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Adverse Event Profiles of Anti-CTLA-4 and Anti-PD-1 Monoclonal Antibodies Alone or in Combination: Analysis of Spontaneous Reports Submitted to FAERS

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Abstract

Background and Objective

Immune checkpoint inhibitors (ICIs)—cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death receptor-1 (PD-1) monoclonal antibodies (mAbs)—either as single agents or in combination have become the standard of care for an increasing number of indications. Understanding both the ICI-associated adverse events (AEs) and the possible rank-order of these drugs in terms of susceptibility is essential if we are to improve the curative effect and reduce toxicity.

Methods

We detected signals of the AEs of ICIs by data mining using the US Food and Drug Administration (FDA) AEs Reporting System (FAERS) database. The definition relied on the preferred terms (PTs) and the standardized MedDRA Queries (SMQs) provided by the Medical Dictionary for Regulatory Activities (MedDRA). Disproportionality analysis was performed by calculating the reporting odds ratios (ROR) with 95% confidence intervals (CIs).

Results

Adverse effects of CTLA-4 and PD-1 mAbs were most commonly observed in the skin, gastrointestinal tract, endocrine systems, liver, and lung, and they included rash, diarrhea, colitis, and thyroid dysfunction. Thyroid dysfunction, type 1 diabetes mellitus, and pneumonitis were more closely associated with the use of anti-PD-1, whereas colitis, diarrhea, hypophysitis, and adrenal insufficiency were more closely associated with anti-CTLA-4; rash and hepatitis occurred similarly in both. Disproportionality signals for less common AEs in other organ systems, including the renal, neurological, cardiac, ocular, musculoskeletal, and hematologic systems, were also detected. Nivolumab and pembrolizumab have very similar safety profiles, but the signal strength of AEs increased when combined with ipilimumab.

Conclusions

The results of this study are in agreement with clinical observations, suggesting the usefulness of pharmacovigilance in “real-world” safety monitoring.

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Authors and Affiliations

  1. Department of Pharmacy, Children’s Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatric, Chongqing, 400014, China

    Huan-huan Ji, Xue-wen Tang, Zhi Dong, Lin Song & Yun-tao Jia

  2. School of Pharmacy, Chongqing Medical University, Chongqing, 400016, China

    Xue-wen Tang

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  1. Huan-huan Ji
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  2. Xue-wen Tang
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  3. Zhi Dong
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  4. Lin Song
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  5. Yun-tao Jia
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Contributions

JHH and TXW planned this study’s content, extracted data, performed statistical analysis, and wrote the manuscript. JYT, SL and DZ participated in the design of the study and helped to write the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Lin Song or Yun-tao Jia.

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Funding

This study was supported by the Health and Family Planning Commission of Chongqing grants (2016ZDXM017), Chongqing Science and Technology Commission grants (cstc2016shmszx130048).

Conflict of interest

Huan-huan JI, Xue-wen TANG, Zhi DONG, Lin SONG, and Yun-tao JIA declare that they have no conflict of interests.

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Ji, Hh., Tang, Xw., Dong, Z. et al. Adverse Event Profiles of Anti-CTLA-4 and Anti-PD-1 Monoclonal Antibodies Alone or in Combination: Analysis of Spontaneous Reports Submitted to FAERS. Clin Drug Investig 39, 319–330 (2019). https://doi.org/10.1007/s40261-018-0735-0

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  • DOI: https://doi.org/10.1007/s40261-018-0735-0

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