Hypophysitis and Secondary Adrenal Insufficiency From Immune Checkpoint Inhibitors: Diagnostic Challenges and Link With Survival

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Jake Johnson Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska

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Whitney Goldner Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska

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Duaa Abdallah Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska

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Fang Qiu Department of Biostatistics, University of Nebraska Medical Center, Omaha, Nebraska

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Apar Kishor Ganti Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska
Division of Oncology and Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
VA Nebraska-Western Iowa Health Care System, Omaha, Nebraska

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Anupam Kotwal Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska

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Background: Hypophysitis is a serious adverse event stemming from immune checkpoint inhibitor (ICI) therapy for malignancy. This study aimed to characterize ICI-induced hypophysitis, identify diagnostic challenges, and evaluate an association with survival in a large cancer cohort. Methods: We performed a retrospective cohort study of adult patients with cancer who received ICIs between December 1, 2012, and December 31, 2019. We identified 839 patients who received CTLA-4, PD-1, or PD-L1 inhibitors or a combination thereof who were followed for a median of 19.4 months. Hypophysitis was defined as MRI evidence of pituitary gland and/or stalk enlargement or biochemical evidence of hypopituitarism if not explained by another etiology. Results: A total of 16 (1.9%) patients developed hypophysitis a median of 7 months after ICI initiation, with most patients having melanoma (9/16; 56.2%) or renal cell carcinoma (4/16; 25%). Two patients also had exogenous glucocorticoid exposure but exhibited secondary hypothyroidism and secondary adrenal insufficiency (AI). Median age at the start of ICI was 61.3 years and 57% were men. Patients who developed hypophysitis were younger compared with those who did not develop hypophysitis (median age, 57 vs 65 years; P=.011). Hypophysitis occurred most frequently after combination therapy (13.7%) compared with CTLA-4 monotherapy (1.9%), PD-1 monotherapy (1.2%), and PD-L1 monotherapy (0.8%) (P<.0001). Pituitary gland enlargement on MRI occurred more frequently after CTLA-4 inhibitor monotherapy or combination therapy (5/7; 71.4%) compared with PD-1/PD-L1 inhibitor monotherapy (1/6; 16.7%). The survival benefit of hypophysitis was not apparent after addressing immortal time bias and adjusting for other variables affecting patient outcomes. Conclusions: Secondary AI occurred in all patients, and secondary hypothyroidism occurred in half. Classic pituitary gland enlargement is usually absent in PD-1/PD-L1 inhibitor–induced hypophysitis. Further pituitary evaluation must be conducted to differentiate secondary AI resulting from exogenous glucocorticoids and hypophysitis in patients with cancer receiving ICIs. The link between hypophysitis and ICI efficacy needs further investigation.

Submitted August 17, 2022; final revision received October 30, 2022; accepted for publication November 7, 2022. Published online February 24, 2023.

Previous presentation: Presented in abstract form at ENDO 2021; March 20–23, 2021 (J Endocrine Soc 2021;5[Suppl 1]:A847–848).

Author contributions: Study conduct: Johnson, Goldner, Kotwal. Data collection: Johnson, Abdallah, Kotwal. Study planning: Goldner, Ganti, Kotwal. Data synthesis: Johnson, Abdallah, Kotwal. Statistical analysis: Qiu. Writing—original draft: Johnson, Goldner, Ganti, Kotwal. Writing—review & editing: Kotwal.

Disclosures: Dr. Ganti has disclosed receiving grant/research support from Merck Pharmaceuticals; and serving on the advisory board for Regeneron Pharmaceuticals and AstraZeneca Pharmaceuticals. The remaining authors have disclosed that they have not received any financial considerations from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: Research reported in this publication was supported by the College of Medicine, University of Nebraska Medical Center Program of Excellence Physician-Scientist Training Program, and the Clinical Translational Research Mentored Scholars Program Pilot Award (A. Kotwal).

Correspondence: Anupam Kotwal, MD, Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, 984120 Nebraska Medical Center, Omaha, NE 68198. Email: Anupam.Kotwal@unmc.edu
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