Immunotherapy for nonalcoholic fatty liver disease-related hepatocellular carcinoma: Lights and shadows

Table 1 The main immune checkpoint inhibitors approved for treatment of advanced hepatocellular carcinoma

Drug	Mechanism of action	Efficacy	Safety	Approval
First-line
Atezolizumab (1200 mg, IV) plus bevacizumab (15 mg/kg, IV) every 3 wk	ICI, anti-PD-L1 antibody (atezolizumab) plus antiangiogenic, anti-VEGF-A antibody (bevacizumab)	Improved OS, PFS, ORR vs sorafenib (IMbrave-150 phase III trial[93])	irAEs1, hypertension, fatigue, proteinuria, pruritus, gastrointestinal bleeding	Approved by FDA and EMA for patients with advanced HCC
Tremelimumab (300 mg, IV) plus durvalumab (1500 mg, IV) once, followed by durvalumab (1500 mg, IV) every 4 wk	ICI, anti-CTLA-4 antibody (tremelimumab) plus ICI, anti-PD-L1 antibody (durvalumab)	Improved OS vs sorafenib and favorable benefit-risk ratio (HIMALAYA phase III trial[89])	Pruritus, irAEs1	Under evaluation for approval. Granted orphan drug designation by FDA for HCC treatment (2020)
Sintilimab (200 mg, IV) plus IBI305 (bevacizumb biosimilar; 15 mg/kg, IV) every 3 wk	ICI, anti-PD-1 antibody (sintilimab) plus antiangiogenic, anti-VEGF-A antibody (IBI305)	Better OS and PFS in HBV-related advanced HCC vs sorafenib (ORIENT-32 phase II/III trial[113])	Proteinuria, irAEs1, thrombocytopenia, leukopenia, hypertension, fatigue	Approved by NMPA in China for patients with advanced HCC (2021)
Second-line
pembrolizumab (200 mg, IV) every 3 wk plus best supportive care	ICI, anti-PD-1 monoclonal antibody	Better OS, PFS and ORR in patients post-sorafenib vs placebo (KEYNOTE-394 phase III trial[114] and KEYNOTE-224 phase II trial[115])	irAEs1, fatigue, pruritus, anorexia	Approved by FDA for advanced HCC post-sorafenib (2018)
Nivolumab (1 mg/kg, IV) plus ipilimumab (3 mg/kg, IV) every 3 wk for 4 cycles, followed by nivolumab (240 mg, IV) every 2 wk	ICI, anti-PD-1 monoclonal antibody (nivolumab) plus ICI, anti-CTLA-4 antibody (ipilimumab)	Promising OS and durable response post-sorafenib (cohort 4 of CheckMate-040 phase I/II trial[90]). CheckMate 9DW phase III trial ongoing[116]	Pruritus, irAEs1	Approval by FDA for advanced HCC post-sorafenib (2020)

¹Immune-related adverse events include hepatitis, colitis, pneumonia, endocrinopathy, skin rash, neurological disorders.

IV: Intravenous administration; ICI: Immune checkpoint inhibitor; VEGF-A: Vascular endothelial growth factor-A; OS: Overall survival; PFS: Progression free survival; ORR: Objective response rate; irAEs: Immune-related adverse events; FDA: Food and Drug Administration; EMA: European Medicines Agency; HCC: Hepatocellular carcinoma; HBV: Hepatitis B virus; NMPA: National Medical Products Administration.

Table 2 Overall survival of patients with hepatocellular carcinoma receiving first-line immunotherapy alone or in combination, based on the etiology of the liver disease

Treatment	HCC etiology	HR (95%CI)	Trial	Phase
Atezolizumab plus bevacizumab vs sorafenib in first-line	Nonviral HCC	1.05 (0.68-1.63)	IMbrave150[93]	III
	HBV-HCC	0.58 (0.40-0.83)
	HCV-HCC	0.43 (0.25-0.73)
Nivolumab vs sorafenib in first-line	Nonviral HCC	0.91 (0.72-1.16)	CheckMate-459[86]	III
	HBV-HCC	0.79 (0.59-1.07)
	HCV-HCC	0.72 (CI 0.51-1.02)
Atezolizumab plus cabozantinib vs sorafenib in first-line	Nonviral HCC	1.18 (0.78–1.79)	COSMIC-312[99]	III
	HBV-HCC	0.53 (0.33-0.87)
	HCV-HCC	1.10 (0.72-1.68)
Tremelimumab 300 mg × 1 dose + Durvalumab 1500 mg vs sorafenib in first-line	Nonviral HCC	0.74 (0.57-0.95)	HIMALAYA[89]	III
	HBV-HCC	0.64 (0.48-0.86)
	HCV-HCC	1.06 (0.76-1.49)

HCC: Hepatocellular carcinoma; OS: Overall survival; HBV: Hepatitis B virus; HCV: Hepatitis C virus.