Regorafenib combined with programmed death inhibitor after initial treatment failure in unresectable hepatocellular carcinoma

Table 1 Baseline characteristics of hepatocellular carcinoma patients treated with second-line regorafenib combination with programmed cell death-1 inhibitor or monotherapy, n (%)

Characteristics	Overall (n = 140)	R group (n = 39)	RP group (n = 101)	P value
Age				0.811
< 65	99 (70.7)	27 (69.2)	72 (71.3)
≥ 65	41 (29.3)	12 (30.8)	29 (28.7)
Gender				0.652
Female	22 (15.7)	7 (17.9)	15 (14.9)
Male	118 (84.3)	32 (82.1)	86 (85.1)
Smoking				0.839
No	95 (67.9)	28 (71.8)	67 (66.3)
Yes	39 (27.9)	10 (25.6)	29 (28.7)
Unknown	6 (4.3)	1 (2.6)	5 (5.0)
Drinking				0.203
No	103 (73.6)	26 (66.7)	77 (76.2)
Yes	30 (21.4)	12 (30.8)	18 (17.8)
Unknown	7 (5.0)	1 (2.6)	6 (5.9)
Hepatitis B infection				0.908
No	31 (22.1)	8 (20.5)	23 (22.8)
Yes	107 (76.4)	31 (79.5)	76 (75.2)
Unknown	2 (1.4)	0 (0.0)	2 (2.0)
Hepatitis C infection				0.106
No	134 (95.7)	38 (97.4)	96 (95.0)
Yes	1 (0.7)	1 (2.6)	0 (0.0)
Unknown	5 (3.6)	0 (0.0)	5 (5.0)
Diabetes				1.000
No	126 (90.0)	36 (92.3)	90 (89.1)
Yes	13 (9.3)	3 (7.7)	10 (9.9)
Unknown	1 (0.7)	0 (0.0)	1 (1.0)
Hypertension				0.285
No	99 (70.7)	25 (64.1)	74 (73.3)
Yes	41 (29.3)	14 (35.9)	27 (26.7)
First-line ICI therapy				0.224
No	53 (37.9)	14 (35.9)	39 (38.6)
Yes	72 (51.4)	18 (46.2)	54 (53.5)
Unknown	15 (10.7)	7 (17.9)	8 (7.9)
Tumor size				0.323
≤ 5 cm	46 (32.9)	12 (30.8)	34 (33.7)
> 5 cm	25 (17.9)	10 (25.6)	15 (14.9)
Unknown	69 (49.3)	17 (43.6)	52 (51.5)
CNLC				0.715
IIa + IIb	50 (35.7)	13 (33.3)	37 (36.6)
IIIa + IIIb	90 (64.3)	26 (66.7)	64 (63.4)
Child-Pugh class				0.714
A	74 (52.9)	22 (56.4)	52 (51.5)
B	21 (15.0)	5 (12.8)	16 (15.8)
C	2 (1.4)	0 (0.0)	2 (2.0)
Unknown	43 (30.7)	12 (30.8)	31 (30.7)
ECOG PS
0	22 (15.7)	5 (12.8)	17 (16.8)	0.908
1	26 (18.6)	9 (23.1)	17 (16.8)
2	9 (6.4)	2 (5.1)	7 (6.9)
3	1 (0.7)	0 (0.0)	1 (1.0)
Unknown	82 (58.6)	23 (59.0)	59 (58.4)
Portal vein invasion tumor
No	66 (47.1)	19 (48.7)	47 (46.5)	0.702
Yes	30 (21.4)	9 (23.1)	21 (20.8)
Unknown	44 (31.4)	11 (28.2)	33 (32.7)
Sites of metastasis
Lung	28 (45.2)	9 (40.9)	19 (47.5)
Bone	8 (12.9)	3 (13.6)	5 (12.5)
Lymph node	16 (25.8)	6 (27.3)	10 (25.0)
Others	10 (16.1)	4 (18.2)	6 (15.0)
Laboratory indicators, median [IQR]
Platelet (× 109/L)	151.00 [111.00, 217.25]	152.00 [110.50, 178.00]	151.00 [111.00, 222.00]	0.577
Hemoglobin (g/L)	132.00 [107.00, 144.25]	127.00 [114.50, 145.50]	134.00 [107.00, 143.00]	0.961
ALT (IU/L)	35.00 [23.00, 65.00]	37.00 [23.00, 54.00]	34.00 [23.00, 73.00]	0.705
AST (IU/L)	41.50 [29.00, 82.75]	46.00 [31.00, 104.00]	41.00 [27.00, 74.00]	0.265
ALB (g/L)	39.70 [36.12, 43.90]	39.70 [36.45, 43.90]	39.70 [36.20, 43.90]	0.917
TBIL (μmol/L)	17.20 [11.15, 23.30]	16.30 [13.20, 26.30]	17.30 [10.65, 21.90]	0.430
DBIL (μmol/L)	7.95 [5.18, 11.73]	7.70 [5.00, 12.00]	8.00 [5.20, 11.35]	0.631
PT (s)	12.55 [11.80, 13.55]	12.70 [11.90, 13.85]	12.50 [11.70, 13.30]	0.503
INR	1.03 [0.98, 1.11]	1.04 [0.90, 1.10]	1.02 [0.99, 1.13]	0.465
AFP (ng/mL)	124.20 [7.60, 2000.00]	101.10 [7.85, 1978.90]	124.20 [7.20, 2403.61]	0.970
Initial daily dose of regorafenib
40 mg	6 (4.3)	1 (2.6)	5 (5.0)	0.057
80 mg	65 (46.4)	13 (33.3)	52 (51.5)
120 mg	12 (8.6)	6 (15.4)	6 (5.9)
160 mg	18 (12.9)	5 (12.8)	13 (12.9)
Unknown	39 (27.9)	14 (35.9)	25 (24.8)

