Immune-related adverse event-related adrenal insufficiency mediates immune checkpoint inhibitors efficacy for cancer treatment

doi:10.21203/rs.3.rs-3410896/v1

Purpose

Immune checkpoint inhibitors (ICIs) have significantly improved the outcomes of patients with cancer. An increasing number of immune-related adverse events (irAEs) have been discovered with the widespread clinical application of ICIs, which appear to be associated with improved treatment efficacy in certain cancers. We aimed to evaluate the correlation between irAE-related adrenal insufficiency (AI) and ICI treatment efficacy.

Methods

Patients were divided into irAE-A (patients with irAE-related AI), irAE-B (patients with other irAEs) and non-irAE groups. Immunotherapy efficacy was assessed based on the disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Survival probabilities were estimated using the Kaplan–Meier method with the log–rank test.

Results

One hundred and ninety-two patients with cancer including gastrointestinal, respiratory, and other cancers, who received ICIs were enrolled in this study. The DCR of the irAE-A and irAE-B groups were higher than that of the non-irAE group (P < 0.05). Multiple extended Cox regression analyses showed that irAE status (irAE-A vs. non-irAE, P = 0.008; irAE-B vs. non-irAE, P = 0.020), ECOG status (P = 0.045), TNM stage (P = 0.000), and treatment line (P = 0.002) were independent predictors of PFS. Meanwhile, irAE status (irAE-A vs. non-irAE, P = 0.009; irAE-B vs. non-irAE, P = 0.013), ECOG status (P = 0.007), TNM stage (P = 0.035), treatment line (P = 0.001) and treatment modality (P = 0.008) were independent predictors for OS.

Conclusions

IrAE-related AI was significantly associated with better clinical outcomes in patients with cancer and is a potentially predictable marker for better ICI treatment efficacy.

adrenal insufficiency

cancers

immune checkpoint inhibitors

immune- related adverse events

treatment efficacy

Cancer treatment has been revolutionized with the recent emergence of immune checkpoint inhibitors (ICIs), which have significantly improved the treatment outcomes in cancers, including melanoma, advanced non-small cell lung cancer (NSCLC), renal cell carcinoma, gastrointestinal cancer, urothelial carcinoma, and squamous cell carcinoma of the head and neck (Bilgin, Sendur, Hizal, & Yalçın, 2019; Borghaei et al., 2015; Ferris et al., 2016; Kato et al., 2019; Motzer et al., 2015; Weber et al., 2015). ICIs can target immune checkpoints, such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1) on immune or tumor cells to enhance the tumor-killing capability of immune cells such as CD8 T lymphocytes (Postow, Sidlow, & Hellmann, 2018). Immune related adverse events (irAEs) have been observed with ICI treatment, possibly occurring via the following mechanisms: the increased T-cell activity against antigens present in tumors and healthy tissues, elevated levels of inflammatory cytokines or pre-existing autoantibodies, and enhanced complement-mediated inflammation owing to the direct binding of an anti-CTLA-4 antibody to CTLA-4 expressed on normal tissues (Janjigian et al., 2021; Postow et al., 2018). IrAEs affect almost all organs, including the skin, gastrointestinal tract, lungs, liver, and endocrine and musculoskeletal systems with varying frequencies and severities (Brahmer et al., 2018).

IrAE-related adrenal insufficiency (AI) is an endocrine adverse event characterized by a malfunctioning hypothalamic-pituitary-adrenal axis and a subsequent deficiency of adrenal cortisol production. It can be divided into primary AI encompassing low serum cortisol levels and elevated plasma adrenocorticotropic hormone (ACTH) levels, and secondary AI, referring to isolated ACTH insufficiency, and multiple pituitary hormone deficiency (Cui, Wang, Zhang, & Zhang, 2022). The incidence of AI in monotherapy ICI treatment was 0.7%, with an incidence of grade 3 or above of 0.2%; however, the incidence of AI in combined ICIs treatment was increased to 4.2% (Lu, Li, Lan, Liang, & Meng, 2019; Percik et al., 2020). AI manifests as non-specific symptoms including headache, fatigue, nausea, emesis, hypotension, and hypoglycemia, which may be overlooked by oncologists (Arima et al., 2019). Patients with severe adrenal crises characterized by shock caused by hypotension, disturbance of consciousness, and electrolyte disorders such as hyponatremia and hyperkalemia require long-term, even lifelong substitutive hormone replacements (Wright, Powers, & Johnson, 2021).

