Immune-Related Adverse Event-Related Adrenal Insufficiency Mediates Immune Checkpoint Inhibitors Efficacy in Cancer Treatment

Figures & data

Table 1 Characteristics of Patients with Different Types of irAEs or Without irAEs

Variable	irAE-A Group No. (%)	irAE-B Group No. (%)	Non-irAE Group No. (%)	p-value
Gender				0.635
Male	11 (64.7)	60 (72.3)	69 (75.0)
Female	6 (35.3)	23 (27.7)	23 (25.0)
Age				0.278
<65	11 (64.7)	49 (59.0)	45 (48.9)
≥65	6 (35.3)	34 (41.0)	47 (51.1)
ECOG PS				0.099
≤1	8 (47.1)	32 (38.6)	24 (26.1)
>1	9 (52.9)	51 (61.4)	68 (73.9)
TNM				0.053
I–III	7 (41.2)	43 (51.8)	31 (33.7)
IV	10 (58.8)	40 (48.2)	61 (66.3)
Treatment line				0.465
1	14 (82.4)	57 (68.7)	62 (67.4)
>1	3 (17.6)	26 (31.3)	30 (32.6)
Cancer type				0.025
Esophageal cancer	5 (29.4)	7 (8.4)	15 (16.3)
Gastric cancer	6 (35.3)	37 (44.6)	53 (57.6)
Hepatocellular cancer	2 (11.8)	17 (20.5)	5 (5.4)
Biliary tract cancer	0 (0.0)	2 (2.4)	0 (0.0)
Respiratory cancer	1 (5.9)	3 (3.6)	3 (3.3)
Others	3 (17.6)	17 (20.5)	16 (17.4)
Treatment modality				0.296
ICI combined therapy	17 (100.0)	74 (89.2)	87 (94.6)
Monotherapy	0 (0.0)	9 (10.8)	5 (5.4)

Abbreviations: irAE, immune-related adverse event; irAE-A group, patients with irAE-related adrenal insufficiency; irAE-B group, the group with other irAEs; PS, performance status.

Table 2 Response to Immunotherapy of Cancer Patients

Comparison	PD	SD	PR	CR	DCR (%)	p-value
irAE-A group vs irAE-B group						0.065
irAE-A group	1	14	2	0	94.1% (95% CI: 71.3–99.9%)
irAE-B group	23	53	6	1	72.3% (95% CI: 62.5–2.1%)
irAE-A group vs Non-irAE group						0.001
irAE-A group	1	14	2	0	94.1% (95% CI: 71.3–99.9%)
Non-irAE group	45	38	9	0	51.1% (95% CI: 40.7–61.5%)
irAE-B group vs Non-irAE group						0.004
irAE-B group	23	53	6	1	72.3% (95% CI: 62.5%-82.1%)
Non-irAE group	45	38	9	0	51.1% (95% CI: 40.7%-61.5%)

Abbreviations: irAE, immune-related adverse event; irAE-A group, patients with irAE-related adrenal insufficiency; irAE-B group, the group with other irAEs; PD, progressive disease; SD, stable disease; PR, partial response; CR, complete response; DCR, disease control rate.

Figure 1 Association between irAE status and prognosis of patients. (A) The Kaplan-Meier curve of progression-free survival (PFS) in cancer patients. (B) The Kaplan-Meier curve of overall survival (OS) in cancer patients. (C) The Kaplan-Meier curve of progression-free survival (PFS) in patients with gastric cancer. (D) The Kaplan-Meier curve of overall survival (OS) in patients with gastric cancer.

