Hepatocellular carcinoma immune microenvironment and check point inhibitors-current status

Table 1 Clinical studies on immunotherapy

No.	Ref.	Study characteristics	Intervention	Patient characteristics	Outcome
1	IMbrave 150[45]	Phase III, Open label RCT	Group I Atez/Bev. Group II SOR	501 BCLC-C, uHCC CP-A, ECOG 0/1	OS: Gp I vs II-67% vs 54%. PFS: Gp I vs II-6.8 months vs 4.3 months
2	Multi-centric (Real world data)[48]	Retrospective	Atez/Bev	216 BCLC-C, uHCC m-HCC	mOS-14.9 months; mPFS-6.8 months; ORR (RECIST)-25%; DCR-73%
3	Himalaya[52]	Phase III RCT	STRIDE regime Treme/Durva. Durva alone. Treme alone. SOR alone	1171, BCLC-C, uHCC	mOS: STRIDE vs SOR (16.3 months vs 13.7 months). ORR: STRIDE vs Durva (20.1 vs 17%). DCR: STRIDE vs Durva vs SOR (60.1% vs 54.8% vs 60.7%)
4	Keynote 224[53]	Phase II, Open label	Pembrolizumab	104, BCLC-C, CP-A ECOG 0/1	ORR-17%
5	Keynote-240[54]	Phase III, Double blind RCT	PEM vs Placebo	413, BCLC-C	mOS: PEM vs Placebo (13.8 months vs 10.6 months). mPFS: PEM vs Placebo (3 months vs 2.8 months)
6	Keynote-394[55]	Phase III, Double blind RCT	PEM vs Placebo	453, BCLC-C	mOS: PEM vs Placebo (14.6 months vs 13 months). mPFS: PEM vs Placebo (2.6 months vs 2.3 months)
7	Check-Mate 040[56]	Phase I/II Open label Noncomparative	Nivolumab	262, BCLC-C CP-A/B ECOG 0/1	ORR: Dose expansion phase 20%. Dose escalation phase 15%

Atez/Bev: Atezolizumab + Bevacizumab; SOR: Sorafenib; RCT: Randomized control study; uHCC: Unresectable HCC; ECOG: Eastern Cooperative Oncology Group; CTP: Child-Turcotte-Pugh; BCLC: Barcelona Clinic Liver Cancer; mHCC: Metastatic hepatocellular carcinoma; OS: Overall survival; PFS: Progression free survival; mOS: Median overall survival; mPFS: Median progression free survival; Treme: Tremelimumab; Durva: Durvalumab; PEM: Pembrolizumab; NIV: Nivolumab; ORR: Objective response rate; DCR: Disease control rate

Table 2 Clinical studies on combination therapies of immunotherapy with locoregional/tyrosine kinase inhibitors

No.	Ref.	Study characteristics	Intervention	Patient characteristics	Outcome
1	Propensity score matched study[58]	Retrospective study	Group I: TACE + Atez/Bev. Group II: TACE + LEN	98, BCLC-C, uHCC	ORR: 12 months. Group I-75%; Group II-79%. mPFS: Group I-7.03 months; Group II-6.03 months. No significant difference in ORR and DCR
2	Chinese study[59]	Retrospective study	Group I: TACE + Atez/Bev. Group II: Atez/Bev only	139, BCLC-C	ORR: Group I-38%; Group II-16.9%. mOS: Group I-14 months; Group II-10 months. mPFS: Group I-10 months; Group II-6 months
3	Keynote-524[61]	Open label Multi-centric study	LEN + PEM	104, uHCC	ORR: mRECIST-46%; RECIST-36%. mPFS: mRECIST-9.3 months; RECIST-8.6 months
4	LEAP 002[62]	Double blind, Randomized control study	Group I: LEN + PEM. Group II: LEN + Placebo	uHCC, CP-A ECOG 0/1	mOS: Group I-21.2 months; Group II-19.0 months. mPFS: Group I-8.2 months; Group II-8.0 months
5	REPLEC study[60]	Multi-centric analysis	Atez/Bev	52, uHCC classified as UT-7, CP-A ECOG0/1	ORR at 6 wk: RECIST-17.7%; mRECIST-42.5%. DCR at 6 wk: RECIST-84.7%; mRECIST-86.2%; mPFS-8 months

TACE: Transarterial chemoembolization; Atez/Bev: Atezolizumab + Bevacizumab; SOR: Sorafenib; RCT: Randomized control study; uHCC: Unresectable hepatocellular carcinoma; ECOG: Eastern Cooperative Oncology Group; CTP: Child-Turcotte-Pugh; BCLC: Barcelona Clinic Liver Cancer; mHCC: Metastatic hepatocellular carcinoma; OS: Overall survival; PFS: Progression free survival; mOS: Median overall survival; mPFS: Median progression free survival; LEN: Lenvatinib; Treme: Tremelimumab; Durva: Durvalumab; PEM: Pembrolizumab; ORR: Objective response rate; DCR: Disease control rate.