R group: Regorafenib monotherapy; RP group: Regorafenib combined with programmed cell death-1 inhibitor; ICI: Immune checkpoint inhibitor; CNLC: China Liver Cancer stage; ECOG PS: Eastern Cooperative Oncology Group performance status; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALB: Albumin; TBIL: Total bilirubin; DBIL: Direct bilirubin; PT: Prothrombin time; INR: International normalized ratio; AFP: Alpha-fetoprotein.

Table 2 Best tumor responses as per Response Evaluation Criteria in Solid Tumors version 1.1 between the regorafenib combined with programmed cell death-1 inhibitor and regorafenib monotherapy groups, n (%)

Best Response	Overall response			Intrahepatic response			Extrahepatic response
	RP group (n = 101)	R group (n = 39)	P value	RP group (n = 101)	R group (n = 39)	P value	RP group (n = 52)	R group (n = 22)	P value
CR	0 (0.00)	0 (0.00)	1.000	0 (0.00)	0 (0.00)	1.000	0 (0.00)	0 (0.00)	1.000
PR	4 (3.96)	0 (0.00)	0.576	4 (3.96)	0 (0.00)	0.575	3 (5.77)	0 (0.00)	0.550
SD	66 (65.35)	15 (38.46)	0.005	80 (79.21)	23 (58.97)	0.031	28 (53.85)	7 (31.82)	0.126
PD	31 (30.69)	24 (61.54)	0.001	17 (16.83)	15 (38.46)	0.007	21 (40.38)	15 (68.18)	0.042
ORR	4 (3.96)	0 (0.00)	0.576	4 (3.96)	0 (0.00)	0.575	3 (5.77)	0 (0.00)	0.550
DCR	70 (69.31)	15 (38.46)	0.001	84 (83.17)	23 (58.97)	0.007	31 (59.62)	7 (31.82)	0.0042

CR: Complete response; PR: Partial response; SD: Stable disease; PD: Progression disease; ORR: Objective response rate; DCR: Disease control rate; ORR = CR + PR; DCR = CR + PR + SD.

