Immune checkpoint inhibitor-mediated colitis is associated with cancer overall survival

Table 1 Baseline characteristics of patients with immune checkpoint inhibitor use

Clinical variables	All patients (n = 128)		Patients with IMC (n = 64)		Patients without IMC (n = 64)		P value
Age, yr (mean ± SD)1	66.6 (± 11.5)		67.4 (± 11.7)		65.8 (± 11.3)		0.420
Sex1
Male, n (%)	74	57.81%	37	57.81%	37	57.81%	1.000
Female, n (%)	54	42.19%	27	42.19%	27	42.19%
Race
White, n (%)	102	79.69%	52	81.25%	50	78.13%	0.660
Black, n (%)	4	3.13%	2	3.13%	2	3.13%	1.000
Asian, n (%)	9	7.03%	4	6.25%	5	7.81%	0.730
Type of malignancy1
Melanoma, n (%)	66	51.56%	33	51.56%	33	51.56%	1.000
RCC, n (%)	15	11.72%	8	12.50%	7	10.94%	0.783
NSCLC, n (%)	12	9.38%	6	9.38%	6	9.38%	1.000
Sarcoma, n (%)	11	8.59%	5	7.81%	6	9.38%	0.752
Head and neck SCC, n (%)	7	5.47%	3	4.69%	4	6.25%	0.697
Other, n (%)	17	13.28%	9	14.06%	8	12.50%	0.795
Stage IV malignancy, n (%)	114	89.07%	56	87.50%	58	90.63%	0.778
Type of immune checkpoint inhibitor1
Ipilimumab plus nivolumab, n (%)	48	37.50%	24	37.50%	24	37.50%	1.000
Ipilimumab, n (%)	22	17.19%	11	17.19%	11	17.19%	1.000
Nivolumab, n (%)	12	9.38%	6	9.38%	6	9.38%	1.000
Pembrolizumab, n (%)	38	29.69%	19	29.69%	19	29.69%	1.000
Atezolizumab, n (%)	8	6.25%	4	6.25%	4	6.25%	1.000
Number of Infusionsa (mean ± SD)1	6.91 (± 8.40)		6.09 (± 7.20)		7.73 (± 9.40)		0.268
Dose of ICI (mg/kg) (mean ± SD)	2.47 (± 1.30)		2.63 (± 1.60)		2.31 (± 1.00)		0.318
Prior ICI use1	19	14.84%	10	15.63%	9	14.06%	0.500
Medical history, n (%)
Non-liver, non-upper GI diseaseb, n (%)	28	21.88%	18	28.13%	10	15.63%	0.087
Personal history of autoimmune diseaseb, n (%)	30	23.44%	20	31.25%	10	15.63%	0.037
Prior irAEb, n (%)	8	12.50%	7	10.90%	1	1.56%	0.062
Family history of autoimmune diseaseb, n (%)	10	7.81%	8	12.50%	2	3.13%	0.048
Prior immune-enhancing therapyb, n (%)	11	8.59%	2	3.13%	9	14.06%	0.027
Prior interferon-γ therapy, n (%)	7	5.47%	1	1.56%	6	9.38%	0.115
Vitamin D use, n (%)	38	29.69%	25	39.06%	13	20.31%	0.020
Smoking (current or prior), n (%)	61	47.66%	33	51.56%	28	43.75%	0.376
NSAID use, n (%)	21	16.41%	10	15.63%	11	17.19%	0.811
Any vaccine, n (%)	25	19.53%	9	14.06%	16	25.00%	0.119
Flu vaccine, n (%)	19	14.84%	7	10.94%	12	18.75%	0.214
Pneumonia vaccine, n (%)	11	8.59%	4	6.25%	7	10.94%	0.344
Other vaccine, n (%)	2	1.56%	1	1.56%	1	1.56%	1.000
Weight at start of ICI (kg) (mean ± SD)	78.1 (± 17.4)		79.4 (± 16.9)		76.8 (± 17.9)		0.396
Medications
Steroid at start of ICI, n (%)	20	15.63%	11	17.19%	9	14.06%	0.626
Steroid duration (d)	N/A		107.7 (± 164.2)		N/A
Infliximab use, n (%)	N/A		10	15.63%	N/A
Vedolizumab use, n (%)	N/A		1	1.56%	N/A
Malignancy outcomes
Mean PFS (mo)	12.8 (± 15.3)		13.7 (± 14.9)		11.9 (± 15.8)		0.524
PFS > 6 mo, n (%)	63	49.22%	35	54.69%	28	43.75%	0.216
OS (mo)	21.0 (± 18.9)		24.3 (± 19.4)		17.7 (± 18.0)		0.050
OS > 12 mo, n (%)	72.0	56.25%	42	65.63%	30	46.88%	0.025
Death, n (%)	20	15.63%	6	9.38%	14	21.88%	0.051

