Immunotherapy for advanced or recurrent hepatocellular carcinoma

Table 1 Activity of single immune checkpoint inhibitor from the clinical trials

Drugs (dose)	Other treatment	Targets	Trial identifier	Patient group	n	mOS in mo	ORR, %	DCR, %	mPFS in mo	Phase	Setting
Nivolumab (3 mg/kg every 2 wk)	No	PD-1	NCT01658878	Advanced HCC	214	NR	20.0	64.0	4.00	I-II	1L
Nivolumab (240 mg every 2 wk)	vs Sorafenib	PD-1	NCT02576509	Advanced HCC	371	16.40	15.0	55.0	3.70	III	1L
Pembrolizumab (200 mg every 3 wk)	No	PD-1	NCT02702414	Advanced HCC	104	12.90	17.0	62.0	4.90	II	2L
Pembrolizumab (200 mg every 3 wk)	vs Placebo	PD-1	NCT02702401	Advanced HCC	278	13.90	18.3	62.2	3.00	III	2L
Pembrolizumab (200 mg every 3 wk)	No	PD-1	NCT02658019	Advanced HCC	29	11.00	32.0	46.0	4.50	II	2L
Camrelizumab (200 mg every 2 wk)	vs Camrelizumab (200 mg q3w)	PD-1	NCT02989922	Advanced HCC	109	14.20	11.9	47.7	2.30	II	2L
Camrelizumab (200 mg every 3 wk)	vs Camrelizumab (200 mg q2w)	PD-1	NCT02989922	Advanced HCC	108	13.20	17.6	44.0	2.00	II	2L
Durvalumab (1500 mg every 4 wk)	vs T300+D and tremelimumab	PD-L1	NCT02519348	Unresectable HCC	104	13.60	10.6	37.5	2.07	II	Mix
Durvalumab (1500 mg every 4 wk)	vs T300+D and sorafenib	PD-L1	NCT03298451	Unresectable HCC	389	16.56	17.0	54.8	3.65	III	1L
Tremelimumab (750 mg every 4 wk)	vs T300+D and durvalumab	CTLA-4	NCT02519348	Unresectable HCC	69	15.10	7.2	49.3	2.69	II	Mix
Tislelizumab (5 mg/kg every 3 wk)	No	PD-1	NCT02407990	Advanced HCC	50		12.2	51.0		Ib	2L

1L: First-line therapy; 2L: Second-line therapy; CTLA-4: Cytotoxic T lymphocyte-associated antigen 4; DCR: Disease control rate; HCC: Hepatocellular carcinoma; mOS: Median overall survival; mPFS: Median progression free survival; NR: Not reached; ORR: Overall response rate; PD-1: Programmed cell death protein 1; PD-L1: Programmed death ligand 1; T300+D: Dose of tremelimumab (300 mg IV, cycle 1) combined with durvalumab (1500 mg IV once every 4 wk).

Table 2 Activity of combinations of immune checkpoint inhibitors from the clinical trials

Drugs	Targets	Other treatment	Trial identifier	Patient group	n	mOS in mo	ORR, %	DCR, %	mPFS in mo	Phase	Setting
Nivolumab + ipilimumab	PD-1; CTLA-4	No	NCT01658878	Advanced HCC	50	22.80	32.0	54.0		I/II	1L
Durvalumab + tremelimumab	PD-L1; CTLA4	vs Durvalumab and tremelimumab	NCT02519348	Unresectable HCC	75	18.70	24.0	45.3	2.17	I/II	2L
Durvalumab + tremelimumab	PD-L1; CTLA4	vs Durvalumab and sorafenib	NCT03298451	Unresectable HCC	393	16.40	20.1	60.1	3.78	III	1L

1L: First-line therapy; 2L: Second-line therapy; CTLA-4: Cytotoxic T lymphocyte-associated antigen 4; DCR: Disease control rate; HCC: Hepatocellular carcinoma; mOS: Median overall survival; mPFS: Median progression free survival; ORR: Overall response rate; PD-1: Programmed cell death protein 1; PD-L1: Programmed death ligand 1.

