressed as n (%).

Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; DCR, disease control rate.

Figure 3 Long-term survival outcomes after HAIC triple therapy. (A) OS; (B) PFS.

Table 4 Univariate and Multivariate Analysis of Risk Factors for OS and PFS

Variables	Univariate Analysis			Multivariate Analysis
	HR	95% CI	P value	HR	95% CI	P value
OS
Liver cirrhosis	2.826	0.979–8.157	0.055
ALBI grade (2 vs 1)	3.119	1.185–8.209	0.021
NLR > 3.82	2.325	1.115–4.845	0.024	2.380	1.116–5.079	0.025
ECOG (1 vs 0)	2.556	1.221–5.349	0.013	2.906	1.373–6.154	0.005
Extrahepatic metastasis	7.309	3.135–17.041	< 0.001	8.373	3.492–20.078	< 0.001
PFS
Liver cirrhosis	2.296	0.948–5.563	0.066
Child-Pugh score	1.247	0.961–1.618	0.097
ECOG (1 vs 0)	2.911	1.475–5.746	0.002	3.170	1.607–6.256	0.001
Extrahepatic metastasis	5.312	2.364–11.932	< 0.001	5.870	2.615–13.175	< 0.001

Abbreviations: OS, overall survival; ALBI, albumin-bilirubin; NLR, neutrophil-to-lymphocyte ratio; ECOG, Eastern Cooperative Oncology Group; PFS, progression-free survival.

Figure 4 Kaplan-Meier analysis of NLR > 3.82 (A), ECOG (B), and EHM (C) with OS.

Table 5 Treatment Related Adverse Events

Adverse Events	Any Grade (%)	Grade 1/2 (%)	Grade 3 (%)	Grade 4 (%)
Neutropenia	7 (12.7%)	5 (9.1%)	2 (3.6%)	0
Thrombocytopenia	9 (16.4%)	6 (10.9%)	3 (5.5%)	0
Elevated ALT	3 (5.5%)	2 (3.6%)	1 (1.8%)	0
Elevated AST	10 (18.2%)	8 (14.5%)	2 (3.6%)	0
Hyperbilirubinemia	9 (16.4%)	6 (10.9%)	3 (5.5%)	0
Fatigue	7 (12.7%)	7 (12.7%)	0	0
Fever	3 (5.5%)	3 (5.5%)	0	0
Nausea/vomiting	6 (10.9%)	6 (10.9%)	0	0
Abdominal pain	3 (5.5%)	2 (3.6%)	1 (1.8%)	0
Proteinuria	2 (3.6%)	2 (3.6%)	0	0
Hypertension	3 (5.5%)	3 (5.5%)	0	0
Hand-foot syndrome	3 (5.5%)	3 (5.5%)	0	0
Immune-related hypothyroidism	2 (3.6%)	2 (3.6%)	0	0
Immune-related myocarditis	0	0	0	1 (1.8%)
Variceal bleeding	1 (1.8%)	0	1 (1.8%)	0

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Data Sharing Statement

All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author (Wei-Dong Wang).