IrAEs have been proven to promote the treatment efficacy of ICIs in patients with melanoma, NSCLC, hepatocellular carcinoma, and gastric cancer (Nakamura et al., 2017; Toi et al., 2018; Xu et al., 2021; Zhang et al., 2022). However, the relationship between irAE-related AI and ICIs treatment efficacy has not yet been evaluate owing to the low incidence and concealment of AI. The Phase II DART study (SWOG S1609) on breast cancer observed AI in all three responders, implying a potential impact of AI on ICIs efficiency (Adams et al., 2022).

In the present study, we evaluated the correlation between irAE-related AI and the treatment efficacy of ICIs in patients with cancer.

Patients

We retrospectively obtained data on 192 patients (esophageal, gastric, liver, biliary tract, lung, head and neck, kidney, endometrial, cervical, pancreatic, colon, thyroid, and bladder cancers, and melanoma) treated with anti-PD-1 antibody/anti-PD-L1 antibody monotherapy or in combination with chemotherapy or targeted drugs between February 2019 and February 2023 at the Fourth Hospital of Hebei Medical University. The inclusion criteria were: histopathology confirmed malignant tumors before treatment initiation, patients received ICIs treatment, detailed and complete clinical data, and no infectious inflammatory diseases. The exclusion criteria were: ICI treatment information combined with other tumor histories, infectious inflammatory diseases, patients who discontinued treatment or refused to accept the assessment, and patients without complete medical records. All clinical data, including age, sex, cancer type, Eastern Cooperative Oncology Group Performance Status (ECOG PS), TNM stage, treatment lines, treatment modality, and irAE status, were collected for analysis. All the study procedures were reviewed and approved by the Ethics Committee of the Fourth Hospital of Hebei Medical University. Owing to the retrospective nature of this study, the requirement for informed consent was waivered.

Treatment and assessment

Patients received standard anti-PD-1 antibody/anti-PD-L1 antibody (monotherapy or combined with chemotherapy or targeted drugs) every three weeks until disease progression, clinical deterioration, unacceptable toxicity, or patient refusal. The immunotherapeutic drugs administered were pembrolizumab, camrelizumab, tislelizumab, sintilimab, toripalimab and durvalumab. Objective tumor response was evaluated using computed tomography (CT) or magnetic resonance imaging (MRI) scans repeated every 6–9 weeks according to the Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (Eisenhauer et al., 2009). The endpoints were response time, progression-free survival (PFS), and overall survival (OS). OS was defined as the time from treatment initiation to death from any cause or study cut-off. The disease control rate (DCR) was defined as the percentage of patients who have achieved complete response, partial response, and stable disease. PFS was defined as the period from treatment initiation to the date of disease progression, death, or study cut-off. IrAEs were defined as inflammatory side effects caused by an imbalance in immunological tolerance owing to ICIs treatment. IrAEs were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events ver.4.03 (https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40). Patients were divided into irAE-A (patients with irAE-related AI), irAE-B (patients with other irAEs), and non-irAE groups. Diagnostic criteria for irAE-related AI were as follows: primary AI was defined as suspected clinical manifestations of adrenocortical hypofunction with low morning serum cortisol levels (< 138nmol/L) accompanied by increased plasma ACTH levels, excluding adrenal metastasis, bleeding, or infection; secondary AI was defined as low morning serum cortisol levels (< 138nmol/L) with low plasma ACTH levels (< 5pg/mL) and an inadequate response to a 250mcg ACTH stimulation test with or without abnormal pituitary findings on MRI, excluding pituitary metastases, infectious pituitary diseases, and pituitary adenomas (Bornstein et al., 2016; Puzanov et al., 2017).

Statistical analysis

Statistical analyses were performed using SPSS software (version 24.0; SPSS Inc., Chicago, IL, USA). Differences between the groups were compared using the chi-square test or Fisher's exact test for categorical variables. Survival probabilities were estimated using the Kaplan–Meier method with the log-rank test. To address immortal time bias resulting from the time-dependent nature of irAE status, multivariable extended Cox regression models with irAE state as a time-dependent covariate were used to evaluate their impact on the PFS and OS of the patients. P < 0.05 was considered statistically significant.

