Progress in the treatment of advanced hepatocellular carcinoma with immune combination therapy

Table 1 Summary of clinical study data for hepatocellular carcinoma immunotherapy

Study	NCT ID	Study phase	Patient population	Sample size	Intervention measures	Finding	Region
Checkmate 040	NCT01658878	I/II	Advanced HCC with or without chronic viral hepatits	659	Envafolimab/Pembrolizumab	ORR: 15% vs 20%; DCR: 58% vs 64%; median TTP: 3.4 months vs 4.1 months; median DOR: 17 months vs 9.9 months	Asia, Europe, United States
Keynote 224	NCT02702414	II	Advanced HCC	156	Pembrolizumab	ORR: 17%; DCR: 62%; mPFS: 4.9 months; mOS: 12.9%	Asia, Europe, North America
Reflect	NCT01761266	Ⅲ	Unresectable HCC	954	Lenvatinib/Sorafenib	mOS: 13.6 months vs 12.3 months; mPFS: 7.4 months vs 3.7 months; medianTTP: 8.9 months vs 3.7 months; ORR: 24.1% vs 9.2%	Asia, Europe, North America
Keynote 524	NCT03006926	I	HCC	104	Pembrolizumab + Lenvatinib	ORR: 46% vs 36%; DCR: 88% vs 88%; median DOR: 8.6 months vs 12.6 months; mPFS: 9.3 months vs 8.6 months; mOS: 22 months vs 22 months	United States, France, Italy, Japan
Leap002	NCT03713593	III	Advanced HCC	794	Pembrolizumab + Lenvatinib/Lenvatinib	mOS: 21.1 months vs 19.0 months; mPFS: 8.2 months vs 8.0 months; ORR: 26.1% vs 17.5%; DCR: 81.3% vs 78.4%	Asia, Europe, United States
Study117	NCT03418922	Ib	HCC	30	Lenvatinib + Nivolumab	ORR: 37.5% vs 7.7%; DCR: 62.5% vs 69.2%; 12 mPFS: 30.0% vs 49.2%; 12 mOS: 52.1% vs 51.3%	NA
COSMIC-312	NCT03755791	III	Advanced HCC without prior systemic anticancer therapy	837	Cabozantinib + Atezolizumab/Cabozantinib + Sorafenib	mPFS: 6.8 months vs 4.2 months; mOS: 15.4 months vs 15.5 months; ORR: 13% vs 5%; DCR: 82% vs 63%	Asia, Europe, United States
RESCUE	NCT03463876	Ⅱ	Advanced HCC	190	Camrelizumabfor + Apatinib	ORR: 34.3% vs 23.8%; DCR: 77.1% vs 75.8%; median DOR: 14.8 months vs NE; mPFS: 5.7 months vs 5.5 months	NA
Imbrave 150	NCT03434379	III	locally advanced or metastatic HCC	558	Atezolizumab + Bevacizumab/Sorafenib	ORR: 33.2% vs 13.3%; DCR: 72.3% vs 55.1%; median DOR: NE vs 6.3 months	Asia, Europe, United States
ORIENT-32	NCT03794440	II/III	Advanced HCC	571	Sintilimab + Bevacizumab/Sorafenib	mOS: NE vs 10.4 months; mPFS: 6.9 months vs 4.3 months; ORR: 24% vs 8%	China
Study 22	NCT02519348	Ⅱ	Advanced HCC	332	Tremelimumab + Durvalumab/Tremelimumab/Durvalumab	mOS: 18.7 months vs 13.6 months vs 15.1 months vs 11.3 months; DCR: 34% vs 39% vs 34% vs 31%; ORR: 24% vs 10.6% vs 7.2% vs 9.5%; median DOR: NR vs 11.17 months vs 23.95 months vs 13.21 months	Asia, United States, Italy
HIMALAYA	NCT03298451	III	No prior systemic therapy for unresectable HCC	1504	Tremelimumab/Durvalumab	OS: 16.4 months vs 13.8 months; ORR: 20.1% vs 5.1%	Asia, Europe, United States
Checkmate-9DW	NCT04039607	III	No prior systemic therapy for Advanced HCC	732	Nivolumab + Pembrolizumab/Sorafenib/Lenvatinib	NE	Asia, Europe, United States
CHANCE001	NCT04975932	Retrospective study	HCC	556	TACE + PD-L1 inhibitors + Inhibitor molecule targeted drugs/TACE	mPFS: 9.5 months vs 8.0 months; mOS: 19.2 months vs 15.7 months; ORR: 60.1% vs 32.0%	China