Table 3 Univariate and Multiple Extended Cox Regression Model on PFS and OS in Cancer Patients

Covariate	PFS						OS
	Univariate Analysis (n=187)			Multivariate Analysis (n=187)			Univariate Analysis (n=179)			Multivariate Analysis (n=179)
	HR	95% CI	p-value	HR	95% CI	p-value	HR	95% CI	p-value	HR	95% CI	p-value
Gender
Male	Reference			Reference			Reference			Reference
Female	0.965	0.670–1.390	0.848	0.993	0.684–1.441	0.969	1.181	0.783–1.783	0.427	1.184	0.776–1.807	0.433
Age
<65	Reference			Reference			Reference			Reference
≥65	1.045	0.754–1.450	0.790	1.033	0.729–1.463	0.855	1.200	0.814–1.769	0.356	1.280	0.839–1.955	0.252
ECOG PS
≤1	Reference			Reference			Reference			Reference
>1	1.543	1.079–2.205	0.017	1.462	1.008–2.120	0.045	2.321	1.469–3.668	0.000	1.954	1.204–3.172	0.007
TNM
I–III	Reference			Reference			Reference			Reference
IV	1.874	1.330–2.641	0.000	2.015	1.372–2.958	0.000	1.737	1.161–2.600	0.007	1.620	1.034–2.539	0.035
Treatment line
1	Reference			Reference			Reference			Reference
>1	1.846	1.309–2.603	0.000	1.737	1.222–2.471	0.002	2.123	1.432–3.149	0.000	2.021	1.319–3.097	0.001
Cancer type
Gastrointestinal cancers	Reference			Reference			Reference			Reference
Respiratory cancer	1.345	0.547–3.306	0.519	0.976	0.393–2.427	0.959	0.715	0.260–1.960	0.514	0.604	0.219–1.662	0.329
Others	1.114	0.743–1.669	0.602	1.095	0.723–1.659	0.669	1.020	0.639–1.628	0.934	0.771	0.467–1.274	0.310
Treatment modality
ICI combined therapy	Reference			Reference			Reference			Reference
Monotherapy	1.286	0.711–2.323	0.405	1.633	0.862–3.093	0.133	1.755	0.914–3.373	0.091	2.686	1.298–5.558	0.008
irAEs
Non-irAE group	Reference			Reference			Reference			Reference
irAE-A group	0.187	0.085–0.411	0.000	0.003	0.000–0.210	0.008	0.113	0.040–0.317	0.000	0.000	0.000–0.059	0.009
irAE-B group	0.613	0.436–0.862	0.005	0.095	0.013–0.686	0.020	0.440	0.291–0.664	0.000	0.006	0.000–0.336	0.013

Abbreviations: PFS, progression-free survival; OS, overall survival; PS, performance status; irAEs, immune-related adverse events; irAE-A group, patients with irAE-related adrenal insufficiency; irAE-B group, the group with other irAEs; HR, hazard ratio; CI, confidence interval.

Table 4 Characteristics of Gastric Cancer Patients Among Different Groups

Variable	irAE-A Group No. (%)	irAE-B group No. (%)	Non-irAE group No. (%)	p-value
Gender				0.413
Male	3 (50.0)	26 (70.3)	40 (75.5)
Female	3 (50.0)	11 (29.7)	13 (24.5)
Age				0.272
<65	5 (83.3)	21 (56.8)	26 (49.1)
≥65	1 (16.7)	16 (43.2)	27 (50.9)
ECOG PS				0.064
≤1	1 (16.7)	18 (48.6)	14 (26.4)
>1	5 (83.3)	19 (51.4)	39 (73.6)
TNM				0.851
I–III	2 (33.3)	14 (37.8)	13 (24.5)
IV	4 (66.7)	23 (62.2)	40 (75.5)
Treatment line				1.000
1	4 (66.7)	23 (62.2)	34 (64.2)
>1	2 (33.3)	14 (37.8)	19 (35.8)
Treatment modality				0.757
ICI combined chemotherapies	4 (66.6)	26 (70.3)	32 (60.4)
ICI combined targeted drugs	1 (16.7)	8 (21.6)	12 (22.6)
ICI combined chemotherapies and targeted drugs	1 (16.7)	3 (8.1)	9 (17.0)

Abbreviations: irAE, immune-related adverse event; irAE-A group, patients with irAE-related adrenal insufficiency; irAE-B group, the group with other irAEs; PS, performance status.