Patient characteristics

In total 192 patients, including 140 man and 52 women, with a median age of 63 years (range 20–90 years), were included in this study.

Based on the National Cancer Institute Common Terminology Criteria for irAEs, 100 of 192 patients (52.1%) experienced irAEs, of which 17 (8.85%) experienced AI, including primary AI (1.56%) and secondary AI (7.29%). Patients were divided into irAE-A (patients with irAE-related AI), irAE-B (patients with other irAEs), and non-irAE groups according to the occurrence and category of irAEs to evaluate the impact of irAEs on treatment efficacy. In our cohort, 64 patients had a good PS of 0 or 1, whereas 128 patients had a poor PS of 2–4. The main cancer types were gastric cancer (50.00%), esophageal cancer (14.06%), hepatocellular carcinoma (12.50%), head and neck cancer (9.90%), and lung cancer (3.65%). Approximately, 81 and 111 patients belonged to stages Ⅰ-Ⅲ and Ⅳ, respectively. Among these patients, 105 received a PD-1 inhibitor combined with chemotherapy, 56 received a PD-1 inhibitor combined with targeted drugs, 15 received a PD-1 inhibitor combined with both chemotherapy and targeted drugs, and 14 received a mono-PD-1 inhibitor. Two received PD-L1 inhibitors combined with chemotherapy. First-line therapy was administered to 133 patients, whereas 59 received second-line or later treatment. The detailed baseline clinical characteristics of the different groups are listed in Table 1.

Table 1

Characteristics of patients with different types of irAEs and 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 Gastric cancer Hepatocellular cancer Biliary tract cancer	5 (29.4)	7 (8.4)	15 (16.3)
	6 (35.3)	37 (44.6)	53 (57.6)
	2 (11.8)	17 (20.5)	5 (5.4)
	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)
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.

IrAE-related AI mediates the treatment efficacy of ICIs

The overall DCR of ICIs treatment was 64.06% (123 patients), with 94.12% (16) in the irAE-A group, 72.29% (60) in the irAE-B group, and 51.09% (47) in the non-irAE group. The results revealed no statistically significant difference in DCR between the irAE-A and irAE-B groups (P = 0.065); however, the DCR of both groups was higher than that of the non-irAE group (P < 0.05) (Table 2).

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%-82.1%)
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%)
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.

PFS was analyzed in 187 patients (97.40%) and OS in 179 patients (93.23%), with a median follow-up time of 645 days (range, 27–1126 days). The Kaplan–Meier curves of PFS and OS among the groups are presented in Fig. 1. The median PFS of the irAE-A group was not reached, but was significantly longer compared with that of the irAE-B group at 264 days (95% confidence interval [CI]: 213–315 days, P = 0.001) and the non-irAE group at 116 days (95%CI: 61–171 days, P = 0.000). The PFS of the irAE-B group was also longer than that of the non-irAE group (P = 0.005). The median OS of 860 days (95%CI: 577–1143 days) for the irAE-A group was significantly longer than the median OS of 491 days (95%CI: 331–651 days, P = 0.004) for the irAE-B group and 302 days (95%CI: 203–401 days, P = 0.000) for the non-irAE group. The OS of the irAE-B group was also longer than that of the non-irAE group (P = 0.000) (Fig. 1a, Fig. 1b).

In the univariate analysis of PFS and OS with clinical characteristics including sex, age, ECOG status, TNM stage, treatment line, cancer type, treatment modality and irAE status as covariates, irAE status (PFS: irAE-A vs. non-irAE, P = 0.000; irAE-B vs. non-irAE, P = 0.005; irAE-A vs. irAE-B, P = 0.003; OS: irAE-A vs. non-irAE, P = 0.000; irAE-B vs. non-irAE, P = 0.000; irAE-A vs. irAE-B, P = 0.009), ECOG status (PFS: P = 0.017; OS: P = 0.000), TNM stage (PFS: P = 0.000; OS: P = 0.007), and treatment line (PFS: P = 0.000; OS: P = 0.000) were significantly associated with PFS and OS, whereas sex, age, cancer type and treatment modality had no significant effect on PFS and OS (P > 0.05) (Table 3).

