Gastroenterol Res

Gastroenterology Research, ISSN 1918-2805 print, 1918-2813 online, Open Access

Article copyright, the authors; Journal compilation copyright, Gastroenterol Res and Elmer Press Inc

Journal website https://www.gastrores.org

Original Article

Volume 15, Number 2, April 2022, pages 56-66

Gastrointestinal Toxicities of Immune Checkpoint Inhibitors Are Associated With Enhanced Tumor Responsiveness and Improved Survival

Figure 2. Cumulative incidence of immunotherapy-induced gastrointestinal adverse events. (a) Dual-immunotherapy (black) vs. mono-immunotherapy (gray). Cancer types in all patients (b), in monotherapy cohort (c), and in dual-immunotherapy cohort (d); melanoma (black), renal cell carcinoma (orange), other (red), non-small cell lung cancer (blue), bladder/urothelial (gray). (e) Drug names in mono-immunotherapy cohort: avelumab (black), ipilimumab (blue), pembrolizumab (red), atezolizumab (gray), nivolumab (orange), and durvalumab (green). (f) Drug names in dual-immunotherapy cohort: nivolumab and ipilimumab (black), pembrolizumab and ipilimumab (blue).

Figure 3. Overall survival of metastatic cancer patients with versus without immunotherapy-induced gastrointestinal adverse events among different cancer types. Gray line represents patients with immunotherapy-induced gastrointestinal adverse events. Black line represents patients without immunotherapy-induced gastrointestinal adverse events. (a) All malignancies. (b) Melanoma. (c) Non-small cell lung carcinoma. (d) Renal cell carcinoma. (e) All other cancer types.

**Table 1.** Gastrointestinal Toxicity and Baseline Characteristics
Characteristics	All patients, n (%)	GI adverse event, n (%)	No GI adverse event, n (%)	P value
^aDominator is number of total immunotherapy cycles, not number of patients. GI: gastrointestinal; BMI: body mass index.
Number of patients	567 (100)	41 (100)	526 (100)	-
Age, years
Median (range)	66 (20 - 94)	67 (20 - 94)	64 (34 - 81)	0.41
> 60	377 (66.5)	28 (68.3)	349 (65.8)	0.80
Male gender	369 (65.1)	30 (73.2)	339 (64.4)	0.26
White race	510 (89.9)	41 (100)	469 (89.2)	0.026
BMI, kg/m², median (range)	26 (14 - 51)	26 (17 - 40)	26 (14 - 51)	0.34
Malignancy
Melanoma	96 (16.9)	18 (43.9)	78 (14.8)	< 0.0001
Non-small cell lung cancer	250 (44.1)	9 (22.0)	241 (45.8)	0.003
Renal cell carcinoma	76 (13.4)	7 (17.1)	69 (13.1)	0.47
Breast	7 (1.2)	2 (4.9)	5 (1.0)	0.028
Bladder/urothelial cancer	49 (8.6)	1 (2.4)	48 (9.1)	0.14
Small cell lung cancer	19 (3.4)	1 (2.4)	18 (3.4)	0.74
Lymphoma/multiple myeloma	19 (3.4)	1 (2.4)	18 (3.4)	0.74
Ovarian	9 (1.6)	1 (2.4)	8 (1.5)	0.65
Other	22 (3.9)	1 (2.4)	21 (4.0)	0.62
Head and neck	20 (3.5)	0 (0)	20 (3.8)	0.20
No of cycles of immunotherapy	608	41	567	-
Response to immunotherapy^a				0.003
Yes	167 (27.5)	17 (41.4)	150 (26.5)
No	334 (54.9)	12 (29.3)	322 (56.8)
Unknown	107 (17.6)	12 (29.3)	95 (16.7)
Intensity of each immunotherapy cycle^a				< 0.0001
Dual immunotherapy	55 (9.0)	12 (29.3)	43 (7.6)
Mono-immunotherapy	553 (91.0)	29 (70.7)	524 (92.4)
Immunotherapy regimens^a
Nivolumab	306 (50.3)	13 (31.7)	293 (51.7)	0.014
Pembrolizumab	142 (23.4)	9 (22.0)	133 (23.5)	0.83
Ipilimumab	29 (4.8)	3 (7.3)	26 (4.6)	0.43
Atezolizumab	62 (10.2)	2 (4.9)	60 (10.6)	0.24
Avelumab	8 (1.3)	2 (4.9)	6 (1.1)	0.038
Durvalumab	6 (1.0)	0 (0)	6 (1.1)	0.51
Nivolumab and ipilimumab	44 (7.2)	11 (26.8)	33 (5.8)	< 0.0001
Pembrolizumab and ipilimumab	5 (0.8)	1 (2.4)	4 (0.7)	0.24
Nivolumab and atezolizumab	3 (0.5)	0 (0)	3 (0.5)	0.64
Nivolumab and pembrolizumab	1 (0.2)	0 (0)	1 (0.2)	0.79
Pembrolizumab and atezolizumab	1 (0.2)	0 (0)	1 (0.2)	0.79
Pembrolizumab and avelumab	1 (0.2)	0 (0)	1 (0.2)	0.79