¹Variable matched between cases and controls.

^aNumber of infusions of immune checkpoint inhibitor prior to immune checkpoint inhibitor-mediated colitis diagnosis (cases) or total (controls).

^bSee Supplementary Table 2.

IMC: Immune checkpoint inhibitor-mediated colitis; ICI: Immune checkpoint inhibitor; SD: Standard deviation; RCC: Renal cell carcinoma; NSCLC: Non-small cell lung cancer; SCC: Squamous cell carcinoma; PFS: Progression-Free Survival; irAE: Immune related adverse event; OS: Overall survival.

Table 2 Univariate and multivariate predictors of overall survival > 12 mo among patients with malignancy using immune checkpoint inhibitor (n = 128)

Clinical variables	Univariate predictors			Multivariate predictors
	OR	95%CI	P value	OR	95%CI	P value
Demographics
Age (yr)	1.00	0.97-1.03	0.970
Male	0.92	0.45-1.87	0.822
Female	1.08	0.53-2.20	0.822
Race
White	1.37	0.58-3.25	0.473
Black	2.39	0.24-23.6	0.456
Asian	0.97	0.25-3.79	0.965
Other	0.45	0.14-1.45	0.181
Type of malignancy
Melanoma	0.87	0.43-1.74	0.688
RCC	1.65	0.53-5.12	0.390
NSCLC	2.52	0.65-9.80	0.181
Sarcoma	0.15	0.03-0.72	0.018	0.17	0.03-0.95	0.043
Head and neck SCC	1.04	0.22-4.84	0.961
Other	1.50	0.52-4.35	0.453
Presence of IMC	2.16	1.06-4.41	0.034	2.81	1.17-6.77	0.021
Presence of high grade IMC	0.47	0.16-1.38	0.167
Stage IV malignancy	0.48	0.14-1.61	0.233
Type of Immune Checkpoint Inhibitor
Ipilimumab plus nivolumab	1.32	0.30-5.77	0.714
Ipilimumab	0.74	0.29-1.85	0.517
Nivolumab	1.63	0.46-5.70	0.448
Pembrolizumab	2.93	1.27-6.73	0.011	1.06	0.38-2.98	0.911
Atezolizumab	1.32	0.30-5.77	0.714
Number of ICI infusionsa	1.19	1.08-1.32	0.001	1.23	1.09-1.40	0.001
Dose of ICI (mg/kg)	1.33	0.86-2.05	0.198
Prior ICI use	0.51	0.19-1.37	0.183
Medical history
Non-liver, non-upper GI diseaseb	0.87	0.38-2.02	0.747
Personal history of autoimmune diseaseb	1.47	0.63-3.40	0.373
Family history of autoimmune diseaseb	1.03	0.32-4.41	0.804
Prior irAE	2.84	0.31 - 25.9	0.356
Prior immune-enhancing therapyb	0.62	0.18-2.15	0.454
Vitamin D use	0.60	0.28-1.29	0.190
Smoking (current or prior)	0.74	0.37-1.50	0.410
NSAID use	1.04	0.41-2.69	0.928
Any vaccine	0.36	0.14-0.89	0.026	1.03	0.16-6.70	0.972
Flu vaccine	0.22	0.08-0.67	0.007	0.30	0.04-2.31	0.248
Pneumonia vaccine	0.41	0.11-1.48	0.175
Other vaccine	0.77	0.05-12.66	0.858
Weight at start of ICI (kg)	0.99	0.97-1.01	0.207
Medications
Steroid at start of ICI	0.74	0.29-1.93	0.541
Steroid duration (d)	1.00	0.997-1.01	0.368
Infliximab use	0.76	0.21-2.77	0.226
Vedolizumab use	1.00	0.99-1.01	1.000