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
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.

Finally, we performed multiple extended Cox regression analyses with covariates of age, sex, ECOG status, TNM stage, treatment line, cancer type, treatment modality, and time-dependent covariates of irAE status as covariates to account for immortal time bias and identify independent prognostic factors for PFS and OS. As presented in Table 3, the irAE status (irAE-A vs. non-irAE, P = 0.008; irAE-B vs. non-irAE, P = 0.020; irAE-A vs. irAE-B, P = 0.005), ECOG status (P = 0.045), TNM stage (P = 0.000), and treatment line (P = 0.002) were independent predictors of PFS. Whereas irAE status (irAE-A vs. non-irAE, P = 0.009; irAE-B vs. non-irAE, P = 0.013; irAE-A vs. irAE-B, P = 0.008), ECOG status (P = 0.007), TNM stage (P = 0.035), treatment line (P = 0.001) and treatment modality (P = 0.008) were independent predictors for the OS.

Owing to the sample size for other cancer types, we performed further subgroup analysis for only 96 patients with gastric cancer. The detailed baseline clinical characteristics of the subgroups are listed in Table 4, with no statistical differences. No difference in DCR was observed between irAE-A and irAE-B (P = 1.000) or irAE-A vs. non-irAE (P = 0.228); however, the DCR of the irAE-B group was higher than that of the non-irAE group (P = 0.021) (Table 5).

Table 4

Characteristics of patients with gastric cancer 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)
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 patients with gastric cancer.
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%)
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.

PFS and OS were analyzed in the 91 patients. The Kaplan–Meier curves of PFS among the groups showed that the median PFS of the irAE-A group was higher than that of the non-irAE group (P = 0.009), but not higher than that of the irAE-B group (P = 0.063). The PFS in the irAE-B group was longer than that in the non-irAE group (P = 0.022). The median OS of the irAE-A group was longer compared with those of both the irAE-B group (P = 0.039) and the non-irAE groups (P = 0.002), and the OS of the irAE-B group was also longer than the non-irAE group (P = 0.034) (Fig. 1c, Fig. 1d). The irAE status (PFS: irAE-A vs. non-irAE, P = 0.012; irAE-B vs. non-irAE, P = 0.024; irAE-A vs. irAE-B, P = 0.087; OS: irAE-A vs. non-irAE, P = 0.015; irAE-B vs. non-irAE, P = 0.028; irAE-A vs. irAE-B, P = 0.069) was significantly associated with PFS and OS in the univariate analysis, but no statistical difference was obtained in the multiple extended Cox regression analyses of irAE status (Table 6).

Table 6

Univariate and multiple extended Cox regression model on PFS and OS in patients with gastric cancer.
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
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.

Hypophysitis includes many subtypes: AI, secondary hypothyroidism, prolactin deficiency, growth hormone deficiency, and secondary hypogonadism. Previous data have demonstrated mixed results on the association between hypophysitis (including the subtypes above) and outcomes of cancers, mainly melanoma and lung cancer (Johnson et al., 2023; Kobayashi et al., 2020; Kotwal et al., 2022; Snyders et al., 2019). However, in this study, we only focused on primary AI and the hypophysitis subtype of AI (secondary AI) on ICI treatment efficacy. We found that AI was related to the efficacy of ICIs for cancer treatment, which differs from the findings of previous studies on the relationship between hypophysitis and cancer outcomes. Additionally, we demonstrated that irAE-related AI was associated with better outcomes in patients with cancer, particularly gastrointestinal tumors. A study of patients with advanced hepatocellular carcinoma treated with ICIs showed that one of five patients with long-term survival developed AI (Monge, Xie, Steinberg, & Greten, 2021). All three responders in the Phase II DART study (SWOG S1609) for breast cancer treated with ICIs developed AI (Adams et al., 2022). These results support the hypothesis that irAE-related AI promotes ICIs efficacy in patients with cancer.

