Gastroenterol Res

Gastroenterology Research, ISSN 1918-2805 print, 1918-2813 online, Open Access

Article copyright, the authors; Journal compilation copyright, Gastroenterol Res and Elmer Press Inc

Journal website https://www.gastrores.org

Original Article

Volume 17, Number 1, February 2024, pages 15-22

A Real-World Experience on a Chinese Population of Patients With Unresectable Hepatocellular Carcinoma Treated With Nivolumab

Figure 1. The progression-free survival of patients with different tumor radiological responses (CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease).

Figure 2. The overall survival of patients with different tumor radiological responses (CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease).

**Table 1.** The General Data of Patients
	All (n = 57)
BCLC: Barcelona Clinic Liver Cancer; AFP: alpha-fetoprotein; EHS: extrahepatic spread; HBV: hepatitis B virus; HCV: hepatitis C virus; LRT: local regional therapy; MVI: microscopic vascular invasion; N: number of patients; NLR: neutrophil to lymphocyte ratio; SD: standard derivation; TKI: tyrosine kinase inhibitor; ALBI: albumin-bilirubin.
Age (years)	66.7 ± 9.8
≤ 65		34 (59.6%)
> 65		23 (40.4%)
Gender
Male		48 (84.2%)
Female		9 (15.8%)
Viral hepatitis
HBV		26 (45.5%)
HCV		12 (21.1%)
HBV/HCV		2 (3.5%)
Nil		17 (29.9%)
Child-Pugh stage
A		40 (70.2%)
B		17 (29.8%)
ALBI grade
1		25 (43.9%)
2		30 (52.6%)
3		2 (3.5%)
BCLC stage
B		19 (33.3%)
C		38 (66.7%)
MVI		21 (36.8%)
EHS		25 (43.9%)
Systemic therapy line
First-line		14 (24.6%)
Second-line		43 (75.4%)
Combined TKI		9 (15.8%)
Combined LRT		8 (14.0%)
Nivolumab dosage (mg/kg)	2.5 ± 0.7
≤ 2 mg/kg		19 (33.3%)
> 2 mg/kg		38 (66.7%)
Nivolumab duration (months)	6.5 ± 5.9
Total bilirubin (mg/dL)	1.0 ± 0.7
Albumin (g/dL)	3.7 ± 0.6
NLR
> 5		14 (24.6%)
≤ 5		43 (75.4%)
AFP (ng/mL)	10,544.1 ± 46,120.1
> 400 ng/mL		18 (31.6%)
≤ 400 ng/mL		39 (68.4%)

Table 1. The General Data of Patients

All (n = 57)

Mean ± SD

N (%)

BCLC: Barcelona Clinic Liver Cancer; AFP: alpha-fetoprotein; EHS: extrahepatic spread; HBV: hepatitis B virus; HCV: hepatitis C virus; LRT: local regional therapy; MVI: microscopic vascular invasion; N: number of patients; NLR: neutrophil to lymphocyte ratio; SD: standard derivation; TKI: tyrosine kinase inhibitor; ALBI: albumin-bilirubin.

Age (years)

66.7 ± 9.8

≤ 65

34 (59.6%)

> 65

23 (40.4%)

Gender

Male

48 (84.2%)

Female

9 (15.8%)

Viral hepatitis

HBV

26 (45.5%)

HCV

12 (21.1%)

HBV/HCV

2 (3.5%)

Nil

17 (29.9%)

Child-Pugh stage

40 (70.2%)

17 (29.8%)

ALBI grade

25 (43.9%)

30 (52.6%)

2 (3.5%)

BCLC stage

19 (33.3%)

38 (66.7%)

MVI

21 (36.8%)

EHS

25 (43.9%)

Systemic therapy line

First-line

14 (24.6%)

Second-line

43 (75.4%)

Combined TKI

9 (15.8%)

Combined LRT

8 (14.0%)

Nivolumab dosage (mg/kg)

2.5 ± 0.7

≤ 2 mg/kg

19 (33.3%)

