Tyrosine kinase inhibitors after progression on atezolizumab-bevacizumab in advanced hepatocellular carcinoma: A systematic review and meta-analysis

Table 1 Baseline characteristics of patients treated with tyrosine kinase inhibitors following atezolizumab-bevacizumab in advanced hepatocellular carcinoma, n (%)

Ref.	Country	Study type	TKI	n	Age, years (mean)	Female	ECOG 0	ECOG 1	ECOG 2	Viral/nonviral3	BCLC B	BCLC C	Child-Pugh A	Child-Pugh B	Extrahepatic metastases	Vascular invasion
Falette-Puisieux et al[21], 2023	France	Retrospective	Regorafenib	29	63	6 (20.7)	1 (3.4)	26 (89.7)	2 (6.9)	12/17 (41.4/58.6)	2 (6.9)	27 (93.1)	27 (93.1)	2 (6.9)	25 (86.2)	8 (27.6)
			Sorafenib	41	62	9 (21.9)	5 (12.2)	30 (73.2)	6 (14.6)	12/29 (29.3/70.7)	2 (4.9)	39 (95.1)	34 (82.9)	7 (17.1)	34 (82.9)	20 (48.8)
			Cabozantinib	4	46	1 (25.0)	0 (0.0)	3 (75.0)	1 (25.0)	2/2 (50.0/50.0)	0 (0.0)	4 (100.0)	4 (100.0)	0 (0.0)	3 (75.0)	1 (25.0)
			Lenvatinib	8	65	1 (12.5)	0 (0.0)	5 (62.5)	3 (37.5)	1/7 (12.5/87.5)	2 (25.0)	6 (75.0)	3 (37.5)	5 (62.5)	4 (50.0)	4 (50.0)
Muto et al[22], 2023	Japan	Retrospective	Lenvatinib	20	70	3 (15.0)	12 (60.0)	8 (40.0)	0 (0.0)	6/14 (30.0/70.0)	6 (30.0)	14 (70.0)	16 (80.0)	4 (20.0)	9 (45.0)	9 (45.0)
Chon et al[23], 2023	South Korea	Retrospective	Lenvatinib	36	61	4 (11.1)	23 (63.9)	13 (36.1)	13 (36.1)	27/9 (75.0/25.0)	4 (11.1)	32 (88.9)	33 (91.7)	3 (8.3)	27 (75.0)	14 (38.9)
			Sorafenib	36	63	5 (13.8)	21 (58.3)	15 (41.7)	15 (41.7)	26/10 (72.2/27.8)	4 (11.1)	32 (88.9)	32 (88.9)	4 (11.1)	29 (80.6)	16 (44.4)
Hiraoka et al[24], 2023	Japan	Retrospective	Lenvatinib	101	72	24 (23.8)	76 (75.2)	19 (18.8)	4 (3.9)	46/55 (45.5/54.5)	35 (34.7)	61 (60.4)	82 (81.2)	18 (17.8)	45 (45.6)	30 (29.7)
Kimura et al[25], 2024	Japan	Retrospective	Lenvatinib	13	73	8 (61.5)	10 (76.9)	3 (23.1)	0 (0.0)	6/7 (46.2/53.8)	NR	NR	NR	NR	NR	NR
Persano et al[9], 2024	Italy	Retrospective	Lenvatinib	86	1	19 (22.1)	85 (98.8)	85 (98.8)	1 (1.2)	43/43 (50.0/50.0)	33 (38.4)	53 (61.6)	85 (98.8)	1 (1.2)	38 (44.2)	NR
			Sorafenib	51	2	7 (13.7)	50 (98.0)	50 (98.0)	1 (2.0)	26/25 (50.99/49.01)	17 (33.3)	34 (66.7)	48 (94.1)	3 (5.9)	19 (37.2)	NR
Kuzuya et al[26], 2023	Japan	Retrospective	Cabozantinib	19	67	4 (21.1)	10 (52.63)	6 (31.57)	3 (15.78)	10/9 (52.6/47.4)	4 (21.1)	15 (78.9)	12 (63.2)	7 (36.8)	11 (57.9)	NR
Yano et al[27], 2023	Japan	Retrospective	Lenvatinib	24	75	4 (16.7)	19 (79.2)	4 (16.66)	1 (4.16)	16/8 (66.7/33.3)	16 (66.7)	0 (0.0)	NR	NR	11 (45.8)	8 (33.3)
Lee et al[28], 2025	South Korea	Retrospective	Sorafenib	324	61	60 (18.5)	124 (38.3)	192 (59.3)	7 (2.2)	244/59 (80.6/19.5)	28 (8.6)	247 (76.2)	235 (72.5)	80 (24.7)	106 (32.7)	90 (27.8)
			Lenvatinib	154	61	26 (16.9)	77 (50.0)	71 (46.1)	6 (3.9)	117/34 (76.0/22.1)	22 (14.3)	125 (81.2)	135 (87.7)	13 (8.4)	11 (7.1)	42 (27.3)
			Regorafenib	36	55	8 (22.2)	15 (41.7)	21 (58.3)	0 (0)	33/1 (91.6/2.7)	1 (2.8)	12 (33.3)	34 (94.5)	2 (5.6)	11 (30.6)	5 (13.9)
			Cabozantinib	12	54	1 (8.3)	2 (16.7)	10 (83.3)	0 (0)	9/1 (75.0/8.3)	1 (8.3)	9 (75.0)	11 (91.6)	1 (8.3)	8 (66.7)	2 (16.7)

