Second-line therapy for advanced hepatocellular carcinoma with regorafenib or cabozantinib: Multicenter French clinical experience in real-life after matching

Table 1 Patient characteristics prior to second-line treatment (entire cohort)

Characteristics at baseline	n = 86
Age–median (Q1Q3), yr	68.0 (60-74)
Gender, n (%)
Male	77 (90)
Female	9 (10)
Etiology of HCC, n (%)
Alcohol use	30 (35)
Virus/Virus + Alcohol	26 (30)/8 (9)
Non-alcoholic steatohepatitis	13 (15)
Other	9 (10)
ECOG performance status, n (%)
0	33 (38)
1	34 (40)
2	19 (22)
Esophageal varices1, n (%)	36 (45)
Macrovascular invasion, n (%)	41 (48)
Extrahepatic disease, n (%)	37 (43)
Child-Pugh class, n (%)
A	65 (76)
B2	21 (24)
BCLC stage, n (%)
B	15 (17)
C	71 (83)
AFP, ng/mL, n (%)
< 400	45 (52)
≥ 400	41 (48)
HCC morphology3, n (%)
Diffuse	15 (18)
Mass forming	24 (29)
Multinodular	44 (53)
Maximal tumor diameter, mm–median (Q1Q3)	69 (40-100)
Hemoglobin, g/dL–median (Q1Q3)	13 (12-14)
Platelet’s count (× 100/L)–median (Q1Q3)	153 (95-213)
Neutrophil count/L–median (Q1Q3)	3675 (2700-4600)
Lymphocyte count/L–median (Q1Q3)	1118 (810-1650)
Neutrophil-to-lymphocyte ratio, n (%)
≤ 3	40 (47)
> 3	46 (53)
CRP, mg/L–median (Q1Q3)	22 (8-51)
AST, IU/L–median (Q1Q3)	62 (46-117)
ALT, IU/L–median (Q1Q3)	40 (28-64)
GGT, IU/L–median (Q1Q3)	187 (112-360)
ALP, IU/L–median (Q1Q3)	166 (128-267)
Total bilirubin, μmol/L–median (Q1Q3)	17 (12-27)
Albumin, g/L–median (Q1Q3)	35 (29-39)
Creatinine, μmol/L–median (Q1Q3)	70 (57-85)
Prothrombin time, %–median (Q1Q3)	79 (68-93)
Duration of prior Sorafenib treatment, months–median (Q1Q3)	3.5 (2.7-9.2)

¹Esophageal varices, missing data n = 6.

²Child–Pugh grade B: Child–Pugh (CP)-B7 n = 14, CP-B8 n = 4, CP-B9 n = 3.

³Hepatocellular carcinoma morphology, patients with metastatic recurrence and without intrahepatic tumor, n = 3.

HCC: Hepatocellular carcinoma; NASH: Non-alcoholic steatohepatitis; PS: Performance status; BCLC: Barcelona clinic liver cancer; AFP: Alfa-fetoprotein; CRP: C-reactive protein; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; GGT: γ-glutamyl transpeptidase; ALP: Alkaline phosphatase.

Table 2 Patient characteristics prior to second-line treatment with cabometyx or regorafenib (without matching)