> 2 mg/kg

38 (66.7%)

Nivolumab duration (months)

6.5 ± 5.9

Total bilirubin (mg/dL)

1.0 ± 0.7

Albumin (g/dL)

3.7 ± 0.6

NLR

> 5

14 (24.6%)

≤ 5

43 (75.4%)

AFP (ng/mL)

10,544.1 ± 46,120.1

> 400 ng/mL

18 (31.6%)

≤ 400 ng/mL

39 (68.4%)

**Table 2.** The Therapeutic Responses of Patients Treated With Nivolumab
	All (n = 57)
^aDefined as decline AFP level over 10% from baseline during nivolumab therapy. AFP: alpha-fetoprotein; CR: complete response; DCR: disease control rate; IRAE: immune-related adverse event; N: number of patients; ORR: objective response rate; OS: overall survival; PD: progressive disease; PFS: progression-free survival; PR: partial response; SD: stable disease; CI: confidence interval.
Radiological tumor responses
CR			2 (3.5%)
PR			12 (21.1%)
SD			10 (17.5%)
PD			33 (57.9%)
ORR			14 (24.6%)
DCR			24 (42.1%)
OS (months)	11.5	4.3 - 17.8
PFS (months)	5.8	1.1 - 10.6
IRAE			5 (8.8%)
AFP response^a			17 (30.4%)

Table 2. The Therapeutic Responses of Patients Treated With Nivolumab

All (n = 57)

Mean

95% CI

N (%)

^aDefined as decline AFP level over 10% from baseline during nivolumab therapy. AFP: alpha-fetoprotein; CR: complete response; DCR: disease control rate; IRAE: immune-related adverse event; N: number of patients; ORR: objective response rate; OS: overall survival; PD: progressive disease; PFS: progression-free survival; PR: partial response; SD: stable disease; CI: confidence interval.

Radiological tumor responses

2 (3.5%)

12 (21.1%)

10 (17.5%)

33 (57.9%)

ORR

14 (24.6%)

DCR

24 (42.1%)

OS (months)

11.5

4.3 - 17.8

PFS (months)

5.8

1.1 - 10.6

IRAE

5 (8.8%)

AFP response^a

17 (30.4%)

**Table 3.** The Strength of Association Between Clinical Parameters and Tumor Objective Response Following Nivolumab Usage
	Univariable analysis	Multivariable analysis
^aDefined as decline AFP level over 10% from baseline during nivolumab therapy. BCLC: Barcelona Clinic Liver Cancer; AFP: alpha-fetoprotein; CI: confidence interval; EHS: extrahepatic spread; HBV: hepatitis B virus; HCV: hepatitis C virus; HR: hazard ratio; IRAE: immune-related adverse event; LRT: local regional therapy; MVI: microscopic vascular invasion; NLR: neutrophil to lymphocyte ratio; TKI: tyrosine kinase inhibitor; ALBI: albumin-bilirubin.
Age (≤ 65 vs. > 65 years old)	0.17	0.03 - 0.88	0.034	0.25	0.04 - 1.38	0.110
Gender (male vs. female)	0.86	0.16 - 4.70	0.859
HBV (HbsAg + vs. -)	0.72	0.21 - 2.42	0.590
HCV (anti-HCV + vs. -)	5.14	1.36 - 19.33	0.015	2.98	0.64 - 13.73	0.162
Child-Pugh stage (B vs. A)	0.31	0.61 - 1.58	0.159
ALBI grade (2/3 vs. 1)	0.72	0.21 - 2.42	0.595
BCLC stage (C vs. B)	0.87	0.25 - 3.08	0.828
Baseline AFP (> 400 vs. ≤ 400 ng/mL)	1.94	0.55 - 6.77	0.300
AFP response^a (yes vs. no)	7.65	2.01 - 29.14	0.003	4.89	1.14 - 21.00	0.033
MVI (yes vs. no)	0.61	0.16 - 2.27	0.463
EHS (yes vs. no)	0.95	0.28 - 3.20	0.931
Systemic therapy (second-line vs. first-line)	0.76	0.19 - 2.95	0.737
Combined TKI (yes vs. no)	1.68	0.36 - 7.85	0.508
Combined LRT (yes vs. no)	1.03	0.18 - 5.78	0.975
Nivolumab dosage (> 2 vs. ≤ 2 mg/kg)	1.34	0.36 - 5.00	0.664
NLR (≤ 5 vs. > 5)	1.26	0.30 - 5.37	0.754
IRAE (yes vs. no)	5.59	0.83 - 37.71	0.077