^aNumber of infusions of immune checkpoint inhibitor prior to immune checkpoint inhibitor-mediated colitis diagnosis (cases) or total (controls).

^bSee Supplementary Table 2.

ICI: Immune checkpoint inhibitor; IMC: Immune checkpoint inhibitor-mediated colitis; OR: Odds ratios; CI: Confidence interval; SD: Standard deviation; RCC: Renal cell carcinoma; NSCLC: Non-small cell lung cancer; SCC: Squamous cell carcinoma; irAE: Immune related adverse event.

Table 3 Univariate and multivariate predictors of overall survival > 12 mo among patients with immune checkpoint inhibitor colitis (n = 64)

Clinical variables	Univariate predictors			Multivariate predictors
	OR	95%CI	P value	OR	95%CI	P value
Demographics
Age (yr)	0.96	0.92-1.01	0.103	0.93	0.88-0.99	0.023
Male	0.82	0.29-2.32	0.711
Female	1.22	0.43-3.44	0.711
Race
White	0.87	0.23-3.27	0.835
Black	1.00	0.90-1.34	0.996
Asian	0.54	0.07-4.10	0.550
Other	1.07	0.97-1.11	0.912
Type of malignancy
Melanoma	1.26	0.45-3.51	0.654
RCC	0.51	0.12-2.28	0.381
NSCLC	0.53	0.10-2.85	0.456
Sarcoma	2.38	0.25-22.65	0.451
Head and neck SCC	1.05	0.89-1.10	0.865
Other	5.33	0.62-45.68	0.127
Stage IV malignancy	0.60	0.11-3.26	0.554
Presence of high grade IMC	0.91	0.32-2.57	0.855
Type of immune checkpoint inhibitor
Ipilimumab plus nivolumab	0.95	0.31-2.88	0.922
Ipilimumab	0.98	0.25-3.77	0.974
Nivolumab	0.09	0.01-0.83	0.033	0.13	0.01-1.43	0.096
Pembrolizumab	2.74	0.78-9.58	0.114	3.46	0.84-14.19	0.084
Atezolizumab	1.74	0.17-17.73	0.641
Number of ICI infusionsa	0.28	0.04-1.82	0.183
Dose of ICI (mg/kg)	1.88	0.36-9.83	0.457
Prior ICI use	0.46	0.12-1.80	0.265
Medical history
Non-liver, non-upper GI diseaseb	1.67	0.51-5.49	0.397
Personal history of autoimmune diseaseb	0.78	0.26-2.31	0.648
Family history of autoimmune diseaseb	0.93	0.20-4.29	0.922
Prior immune-enhancing therapyb	0.55	0.03-9.23	0.678
Prior interferon-g therapy	1.00	0.99-1.10	0.976
Vitamin D use	2.45	0.80-7.46	0.116	2.77	0.75-10.20	0.124
Smoking (current or prior)	1.66	0.59-5.65	0.334
NSAID use	2.55	0.49-13.16	0.265
Any vaccine	5.33	0.62-45.68	0.127
Flu vaccine	1.46	0.26-8.19	0.668
Pneumonia vaccine	1.00	0.99-1.05	0.995
Other vaccine	1.00	1.00-1.01	0.941
Weight at start of ICI (kg)	1.02	0.98-1.05	0.329
Medications
Steroid at start of ICI	0.98	0.25-3.77	0.974
Steroid duration (d)	1.00	1.00-1.01	0.736
Infliximab use	2.55	0.49-13.16	0.265
Vedolizumab use	1.00	1.00-1.01	0.936

^aNumber of infusions of immune checkpoint inhibitor prior to immune checkpoint inhibitor-mediated colitis diagnosis (cases) or total (controls).

