Immune checkpoint inhibitor-related hepatotoxicity: A review

Table 1 Incidence of severe hepatotoxicity by immunotherapy agent used as reported in key phase II and III clinical trials

Class	Agent	Ref.	Indication	Incidence of hepatoxicity (all grades) % (no. of patients)	Incidence of ≥ grade 3 hepatoxicity % (no. of patients)
CTLA-4	Ipilimumab (standard dose) 3 mg/kg	Hodi et al[71], 2018	Melanoma	0.3 (1/311)	0 (0/311)
		Weber et al[72], 2009	Melanoma	15.5 (9/58)	10.3 (6/58)
		Hodi et al[2], 2010	Melanoma	3.8 (5/131)	0 (0/131)
			Melanoma	2.1 (8/380) Ipilimumab with gp100	1.1 (4/380) pilimumab with gp100
		Wolchok et al[73], 2010	Melanoma	26.4% (19/72)	0 (0/72)
		Robert et al[74], 2011	Melanoma	29.1 (72/247)	20.6 (51/247)
	Ipilimumab (high dose) 10 mg/kg	Wolchok et al[73], 2010	Melanoma	70.4 (50/71)	15.5 (11/71)
	Tremelimumab	Ribas et al[75], 2013	Melanoma	0.6 (2/325)	0.6 (2/325)
Anti-PD-1	Nivolumab	Hodi et al[71], 2018	Melanoma	0.3 (1/313)	0.3 (1/313)
		Weber et al[76], 2017	Melanoma	1.9 (11/576)	0.7 (4/576)
		Brahmer et al[77], 2015	Squamous cell NSCLC	1.5 (2/131)	0 (0/131)
		Borghaei et al[78], 2015	Non-squamous NSCLC	3.1 (9/287)	0 (0/287)
		Robert et al[79], 2014	Melanoma	1.1 (1/89)	1.1 (1/89)
	Pembrolizumab	Robert et al[79], 2014	Melanoma	0 (0/84)	0 (0/84)
		Eggermont et al[80], 2018	Melanoma	1.8 (9/509)	1.4 (7/509)
	Cemiplimab	Migden et al[81], 2018	Cutaneous Squamous-Cell Carcinoma	8.5 (5/59)	0 (0/59)
Anti-PD-L1	Atezolizumab	Jotte et al[82], 2020	Squamous NSCLC	17.4 (58/334)	5.4 (18/334)
	Atezolizumab + Bevacizumab (anti-VEGF antibody)	Finn et al[3], 2020	HCC	33.4 (110/329)	10.6 (35/329)
	Avelumab	D’Angelo et al[83], 2020	Metastatic Merkel cell carcinoma	1.1 (1/88)	1.1 (1/88)
	Durvalumab	Garassino et al[84], 2018	Advanced NSCLC	0.2 (1/444)	0.2 (1/444)
Combination Therapy	Ipilimumab + Nivolumab	Hodi et al[71], 2018	Melanoma	3.2 (10/313)	2.6 (8/313)
		Postow et al[85], 2015	Melanoma	22.3 (21/94)	10.6 (10/94)
		Larkin et al[86], 2015	Melanoma	17.6 (55/313)	8.3 (26/313)
		Wolchok et al[73], 2010	Melanoma	20.8 (11/53)	11.3 (6/53)

Grading of severity is according to common terminology criteria for adverse events. CTLA-4: Cytotoxic T-lymphocyte-associated protein 4; HCC: Hepatocellular carcinoma; no. of: Number of; NSCLC: Non-small cell lung cancer; PD-1: Programmed cell death protein 1; PD-L1: Programmed death-ligand 1; VEGF: Vascular endothelial growth factor.