Checkpoint on Adrenal Insufficiency: Optimizing Screening in Immune Checkpoint Inhibitor Therapy

Background Differentiating immune checkpoint inhibitor (ICI)-induced endocrinopathies from cancer-related symptoms or other treatment toxicities is challenging. Biochemical surveillance is essential, especially in patients with new or worsening fatigue and weakness. Current professional society guidelines differ on recommendations for baseline and follow-up biochemical screening for adrenal insufficiency (AI ), and real-world adherence to these protocols remains uncertain. This study evaluates current screening practices for AI in patients receiving ipilimumab-nivolumab combination therapy (a CTLA-4-containing regimen), quantifies the incidence of AI, and identifies gaps in early detection of these endocrinopathies. Methods We conducted a retrospective cohort study of adult patients who received ipilimumab either as monotherapy or in combination with nivolumab at a tertiary academic hospital between June 1, 2023, and June 30, 2024. Data were extracted from the Epic electronic health record and included demographics, cancer type and stage, ICI regimen, and laboratory values, including 8:00 AM cortisol, adrenocorticotropic hormone (ACTH), and thyroid-stimulating hormone (TSH) obtained at baseline and during follow-up. The primary outcome was the proportion of patients screened for adrenal insufficiency during therapy. Secondary outcomes included the incidence of secondary AI, screening rates for ICI-associated thyroid dysfunction, and timing and clinical setting of AI diagnosis. Results A total of 185 patients received ipilimumab-nivolumab during the study period. Only one patient underwent both baseline and interval ACTH and cortisol measurements. All patients had baseline TSH levels, checked prior to starting immunotherapy, and follow-up TSH levels were measured at every treatment cycle. Secondary AI was diagnosed in 17 patients (9.1%). Diagnosis occurred in six patients (35.3%) during inpatient hospitalization, three (17.6%) in the emergency department, and eight (47.1%) in the outpatient setting. The most common presenting symptom was fatigue (35.3%), followed by nausea (29.4%) and vomiting (23.5%).  Conclusion Adrenal insufficiency secondary to ICI-induced hypophysitis remains under-recognized in patients receiving ipilimumab-nivolumab combination therapy, with most cases identified only after symptom onset in acute care settings. While thyroid function was consistently monitored, adrenal insufficiency screening was rarely performed. Standardized protocols that include baseline and periodic ACTH and cortisol testing are needed to enable earlier detection and intervention, potentially reducing morbidity, hospitalizations, and healthcare utilization in this high-risk population.