Table 3. The Strength of Association Between Clinical Parameters and Tumor Objective Response Following Nivolumab Usage

Univariable analysis

Multivariable analysis

95% CI

P value

95% CI

P value

^aDefined as decline AFP level over 10% from baseline during nivolumab therapy. BCLC: Barcelona Clinic Liver Cancer; AFP: alpha-fetoprotein; CI: confidence interval; EHS: extrahepatic spread; HBV: hepatitis B virus; HCV: hepatitis C virus; HR: hazard ratio; IRAE: immune-related adverse event; LRT: local regional therapy; MVI: microscopic vascular invasion; NLR: neutrophil to lymphocyte ratio; TKI: tyrosine kinase inhibitor; ALBI: albumin-bilirubin.

Age (≤ 65 vs. > 65 years old)

0.17

0.03 - 0.88

0.034

0.25

0.04 - 1.38

0.110

Gender (male vs. female)

0.86

0.16 - 4.70

0.859

HBV (HbsAg + vs. -)

0.72

0.21 - 2.42

0.590

HCV (anti-HCV + vs. -)

5.14

1.36 - 19.33

0.015

2.98

0.64 - 13.73

0.162

Child-Pugh stage (B vs. A)

0.31

0.61 - 1.58

0.159

ALBI grade (2/3 vs. 1)

0.72

0.21 - 2.42

0.595

BCLC stage (C vs. B)

0.87

0.25 - 3.08

0.828

Baseline AFP (> 400 vs. ≤ 400 ng/mL)

1.94

0.55 - 6.77

0.300

AFP response^a (yes vs. no)

7.65

2.01 - 29.14

0.003

4.89

1.14 - 21.00

0.033

MVI (yes vs. no)

0.61

0.16 - 2.27

0.463

EHS (yes vs. no)

0.95

0.28 - 3.20

0.931

Systemic therapy (second-line vs. first-line)

0.76

0.19 - 2.95

0.737

Combined TKI (yes vs. no)

1.68

0.36 - 7.85

0.508

Combined LRT (yes vs. no)

1.03

0.18 - 5.78

0.975

Nivolumab dosage (> 2 vs. ≤ 2 mg/kg)

1.34

0.36 - 5.00

0.664

NLR (≤ 5 vs. > 5)

1.26

0.30 - 5.37

0.754

IRAE (yes vs. no)