Table 1. Gastrointestinal Toxicity and Baseline Characteristics

Characteristics

All patients, n (%)

GI adverse event, n (%)

No GI adverse event, n (%)

P value

^aDominator is number of total immunotherapy cycles, not number of patients. GI: gastrointestinal; BMI: body mass index.

Number of patients

567 (100)

41 (100)

526 (100)

Age, years

Median (range)

66 (20 - 94)

67 (20 - 94)

64 (34 - 81)

0.41

> 60

377 (66.5)

28 (68.3)

349 (65.8)

0.80

Male gender

369 (65.1)

30 (73.2)

339 (64.4)

0.26

White race

510 (89.9)

41 (100)

469 (89.2)

0.026

BMI, kg/m², median (range)

26 (14 - 51)

26 (17 - 40)

26 (14 - 51)

0.34

Malignancy

Melanoma

96 (16.9)

18 (43.9)

78 (14.8)

< 0.0001

Non-small cell lung cancer

250 (44.1)

9 (22.0)

241 (45.8)

0.003

Renal cell carcinoma

76 (13.4)

7 (17.1)

69 (13.1)

0.47

Breast

7 (1.2)

2 (4.9)

5 (1.0)

0.028

Bladder/urothelial cancer

49 (8.6)

1 (2.4)

48 (9.1)

0.14

Small cell lung cancer

19 (3.4)

1 (2.4)

18 (3.4)

0.74

Lymphoma/multiple myeloma

19 (3.4)

1 (2.4)

18 (3.4)

0.74

Ovarian

9 (1.6)

1 (2.4)

8 (1.5)

0.65

Other

22 (3.9)

1 (2.4)

21 (4.0)

0.62

Head and neck

20 (3.5)

0 (0)

20 (3.8)

0.20

No of cycles of immunotherapy

608

567

Response to immunotherapy^a

0.003

Yes

167 (27.5)

17 (41.4)

150 (26.5)

334 (54.9)

12 (29.3)

322 (56.8)

Unknown

107 (17.6)

12 (29.3)

95 (16.7)

Intensity of each immunotherapy cycle^a

< 0.0001

Dual immunotherapy

55 (9.0)

12 (29.3)

43 (7.6)

Mono-immunotherapy

553 (91.0)

29 (70.7)

524 (92.4)

Immunotherapy regimens^a

Nivolumab

306 (50.3)

13 (31.7)

293 (51.7)

0.014

Pembrolizumab

142 (23.4)

9 (22.0)

133 (23.5)

0.83

Ipilimumab

29 (4.8)

3 (7.3)

26 (4.6)

0.43

Atezolizumab

62 (10.2)

2 (4.9)

60 (10.6)

0.24

Avelumab

8 (1.3)

2 (4.9)

6 (1.1)

0.038

Durvalumab

6 (1.0)

0 (0)

6 (1.1)

0.51

Nivolumab and ipilimumab

44 (7.2)

11 (26.8)

33 (5.8)

< 0.0001

Pembrolizumab and ipilimumab

5 (0.8)

1 (2.4)

4 (0.7)

0.24

Nivolumab and atezolizumab

3 (0.5)

0 (0)

3 (0.5)

0.64

Nivolumab and pembrolizumab

1 (0.2)

0 (0)

1 (0.2)

0.79

Pembrolizumab and atezolizumab

1 (0.2)

0 (0)

1 (0.2)

0.79

Pembrolizumab and avelumab

1 (0.2)

0 (0)

1 (0.2)