Characteristics at baseline	Cabozantinib (n = 28)	Regorafenib (n = 58)	P value
Age–median (Q1Q3), yr	68 (60-73)	68 (62.74)	0.6828
Gender, n (%)			0.4645
Male	24 (86)	53 (91)
Female	4 (14)	5 (9)
Etiology of HCC, n (%)			0.4219
Alcohol use	6 (21)	24 (41)
Virus/virus + alcohol	10 (36)/4 (14)	16 (28)/4 (7)
NASH	5 (18)	8 (14)
Other	3 (11)	6 (10)
PS, n (%)			0.6286
0	12 (44)	21 (38)
1	9 (32)	25 (43)
2	7 (24)	12 (20)
Esophageal varices1, n (%)	12 (44)	24 (45)	0.9432
Macrovascular invasion, n (%)	13 (46)	28 (51)	0.6995
Extrahepatic disease, n (%)	10 (36)	27 (50)	0.2177
Child-Pugh class, n (%)			1.0000
A	21 (75)	44 (76)
B	7 (25)	14 (24)
BCLC, n (%)			0.2375
B	7 (25)	8 (14)
C	21 (75)	50 (86)
AFP, ng/mL, n (%)			0.4468
< 400	13 (46)	32 (55)
≥ 400	15 (54)	26 (45)
Morphology2, n (%)			0.0830
Diffuse	7 (26)	8 (14)
Mass forming	4 (15)	20 (36)
Multinodular	16 (59)	28 (50)
Maximal tumor diameter, mm–median (Q1Q3)	69.5 (37.5-118.5)	68.5 (40-100)	0.7495
Hemoglobin, g/dL–median (Q1Q3)	13.3 (12-14)	13 (11-14.7)	0.9730
Platelet’s count (× 100/L)–median (Q1Q3)	136 (94-197)	173 (97-215)	0.2582
Neutrophil count/L-median (Q1Q3)	3118 (2120-3720)	4081 (3000-5668)	0.0042
Lymphocyte count/L–median (Q1Q3)	1130 (820-1675)	1105 (810-1643)	0.7723
Neutrophil-to- lymphocyte ratio, n (%)			0.0217
≤ 3	18 (64)	22 (38)
> 3	10 (36)	36 (62)
CRP, mg/L–median (Q1Q3)	14.5 (6.7-36.2)	29.7 (8.3-58)	0.1665
AST, IU/L–median (Q1Q3)	73 (52-132)	59 (41-95)	0.0681
ALT, IU/L–median (Q1Q3)	47 (33-73)	37 (26-51)	0.0970
GGT, IU/L–median (Q1Q3)	150 (100-350)	194 (117-362)	0.3538
ALP, IU/L–median (Q1Q3)	159 (137-231)	182 (122-269)	0.6232
Total bilirubin, μmol/L–median (Q1Q3)	21 (14-29)	17 (11-25)	0.1135
Albumin, g/L–median (Q1Q3)	36 (31-39)	34 (29-40)	0.7476
Creatinine, μmol/L–median (Q1Q3)	67 (55-87)	71 (57-84)	0.6051
Prothrombin time, %–median (Q1Q3)	81 (68-99)	78 (68-88)	0.1878
Duration of prior Sorafenib treatment, months–median (Q1Q3)	3 (2-4)	4 (2.9-11.8)	0.0226

¹Esophageal varices, Cabozantinib (CBZ): Missing data n = 1; Regorafenib (REG): Missing data n = 5.

²Hepatocellular carcinoma morphology, patients with metastatic recurrence and without intrahepatic tumor, CBZ n = 1, REG n = 2.

HCC: Hepatocellular carcinoma; NASH: Non-alcoholic steatohepatitis; PS: Performance Status; BCLC: Barcelona clinic liver cancer; AFP: Alpha-fetoprotein; CRP: C-reactive protein; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; GGT: γ-glutamyl transpeptidase; ALP: Alkaline phosphatase.

Table 3 Patient characteristics prior to second-line treatment with cabometyx or regorafenib: Matching-adjusted comparison study

