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Immune checkpoint inhibitor-induced hypophysitis: lessons learnt from a large cancer cohort
  1. Anupam Kotwal1,2,
  2. Samuel G Rouleau3,
  3. Surendra Dasari4,
  4. Lisa Kottschade5,
  5. Mabel Ryder2,5,
  6. Yogish C Kudva2,
  7. Svetomir Markovic5,
  8. Dana Erickson2
  1. 1Division of Diabetes, Endocrinology and Metabolism; Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
  2. 2Division of Endocrinology, Diabetes, Metabolism, and Nutrition; Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
  3. 3Mayo Clinic Alix School of Medicine, Mayo Clinic, Rochester, Minnesota, USA
  4. 4Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
  5. 5Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA
  1. Correspondence to Dr Dana Erickson, Division of Endocrinology, Diabetes, Metabolism, and Nutrition; Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA; erickson.dana{at}mayo.edu

Abstract

Immune checkpoint inhibitors (ICIs) can cause pituitary dysfunction due to hypophysitis. We aimed to characterize ICI-induced hypophysitis and examine its association with overall survival in this single-center retrospective cohort study of adult patients with cancer who received an ICI from January 1, 2012 through December 31, 2016. A total of 896 patients were identified who received ipilimumab alone (n=120); ipilimumab and nivolumab (n=50); ipilimumab before or after pembrolizumab (n=70); pembrolizumab alone (n=406); and nivolumab alone (n=250). Twenty-six patients (2.9%) developed hypophysitis after a median of 2.3 months. Median age at the start of ICI was 57.9 years and 54% were men. Hypophysitis occurred in 7.9% of patients receiving ipilimumab alone or in combination or sequence with a programmed cell death protein 1 inhibitor; 1.7% after pembrolizumab alone, never after nivolumab alone. Secondary adrenal insufficiency occurred in all hypophysitis cases. Use of ipilimumab alone or in combination was associated with pituitary enlargement on imaging and mass effects more frequently than pembrolizumab alone. Occurrence of hypophysitis was associated with improved overall survival by univariate analysis (median 50.7 vs 16.5 months; p=0.015) but this association was not observed in multivariable landmark survival analysis (HR for mortality 0.75; 95% CI 0.38 to 1.30; p=0.34) after adjusting for age, sex and malignancy type. To conclude, hypophysitis occurred most frequently after ipilimumab and manifested as anterior hypopituitarism affecting the corticotrophs more commonly than thyrotrophs and gonadotrophs. Mass effects and pituitary enlargement occurred more frequently in ipilimumab-induced hypophysitis. The association of hypophysitis with overall survival needs further investigation.

  • adrenal insufficiency
  • immunotherapy
  • pituitary-adrenal system
  • endocrinology

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Data are available upon reasonable request.

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Data availability statement

Data are available upon reasonable request.

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Footnotes

  • AK and SGR are joint first authors.

  • Twitter @DrAKotwal

  • Contributors AK and SGR contributed equally to the study planning, data collection, data synthesis and manuscript preparation. LK, MR, YCK and SM contributed to the review and revision of the manuscript. SD contributed to the statistical analysis of the study. DE served as senior author and guarantor, and accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.

  • Funding This publication was made possible by CTSA Grant Number UL1 313 TR002377 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH). An abstract of this study was accepted as oral presentation at the Annual Meeting of the Endocrine Society, ENDO 2020 and published in supplemental issue of Journal of the Endocrine Society at https://academic.oup.com/jes/article/4/Supplement_1/OR32-02/5833171.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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