0.79

**Table 2.** Features and Severity of Gastrointestinal Toxicity Subtypes
Characteristics	All GI adverse events, n (%)	Colitis, n (%)	Hepatitis, n (%)	Gastritis, n (%)	Pancreatitis, n (%)
GI: gastrointestinal.
Number of patients	41 (100)	17 (100)	23 (100)	2 (100)	4 (100)
Severity grade
1 or 2	23 (56.1)	7 (41.2)	16 (72.7)	2 (100)	2 (50.0)
3 or more	18 (43.9)	10 (58.8)	6 (27.3)	0 (0)	2 (50.0)
1	9 (22.0)	2 (11.8)	8 (34.8)	1 (50.0)	0 (0)
2	14 (34.1)	5 (29.4)	9 (39.1)	1 (50.0)	2 (50.0)
3	14 (34.1)	8 (47.0)	4 (17.4)	0 (0)	2 (50.0)
4	3 (7.3)	2 (11.8)	1 (4.3)	0 (0)	0 (0)
5	1 (2.4)	0 (0)	1 (4.3)	0 (0)	0 (0)
Dominant symptoms
Laboratory abnormalities only	16 (39.0)	0 (0)	15 (65.2)	0 (0)	1 (25.0)
Diarrhea	13 (31.7)	12 (70.6)	2 (8.7)	1 (50.0)	2 (50.0)
Abdominal pain	7 (17.1)	2 (11.8)	4 (17.4)	0 (0)	1 (25.0)
Abdominal pain and diarrhea	2 (4.9)	2 (11.8)	1 (4.3)	0 (0)	0 (0)
Severe fatigue	2 (4.9)	1 (5.9)	1 (4.3)	0 (0)	0 (0)
Dyspepsia	1 (2.4)	0 (0)	0 (0)	1 (50.0)	0 (0)
Treated with steroid
Yes (> 4 weeks)	27 (65.9)	10 (58.8)	18 (78.3)	1 (50.0)	1 (25.0)
Yes (< 4 weeks)	8 (19.5)	5 (29.4)	2 (8.7)	1 (50.0)	1 (25.0)
No	3 (7.3)	0 (0)	2 (8.7)	0 (0.0)	1 (25.0)
Unknown	3 (7.3)	2 (11.8)	1 (4.3)	0 (0.0)	1 (25.0)

Table 2. Features and Severity of Gastrointestinal Toxicity Subtypes

Characteristics

All GI adverse events, n (%)

Colitis, n (%)

Hepatitis, n (%)

Gastritis, n (%)

Pancreatitis, n (%)

GI: gastrointestinal.

Number of patients

41 (100)

17 (100)

23 (100)

2 (100)

4 (100)

Severity grade

1 or 2

23 (56.1)

7 (41.2)

16 (72.7)

2 (100)

2 (50.0)

3 or more

18 (43.9)

10 (58.8)

6 (27.3)

0 (0)

2 (50.0)

9 (22.0)

2 (11.8)

8 (34.8)

1 (50.0)

0 (0)

14 (34.1)

5 (29.4)

9 (39.1)

1 (50.0)

2 (50.0)

14 (34.1)

8 (47.0)

4 (17.4)

0 (0)

2 (50.0)

3 (7.3)

2 (11.8)

1 (4.3)

0 (0)

1 (2.4)

0 (0)

1 (4.3)

0 (0)

Dominant symptoms

Laboratory abnormalities only

16 (39.0)

0 (0)

15 (65.2)

0 (0)

1 (25.0)

Diarrhea

13 (31.7)

12 (70.6)

2 (8.7)

1 (50.0)

2 (50.0)

Abdominal pain

7 (17.1)

2 (11.8)

4 (17.4)

0 (0)

1 (25.0)

Abdominal pain and diarrhea

2 (4.9)

2 (11.8)

1 (4.3)

0 (0)

Severe fatigue

2 (4.9)

1 (5.9)

1 (4.3)

0 (0)

Dyspepsia

1 (2.4)

0 (0)

1 (50.0)

0 (0)

Treated with steroid

Yes (> 4 weeks)

27 (65.9)

10 (58.8)

18 (78.3)

1 (50.0)

1 (25.0)

Yes (< 4 weeks)

8 (19.5)

5 (29.4)

2 (8.7)

1 (50.0)

1 (25.0)

3 (7.3)

0 (0)

2 (8.7)

0 (0.0)

1 (25.0)

Unknown

3 (7.3)

2 (11.8)

1 (4.3)

0 (0.0)

1 (25.0)

