SUN-442 - When Immunotherapy Hits the Pituitary: Pembrolizumab-Induced Secondary Adrenal Insufficiency, A Case Report

Introduction:
Pembrolizumab is a programmed cell death protein-1 (PD-1) inhibitor and is increasingly used in the treatment of multiple malignancies. Immune-mediated hypophysitis leading to secondary adrenal insufficiency is a rare but potentially life-threatening adverse effect. Due to overlapping biochemical features with SIADH, a high index of suspicion is required to avoid delays in diagnosis and treatment.

Case 1:
A 70-year-old woman with recurrent metastatic endometrial cancer status post total abdominal hysterectomy and bilateral salpingo-oophorectomy on pembrolizumab presented with nausea, vomiting, fatigue, and weakness one week after her most recent dose. She had a prior episode of severe hyponatremia (108 mmol/L) six months earlier after her fifth dose of pembrolizumab, treated with prednisone that was later tapered off. She remained asymptomatic until restarting pembrolizumab on October 30. On admission, serum sodium was 118 mmol/L (138 mmol/L one week prior), serum osmolality 247 mOsm/kg, urine osmolality 231 mOsm/kg, urine sodium 71 mmol/L, and eosinophils 9%. Brain MRI was unremarkable. Despite treatment with hypertonic saline, sodium failed to improve. Further evaluation revealed undetectable morning cortisol ( < 0.2 µg/dL) and suppressed ACTH ( < 1.5 pg/mL), with preserved other pituitary axes. Hydrocortisone therapy resulted in correcting hyponatremia to 139 mmol/L. Pembrolizumab was discontinued, and patient remains stable on glucocorticoid replacement.

Case 2:
A 69-year-old man with stage IV lung adenocarcinoma treated with pembrolizumab developed immune-related endocrinopathies. Two months into therapy, he developed hypothyroidism requiring levothyroxine. In late 2024, he reported persistent fatigue and was found to have secondary adrenal insufficiency with suppressed ACTH ( < 1.5 pg/mL), very low cortisol (0.57 µg/dL), and inadequate cosyntropin response. He improved rapidly after initiation of hydrocortisone and is currently maintained on physiologic replacement with appropriate stress-dose education.

Discussion:
Pembrolizumab-induced hypophysitis predominantly affects ACTH-secreting cells, often without radiographic abnormalities. Secondary AI and SIADH share biochemical features of euvolemic hypotonic hyponatremia with inappropriately concentrated urine, frequently leading to misdiagnosis and delayed glucocorticoid therapy. These cases highlight the importance of early cortisol and ACTH testing in patients on immune checkpoint inhibitors presenting with hyponatremia. ACTH deficiency is often irreversible, necessitating lifelong glucocorticoid replacement.

Reference:
1. Front Endocrinol. 2024;15:1400841. doi:10.3389/fendo.2024.1400841
2. Endocr Pract. 2022; S1530-891X(22)00489-X
3. Esteves-Ferreira S, Rosinha P. J Cancer Res Clin Oncol. 2023;149(10):7925-7932. doi:10.1007/s00432-023-04659-5

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