Immune-related adverse events associated with immune checkpoint inhibitors for advanced gastric and gastroesophageal junction cancer: A meta-analysis

Table 1 Population, Intervention, Comparison, Outcome, and Study design

Query	Search term
#1	P (Neoplasm, Stomach[Title/Abstract] OR Stomach oplasm[Title/Abstract] OR Neoplasms, Stomach[Title/Abstract] OR Gastric Neoplasms[Title/Abstract] OR Gastric Neoplasm[Title/Abstract] OR Neoplasm, Gastric[Title/Abstract] OR Cancer of Stomach[Title/Abstract] OR Stomach Cancers[Title/Abstract] OR Gastric Cancer[Title/Abstract] OR Cancer, Gastric[Title/Abstract] OR gastroesophageal junction cancer[Title/Abstract] OR gastroesophageal junction adenocarcinoma[Title/Abstract] OR adenocarcinoma gastroesophageal junction[Title/Abstract])
#2	I (Checkpoint Inhibitors, Immune[Title/Abstract] OR Immune Checkpoint Inhibitor[Title/Abstract] OR PD-L1 Inhibitors[Title/Abstract] OR PD L1 Inhibitors[Title/Abstract] OR PD-L1 Inhibitor[Title/Abstract] OR PD L1 Inhibitor[Title/Abstract] OR CTLA-4 Inhibitors[Title/Abstract] OR CTLA 4 Inhibitors[Title/Abstract] OR ipilimumab[Title/Abstract] OR ticilimumab[Title/Abstract] OR nivolumab[Title/Abstract] OR pembrolizumab[Title/Abstract] OR pidilizumab[Title/Abstract] OR atezolizumab[Title/Abstract] OR durvalumab[Title/Abstract] OR avelumab[Title/Abstract])
#3	O (immune-related adverse events[Title/Abstract] OR immune related adverse events checkpoint inhibitors[Title/Abstract] OR immune related adverse events checkpoint blockade[Title/Abstract] OR management of immune related adverse events[Title/Abstract] OR immune related adverse events in patients[Title/Abstract] OR immune related adverse events systemic immunosuppression[Title/Abstract])
#4	S ("randomized controlled trial"[pt] OR "controlled clinical trial"[pt] OR randomized[tiab] OR placebo[tiab] OR "drug therapy"[sh] OR randomly[tiab] OR trial[tiab] OR groups[tiab] OR "randomized controlled trial"[pt] OR "controlled clinical trial"[pt] OR "clinical trials as topic"[mesh] OR "random allocation"[mesh] OR "double-blind method"[mesh] OR "single-blind method"[mesh])
#5	#1 AND #2 AND #3 AND #4

PD-1: Programmed cell death receptor-1; PD-L1: Programmed death receptor-ligand 1; CTLA-4: Cytotoxic T lymphocyte-associated antigen-4.

Table 2 Study characteristics of included clinical trials

Trial	Design	Design details	Cancer types	Enrollment size, n	ICIs	Dose, mg/kg	IrAEs, all grades, n	IrAEs, severe grades, n	mOS	mPFS
Shitara et al[17], 2018	RCT	Open-label, multicenter, phase III	Advanced GC/GEJC	294	PD-1 (pembrolizumab)	200 mg, q3w	61	10	9.1 mo (95%CI: 6.2 to 10.7 mo)	1.5 mo (95%CI: 1.4 to 2.0 mo)
Fuchs et al[18], 2022	RCT	Open-label, multicenter, phase III	Advanced GC/GEJC	294	PD-1 (pembrolizumab)	200 mg, q3w	55	11	NA	NA
Moehler et al[19], 2021	RCT	Open-label, multicenter, phase III	Advanced GC/GEJC	249	PD-L1 (avelumab)	10, q2w	32	8	10.4 mo (95%CI: 9.1 to 12.0 mo)	3.2 mo (95%CI: 2.8 to 4.1 mo)
Doi et al[20], 2019	RCT	Open-label, multicenter, phase I	Advanced GC/GEJC	40	PD-L1 (avelumab)	10, q2w	9	0	9.1 mo (95%CI: 7.2 to 11.2 mo)	2.4 mo (95%CI: 1.4 to 2.8 mo)
Doi et al[21], 2018	RCT	Open-label, multicenter, phase I	Advanced GC/GEJC	40	PD-L1 (avelumab)	10, q2w	5	0	9.1 mo (95%CI: 7.2 to 11.2 mo)	2.5 mo (95%CI: 1.4 to 2.8 mo)
Chung et al[22], 2019	RCT	Open-label, multicenter, phase I	Advanced GC/GEJC	90	PD-L1 (avelumab)	10, q2w	17	2	NA	NA
Bang et al[23], 2018	RCT	Open-label, multicenter, phase III	Advanced GC/GEJC	185	PD-L1 (avelumab)	10, q2w	12	4	4.6 mo (95%CI: 3.6 to 5.7 mo)	1.4 mo (95%CI: 1.4 to 1.5 mo)
Bang et al[24], 2017	RCT	Open-label, multicenter, phase II	Advanced GC/GEJC	57	CTLA-4 (ipilimumab)	10, q3w	10	0	12.7 mo (95%CI: 10.5 to 18.9 mo)	2.7 mo

ICIs: Immune checkpoint inhibitors; irAEs: Immune-related adverse events; mOS: Median overall survival; mPFS: Median progression-free survival; RCT: Randomized controlled trial; GC: Gastric cancer; GEJC: Gastroesophageal junction cancer; NA: Not available; PD-1: Programmed cell death receptor-1; PD-L1: Programmed death receptor-ligand 1; CTLA-4: Cytotoxic T lymphocyte-associated antigen-4.

Table 3 Characteristics of the included case series studies

Case series	Enrollment size, n	Cancer types	ICIs	IrAEs, all grades, n	IrAEs, severe grades, n	mOS	mPFS
Suzuki et al[44], 2021 (Low ascites burden)	50	AGC	PD-1 (nivolumab)	9	1	5.3 mo (95%CI: 3.4 to 7.3 mo)	1.5 mo (95%CI: 1.0 to 2.0 mo)
Suzuki et al[44], 2021 (High ascites burden)	22	AGC	PD-1 (nivolumab)	5	0	2.5 mo (95%CI: 0 to 5.0 mo)	1.0 mo (95%CI: 0.9 to 1.1 mo)
Ohta et al[43], 2020	15	AGC	PD-1 (nivolumab)	5	0	6.3 mo	NA
Namikawa et al[42], 2020	29	AGC	PD-1 (nivolumab)	10	0	5.6 mo (95%CI: 0.6 to 26.8 mo)	2.3 mo (95%CI: 0.5 to 24.8 mo)
Kono et al[41], 2021	52	AGC	PD-1 (nivolumab)	13	1	7.9 mo (95%CI: 5.9 to 13.5 mo)	1.9 mo (95%CI: 1.4 to 3.0 mo)
Booka et al[40], 2021	50	GEA/ESCC	PD-1 (nivolumab)	13	5	NA	NA
Ando et al[39], 2021	108	AGC	PD-1 (nivolumab)	17	5	3.6 mo (95%CI: 3.0 to 5.3 mo)	1.4 mo (95%CI: 1.2 to 1.8 mo)

ICIs: Immune checkpoint inhibitors; irAEs: Immune-related adverse events; mOS: Median overall survival; mPFS: Median progression-free survival; NA: Not available; PD-1: Programmed cell death receptor-1; AGC: Advanced gastric cancer; GEA: Gastroesophageal adenocarcinoma; ESCC: Esophageal squamous cell carcinoma.