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

Table 1 Common terminology criteria for adverse events

Grade	Diarrhea	Colitis
1	Increase of < 4 stools/d over baseline	Asymptomatic
2	Increase of > 4-6 stools/d	Abdominal pain, mucus, and blood in stools
3	Increase of ≥ 7 stools/d, incontinence, and limiting self-care activity of daily living	Severe pain, fever, peritoneal signs, ileus
4	Life-threatening consequences (hemodynamic collapse)	Life-threatening consequences (perforation, ischemia, necrosis, bleeding, and toxic megacolon)
5	Death	Death

Table 2 Meta-analyses of immune checkpoint inhibitor-mediated colitis and diarrhea with immune checkpoint inhibitor use

Meta-analysis	No. of studies	ICI targets	Malignancies	GI malignancy	Trial Phase	Diarrhea (incidence, %)					Colitis (incidence, %)
Ref.						Total	Anti-CTLA-4	Combo1	Anti-PD-1		Anti-PD-L1	Total	Anti-CTLA-4	Combo1	Anti-PD-1	Anti-PD-L1
Khoja et al[25], 2017	48	CTLA-4	Melanoma	Colorectal	1-3		30.2		12.1		7.3		5.7		0.7	0.0
		PD-1	Solid tumors	GEJ
		PD-L1		Liver
				Pancreas
Wang et al[29], 2017	34	CTLA-4	Melanoma	None	1-3		7.92	9.22	1.32		0.32	2.4	9.1	13.6	1.4	1.0
		Combination1	Solid tumors
		PD-1
		PD-L1
De Velasco et al[30], 2017	21	CTLA-4	Melanoma	None	2-3							2.3
		PD-1	Solid tumors
		PD-L1
Wang et al[33], 2017	46	PD-1	Melanoma	Colorectal	1-3	4-13						1.0
		PD-L1	Solid tumors	Gastric
			Hematologic
Zhang et al[31], 2018	11	CTLA-4	Melanoma	None	1-3		173	32.7	173				2.93	14.2	2.93
		Combination1	Sarcoma
		PD-1	Solid tumors
Tandon et al[27], 2018	18	CTLA-4	Melanoma	None	1-3		35.4	44.2	13.7				11.0	14.5	2.0
		Combination1
		PD-1
Baxi et al[32], 2018	13	PD-1	Melanoma	None	2-3							0.7			0.3-1.1	0.5
		PD-L1	Solid tumors
Komaki et al[28], 2018	22	CTLA-4	Melanoma	None	2-3		40.0		9.9	10.7			8.4		0.9
		PD-1	Solid tumors
		PD-L1
Bishay et al[34], 2020	27	Combination1	NSCLC	None	1-3			13.2-40.4	9.1	11.0				7.3-12.1	0.9	0.4
		PD-1
		PD-L1
Yang et al[35], 2020	10	CTLA-4	Melanoma	None	2-3		31.5		30.0	7.6			5.8		2.3
		PD-1	NSCLC
		PD-L1	Breast
Yao et al[36], 2020	40	CTLA-4	Melanoma	Colorectal	2-3								8.1	14.5	1.44	1.44
		Combination1	Solid tumors	Gastric/GEJ
		PD-1		HCC
		PD-L1

¹Combination anti-cytotoxic T-lymphocyte antigen 4 plus anti-programmed cell death protein-1.

²Grade 3-4 diarrhea only.

³Did not distinguish between monotherapy with ipilimumab or nivolumab.

⁴Combined incidence with programmed cell death protein-1 and programmed cell death-ligand 1.

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; GEJ: Gastroesophageal junction; NSCLC: Non-small cell lung cancer; HCC: Hepatocellular carcinoma.

Table 3 Risk factors for immune checkpoint inhibitor-mediated colitis and diarrhea

Ref.	Number of patients	ICI targets	Malignancies	GI malignancies	Risk factors for IMC	OR or RR	95%CI	Fisher's exact P value
Wolchok et al[49], 2010	217	CTLA-4	Melanoma	None	High dose ipilimumab	2.01	0.52-7.82
Ascierto et al[50], 2017	727	CTLA-4	Melanoma	None	High dose ipilimumab	1.83	1.07-0.14
Wang et al[46], 2018	327	CTLA-4	Melanoma	None	Race (Caucasian)	5.76	2.03-16.36
		Combination1	Solid tumors		Cancer stage IV vs stage III	0.09	0.03-0.30
		PD-1	Hematologic		Melanoma	1.96	1.04-3.67
		PD-L1			Ipilimumab or combination1	2.23	1.03-4.81
Abu-Sbeih et al[53], 2019	346	CTLA-4	Melanoma	None	Race (Caucasian)	NA	NA	0.023
		Combination1			Lower mean lactate dehydrogenase	NA	NA	0.011
		PD-1
		PD-L1
Grover et al[40], 2020	213	CTLA-4	Melanoma	None	Combination1 vs pembrolizumab	3.34	1.1-9.8
		Combination1			CTLA-4 vs PD-1	7.14	2.2-25.0
		PD-1			Neutrophil-to-lymphocyte ratio ≥ 5	0.34	0.1-0.9
					Vitamin D intake	0.35	0.1-0.9	0.03
					Pneumococcal pneumonia vaccine	NA	NA	0.05
					Influenza or pneumonia vaccine	NA	NA	0.05

¹Combination anti- cytotoxic T-lymphocyte antigen 4 plus anti-programmed cell death protein-1.

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; OR: Odds ratio; RR: Relative risk; CI: Confidence interval; NA: Not available.

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.

Table 5 Selected retrospective studies reporting prevalence of gastrointestinal immune-related adverse events in inflammatory bowel disease patients treated with all immune checkpoint inhibitor regimens

Ref.	Number of IBD patients	Single or multi center	Prevalence of GI irAE (%)
Abu-Sbeih et al[112], 2020	102	Multi	41.2
Grover et al[113], 2020	21	Single	28.0
Braga Neto et al[114], 2021	13	Single	30.7
Meserve et al[115], 2021	193 across 12 studies	Meta-analysis	40.0

IBD: Inflammatory bowel disease; GI: Gastrointestinal; irAE: Immune-related adverse events.