Clinical characteristics of gastrointestinal immune-related adverse events of immune checkpoint inhibitors and their association with survival

Table 1 Clinical characteristics of all patients in the programmed cell death-1/programmed death-ligand 1 and cytotoxic T-lymphocyte antigen 4 groups

Characteristic	PD-1/PD-L1, n = 605	CTLA-4, n = 56	P value
Age, yr, median (range)	69 (22-87)	65 (21-85)	0.039
Sex, n (%)			0.228
Male	419 (69.3)	34 (60.7)
Female	186 (30.7)	22 (39.3)
BMI, kg/m2	21.3 (12.0-37.0)	21.6 (13.9-43.0)	0.532
ECOG PS, n (%)			0.073
0-1	534 (88.3)	54 (96.4)
2-3	71 (11.7)	2 (3.6)
Cancer type, n (%)
NSCLC	241 (39.8)	0 (0.0)
MM	110 (18.2)	39 (69.6)
RCC	52 (8.6)	17 (30.4)
GC	49 (8.1)	0 (0.0)
Others	153(25.3)	0 (0.0)
Drugs, n (%)
Nivolumab	317 (52.4)	0 (0.0)
Pembrolizumab	180 (29.8)	0 (0.0)
Atezolizumab	74 (12.2)	0 (0.0)
Durvalumab	32 (5.3)	0 (0.0)
Avelumab	2 (0.3)	0 (0.0)
Ipilimumab	0 (0.0)	28 (50.0)
Nivolumab + ipilimumab	0 (0.0)	28 (50.0)

BMI: Body mass index; CTLA-4: Cytotoxic T-lymphocyte antigen 4; ECOG PS: Eastern Cooperative Oncology Group performance status; GC: Gastric cancer; MM: Malignant melanoma; NSCLC: Non-small cell lung cancer; PD-1/PD-L1: Programmed cell death-1/programmed death-ligand 1; RCC: Renal cell carcinoma.

Table 2 Clinical characteristics of patients who developed gastrointestinal-immune-related adverse events in the programmed cell death-1/programmed death-ligand 1 and cytotoxic T-lymphocyte antigen 4 groups

Characteristic	PD-1/PD-L1, n = 34	CTLA-4, n = 9	P value
Age, yr, median (range)	69 (37-86)	56 (46-80)	0.187
Sex, n (%)			0.427
Male	29 (85.3)	7 (77.8)
Female	5 (14.7)	2 (22.2)
Drugs, n (%)
Nivolumab	12 (35.3)	0 (0.0)
Pembrolizumab	16 (47.0)	0 (0.0)
Atezolizumab	2 (5.9)	0 (0.0)
Durvalumab	4 (11.8)	0 (0.0)
Ipilimumab	0 (0.0)	6 (66.7)
Nivolumab + ipilimumab	0 (0.0)	3 (33.3)
Median ICI duration before GI-irAE onset (d), median (range)	77 (4-733)	42 (11-92)	0.127
Diarrhea frequency per day, times (range)	5.0 (0-10)	6.5 (4-15)	0.031
CTCAE Grade, n (%)			0.288
1	9 (26.5)	0 (0.0)
2-3	25 (73.5)	9 (100)
GI-irAE treatment, n (%)
Improvement without medication	13 (38.2)	1 (11.1)	0.017
Corticosteroids	11 (32.4)	8 (88.9)	0.006
Loperamide	8 (23.5)	1 (11.1)	0.657

CTCAE: Common Terminology Criteria for Adverse Events; CTLA-4: Cytotoxic T-lymphocyte antigen 4; GI-irAE: Gastrointestinal-immune-related adverse event; ICI: Immune checkpoint inhibitor; PD-1/PD-L1: Programmed cell death-1/programmed death-ligand 1.

Table 3 Site of inflammation on abdominal computed tomography in the programmed cell death-1/programmed death-ligand 1 and cytotoxic T-lymphocyte antigen 4 groups

Site of inflammation	PD-1/PD-L1, n = 23	CTLA-4, n = 8
Jejunum, n (%)	1 (4.3)	2 (25.0)
Ileum, n (%)	2 (8.7)	2 (25.0)
Cecum, n (%)	2 (8.7)	2 (25.0)
Ascending colon, n (%)	3 (13.0)	4 (50.0)
Transverse colon, n (%)	3 (13.0)	3 (37.5)
Descending colon, n (%)	6 (26.1)	3 (37.5)
Sigmoid colon, n (%)	7 (30.4)	2 (25.0)
Rectum, n (%)	8 (34.8)	2 (25.0)
No findings, n (%)	9 (39.1)	2 (25.0)

CT: Computed tomography; CTLA-4: Cytotoxic T-lymphocyte antigen 4; PD-1/PD-L1: Programmed cell death-1/programmed death-ligand 1.

