Clinical characteristics and management of PD-1/PD-L1 inhibitor-induced secondary adrenal insufficiency

Abstract: Programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors significantly improve outcomes in multiple malignancies; however, they can induce immune-related endocrine adverse events, such as secondary adrenal insufficiency (SAI), a rare but potentially severe complication. We aimed to systematically analyze the clinical characteristics, changes in endocrine function, and treatment outcomes of SAI induced by PD-1/PD-L1 immune checkpoint inhibitors. This single-center retrospective study included 75 patients with tumors diagnosed with SAI following PD-1/PD-L1 inhibitor therapy. Clinical data were collected via electronic medical records, and clinical characteristics and prognosis data were analyzed using descriptive statistical methods. SAI occurred at any cycle during immunotherapy, with a median onset of 5.70 months. Clinically, fatigue was the most common symptom (80.0%), followed by loss of appetite (26.7%) and nausea (9.3%). Endocrine function assessments revealed that severe hypothalamic-pituitary-adrenal (HPA) axis impairment occurred in all patients; thyroid function abnormalities occurred in 34.7% of patients, with PD-1/PD-L1 inhibitor-related hypothyroidism accounting for 88.5%, of which 65.2% of hypothyroidism cases preceded SAI diagnosis. Central hypothyroidism (4.0%) and gonadal involvement (1.3%) were relatively rare; treatment outcome analysis showed that only 8.3% (1/12) of patients receiving high-dose glucocorticoid therapy recovered HPA axis function; 98.7% (74/75) of patients on long-term glucocorticoid replacement therapy tolerated subsequent anti-tumor treatment, and 59.5% maintained the regimen, including ICIs. These findings reveal the need to enhance endocrine monitoring during immunotherapy, prioritize HPA axis evaluation in patients with thyroid dysfunction, and promptly initiate standardized glucocorticoid replacement therapy upon SAI diagnosis to ensure continuity of anti-tumor treatment.