Table 3 Univariate and multivariate Cox analysis for overall survival

Characteristics	Univariate analysis		Multivariate analysis
	HR (95%CI)	P value	HR (95%CI)	P value
Gender (female vs male)	1.551 (0.604-3.984)	0.362
Age (< 65 vs ≥ 65 years)	0.937 (0.428-2.054)	0.871
Hepatitis B infection (no vs yes)	0.910 (0.426-1.944)	0.807
Hepatitis C infection (no vs yes)	0.000 (0.000-inf)	0.997
Diabetes (no vs yes)	3.291 (1.362-7.952)	0.008	4.319 (0.783-23.801)	0.093
Hypertension (no vs yes)	1.267 (0.646-2.483)	0.491
Smoking (no vs yes)	1.042 (0.516-2.101)	0.909
Drinking (no vs yes)	1.120 (0.531-2.360)	0.766
Tumor size (≤ 5 vs > 5 cm)	1.626 (0.728-3.631)	0.235
Child-Pugh class (A vs B + C)	2.456 (1.127-5.352)	0.024	1.100 (0.349-53.465)	0.871
ECOG PS (0 vs ≥ 1)	1.002 (0.454-2.212)	0.996
Portal vein invasion tumor (no vs yes)	1.473 (0.688-3.153)	0.319
CNLC (IIa + IIb vs IIIa + IIIb)	1.347 (0.685-2.649)	0.388
ALT (≤ 50 vs > 50 IU/L)	2.044 (0.993-4.207)	0.052	2.221 (0.984-5.011)	0.055
AST (≤ 40 vs > 40 IU/L)	1.353 (0.656-2.793)	0.413
ALB (< 35 vs ≥ 35 g/L)	0.659 (0.313-1.389)	0.273
TBIL (≤ 23 vs > 23 μmol/L)	0.622 (0.238-1.622)	0.331
AFP (< 400 vs ≥ 400 ng/mL)	2.332 (1.140-4.769)	0.020	1.805 (0.743-4.383)	0.192
INR (≤ 1.2 vs > 1.2)	0.720 (0.098-5.294)	0.747
First-line ICI therapy (no vs yes)	1.891 (0.921-3.883)	0.083	2.159 (0.794-5.868)	0.132
Initial daily dose of regorafenib (< 160 vs 160 mg)	1.440 (0.594-3.491)	0.419
Second-line PD-1 inhibitors therapy (no vs yes)	0.505 (0.260-0.983)	0.044	0.502 (0.203-1.239)	0.135

ECOG PS: Eastern Cooperative Oncology Group performance status; CNLC: China Liver Cancer stage; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALB: Albumin; AFP: Alpha-fetoprotein; TBIL: Total bilirubin; INR: International normalized ratio; ICI: Immune checkpoint inhibitor; PD-1: Programmed cell death1 inhibitors.

Table 4 Univariate and multivariate Cox analysis for progression-free survival

Characteristics	Univariate analysis		Multivariate analysis
	HR (95%CI)	P value	HR (95%CI)	P value
Gender (female vs male)	1.552 (0.939-2.566)	0.087	1.800 (0.891, 3.635)	0.101
Age (< 65 vs ≥ 65 years)	0.909 (0.606-1.364)	0.645
Hepatitis B infection (no vs yes)	1.246 (0.793-1.957)	0.340
Hepatitis C infection (no vs yes)	0.923 (0.128-6.635)	0.936
Diabetes (no vs yes)	1.484 (0.794-2.772)	0.216
Hypertension (no vs yes)	0.927 (0.627-1.372)	0.707
Smoking (no vs yes)	0.748 (0.501-1.117)	0.156
Drinking (no vs yes)	0.762 (0.488-1.192)	0.234
Tumor size (≤ 5 vs > 5 cm)	1.021 (0.618-1.688)	0.935
Child-Pugh class (A vs B + C)	1.680 (0.995-2.837)	0.052	1.260 (0.658-2.414)	0.485
ECOG PS (0 vs ≥ 1)	1.171 (0.662-2.072)	0.587
Portal vein invasion tumor (no vs yes)	1.210 (0.762-1.919)	0.419
CNLC (IIa + IIb vs IIIa + IIIb)	1.139 (0.787-1.649)	0.490
ALT (≤ 50 vs > 50 IU/L)	1.037 (0.689-1.560)	0.863
AST (≤ 40 vs > 40 IU/L)	1.233 (0.840-1.810)	0.284
ALB (< 35 vs ≥ 35 g/L)	0.692 (0.466-1.027)	0.068	0.698 (0.425-1.176)	0.177
TBIL (≤ 23 vs > 23 μmol/L)	0.982 (0.641-1.505)	0.934
AFP (< 400 vs ≥ 400 ng/mL)	1.908 (1.285-2.834)	0.001	1.749 (1.027-2.980)	0.040
INR (≤ 1.2 vs > 1.2)	0.878 (0.380-2.026)	0.760
First-line ICI therapy (no vs yes)	1.344 (0.915-1.974)	0.132
Initial daily dose of regorafenib (< 160 vs 160 mg)	1.020 (0.593-1.755)	0.942
Second-line PD-1 therapy (no vs yes)	0.561 (0.379-0.830)	0.004	0.549 (0.31-0.953)	0.033

ECOG PS: Eastern Cooperative Oncology Group performance status; CNLC: China Liver Cancer stage; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALB: Albumin; AFP: Alpha-fetoprotein; TBIL: Total bilirubin; INR: International normalized ratio; ICI: Immune checkpoint inhibitor; PD-1: Programmed cell death1 inhibitors.