Risk and incidence of fatal adverse events associated with immune checkpoint inhibitors: a systematic review and meta-analysis

Figures & data

Figure 1 Flow diagram of study selection.

Note: *Two trials were excluded because FAEs did not occur in either study group or control group.
Abbreviation: FAE, fatal adverse event.

Table 1 Baseline characteristics of the included studies

Study	Phase	Cancer type	Study ICI	Arms	Dose of ICI	Numbers of patients	FAEs (%)
Beer et al,^Citation4 2017	III	Prostate	Ipilimumab	Arm A: ipilimumab	10 mg/kg Q3W	Arm A: 399	Arm A: 9 (2.3)
				Arm B: placebo		Arm B: 199	Arm B: 0 (0)
Eggermont et al,^Citation7 2015	III	Melanoma	Ipilimumab	Arm A: ipilimumab	10 mg/kg Q3W	Arm A: 471	Arm A: 5 (1.1)
				Arm B: placebo		Arm B: 474	Arm B: 0 (0)
Govindan et al,^Citation5 2017	III	NSCLC	Ipilimumab	Arm A: ipilimumab plus chemotherapy	10 mg/kg Q3W	Arm A: 388	Arm A: 7 (1.8)
				Arm B: placebo plus chemotherapy		Arm B: 361	Arm B: 1 (0.2)
Hodi et al,^Citation9 2010	III	Melanoma	Ipilimumab	Arm A: ipilimumab plus gp100	3 mg/kg Q3W	Arm A: 380	Arm A: 8 (2.1)
				Arm B: gp100		Arm B: 132	Arm B: 2 (1.5)
Kwon et al,^Citation8 2014	III	Prostate	Ipilimumab	Arm A: ipilimumab plus radiotherapy	10 mg/kg Q3W	Arm A: 393	Arm A: 7 (1.8)
				Arm B: placebo plus radiotherapy		Arm B: 396	Arm B: 3 (0.8)
Lynch et al,^Citation6 2012	II	NSCLC	Ipilimumab	Arm A: concurrent ipilimumab plus chemotherapy	10 mg/kg Q3W	Arm A: 71	Arm A: 2 (2.8)
Lynch et al,^Citation6 2012*	II	NSCLC	Ipilimumab	Arm B: phased ipilimumab plus chemotherapy	10 mg/kg Q3W	Arm B: 67	Arm B: 0 (0)
				Arm C: Placebo plus chemotherapy		Arm C: 65	Arm C: 1 (1.5)
Reck et al,^Citation3 2013	II	SCLC	Ipilimumab	Arm A: concurrent ipilimumab plus chemotherapy	10 mg/kg Q3W	Arm A: 42	Arm A: 1 (2.4)
				Arm B: placebo plus chemotherapy		Arm B: 44	Arm B: 0 (0)
Robert et al,^Citation11 2011	III	Melanoma	Ipilimumab	Arm A: ipilimumab plus dacarbazine	3 mg/kg Q3W	Arm A: 247	Arm A: 0 (0)
				Arm B: placebo plus dacarbazine		Arm B: 251	Arm B: 1 (0.4)
Larkin et al,^Citation10 2015	III	Melanoma	Ipilimumab	Arm A: ipilimumab plus nivolumab	3 mg/kg Q3W	Arm A: 313	Arm A: 0 (0)
Larkin et al,^Citation10 2015$	III	Melanoma	Nivolumab	Arm B: nivolumab plus placebo	1 mg/kg Q3W	Arm B: 313	Arm B: 1 (0.3)
				Arm C: ipilimumab plus placebo		Arm C: 313	Arm C: 1 (0.3)
Kang et al,^Citation12 2017	III	G/GJC	Nivolumab	Arm A: nivolumab	3 mg/kg Q2W	Arm A: 330	Arm A: 5 (1.5)
				Arm B: placebo		Arm B: 163	Arm B: 2 (1.2)
Langer et al,^Citation13 2016	II	NSCLC	Pembrolizumab	Arm A: pembrolizumab plus chemotherapy	200 mg Q3W	Arm A: 59	Arm A: 1 (1.7)
				Arm B: chemotherapy		Arm B: 62	Arm B: 2 (3.2)
Postow et al,^Citation14 2015	II	Melanoma	Nivolumab	Arm A: nivolumab plus ipilimumab	1 mg/kg Q3W	Arm A: 94	Arm A: 3 (3.2)
				Arm B: placebo plus ipilimumab		Arm B: 47	Arm B: 0 (0)

Notes:

* In the annotated study, Arm B was compared with the control group;

$ In the annotated study, Arm B was compared with the control group.

Abbreviations: FAE, fatal adverse event; G/GJC, gastric or gastroesophageal junction cancer; NSCLC, non-small-cell lung cancer; SCLC, small-cell lung cancer.

Figure 2 Forest plots of odds ratios of FAEs with ICIs compared with controls (subgrouped by the types of ICIs).

Notes: *In the annotated study, Arm B was compared with the control group; ^$In the annotated study, Arm B was compared with the control group.
Abbreviations: FAE, fatal adverse event; ICI, immune checkpoint inhibitor; CTLA-4, cytotoxic T-lymphocyte-associated protein-4; PD-1, programmed cell death protein 1.

Figure 3 Forest plots of odds ratios of FAEs with ICIs compared with controls (subgrouped by the types of tumors).

Notes: *In the annotated study, Arm B was compared with the control group; ^$In the annotated study, Arm B was compared with the control group.
Abbreviations: FAE, fatal adverse event; ICI, immune checkpoint inhibitor; G/GJC, gastric or gastroesophageal junction cancer; NSCLC, non-small-cell lung cancer; SCLC, small-cell lung cancer.

Table 2 Characteristics of FAE type

	Numbers of cases (%)	OR (95% CI)
CTLA-4 inhibitors
Gastrointestinal toxicity	10 (25.6)	2.52 (0.75, 8.52)
Pulmonary toxicity	8 (20.5)	3.48 (0.78, 15.61)
Hepatic toxicity	4 (10.3)	2.80 (0.45, 17.42)
Cardiac toxicity	3 (7.7)	2.73 (0.30, 24.97)
Others	14 (35.9)
Total	39
PD-1 inhibitors
Pulmonary toxicity	2 (22.2)	1.51 (0.16, 14.61)
Cardiac toxicity	2 (22.2)	0.88 (0.16, 4.79)
Hepatic toxicity	1 (11.1)	1.49 (0.06, 36.74)
Others	4 (44.4)
Total	9

Abbreviations: CTLA-4, cytotoxic T-lymphocyte-associated protein-4; FAE, fatal adverse event; PD-1, programmed cell death protein 1.

Figure 4 Forest plots of odds ratios of FAEs with ipilimumab compared with controls (subgrouped by the dose of ipilimumab).

Note: *In the annotated study, Arm B was compared with the control group.
Abbreviation: FAE, fatal adverse event.

Figure 5 Risk of bias graph: review authors’ judgments about each risk of bias item presented as percentages across all included studies.

Notes: *In the annotated study, Arm B was compared with the control group; ^$In the annotated study, Arm B was compared with the control group.

Figure 6 Funnel plot of publication bias.

Figure 7 Begg’s funnel plot for publication bias testing.

Figure 8 Egger’s funnel plot for publication bias testing.

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