Immune checkpoint inhibitor-mediated colitis in gastrointestinal malignancies and inflammatory bowel disease

Table 4 Immune checkpoint inhibitor-mediated colitis and diarrhea in gastrointestinal malignancies

	Ref.	Number of Patients	Trial phase	Type of study	Therapies	Objective response rate (%)	Incidence of diarrhea (%)	Incidence of colitis (%)
Colorectal cancer
Checkmate-142	Overman et al[78], 2017	74	Phase 2	Open-label	Nivolumab	31.3	21.6	1
IMblaze 370	Eng et al[73], 2019	363	Phase 3	RCT	Atezolizumab plus cobimetinib	3	65.3	-
					Atezolizumab	2	18.9	-
					Regorafenib	2	37.5	-
KEYNOTE-164	Le et al[79], 2020	124	Phase 2	Open-label	Pembrolizumab	33	12.1	2.4
KEYNOTE-177	André etal[80], 2020	307	Phase 3	Open-label	Pembrolizumab	43.8	44	7
					5-FU based therapy with or without bevacizumab or cetuximab	33.1	62	0
GERCOR NIPICOL	Cohen et al[81], 2020	57	Phase 2	Open-label	Ipilimumab plus nivolumab	59.7	35.1	-
Gastric and GEJ cancer
	Masuda et al[82], 2019	65	NA	Retrospective cohort	Nivolumab	6.7	7.71	7.71
	Chen et al[83], 2019	2003	Phase 1b-3	Meta-analysis	Nivolumab	9.9	8.2	0.9
					Pembrolizumab
					Avelumab
					Ipilimumab
					Tremelimumab
Checkmate-032	Janjigian et al[84], 2018	160	Phase 1/2	Open-label	Nivolumab 1 mg/kg and ipilimumab 3 mg/kg	24	31	-
					Nivolumab 3 mg/kg and ipilimumab 1 mg/kg	8	10	-
					Nivolumab 3 mg/kg	12	15	-
Attraction-2	Kang et al[70], 2017	493	Phase 3	RCT	Nivolumab	11.2	7	1
					Placebo	0	2	0
Attraction-4	Boku et al[85], 2019	39	Phase 2	Open-label	Nivolumab plus S-1 and oxaliplatin	57.1	66.7	-
					Nivolumab plus capecitabine and oxaliplatin	76.5	44.4	-
KEYNOTE-012	Muro et al[69], 2016	39	Phase 1b	Open-label	Pembrolizumab	33.3	-	3
KEYNOTE-059	Fuchs et al[86], 2018	259	Phase 2	Open-label	Pembrolizumab	11.6	6.6	-
KEYNOTE-061	Shitara et al[71], 2018	570	Phase 3	Open-label	Pembrolizumab	16	5	1
					Paclitaxel	14	14	1
	Bang et al[87], 2017	114	Phase 2	Open-label	Ipilimumab	1.8	24.6	5.3
					Best supportive care	7	6.7	0
	Ralph et al[88], 2010	122	Phase 2	Open-label	Tremelimumab	0	22.22	5.62
JAVELIN Gastric 300	Bang et al[89], 2018	371	Phase 3	Open-label	Avelumab	2.2	6	-
					Chemotherapy (physician's choice)	4.3	26.6	-
Esophageal cancer
	Ralph et al[88], 2010	63	Phase 2	Open-label	Tremelimumab	16.7	22.22	5.62
Attraction-3	Kato et al[90], 2019	419	Phase 3	Open-label	Nivolumab	19	10.5	-
					Chemotherapy (physician's choice)	22	9.6	-
KEYNOTE-180	Shah et al[91], 2019	121	Phase 2	Open-label	Pembrolizumab	9.9	5.8	-
KEYNOTE-181	Kojima et al[92], 2020	628	Phase 3	Open-label	Pembrolizumab	16.7	5.4	-
					Chemotherapy (physician's choice)	7.4	20.3	-
Hepatocellular carcinoma
Checkmate-040	El-Khoueiry et al[93], 2017	262	Phase 1/2	Open-label	Nivolumab	15-20	10	-
Checkmate-040	Yau et al[94], 2020	148	Phase 1/2	Open-label	Nivolumab 1 mg/kg and ipilimumab 3 mg/kg (4 doses)	32	24	10
					Nivolumab 3 mg/kg and ipilimumab 1 mg/kg (4 doses)	27	12	2
					Nivolumab 3 mg/kg and ipilimumab 1 mg/kg (every 6 wk)	29	17	2
KEYNOTE-224	Zhu et al[95], 2018	104	Phase 2	Open-label	Pembrolizumab	17	11	2
KEYNOTE-240	Finn et al[72], 2020	413	Phase 3	RCT	Pembrolizumab	18.3	17.2	1.4
					Placebo	4.4	15.7	1.5
IMbrave 150	Finn et al[96], 2020	501	Phase 3	Open-label	Atezolizumab plus bevacizumab	33.2	18.8	-
					Sorafenib	13.3	49.4	-
Biliary tract cancers
	Ueno et al[98], 2019	60	Phase 1	Open-label	Nivolumab	3	-	-
					Nivolumab plus gemcitabine and cisplatin	37	-	-
KEYNOTE-028	Piha-Paul et al[99], 2020	24	Phase 1b	Open-label	Pembrolizumab	13	8.3	4.2
KEYNOTE-158	Piha-Paul et al[99], 2020	104	Phase 2	Open-label	Pembrolizumab	5.8	6.7	1
	Klein et al[100], 2020	33	Phase 2	Open-label	Ipilimumab plus nivolumab	23	61	61
Pancreatic cancer
KEYNOTE-158	Marabelle et al[101], 2020	22	Phase 2	Open-label	Pembrolizumab	18.2	122	3.92
	Royal et al[102], 2010	27	Phase 2	Open-label	Ipilimumab	0	-	3.7
	O'Reilly et al[102], 2019	65	Phase 2	Open-label	Durvalumab	0	6	-
					Durvalumab plus trememlimumab	3.1	13	-

¹Reported as combined diarrhea/colitis.

²Combined rates across all malignancies in study.

³Also included 12 patients with gastric and gastroesophageal junction cancer.

ICI: Immune checkpoint inhibitor; IMC: Immune checkpoint inhibitor-mediated colitis and diarrhea; CTLA-4: Cytotoxic T-lymphocyte antigen 4; PD-1: Programmed cell death protein-1; PD-L1: Programmed cell death-ligand 1; RCT: Randomized controlled trial; 5-FU: 5-Fluorouracil; S-1: Tegafur–gimeracil–oteracil potassium; GEJ: Gastroesophageal junction; NA: Not available.