^bSee Supplementary Table 2.

ICI: Immune checkpoint inhibitor; IMC: Immune checkpoint inhibitor-mediated colitis; SD: Standard deviation; RCC: Renal cell carcinoma; NSCLC: Non-small cell lung cancer; SCC: Squamous cell carcinoma; irAE: Immune related adverse event.

Table 4 Univariate and multivariate predictors of immune checkpoint inhibitor-mediated colitis among patients using immune checkpoint inhibitor (n = 128)

Clinical variables	Univariate predictors			Multivariate predictors
	OR	95%CI	P value	OR		95%CI	P value
Demographics
Age (yr)	1.01	0.98-1.04	0.417
Male	1.00	0.50-2.02	1.000
Female	1.00	0.50-2.02	1.000
Race
White	1.21	0.51-2.88	0.661
Black	1.00	0.14-7.33	1.000
Asian	0.79	0.20-3.07	0.730
Other	0.84	0.27-2.66	0.770
Type of malignancy
Melanoma	1.00	0.50-2.00	1.000
RCC	1.16	0.40-3.42	0.784
NSCLC	1.00	0.30-3.28	1.000
Sarcoma	0.82	0.24-2.83	0.753
Head and neck SCC	0.74	0.16-3.44	0.698
Other	1.15	0.41-3.18	0.795
Stage IV malignancy	0.72	0.24-2.22	0.572
Type of Immune Checkpoint Inhibitor
Ipilimumab plus nivolumab	1.00	0.49-2.05	1.000
Ipilimumab	1.00	0.40-2.51	1.000
Nivolumab	1.00	0.30-3.28	1.000
Pembrolizumab	1.00	0.47-2.13	1.000
Atezolizumab	1.00	0.24-4.18	1.000
Number of Infusionsa	0.98	0.93-1.02	0.273
Dose of ICI (mg/kg)	1.23	0.82-1.84	0.327
Medical History
Non-liver, non-upper GIb	2.11	0.89-5.03	0.091
Autoimmune diseaseb	2.45	1.04-5.78	0.040	1.87	0.74-4.74		0.186
Prior irAE	7.74	0.92-64.82	0.059
Family history of autoimmune diseaseb	4.43	0.90-21.74	0.067	3.98	0.74-21.38		0.107
Prior immune-enhancing therapyb	0.20	0.04-0.95	0.043	0.19	0.04-1.01		0.052
Prior interferon-γ therapy	0.15	0.018-1.31	0.087
Vitamin D use	2.51	1.14-5.54	0.022	2.48	1.01-6.07		0.047
Smoking (current or prior)	1.37	0.68-2.74	0.377
NSAID use	0.89	0.35-2.28	0.811
Any vaccine	0.49	0.20-1.21	0.123
Flu vaccine	0.53	0.19-1.45	0.219
Pneumonia vaccine	0.54	0.15-1.95	0.350
Other vaccine	1.00	0.06-16.34	1.000
Weight at start of ICI (kg)	1.01	0.99-1.03	0.393

^aNumber of infusions of immune checkpoint inhibitor prior to immune checkpoint inhibitor-mediated colitis diagnosis (cases) or total (controls).

^bSee Supplementary Table 2.

ICI: Immune checkpoint inhibitor; IMC: Immune checkpoint inhibitor-mediated colitis; RCC: Renal cell carcinoma; NSCLC: Non-small cell lung cancer; SCC: Squamous cell carcinoma; irAE: Immune related adverse event.