**Table 3.** Gastrointestinal Toxicity by Immunotherapy Regimen
Characteristics	Nivolumab, n (%)	Pembrolizumab, n (%)	Ipilimumab, n (%)	Atezolizumab, n (%)	Avelumab, n (%)	Nivolumab and ipilimumab, n (%)	Pembrolizumab and ipilimumab, n (%)
No. of total cycles	306 (100)	142 (100)	29 (100)	62 (100)	8 (100)	44 (100)	5 (100)
Severity grade
1 or 2	9 (2.9)	10 (7.0)	1 (3.4)	1 (1.6)	2 (25)	7 (15.9)	0 (0)
3 or more	4 (1.0)	4 (2.8)	2 (6.9)	1 (1.6)	0 (0)	6 (13.6)	1 (20)
1	4 (1.3)	2 (1.4)	1 (3.4)	0 (0)	1 (12.5)	2 (4.5)	0 (0)
2	5 (1.6)	4 (2.8)	0 (0)	1 (1.6)	1 (12.5)	5 (11.4)	0 (0)
3	2 (0.7)	4 (2.8)	1 (3.4)	1 (1.6)	0 (0)	5 (11.4)	1 (20)
4	1 (0.3)	0 (0)	1 (3.4)	0 (0)	0 (0)	1 (2.3)	0 (0)
5	1 (0.3)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
Type of adverse event
Colitis	3 (1.0)	3 (2.1)	2 (6.9)	1 (1.6)	0 (0)	7 (15.9)	1 (20)
Hepatitis	9 (2.9)	7 (4.9)	1 (3.4)	0 (0)	2 (25)	4 (9.1)	0 (0)
Gastritis	0 (0)	0 (0)	0 (0)	1 (1.6)	0 (0)	1 (2.3)	0 (0)
Pancreatitis	1 (0.3)	1 (0.7)	0 (0)	0 (0)	0 (0)	2 (4.5)	0 (0)

Table 3. Gastrointestinal Toxicity by Immunotherapy Regimen

Characteristics

Nivolumab, n (%)

Pembrolizumab, n (%)

Ipilimumab, n (%)

Atezolizumab, n (%)

Avelumab, n (%)

Nivolumab and ipilimumab, n (%)

Pembrolizumab and ipilimumab, n (%)

No. of total cycles

306 (100)

142 (100)

29 (100)

62 (100)

8 (100)

44 (100)

5 (100)

Severity grade

1 or 2

9 (2.9)

10 (7.0)

1 (3.4)

1 (1.6)

2 (25)

7 (15.9)

0 (0)

3 or more

4 (1.0)

4 (2.8)

2 (6.9)

1 (1.6)

0 (0)

6 (13.6)

1 (20)

4 (1.3)

2 (1.4)

1 (3.4)

0 (0)

1 (12.5)

2 (4.5)

0 (0)

5 (1.6)

4 (2.8)

0 (0)

1 (1.6)

1 (12.5)

5 (11.4)

0 (0)

2 (0.7)

4 (2.8)

1 (3.4)

1 (1.6)

0 (0)

5 (11.4)

1 (20)

1 (0.3)

0 (0)

1 (3.4)

0 (0)

1 (2.3)

0 (0)

1 (0.3)

0 (0)

Type of adverse event

Colitis

3 (1.0)

3 (2.1)

2 (6.9)

1 (1.6)

0 (0)

7 (15.9)

1 (20)

Hepatitis

9 (2.9)

7 (4.9)

1 (3.4)

0 (0)

2 (25)

4 (9.1)

0 (0)

Gastritis

0 (0)

1 (1.6)

0 (0)

1 (2.3)

0 (0)

Pancreatitis

1 (0.3)

1 (0.7)

0 (0)

2 (4.5)

0 (0)

**Table 4.** Multivariable Cox Proportional Hazards Analysis of Overall Survival
Variables	Multivariable analysis^a
^aAnalysis was adjusted for age (per 1-year increase) and immunotherapy (mono- vs. dual-therapy). CI: confidence interval.
Gastrointestinal adverse events (yes vs. no)
All patients	0.528 (0.331 - 0.844)	0.008
Cancer subtypes
Melanoma	0.339 (0.119 - 0.962)	0.042
Lung cancer	1.072 (0.519 - 2.212)	0.85
Renal cell carcinoma	0.665 (0.202 - 2.185)	0.50
All other cancers	0.656 (0.240 - 1.793)	0.41

Table 4. Multivariable Cox Proportional Hazards Analysis of Overall Survival

Variables

Multivariable analysis^a

Hazard ratio (95% CI)

P value

^aAnalysis was adjusted for age (per 1-year increase) and immunotherapy (mono- vs. dual-therapy). CI: confidence interval.

Gastrointestinal adverse events (yes vs. no)

All patients

0.528 (0.331 - 0.844)

0.008

Cancer subtypes

Melanoma

0.339 (0.119 - 0.962)

0.042

Lung cancer

1.072 (0.519 - 2.212)

0.85

Renal cell carcinoma

0.665 (0.202 - 2.185)

0.50

All other cancers

0.656 (0.240 - 1.793)

0.41