5.59

0.83 - 37.71

0.077

**Table 4.** The Strength of Association Between Clinical Parameters and Tumor Disease Control Following Nivolumab Usage
	Univariable analysis	Multivariable analysis
^aDefined as decline AFP level over 10% from baseline during nivolumab therapy. BCLC: Barcelona Clinic Liver Cancer; AFP: alpha-fetoprotein; CI: confidence interval; EHS: extrahepatic spread; HBV: hepatitis B virus; HCV: hepatitis C virus; HR: hazard ratio; IRAE: immune-related adverse event; LRT: local regional therapy; MVI: microscopic vascular invasion; NLR: neutrophil to lymphocyte ratio; TKI: tyrosine kinase inhibitor; ALBI: albumin-bilirubin.
Age (≤ 65 vs. > 65 years old)	0.31	0.10 - 0.99	0.048	0.41	0.12 - 1.40	0.156
Gender (male vs. female)	0.64	0.14 - 2.88	0.564
HBV (HbsAg + vs. -)	0.60	0.21 - 1.72	0.338
HCV (anti-HCV + vs. -)	2.25	0.66 - 7.67	0.195
Child-Pugh stage (B vs. A)	0.75	0.24 - 2.35	0.622
ALBI grade (2/3 vs. 1)	0.87	0.30 - 2.51	0.798
BCLC stage (C vs. B)	0.72	0.24 - 2.20	0.569
Baseline AFP (> 400 vs. ≤ 400 ng/mL)	2.23	0.72 - 6.96	0.166
AFP response^a (yes vs. no)	5.40	1.55 - 18.76	0.008	4.71	1.32 - 16.81	0.017
MVI (yes vs. no)	0.56	0.18 - 1.71	0.308
EHS (yes vs. no)	0.85	0.30 - 2.48	0.776
Systemic therapy (second-line vs. first-line)	0.65	0.19 - 2.20	0.492
Combined TKI (yes vs. no)	1.91	0.45 - 8.02	0.378
Combined LRT (yes vs. no)	0.80	0.17 - 3.73	0.776
Nivolumab dosage (> 2 vs. ≤ 2 mg/kg)	1.39	0.45 - 4.30	0.570
NLR (≤ 5 vs. > 5)	1.53	0.45 - 5.14	0.492
IRAE (yes vs. no)	6.40	0.70 - 61.42	0.108

Table 4. The Strength of Association Between Clinical Parameters and Tumor Disease Control Following Nivolumab Usage

Univariable analysis

Multivariable analysis

95% CI

P value

95% CI

P value

Age (≤ 65 vs. > 65 years old)

0.31

0.10 - 0.99

0.048

0.41

0.12 - 1.40

0.156

Gender (male vs. female)

0.64

0.14 - 2.88

0.564

HBV (HbsAg + vs. -)

0.60

0.21 - 1.72

0.338

HCV (anti-HCV + vs. -)

2.25

0.66 - 7.67

0.195

Child-Pugh stage (B vs. A)

0.75

0.24 - 2.35

0.622

ALBI grade (2/3 vs. 1)

0.87

0.30 - 2.51

0.798

BCLC stage (C vs. B)

0.72

0.24 - 2.20

0.569

Baseline AFP (> 400 vs. ≤ 400 ng/mL)

2.23

0.72 - 6.96

0.166

AFP response^a (yes vs. no)

5.40

1.55 - 18.76

0.008

4.71

1.32 - 16.81

0.017

MVI (yes vs. no)

0.56

0.18 - 1.71

0.308

EHS (yes vs. no)

0.85

0.30 - 2.48

0.776

Systemic therapy (second-line vs. first-line)

0.65

0.19 - 2.20

0.492

Combined TKI (yes vs. no)

1.91

0.45 - 8.02

0.378

Combined LRT (yes vs. no)

0.80

0.17 - 3.73

0.776

Nivolumab dosage (> 2 vs. ≤ 2 mg/kg)

1.39

0.45 - 4.30

0.570

NLR (≤ 5 vs. > 5)

1.53

0.45 - 5.14

0.492

IRAE (yes vs. no)