HCC: Hepatocellular carcinoma; NA: Not Available; TACE: Transcatheter arterial chemoembolization; MTT: Molecular targeted therapy; PFS: Progressive free survival; ORR: Objective response rate; DCR: Disease control rate; NR: Not reported; TTP: Time to progression; NCT: National clinical trials; OS: overall survival; PD-L1: programmed death ligand-1; DOR: During of response; mPFS: Median PFS; mOS: Median OS; NE: Not estimable.

Table 2 Clinical Trials of hepatocellular carcinoma immunotherapy completed in the last five years (ClinicalTrials.gov)

NCT ID	Study phase	Patient population	Intervention measures	Region
NCT04393220	II	Advanced HCC	Bevacizumab + Nivolumab	China
NCT03785210	II	Primary HCC or liver dominant metastatic cancer from colorectal or pancreatic cancers	Nivolumab + Tadalafil + Vancomycin	United States
NCT03939975	II	Advanced HCC	Pembrolizumab/Nivolumab/JS001	China
NCT04172506	I/II	Advanced solid tumors	AK105	China
NCT03419897	II	Previously treated HCC unresectable carcinoma	Atezolizumab	China, Europe
NCT05471674	II	Borderline resectable HCC	Nivolumab	China
NCT03980288	I	Advanced HCC	CAR-GPC3 T Cell	China
NCT03841110	I	Advanced solid tumors	FT500/FT500 + Nivolumab/FT500 + Pembrolizumab/FT500 + Atezolizumab/FT500 + IL-2 + Nivolumab/FT500 + IL-2 + Pembrolizumab/FT500 + IL-2 + Atezolizumab	United States
NCT04161911	NA	Advanced HCC	Nivolumab	United States
NCT03735628	I	Advanced solid tumors	Copanlisib + Nivolumab	United States, Canada
NCT04310709	II	Unresectable or metastatic HCC	Regorafenib/Nivolumab	Korea
NCT03299946	I	Locally advanced HCC	Cabozantinib/Nivolumab	United States
NCT05535998	Retrospective study	HCC with portal vein tumor thrombus	TACE-HAIC + TKIs + PD-1 inhibitors/TACE	China
NCT03849469	I	Advanced solid tumors	Pembrolizumab	United States
NCT03652077	I	Advanced solid tumors	INCAGN02390 (TIM3 inhibitors)	United States

HCC: Hepatocellular carcinoma; NA: Not available; TACE: Transcatheter arterial chemoembolization; NCT: National clinical trials; HAIC: Hepatocellular arterial infusion chemotherapy; TKIs: Tyrosine kinase inhibitors; PD-1: Programmed cell death protein 1; IL: Interleukin.

Table 3 Summarize the limitations of current clinical trials and propose solutions

Limitations	Solution
Most clinical trials do not take into account the etiology of HCC	Subgroup analysis according on real-world causes
Insufficient exploratory analysis of subgroups during safety evaluation	Further analysis will be performed based on the subject's characteristics (e.g., height, weight, underlying disease) or the subject's population (e.g., sex, age)
The sample size of some studies was too small and easy to shift the results	Strict adherence to the inclusion and exclusion criteria, increasing the sample size
Assessing QOL after treatment could help assess the negative impact and clinical decisions of appropriate treatment, but the primary endpoint of most experiments does not include QOL	The primary endpoint, in addition to tumor treatment response and imaging assessment

HCC: Hepatocellular carcinoma; QOL: Quality of life.

Table 4 Immunotherapy drug approved for hepatocellular carcinoma

Drug target	Drug name	Drug launch time	Listed in China
PD-1	Nivolumab	2017	No
PD-1	Pembrolizumab	2018	Yes
CTLA-4	Ipilimumab	2020	No
PD-1	Tislelizumab	2021	Yes
PD-1	Sintilimab	2021	Yes
PD-1 + CTLA-4	Tremelimumab + durvalumab	2022	No

PD-1: Programmed cell death protein 1; CTLA-4: Cytotoxic t-lymphocyte associated antigen-4.