Characteristics at baseline	Cabozantinib (n = 25)	Regorafenib (n = 25)	P value
Age–median (Q1Q3), yr	69 (60-74)	68 (58-72)	0.7870
Gender, n (%)			1.0000
Male	23 (92)	22 (88)
Female	2 (8)	3 (12)
Etiology of HCC, n (%)			0.6370
Alcohol	6 (24)	10 (40)
Virus/virus + alcohol	8 (32)/4 (16)	7 (28)/2 (8)
NASH	4 (16)	2 (8)
Other	3 (12)	4 (16)
PS, n (%)			0.4591
0	9 (36)	8 (29)
1	9 (36)	10 (42)
2	7 (28)	7 (29)
Esophageal varices1, n (%)	10 (42)	10 (45)	0.7957
Macrovascular invasion, n (%)	12 (48)	14 (58)	0.4687
Extrahepatic disease, n (%)	10 (40)	13 (54)	0.3206
Child-Pugh class, n (%)			0.5512
A	18 (72)	15 (60)
B	7 (28)	10 (40)
BCLC, n (%)			0.7585
B	5 (20)	5 (20)
C	20 (80)	20 (80)
AFP, ng/mL, n (%)			0.5713
< 400	12 (48)	14 (56)
≥ 400	13 (52)	11 (44)
Morphology2, n (%)			0.2393
Diffuse	7 (29)	4 (14)
Mass	4 (17)	9 (36)
Multinodular	13 (54)	12 (50)
Maximal tumor diameter, mm–median (Q1Q3)	74 (38-130)	70 (40-94)	0.6067
Hemoglobin g/dL–median (Q1Q3)	13 (12-13.9)	12.5 (10-13.7)	0.2875
Platelet’s count (× 100/L)–median (Q1Q3)	148 (95-193)	152 (97-206)	0.6229
Neutrophil count/L–median (Q1Q3)	3150 (1970-3760)	4100 (3000-5676)	0.0276
Lymphocyte count/L–median (Q1Q3)	1140 (810-1700)	940 (739-1600)	0.5828
Neutrophil-to-lymphocyteratio, n (%)			0.1564
≤ 3	16 (64)	10 (40)
> 3	9 (36)	15 (60)
CRP, mg/L–median (Q1Q3)	14.5 (7.2-41.1)	32 (8-65)	0.2900
AST, IU/L–median (Q1Q3)	75 (56-134)	64 (4 6-79)	0.0940
ALT, IU/L–median (Q1Q3)	48 (33-77)	30 (26-47)	0.0556
GGT, IU/L–median (Q1Q3)	179 (99-360)	187 (112-322)	0.7925
ALP, IU/L–median (Q1Q3)	162 (138-252)	203 (122-269)	0.6094
Total bilirubin, μmol/L–median (Q1Q3)	17.5 (14-29)	15.6 (12-27)	0.5123
Albumin, g/L–median (Q1Q3)	36 (29-39)	31.6 (28-35)	0.1772
Creatinine, μmol/L–median (Q1Q3)	69 (57-89)	72 (58-91)	0.4996
Prothrombin time, %–median (Q1Q3)	80 (68-100)	71 (61-78)	0.0792
Duration of prior Sorafenib treatment, months–median (Q1Q3)	3 (1.7-4.1)	3.2 (2.7-10.9)	0.1865

¹Esophageal varices, Cabozantinib (CBZ): Missing data n = 1; Regorafenib (REG): Missing data n = 3.

²Hepatocellular carcinoma morphology, patients with metastatic recurrence and without intrahepatic tumor, CBZ n = 1.

HCC: Hepatocellular carcinoma; NASH: Non-alcoholic steatohepatitis; PS: Performance status; BCLC: Barcelona clinic liver cancer; AFP: Alpha-fetoprotein; CRP: C-reactive protein; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; GGT: γ-Glutamyl transpeptidase; ALP: Alkaline phosphatase.