Table 3 Activity of combinations of an immune checkpoint inhibitor and a vascular endothelial growth factor inhibitor from clinical trials

Drugs	Other treatment	Targets	Trial identifier	Patient group	n	mOS in mo	ORR, %	DCR, %	mPFS in mo	Phase	Setting
Atezolizumab + bevacizumab	vs Sorafenib	PD-L1; VEGF	NCT03434379	Unresectable HCC	326	19.20	27.3	74.0	6.90	III	1L
Pembrolizumab + lenvatinib	No	PD-1; VEGFR	NCT03006926	Unresectable HCC	104	22.00	36.0	88.0	8.60	Ib	1L
Sintilimab + IBI305	vs Sorafenib	PD-1; VEGF	NCT03794440	Unresectable HCC	380	NR	21.0	72.0	4.60	III	1L
Atezolizumab + cabozantinib	vs Sorafenib	PD-L1; VEGFR	NCT03755791	Advanced HCC	432	15.40	11.0	78.0	6.10	III	1L
Camrelizumab + apatinib	No	PD-1; VEGFR	NCT03463876	Advanced HCC	70	NR	34.3	77.1	5.70	II	1L
Camrelizumab + apatinib	No	PD-1; VEGFR	NCT03463876	Advanced HCC	120	NR	22.5	75.8	5.50	II	2L

1L: First-line therapy; 2L: Second-line therapy; CTLA-4: Cytotoxic T lymphocyte-associated antigen 4; DCR: Disease control rate; HCC: Hepatocellular carcinoma; mOS: Median overall survival; mPFS: Median progression free survival; NR: Not reached; ORR: Overall response rate; PD-1: Programmed cell death protein 1; PD-L1: Programmed death ligand 1; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor.

Table 4 Ongoing phase I-III trials testing immune checkpoint inhibitors in advanced hepatocellular carcinoma

Drugs	Other treatment	Targets	Trial identifier	Patient group	Status	n	Estimated completion date	Phase	Setting
Single ICI
Pembrolizumab	Placebo	PD-1	NCT03062358	Advanced HCC	Active, not recruiting	454	June 30, 2023	III	2L
Tislelizumab	vs Sorafenib	PD-1	NCT03412773	Advanced HCC	Active, not recruiting	674	May 1, 2022	III	1L
Durvalumab	No	PD-L1	NCT04294498	Advanced HCC	Recruiting	43	December 31, 2023	II	2L
Tislelizumab	vs Sorafenib	PD-1	NCT03419897	Unresectable HCC	Active, not recruiting	249	June 30, 2022	II	2L
Combination of ICIs
Nivolumab + ipilimumab	vs Sorafenib and lenvatinib	CTLA-4, PD-1	NCT04039607	Advanced HCC	Recruiting	728	September 30, 2019	III	1L
Sintilimab + IBI310	vs Sorafenib	PD-1, CTLA-4	NCT04720716	Advanced HCC	Recruiting	490	February 7, 2021	III	1L
Combination of ICIs and antiangiogenic drugs
Nivolumab + regorafenib	No	PD-1, VEGFR	NCT04310709	Unresectable HCC	Recruiting	42	May 30, 2023	II	1L
Pembrolizumab + lenvatinib	Placebo and lenvatinib	PD-1, VEGFR	NCT03713593	Advanced HCC	Recruiting	750	December 31, 2023	III	1L
Pembrolizumab + futibatinib	No	PD-1, FGFR	NCT04828486	Advanced HCC	Recruiting	25	May 6, 2024	II	2L
Pembrolizumab + regorafenib	No	PD-1, VEGFR	NCT03347292	HCC	Active, not recruiting	57	September 26, 2022	I	1L
Pembrolizumab + sorafenib	No	PD-1, VEGFR	NCT03211416	Advanced or metastatic HCC	Recruiting	41	December 7, 2022	I/II	1L
Pembrolizumab + cabozantinib	No	PD-1 VEGFR	NCT04442581	Advanced HCC	Recruiting	29	September 13, 2024	II	1L
Camrelizumab + apatinib	No	PD-1, VEGFR	NCT04826406	HCC	Recruiting	40	August 30, 2023	II	1L
Camrelizumab + lenvatinib	No	PD-1, VEGFR	NCT04443309	Advanced HCC	Recruiting	53	August 1, 2023	I/II	1L
Camrelizumab + apatinib	vs Sorafenib	PD-1 VEGFR	NCT03764293	Advanced HCC	Active, not recruiting	543	June 1, 2022	III	1L
Toripalimab + lenvatinib	No	PD-1, VEGFR	NCT04368078	Advanced HCC	Recruiting	76	April 1, 2023	II	2L
Tislelizumab + regorafenib	No	PD-1, VEGFR	NCT04183088	Advanced HCC	Recruiting	125	March 1, 2025	II	1L
Tislelizumab + lenvatinib	No	PD-1, VEGFR	NCT04401800	Locally advanced or Unresectable HCC	Recruiting	66	December 1, 2022	II	1L
Sintilimab + lenvatinib	No	PD-1, VEGFR	NCT04042805	Advanced HCC	Recruiting	36	August 30, 2024	II	1L
Sintilimab + anlotinib	No	PD-1, VEGFR	NCT04052152	Advanced HCC	Recruiting	20	December 30, 2021	II	1L
Sintilimab + IBI305	vs Sorafenib	PD-1, VEGFR	NCT03794440	Advanced HCC	Active, not recruiting	595	December 1, 2022	II/III	1L
Sintilimab + regorafenib	vs Regorafenib	PD-1, VEGFR	NCT04718909	Unresectable HCC	Recruiting	180	December 31, 2022	II	1L
Sintilimab + donafenib	No	PD-1, VEGFR	NCT05162352	Advanced HCC	Recruiting	30	May 1, 2023	II	1L
Atezolizumab + lenvatinib or sorafenib	vs Sorafenib or lenvatinib	PD-L1, VEGFR	NCT04770896	Unresectable HCC	Recruiting	554	October 8, 2024	III	2L
Atezolizumab + bevacizumab	No	PD-L1, VEGFR	NCT04829383	Unresectable HCC	Recruiting	50	July 1, 2024	II	1L
Atezolizumab + bevacizumab	No	PD-L1, VEGFR	NCT04732286	Unresectable HCC	Active, not recruiting	100	September 25, 2023	III	1L
Atezolizumab + bevacizumab	No	PD-L1, VEGFR	NCT04487067	Unresectable HCC	Active, not recruiting	152	July 31, 2023	IIIb	1L
Durvalumab + tivozanib	No	PD-L1, VEGFR	NCT03970616	Advanced HCC	Recruiting	42	August 1, 2022	I/II	Mix
Durvalumab + lenvatinib	No	PD-L1, VEGFR	NCT05312216	Unresectable HCC	Not yet recruiting	25	April 1, 2022	II	1L
Durvalumab + bevacizumab	Placebo	PD-L1, VEGFR	NCT03847428	High risk of recurrence HCC	Active, not recruiting	877	May 31, 2024	III	1L