Table 4 Clinical characteristics and frequency of each type of immune-related adverse event in patients with non-small cell lung carcinoma and malignant melanoma

Characteristic	NSCLC, n = 209	MM, n = 130
Age, yr	66 ± 11	66 ± 13
Sex, n (%)
Male	143 (68.4)	75 (57.7)
Female	66 (31.6)	55 (42.3)
BMI, kg/m2	21.7 ± 3.4	22.4 ± 4.3
ECOG PS, n
0-1	184	119
2-3	25	11
Drugs, n (%)
Nivolumab	61 (29.2)	58 (44.6)
Pembrolizumab	87 (41.6)	35 (26.9)
Atezolizumab	61 (29.2)	0 (0.0)
Ipilimumab	0 (0.0)	27 (20.8)
Nivolumab + ipilimumab	0 (0.0)	10 (7.7)
History of ICI use, n (%)	11 (5.3)	34 (26.2)
Follow-up, d	365 ± 335	466 ± 419
Total irAEs, n (%)
GI-irAEs	9 (4.3)	13 (10.0)
Liver-irAEs	7 (3.3)	13 (10.0)
Lung-irAEs	10 (4.8)	11 (8.5)
Skin-irAEs	9 (4.3)	9 (6.9)
Thyroid-irAEs	12 (5.7)	9 (6.9)

BMI: Body mass index; ECOG PS: Eastern Cooperative Oncology Group performance status; GI: Gastrointestinal; irAE: Immune-related adverse event; ICI: Immune checkpoint inhibitor; MM: Malignant melanoma; NSCLC: Non-small cell lung carcinoma.

Table 5 Clinical characteristics of patients with non-small cell lung carcinoma and malignant melanoma who developed gastrointestinal-immune-related adverse event

Characteristic	NSCLC, n = 12	MM, n = 13
Age, yr	67 ± 11	67 ± 12
Sex, n
Male	10	9
Female	2	4
BMI, kg/m2	22.2 ± 3.7	22.1 ± 4.4
ECOG PS, n
0-1	12	13
2-3	0	0
Stage, n
III	1	2
IV	11	11
Latest ICI, n
Nivolumab	2	5
Pembrolizumab	8	3
Atezolizumab	2	0
Ipilimumab	0	5
Nivolumab + ipilimumab	0	0
Diarrhea frequency	4.3 ± 1.8	5.5 ± 2.5
CTCAE Grade, n
1	4	3
2	7	8
3	1	2
Median ICI duration before GI-irAE onset (d), median (range)	60 (7-567)	75 (24-733)
Treatment with ICIs after the onset of GI-irAEs
Continued or resumed	8	10
Discontinued	4	3

BMI: Body mass index; CTCAE: Common Terminology Criteria for Adverse Events; ECOG PS: Eastern Cooperative Oncology Group performance status; GI-irAE: Gastrointestinal-immune-related adverse event; ICI: Immune checkpoint inhibitor; MM: Malignant melanoma; NSCLC: Non-small cell lung carcinoma.

Table 6 Univariate and multivariate analyses of clinical factors related to overall survival in non-small cell lung carcinoma

Factor	Univariate analysis			Multivariate analysis
	HR	95%CI	P value	HR	95%CI	P value
Age, yr
< 75	1			1
≥ 75	0.520	0.277-0.976	0.042	0.658	0.345-1.253	0.203
Sex
Male	1
Female	1.301	0.845-2.003	0.233
BMI, kg/m2
Underweight (< 18.5)	1			1
Normal (18.5-24.9)	0.527	0.316-0.878	0.014	0.635	0.377-1.067	0.086
Overweight (> 25.0)	0.394	0.195-0.795	0.009	0.506	0.250-1.040	0.064
Stage
III	1			1
IV	2.447	1.227-4.881	0.011	2.182	1.085-4.387	0.029
ECOG PS
0-1	1			1
2-3	15.197	8.486-27.214	< 0.001	12.772	7.067-23.085	< 0.001
GI-irAE
Continued administration of ICIs	1
Discontinued administration of ICIs	0.904	0.165-4.945	0.907
Non-GI-irAEs	1.334	0.489-3.642	0.574

BMI: Body mass index; CI: Confidence interval; ECOG PS: Eastern Cooperative Oncology Group performance status; GI-irAE: Gastrointestinal-immune-related adverse event; HR: Hazard ratio; ICI: Immune checkpoint inhibitor.

Table 7 Univariate and multivariate analyses of clinical factors related to overall survival in malignant melanoma

Factor	Univariate analysis			Multivariate analysis
	HR	95%CI	P value	HR	95%CI	P value
Age, yr
< 75	1			1
≥ 75	1.717	1.067-2.761	0.026	1.474	0.816-2.663	0.199
Sex
Male	1			1
Female	0.593	0.354-0.993	0.047	0.793	0.418-1.506	0.479
BMI, kg/m2
Underweight (< 18.5)	1
Normal (18.5-24.9)	1.252	0.671-2.336	0.48
Overweight (> 25.0)	1.044	0.510-2.137	0.906
Stage
III	1
IV	1.758	0.838-3.686	0.135
ECOG PS
0-1	1			1
2-3	3.014	1.427-6.366	0.004	2.406	1.125-5.147	0.024
GI-irAE
Continued administration of ICIs	1			1
Discontinued administration of ICIs	3.818	0.767-18.996	0.102	4.079	0.779-21.368	0.096
Non-GI-irAEs	3.25	1.020-10.360	0.046	3.081	0.963-9.861	0.058
ICI
Anti PD-1/PD-L1 antibody	1
Anti CTLA-4 antibody	1.366	0.837-2.228	0.212

BMI: Body mass index; CI: Confidence interval; CTLA-4: Cytotoxic T-lymphocyte antigen 4; GI-irAE: Gastrointestinal-immune-related adverse event; HR: Hazard ratio; ICI: Immune checkpoint inhibitor; PD-1: Programmed cell death-1.