Table 4 Patient characteristics prior to third-line treatment with cabometyx

Characteristics at baseline	Cabozantinib (n = 16)
Age–median (Q1Q3), yr	68 (64-75)
Gender, n (%)
Male	15 (94)
Female	1 (6)
PS, n (%)
0	8 (50)
1	7 (44)
2	1 (6)
Macrovascular invasion, n (%)	6 (38)
Extrahepatic disease, n (%)	10 (62)
Child-Pugh class, n (%)
A	10 (62)
B	6 (38)
BCLC, n (%)
B	3 (19)
C	13 (81)
AFP, ng/mL, n (%)
< 400	8 (50)
≥ 400	8 (50)
Maximal tumor diameter, mm–median (Q1Q3)	60 (32-106)
Hemoglobin, g/dL–median (Q1Q3)	13.7 (11.4-14.7)
Platelet’s count (× 100/L)–median (Q1Q3)	159 (107-246)
Neutrophil count/L–median (Q1Q3)	4690 (3128-7463)
Lymphocyte count/L–median (Q1Q3)	1063 (783-1359)
Neutrophil–lymphocyte ratio, n (%)
≤ 3	3 (19)
> 3	13 (81)
CRP, mg/L–median (Q1Q3)	33 (7-78)
AST, IU/L–median (Q1Q3)	51 (33-76)
ALT, IU/L–median (Q1Q3)	29 (21-53)
GGT, IU/L–median (Q1Q3)	188 (111-323)
ALP, IU/L–median (Q1Q3)	162 (120-253)
Total bilirubin, μmol/L–median (Q1Q3)	15.9 (11.1-25.6)
Albumin, g/L–median (Q1Q3)	33.5 (27.9-39.2)
Creatinine, μmol/L–median (Q1Q3)	82 (56-91)
Prothrombin time, %–median (Q1Q3)	81 (70-92)

PS: Performance status; BCLC: Barcelona Clinic Liver Cancer; AFP: Alpha-fetoprotein; CRP: C-reactive protein; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; GGT: γ-Glutamyl transpeptidase; ALP: Alkaline phosphatase.

Table 5 Adverse events associated with regorafenib or cabometyx as second-line therapy

Adverse event	Cabozantinib (n = 28)	Regorafenib (n = 58)	P value
Fatigue and/or decreased appetite and/or weight loss, n (%)	22 (79)	46 (79)	1.0000
Grade 1-2/3-4	20 (89)/2 (11)	40 (85)/7 (15)	1.0000
Hand-foot skin, n (%)	9 (32)	16 (28)	0.8005
Grade 1-2/3-4	8 (89)/1 (11)	11 (69)/5 (31)	0.3644
Diarrhea, n (%)	11 (39)	13 (22)	0.1021
Grade 1-2/3-4	11 (100)/0	13 (100)/0	1.0000
Increased blood Bilirubin and/or AST and/or ALT, n (%)	9 (32)	17 (29)	0.8063
Grade 1-2/3-4	4 (44)/5 (56)	11 (65)/6 (35)	0.4185
Hypertension, n (%)	6 (21)	12 (21)	1.0000
Grade 1-2/3-4	5 (83)/1 (17)	11 (92)/1 (8)	1.0000
Other disorders1, n (%)	14 (50)	19 (33)	0.1234
Grade 1-2/3-4	12 (86)/2 (14)	18 (95)/1 (5)	0.5612
Interruptions, n (%)	12 (43)	31 (53)	0.3573
Dose reduction, n (%)	23 (82)	49 (84)	0.7646

¹Other disorders: Oral mucositis, dysphonia, decrease in platelet count, muscular pain, ascites.

AST: Aspartate aminotransferase; ALT: Alanine aminotransferase.

Table 6 Univariate and multivariate analyses of risk factors for tumor progression over time in matched-pair groups

Variables	Univariate analysis, P value	Multivariate analysis, P value
Treatment with CBZ vs REG	0.8851	-
NLR ≤ 3 vs > 3	0.00061	0.0006
CRP (mg/L) > 10 vs ≤ 10	0.03641	0.0624
ALP (IU) > 200 vs ≤ 200	0.5545	-
Bilirubin total (μmol/L) > 17 vs ≤ 17	0.02701	0.3262
Albumin (g/L) > 36 vs ≤ 36	0.3026	-
PT (%) > 70 vs ≤ 70	0.0534	-
AST (IU) > 45 vs ≤ 45	0.00481	0.0132
AFP (ng/mL) > 400 vs ≤ 400	0.0634	-

¹Included in multivariate analysis.

CBZ: Cabozantinib; REG: Regorafenib; NLR: Neutrophil-to-lymphocyte ratio; CRP: C-reactive protein; ALP: Alkaline phosphatase; PT: Prothrombin time; AST: Aspartate aminotransferase; AFP: Alpha-fetoprotein.