Table 5 Response to Immunotherapy in Gastric Cancer Patients

Comparison	PD	SD	PR	CR	DCR (%)	p-value
irAE-A group vs irAE-B group						1.000
irAE-A group	1	4	1	0	83.3% (95% CI: 35.9–99.6%)
irAE-B group	8	25	3	1	78.4% (95% CI: 64.5–92.3%)
irAE-A group vs Non-irAE group						0.228
irAE-A group	1	4	1	0	83.3% (95% CI: 35.9–99.6%)
Non-irAE group	24	26	3	0	54.7% (95% CI: 40.9–68.6%)
irAE-B group vs Non-irAE group						0.021
irAE-B group	8	25	3	1	78.4% (95% CI: 64.5–92.3%)
Non-irAE group	24	26	3	0	54.7% (95% CI: 40.9–68.6%)

Abbreviations: irAE, immune-related adverse event; irAE-A group, patients with irAE-related adrenal insufficiency; irAE-B group, the group with other irAEs; PD, progressive disease; SD, stable disease; PR, partial response; CR, complete response; DCR, disease control rate.

Table 6 Univariate and Multiple Extended Cox Regression Model on PFS and OS in Gastric Cancer Patients

Covariate	PFS						OS
	Univariate Analysis (n=91)			Multivariate Analysis (n=91)			Univariate Analysis (n=91)			Multivariate Analysis (n=91)
	HR	95% CI	p-value	HR	95% CI	p-value	HR	95% CI	p-value	HR	95% CI	p-value
Gender
Male	Reference			Reference			Reference			Reference
Female	1.093	0.648–1.843	0.738	0.998	0.571–1.745	0.995	1.157	0.651–2.057	0.620	1.392	0.756–2.562	0.289
Age
<65	Reference			Reference			Reference			Reference
≥65	0.952	0.588–1.539	0.839	1.013	0.590–1.741	0.961	1.222	0.711–2.101	0.468	1.730	0.907–3.301	0.096
ECOG PS
≤1	Reference			Reference			Reference			Reference
>1	1.146	0.701–1.874	0.587	0.980	0.576–1.670	0.942	1.229	0.702–2.151	0.471	1.048	0.539–2.037	0.890
TNM
I–III	Reference			Reference			Reference			Reference
IV	1.744	1.009–3.015	0.047	1.114	0.596–2.084	0.735	1.828	0.960–3.483	0.066	1.296	0.620–2.708	0.490
Treatment line
1	Reference			Reference			Reference			Reference
>1	2.525	1.529–4.171	0.000	2.454	1.255–4.799	0.009	2.880	1.675–4.953	0.000	2.328	1.166–4.647	0.017
Treatment modality
ICI combined chemotherapies	Reference			Reference			Reference			Reference
ICI combined targeted drugs	3.170	1.783–5.637	0.000	2.470	1.137–5.368	0.022	3.199	1.753–5.839	0.000	2.258	1.065–4.788	0.034
ICI combined chemotherapies and targeted drugs	3.202	1.579–6.492	0.001	3.228	1.461–7.133	0.004	2.902	1.361–6.185	0.006	1.774	0.685–4.591	0.237
irAEs
Non-irAE group	Reference			Reference			Reference			Reference
irAE-A group	0.160	0.038–0.672	0.012	0.007	0.000–8.523	0.172	0.082	0.011–0.612	0.015	0.006	0.000–316.532	0.354
irAE-B group	0.563	0.342–0.928	0.024	0.184	0.007–4.723	0.306	0.525	0.296–0.932	0.028	0.144	0.001–23.901	0.457

Abbreviations: PFS, progression-free survival; OS, overall survival; PS, performance status; irAEs, immune-related adverse events; irAE-A group, patients with irAE-related adrenal insufficiency; irAE-B group, the group with other irAEs; HR, hazard ratio; CI, confidence interval.