1L: First-line therapy; 2L: Second-line therapy; CTLA-4: Cytotoxic T lymphocyte-associated antigen 4; FGFR: Fibroblast growth factor receptor; HCC: Hepatocellular carcinoma; ICI: Immune checkpoint inhibitor; NR: Not reached; PD-1: Programmed cell death protein 1; PD-L1: Programmed death ligand 1; VEGFR: Vascular endothelial growth factor receptor.

Table 5 Ongoing clinical trials that combine locoregional therapies with immune checkpoint inhibitors

Main intervention methods	Comparison arms	Trial identifier	Status	Estimated or actual enrollment	Patient group	Phase
Pembrolizumab + RAF/MWA/brachytherapy/TACE	vs Pembrolizumab + RAF/MWA/brachytherapy/TACE	NCT03753659	Active, not recruiting	30	Early-stage HCC	II
Nivolumab + TACE	No	NCT03572582	Active, not recruiting	49	Intermediate-stage HCC	II
Pembrolizumab + TACE	No	NCT03397654	Active, not recruiting	26	HCC	I/II
Durvalumab + tremelimumab + TACE/RAF/cryoablation	vs Durvalumab + tremelimumab	NCT02821754	Active, not recruiting	54	Advanced HCC	II
Durvalumab + tremelimumab + TACE	No	NCT03638141	Recruiting	30	Intermediate-stage HCC	II
Durvalumab + tremelimumab + bevacizumab + TACE	No	NCT03937830	Recruiting	22	Advanced HCC	II
Durvalumab + bevacizumab + TACE	vs Durvalumab + TACE vs TACE	NCT03778957	Active, not recruiting	724	Intermediate-stage HCC	III
Apatinib + camrelizumab + HAIC	No	NCT04191889	Recruiting	84	Advanced HCC	II
Pembrolizumab + SBRT	No	NCT03316872	Recruiting	30	Advanced HCC	II
Durvalumab + tremelimumab + SBRT	No	NCT03482102	Recruiting	70	Advanced HCC	II
Nivolumab + curative resection/RAF	vs Curative resection/RAF	NCT03383458	Active, not recruiting	545	Resected HCC	III
Durvalumab + bevacizumab + curative resection/RAF	vs Durvalumab + curative resection/RAF vs Curative resection/RAF	NCT03847428	Active, not recruiting	877	Resected HCC	III
Ipilimumab + nivolumab + TACE	vs Nivolumab + TACE + placebo vs TACE + placebo + placebo	NCT04340193	Active, not recruiting	26	Intermediate-stage HCC	III
Lenvatinib + pembrolizumab + TACE	vs Placebo + placebo + TACE	NCT04246177	Active, not recruiting	950	Incurable/non-metastatic HCC	III
Nivolumab + DEB TACE	vs DEB TACE	NCT04268888	Recruiting	522	Intermediate-stage HCC	II/III

HAIC: Hepatic artery infusion chemotherapy; HCC: Hepatocellular carcinoma; MWA: Microwave ablation; RAF: Radiofrequency ablation; SBRT: Stereotactic body radiation therapy; TACE: Transcatheter arterial chemoembolization.