¹Authors reported age distribution as follows: 41.9% of patients were < 70 years old and 58.1% were ≥ 70 years old.

²Authors reported age distribution as follows: 56.9% of patients were < 70 years old and 39.2% were ≥ 70 years old.

³Viral etiology was defined as infection with hepatitis B virus and/or hepatitis C virus. Non-viral etiologies included alcohol-associated liver disease, metabolic dysfunction-associated steatotic liver disease, and other chronic liver diseases (including autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, Wilson disease, Hereditary hemochromatosis, cryptogenic cirrhosis).

TKI: Tyrosine kinase inhibitor; NR: Not reported; ECOG: Eastern Cooperative Oncology Group; BCLC: Barcelona Clinic Liver Cancer stage.

Table 2 Adverse events, %

Adverse event	Any grade	95%CI (any grade)	I2 (any grade)	≥ Grade 3 %	95%CI (≥ grade 3)	I2 (≥ 3)
AST/ALT elevation	42	-25 to 100	96.4	9	-10 to 29	67.5
Bilirubin elevation	38	12-65	0.00	4	-6 to 13	0.00
Thrombocytopenia	25	-15 to 65	97.6	3	0-6	0.00
Diarrhea	21	11-31	74.7	2	0-4	0.00
Anorexia	38	27-49	44.9	8	4-11	0.01
Proteinuria	30	18-42	55.3	15	10-20	0.00
Fatigue	52	39-65	76.42	6	3-9	0.01
Hypertension	18	7-29	85.32	3	1-6	0.05
Nausea	8	-7 to 22	72.65	4	-6 to 13	0.00
Anemia	54	27-81	0.00	4	-6 to 13	0.00
Hand-foot syndrome	34	21-47	80.6	3	1-5	0.01
Hypothyroidism	25	14-36	26.5	3	-1 to 6	0.03
Neutropenia	31	6-56	0.00	4	-6 to 13	0.00
Vomiting	5	1-10	0.01	2	-1 to 5	0.00
Gastrointestinal bleeding	1	-1 to 3	0.00	1	-1 to 3	0.00
Fever	12	2-23	0.01	2	-2 to 7	0.01
Non-gastrointestinal bleeding	12	2-23	0.01	3	-2 to 9	0.03
Liver failure	6	0-13	52.93	1	-1 to 3	0.00
Acute kidney injury	5	-6 to 15	64.90	1	-1 to 3	0.03
Abdominal pain	1	-1 to 3	0.01	1	-1 to 3	0.01
Hoarseness	6	-2 to 13	0.00	2	-2 to 7	0.01

CI: Confidence interval.