6.40

0.70 - 61.42

0.108

**Table 5.** The Strength of Association Between Clinical Parameters and Overall Survival Following Nivolumab Usage
	Univariable analysis
^aDefined as decline AFP level over 10% from baseline during nivolumab therapy. BCLC: Barcelona Clinic Liver Cancer; AFP: alpha-fetoprotein; CI: confidence interval; EHS: extrahepatic spread; HBV: hepatitis B virus; HCV: hepatitis C virus; HR: hazard ratio; IRAE: immune-related adverse event; LRT: local regional therapy; MVI: microscopic vascular invasion; NLR: neutrophil to lymphocyte ratio; TKI: tyrosine kinase inhibitor; ALBI: albumin-bilirubin.
Age (≤ 65 vs. > 65 years old)	0.60	0.32 - 1.13	0.112
Gender (male vs. female)	0.59	0.27 - 1.29	0.187
HBV (HbsAg + vs. -)	0.74	0.40 - 1.40	0.356
HCV (anti-HCV + vs. -)	2.36	1.02 - 5.40	0.043
Child-Pugh stage (B vs. A)	0.75	0.38 - 1.49	0.418
ALBI grade (2/3 vs. 1)	0.58	0.30 - 1.11	0.101
BCLC stage (C vs. B)	0.61	0.30 - 1.27	0.187
Baseline AFP (> 400 vs. ≤ 400 ng/mL)	0.80	0.41 - 1.57	0.523
AFP response^a (yes vs. no)	1.38	0.69 - 2.80	0.364
MVI (yes vs. no)	0.86	0.45 - 1.64	0.646
EHS (yes vs. no)	0.58	0.31 - 1.10	0.095
Systemic therapy (second-line vs. first-line)	0.85	0.42 - 1.75	0.667
Combined TKI (yes vs. no)	1.34	0.61 - 2.92	0.463
Combined LRT (yes vs. no)	1.75	0.68 - 4.50	0.245
Nivolumab dosage (> 2 vs. ≤ 2 mg/kg)	1.03	0.53 - 2.00	0.921
NLR (≤ 5 vs. > 5)	1.17	0.57 - 2.41	0.663
IRAE (yes vs. no)	5.58	0.76 - 40.88	0.091

Table 5. The Strength of Association Between Clinical Parameters and Overall Survival Following Nivolumab Usage

Univariable analysis

95% CI

P value

Age (≤ 65 vs. > 65 years old)

0.60

0.32 - 1.13

0.112

Gender (male vs. female)

0.59

0.27 - 1.29

0.187

HBV (HbsAg + vs. -)

0.74

0.40 - 1.40

0.356

HCV (anti-HCV + vs. -)

2.36

1.02 - 5.40

0.043

Child-Pugh stage (B vs. A)

0.75

0.38 - 1.49

0.418

ALBI grade (2/3 vs. 1)

0.58

0.30 - 1.11

0.101

BCLC stage (C vs. B)

0.61

0.30 - 1.27

0.187

Baseline AFP (> 400 vs. ≤ 400 ng/mL)

0.80

0.41 - 1.57

0.523

AFP response^a (yes vs. no)

1.38

0.69 - 2.80

0.364

MVI (yes vs. no)

0.86

0.45 - 1.64

0.646

EHS (yes vs. no)

0.58

0.31 - 1.10

0.095

Systemic therapy (second-line vs. first-line)

0.85

0.42 - 1.75

0.667

Combined TKI (yes vs. no)

1.34

0.61 - 2.92

0.463

Combined LRT (yes vs. no)

1.75

0.68 - 4.50

0.245

Nivolumab dosage (> 2 vs. ≤ 2 mg/kg)

1.03

0.53 - 2.00

0.921

NLR (≤ 5 vs. > 5)

1.17

0.57 - 2.41

0.663

IRAE (yes vs. no)

5.58

0.76 - 40.88

0.091

**Table 6.** The Strength of Association Between Survival Outcomes and Best Tumor Radiological Responses Following Nivolumab Usage
	Univariable analysis
CI: confidence interval; DC: disease control; HR: hazard ratio; OR: objective response.
Progression-free survival
OR vs. non-OR	2.63	1.23 - 5.66	0.013
DC vs. non-DC	2.89	1.56 - 5.37	0.008
Overall survival
OR vs. non-OR	1.53	0.71 - 3.34	0.284
DC vs. non-DC	2.09	1.07 - 4.08	0.032

Table 6. The Strength of Association Between Survival Outcomes and Best Tumor Radiological Responses Following Nivolumab Usage

Univariable analysis

95% CI

P value

CI: confidence interval; DC: disease control; HR: hazard ratio; OR: objective response.

Progression-free survival

OR vs. non-OR

2.63

1.23 - 5.66

0.013

DC vs. non-DC

2.89

1.56 - 5.37

0.008

Overall survival

OR vs. non-OR

1.53

0.71 - 3.34

0.284

DC vs. non-DC

2.09

1.07 - 4.08

0.032