Early C‐reactive Protein Kinetics Predict Response to Immune Checkpoint Blockade in Unresectable Hepatocellular Carcinoma

Figures & data

Table 1 Comparison of Baseline Parameters Between CRP Flare-Responders, CRP Responders and CRP Non-Responders

Characteristic	Overall N=132	Flare-Responder N=29	Responder N=45	Non-Responder N=58	p value
Gender					0.816
male	120 (90.9%)	27 (93.1%)	40 (88.9%)	53 (91.4%)
female	12 (9.1%)	2 (6.9%)	5 (11.1%)	5 (8.6%)
Age (year)					0.158
≤60	108 (81.8%)	27 (93.1%)	34 (75.6%)	47 (81.0%)
>60	24 (18.2%)	2 (6.9%)	11 (24.4%)	11 (19.0%)
BCLC stage					0.485
B	35 (26.5%)	10 (34.5%)	12 (26.7%)	13 (22.4%)
C	97 (73.5%)	19 (65.5%)	33 (73.3%)	45 (77.6%)
Child-Pugh grade					0.833
A	112 (84.9%)	25 (86.2%)	37 (82.2%)	50 (86.2%)
B	20 (15.1%)	4 (13.8%)	8 (17.8%)	8 (13.8%)
ECOG PS					0.472
0	113 (85.6%)	24 (82.8%)	33 (73.3%)	41 (70.7%)
≥1	19 (14.4%)	5 (17.2%)	12 (26.7%)	17 (29.3%)
Tumor size (cm)					0.167
≤5	39 (29.5%)	5 (17.2%)	17 (37.8%)	17 (29.3%)
>5	93 (70.5%)	24 (82.8%)	28 (62.2%)	41 (70.7%)
Prior treatment, Ablation					0.183
YES	33 (25.0%)	5 (17.2%)	9 (20.0%)	19 (32.8%)
NO	99 (75.0%)	24 (82.8%)	36 (80.0%)	39 (67.2%)
Prior treatment, Surgery					0.536
YES	15 (11.4%)	3 (10.3%)	7 (15.6%)	5 (8.6%)
NO	117 (88.6%)	26 (89.7%)	38 (84.4%)	53 (91.4%)
Prior treatment, TACE/HAIC					0.819
YES	75 (56.8%)	15 (51.7%)	26 (57.8%)	34 (58.6%)
NO	57 (43.2%)	14 (48.3%)	19 (42.2%)	24 (41.4%)
Prior treatment, Target therapy					0.612
YES	49 (37.1%)	9 (31.0%)	19 (42.2%)	21 (36.2%)
NO	83 (62.9%)	20 (69.0%)	26 (57.8%)	37 (63.8%)
Combined treatment, TACE/HAIC					0.100
YES	56 (42.4%)	17 (89.5%)	19 (42.2%)	20 (34.5%)
NO	76 (57.6%)	12 (10.5%)	26 (57.8%)	38 (65.5%)
Combined treatment, Target therapy					0.721
YES	119 (90.2%)	25 (86.2%)	41 (91.1%)	53 (91.4%)
NO	13 (9.8%)	4 (13.8%)	4 (8.9%)	5 (8.6%)
AFP level (ng/L)					0.916
≤400	62 (47.0%)	14 (48.3%)	20 (44.4%)	28 (48.3%)
>400	70 (53.0%)	15 (51.7%)	25 (65.6%)	30 (51.7%)
NLR					0.160
<3	62 (47.0%)	16 (55.2%)	16 (35.6%)	30 (51.7%)
≥3	70 (53.0%)	13 (44.8%)	29 (64.4%)	28 (48.3%)
CRP level (mg/dL)					<0.001
≤5	38 (28.8%)	9 (31.0%)	3 (6.7%)	26 (44.8%)
>5	94 (71.2%)	20 (69.0%)	42 (93.3%)	32 (55.2%)

Abbreviations: BCLC stage, Barcelona Clinic Liver Cancer stage; ECOG PS, Eastern Cooperative Oncology Group performance status; TACE, transcatheter arterial chemoembolization; HAIC, hepatic arterial infusion of chemotherapy; AFP, a-fetoprotein; NLR, Neutrophil-lymphocyte ratio; CRP, C-reactive protein.

Figure 1 Distribution of baseline CRP across different CRP kinetics groups.