The incidence of irAE-related AI reported here was higher than that in the previous studies, probably because of the non-specific symptoms of AI overlooked by oncologists (Cui et al., 2022; Lu et al., 2019). Routine examinations for cortisol and pituitary function, and clinical education on hypotension, hypoglycemia, and apathy, must be performed before ICIs treatment. As irAE-related AI exhibited a superior capacity for predicting cancer treatment efficacy, promptly identifying and treating irAE-related AI is crucial to ensure efficient and uninterrupted ICIs therapy, thereby benefiting more patients with cancer.

Different doses and application times of hormones may have different effects on different tumors, with some studies reporting that hormones change treatment efficacy, whereas others do not (Faje et al., 2018; Horvat et al., 2015). We used a physiological substitution amount ≤ 30 mg of hydrocortisone for AI treatment; these amounts were low-dose glucocorticoids (7.5mg prednisone) with better OS.

To date, no consensus has been reached on the possible mechanisms underlying irAE-related AI (Helderman, Lucas, & Blank, 2023). Upon ICIs treatment, pre-existing autoreactive helper CD4 + and cytotoxic CD8 + T cells may be activated, subsequently infiltrating and destroying the adrenal cortex (Wright et al., 2021). AI-associated autoantibodies such as anti-21-hydroxylase autoantibody and anti-guanine nucleotide-binding protein G(olf) subunit alpha antibodies also appeared in patients with irAE-related AI (Helderman et al., 2023; Paepegaey et al., 2017; Tahir et al., 2019). Cross-reactive T and B cells activated by the ectopic expression of tissue antigens from tumor cells following ICIs treatment may attack both tumor cells and the adrenal or pituitary glands (Helderman et al., 2023). The efficiency of ICI treatment is mainly achieved by activated cytotoxic T cells, organ damage by autoreactive B cells autoantibodies initiated under T-cell activation, and abnormally enhanced T-cell activity in both the pituitary and adrenal glands, which may largely explain the increased treatment efficacy for irAE-related AI in cancer patients. In future studies, an immunohumanized animal model will be used to explore the mechanism of AI-mediated efficacy of ICI treatment.

This study had some limitations. First, this was a single-center retrospective study, and data from multiple centers should be evaluated in future studies. Second, the sample size was relatively limited, which may have led to wider confidence intervals that may have affected our results. The sample size limited our subgroup analysis for each cancer type, even for the gastric cancer, with the largest sample size among our patients. An increased effect of irAE status on treatment efficiency was observes in the subgroup univariate analysis of gastric cancer but not in multiple analysis. The small sample size of patients with gastric cancer might limit the accurate of the statistical analysis. In further studies, we will utilize a larger sample size to explore the relationship between irAE-related AI and the treatment efficacy of ICIs for gastric cancer. Nonetheless, our findings reveal a relationship between irAE-related AI and ICI treatment efficacy in patients with cancer. This pilot study provides a foundation for future research with larger sample sizes.

In conclusion, irAE-related AI was significantly associated with better clinical outcomes in patients with cancer and is a potentially predictable marker for better ICI treatment efficacy.

Authors’ contributions

SZ and JW made substantial contributions to the conception and design, acquisition of data, and data analysis. SZ drafted the manuscript. ZG and ZZ made substantial contributions to the study design, revision and approved the submitted version. YZ, JZ, XZ, and CW have contributed to the acquisition of data. All authors have read and approved the final manuscript.

Funding

This work was supported by Key Research and Development Projects of Hebei Province (No. 203777109D).

Ethics approval and consent to participate

All procedures of the study were reviewed and approved by the Ethics Committee of the Fourth Hospital of Hebei Medical University. The need for written informed consent was waived by the ethics committee of the Fourth Hospital of Hebei Medical University duo to retrospective nature of the study.

Data availability statement

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.

Acknowledgements

We appreciate the participation of patients and their families, and the assistance of the staff of the Fourth Hospital of Hebei Medical University.

Competing interests

The research was conducted in the absence of any commercial or financial relationships.

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No competing interests reported.

Immune-related adverse event-related adrenal insufficiency mediates immune checkpoint inhibitors efficacy for cancer treatment

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Abstract

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Introduction

Methods

Patients

Treatment and assessment

Statistical analysis

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Patient characteristics

IrAE-related AI mediates the treatment efficacy of ICIs

Discussion

Conclusions

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Version 1