SUN-275 - Cancer Type-Specific Risk Profiles of Endocrine Immune-Related Adverse Events during Immune Checkpoint Inhibitor Therapy using A Large-Scale Claims Database

Background:
Endocrine immune-related adverse events (EirAE), including thyroiditis, hypophysitis, and insulin-dependent type 1 diabetes mellitus (T1DM), are commonly observed during immune checkpoint inhibitor (ICI) therapy. We previously reported the epidemiology of ICI-related T1DM and multiple EirAEs (F Kamitani et al., JCEM 2025, JDI 2025). Although certain EirAEs can be life-threatening, they are generally manageable with hormone replacement therapy and often allow continuation of ICI treatment, highlighting the importance of risk prediction in each patient. However, associations between cancer types and the risk of EirAEs remain unclear because previous studies had a limited number of patients for robust adjustment of confounding factors.

Objective:
To clarify cancer type–specific risks of ICI-related EirAEs using a nationwide population-based database.

Methods:
We conducted a cohort study using the Japanese National Database, which includes data from more than120 million individuals (the whole Japanese population). We identified 214,380 patients treated with ICIs, the incidence of each EirAE after ICI initiation were analyzed using the validated definitions based on replacement therapy and disease-specific codes. Previous reports demonstrated that ICI-related adrenal insufficiency was predominantly due to hypophysitis, and ICI-related diabetes largely corresponds to insulin-dependent T1DM. Cancer types were defined using ICD-10 codes. Multivariable logistic regression models adjusted for age, sex, cancer treatment, ICI type, tyrosine kinase inhibitor use, and radiotherapy were applied.

Results:
Among 214,380 patients treated with ICIs–a median observation period of 334 days–hypothyroidism, adrenal insufficiency, and T1DM were diagnosed in 11.4%, 5.3%, and 0.5% of patients, respectively. Compared with non-small cell lung cancer, the risk of hypothyroidism was higher in head and neck squamous cell carcinoma (odds ratio [OR] 3.08), and lower in mesothelioma (0.79). That of adrenal insufficiency was higher in melanoma (1.95), and lower in hepatobiliary cancer (0.53), whereas that of T1DM was higher in melanoma (3.34), and lower in head and neck squamous cell carcinoma (0.60). Notably, cancer type–specific risk patterns for adrenal insufficiency and T1DM were similar (R² = 0.59, P < 0.01), whereas the other combinations showed no similarities.

Conclusion:
Cancer type is significantly and differentially associated with the risk of each EirAE during ICI therapy. The shared cancer-specific risk profiles of adrenal insufficiency and T1DM suggest a common mechanism involving the pituitary and β-cells. These findings enable more precise prediction for the risk of EirAEs associated with ICI therapy and support a development of individualized endocrine monitoring.

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