Table 2 Efficacy According to Different Early CRP Kinetics

	Flare-Responder N=29	Responder N=45	Non-Responder N=58	p value
Overall survival
Median (95% CI), months	–	20.6 (15.5–25.7)	10.0 (3.1–16.9)	<0.001
Progression-free survival
Median (95% CI), months	11.6 (7.5–15.7)	5.2 (2.3–8.1)	2.3 (1.1–3.6)	<0.001
Best radiological response
CR	3 (10.3%)	1(2.2%)	0 (0.0%)
PR	9 (31.1%)	5(11.1%)	2 (3.5%)
PD	6 (20.7%)	14 (31.1%)	30 (51.7%)
SD	11 (37.9%)	25 (55.6%)	26 (44.8%)
ORR (CR+PR)	12 (41.4%)	6(13.3%)	2 (3.5%)	<0.001
DCR (CR+PR+SD)	23 (79.3%)	31 (68.9%)	28 (48.3%)	<0.001

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

Figure 2 Distribution of response at first staging according to RECIST v1.1 among the different CRP kinetics groups. P value based on Chi-square test for ORR (a) and DCR (b).

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

Figure 3 Kaplan-Meier survival curves showing the progression-free survival (PFS) (a) and overall survival (OS) (b) after ICB initiation stratified according to CRP kinetics groups.

Table 3 Univariable and Multivariable Cox Regression Analyses of Risk Factors for Progression-Free Survival

	Univariable HR (95% CI)	p value	Multivariable HR (95% CI)	p value
Gender
Male	–	0.22
Female	1.46 (0.80–2.67)
Age, y
≤60	–	0.65
>60	1.12 (0.69–1.80)
Child-Pugh grade
A	–	0.87
B	1.05 (0.62–1.78)
BCLC stage
B	–	0.46
C	1.17 (0.77–1.78)
ECOG PS
0	–	0.80
≥1	1.06 (0.68–1.64)
Tumor size (cm)
≤5	–	0.64
>5	1.10 (0.74–1.64)
CRP level
≤5 mg/dl	–	0.21
>5 mg/dl	1.30 (0.86–1.94)
AFP level
≤400 ng/mL	–	0.03	–	0.01
>400 ng/mL	1.51 (1.04–2.20)		1.64 (1.12–2.39)
NLR
<3	–	0.72
≥3	1.07 (0.74–1.55)
Early CRP kinetics
Non-responder	–		–
Responder	0.62 (0.41–0.94)	0.02	0.63 (0.41–0.95)	0.03
Flare-responder	0.28 (0.16–0.48)	<0.001	0.26 (0.15–0.46)	<0.001

Abbreviations: BCLC stage, Barcelona Clinic Liver Cancer stage; ECOG PS, Eastern Cooperative Oncology Group performance status; CRP, C-reactive protein; AFP, a-fetoprotein; NLR, Neutrophil-lymphocyte ratio; HR, hazard ratio; CI, confidence interval.

Table 4 Univariable and Multivariable Cox Regression Analyses of Risk Factors for Overall Survival

	Univariable HR (95% CI)	p value	Multivariable HR (95% CI)	p value
Gender
Male	–	0.32
Female	1.54 (0.66–3.62)
Age, y
≤60	–	0.50
>60	1.27 (0.64–2.51)
Child-Pugh grade
A	–	0.56
B	1.23 (0.61–2.51)
BCLC stage
B	–	0.65
C	1.16 (0.62–2.15)
ECOG PS
0	–	0.46
≥1	1.24 (0.70–2.21)
Tumor size (cm)
≤5	–	0.78
>5	1.08 (0.62–1.90)
CRP level
≤5 mg/dl	–	0.23
>5 mg/dl	1.40 (0.80–2.44)
AFP level
≤400 ng/mL	–	0.04	–	0.04
>400 ng/mL	1.71 (1.00–2.91)		1.71 (1.00–2.91)
NLR
<3	–	0.32
≥3	1.30 (0.77–2.17)
Early CRP kinetics
Non-responder	–		–
Responder	0.57 (0.33–0.97)	0.04	0.55 (0.32–0.94)	0.03
Flare-responder	0.12 (0.04–0.34)	<0.001	0.12 (0.04–0.33)	<0.001

Abbreviations: BCLC stage, Barcelona Clinic Liver Cancer stage; ECOG PS, Eastern Cooperative Oncology Group performance status; CRP, C-reactive protein; AFP, a-fetoprotein; NLR, Neutrophil-lymphocyte ratio; HR, hazard ratio; CI, confidence interval.