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Neuroimmunological adverse events associated with immune checkpoint inhibitor: a retrospective, pharmacovigilance study using FAERS database

  • Clinical Study
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Abstract

Purpose

To investigate the characteristics and risk factors for neurologic adverse events (AEs) induced by immune checkpoint inhibitors (ICIs).

Methods

An observational, retrospective, and pharmacovigilance study based on the FAERS database collected between January 2014 and December 2019 was conducted. ICI-related AEs were defined as adverse reactions in patients using anti-PD-1 (nivolumab and pembrolizumab), anti-PD-L1 (atezolizumab, avelumab, and durvalumab), and anti-CTLA-4 (ipilimumab and tremelimumab). Neurologic AEs previously reported to be associated with ICI were evaluated in the disproportionality analysis using the reporting odds ratio (ROR).

Results

Among 50,406 ICI-related reports, 3619 (7.2%) neurological case was found: 1985 with anti-PD-1, 372 with anti-PD-L1, 366 with anti-CTLA-4, and 896 with the combination of ICIs. In comparison to non-ICI drug use, ICI use demonstrated higher risk for neurologic complication, including hypophysitis/hypopituitarism, myasthenia gravis, encephalitis/myelitis, meningitis, Guillain-Barre syndrome, vasculitis, and neuropathy. The risk of neurologic AEs associated with ICI combination therapy was as high as or even higher than ICI monotherapy, most significantly in hypophysitis/hypopituitarism. The proportion of serious neurological events and death related to combination therapy has been decreasing in recent years. Older age, male and female sex, and metastasis were not significant risk factors for the incidence of neurologic ICI-related AEs. Patients at older age, with melanoma or non-small cell lung cancer, or on dual ICI therapy may be at higher risk of fatal neurologic AEs.

Conclusion

ICI use is associated with a higher risk of neurological complications, with dual ICI therapy posing a higher risk, while older age, sex, or metastasis were not. Patients at older age, with certain cancer types, or on dual ICI therapy may be at higher risk of fatal neurologic AEs.

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Availability of data and material

The FAERS database used in this study is publicly available from the United States Food and Drug Administration (FDA).

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Authors and Affiliations

  1. Department of Neurology, Tufts Medical Center, Boston, MA, USA

    Takahisa Mikami MD, Deborah Green-LaRoche MD & Suriya Jeyapalan MD MPH

  2. Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, Mount Sinai Beth Israel, New York, NY, USA

    Takahisa Mikami MD & Bobby Liaw MD

  3. Department of Pharmacy, Medical Hospital, Tokyo Medical and Dental University, Tokyo, Japan

    Mizuho Asada PhD

  4. Department of Clinical Pharmacology and Therapeutics, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan

    Takahiro Niimura BS & Yoshito Zamami PhD

  5. Department of Pharmacy, Tokushima University Hospital, Tokushima, Japan

    Yoshito Zamami PhD

  6. Department of Hematology and Oncology, Tufts Medical Center, Boston, MA, USA

    Lori Pai MD

  7. Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Michael Levy MD PhD

Authors
  1. Takahisa Mikami MD
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  2. Bobby Liaw MD
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  4. Takahiro Niimura BS
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  9. Suriya Jeyapalan MD MPH
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Contributions

TM had the idea for and designed the study, had full access to all of the data in the study, takes responsibility for the integrity of the data and the accuracy of the data analysis, did the statistical analysis, and drafted the paper. All authors critically revised the manuscript for important intellectual content and gave final approval for the version to be published.

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Correspondence to Takahisa Mikami MD.

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Mikami, T., Liaw, B., Asada, M. et al. Neuroimmunological adverse events associated with immune checkpoint inhibitor: a retrospective, pharmacovigilance study using FAERS database. J Neurooncol 152, 135–144 (2021). https://doi.org/10.1007/s11060-020-03687-2

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  • DOI: https://doi.org/10.1007/s11060-020-03687-2

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