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

  • Huan-huan Ji
  • Xue-wen Tang
  • Zhi Dong
  • Lin SongEmail author
  • Yun-tao JiaEmail author
Original Research Article


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.


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).


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.


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


Author 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.

Compliance with Ethical Standards


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.


  1. 1.
    Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(4):119–42.CrossRefGoogle Scholar
  2. 2.
    Sibaud V, Meyer N, Lamant L, et al. Dermatologic complications of anti-PD-1/PD-L1 immune checkpoint antibodies. Curr Opin Oncol. 2016;28(4):254–63.CrossRefGoogle Scholar
  3. 3.
    Gupta A, De Felice KM, Loftus EV Jr, et al. Systematic review: colitis associated with anti-CTLA-4 therapy. Aliment Pharmacol Ther. 2015;42(4):406–17.CrossRefGoogle Scholar
  4. 4.
    Wei W, Luo Z. Risk of gastrointestinal toxicities with PD-1 inhibitors in cancer patients: a meta-analysis of randomized clinical trials. Medicine (Baltimore). 2017;96(48):e8931.CrossRefGoogle Scholar
  5. 5.
    Wang W, Lie P, Guo M, et al. Risk of hepatotoxicity in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis of published data. Int J Cancer. 2017;141(5):1018–28.CrossRefGoogle Scholar
  6. 6.
    Le Min. Immune-related endocrine disorders in novel immune checkpoint inhibition therapy. Genes Dis. 2016;3(4):252–6.CrossRefGoogle Scholar
  7. 7.
    Sznol M, Postow MA, Davies MJ, et al. Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management. Cancer Treat Rev. 2017;58:70–6.CrossRefGoogle Scholar
  8. 8.
    Harpaz R, DuMouchel W, LePendu P, et al. Performance of pharmacovigilance signal-detection algorithms for the FDA adverse event reporting system. Clin Pharmacol Ther. 2013;93(6):539–46.CrossRefGoogle Scholar
  9. 9.
    Poluzzi E, Raschi E, Piccinni C, et al. Data mining techniques in pharmacovigilance: analysis of the publicly accessible FDA adverse event reporting system (AERS). In: Karahoca A, et al., editors. Data mining applications in engineering and medicine. Croatia: InTech; 2012. p. 265–302.Google Scholar
  10. 10.
    van Puijenbroek EP, Bate A, Leufkens HG, et al. A comparison of measures of disproportionality for signal detection in spontaneous reporting systems for adverse drug reactions. Pharmacoepidemiol Drug Saf. 2002;11(1):3–10.CrossRefGoogle Scholar
  11. 11.
    Bate A, Evans SJ. Quantitative signal detection using spontaneous ADR reporting. Pharmacoepidemiol Drug Saf. 2009;18(6):427–36.CrossRefGoogle Scholar
  12. 12.
    Barroso-Sousa R, Barry WT, Garrido-Castro AC, et al. Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis. JAMA Oncol. 2018;4(2):173–82.CrossRefGoogle Scholar
  13. 13.
    Osorio JC, Ni A, Chaft JE, et al. Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. Ann Oncol. 2017;28(3):583–9.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Morganstein DL, Lai Z, Spain L, et al. Thyroid abnormalities following the use of cytotoxic T-lymphocyte antigen-4 and programmed death receptor protein-1 inhibitors in the treatment of melanoma. Clin Endocrinol (Oxf). 2017;86(4):614–20.CrossRefGoogle Scholar
  15. 15.
    Corsello SM, Barnabei A, Marchetti P, et al. Endocrine side effects induced by immune checkpoint inhibitors. J Clin Endocrinol Metab. 2013;98(4):1361–75.CrossRefGoogle Scholar
  16. 16.
    Mellati M, Eaton KD, Brooks-Worrell BM, et al. Anti-PD-1 and Anti-PDL-1 monoclonal antibodies causing type 1 diabetes. Diabetes Care. 2015;38(9):e137–8.CrossRefGoogle Scholar
  17. 17.
    Wang DY, Ye F, Zhao S, et al. Incidence of immune checkpoint inhibitor-related colitis in solid tumor patients: a systematic review and meta-analysis. Oncoimmunology. 2017;6(10):e1344805.CrossRefGoogle Scholar
  18. 18.
    Zhang X, Ran Y, Wang Y, et al. Incidence and risk of hepatic toxicities with PD-1 inhibitors in cancer patients: a meta-analysis. Drug Des Devel Ther. 2016;10:3153–61.CrossRefGoogle Scholar
  19. 19.
    Chuzi S, Tavora F, Cruz M, et al. Clinical features, diagnostic challenges, and management strategies in checkpoint inhibitor-related pneumonitis. Cancer Manag Res. 2017;9:207–13.CrossRefGoogle Scholar
  20. 20.
    Wu J, Hong D, Zhang X, et al. PD-1 inhibitors increase the incidence and risk of pneumonitis in cancer patients in a dose-independent manner: a meta-analysis. Sci Rep. 2017;7:44173.CrossRefGoogle Scholar
  21. 21.
    Sibaud V. Dermatologic reactions to immune checkpoint inhibitors: skin toxicities and immunotherapy. Am J Clin Dermatol. 2018;19:345–61.CrossRefGoogle Scholar
  22. 22.
    Belum VR, Benhuri B, Postow MA, et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer. 2016;60:12–25.CrossRefGoogle Scholar
  23. 23.
    Boutros C, Tarhini A, Routier E, et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol. 2016;13(8):473–86.CrossRefGoogle Scholar
  24. 24.
    Hua C, Boussemart L, Mateus C, et al. Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol. 2016;152(1):45–51.CrossRefGoogle Scholar
  25. 25.
    Murakami N, MotwaniL S, Riella V. Renal complications of immune checkpoint blockade. Curr Probl Cancer. 2017;41(2):100–10.CrossRefGoogle Scholar
  26. 26.
    Johnson DB, Balko JM, Compton ML, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 2016;375(18):1749–55.CrossRefGoogle Scholar
  27. 27.
    Abdel-Rahman O, Oweira H, Petrausch U, et al. Immune-related ocular toxicities in solid tumor patients treated with immune checkpoint inhibitors: a systematic review. Expert Rev Anticancer Ther. 2017;17(4):387–94.CrossRefGoogle Scholar
  28. 28.
    Cappelli LC, Gutierrez AK, Bingham CO 3rd, et al. Rheumatic and musculoskeletal immune-related adverse events due to immune checkpoint inhibitors: a systematic review of the literature. Arthritis Care Res (Hoboken). 2017;69(11):1751–63.CrossRefGoogle Scholar
  29. 29.
    Zimmer L, Goldinger SM, Hofmann L, et al. Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy. Eur J Cancer. 2016;60:210–25.CrossRefGoogle Scholar
  30. 30.
    Abdel-Rahman O, Eltobgy M, Oweira H, et al. Immune-related musculoskeletal toxicities among cancer patients treated with immune checkpoint inhibitors: a systematic review. Immunotherapy. 2017;9(14):1175–83.CrossRefGoogle Scholar
  31. 31.
    Voskens CJ, Goldinger SM, Loquai C, et al. The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network. PLoS One. 2013;8(1):e53745.CrossRefGoogle Scholar
  32. 32.
    Spain L, Walls G, Julve M, et al. Neurotoxicity from immune-checkpoint inhibition in the treatment of melanoma: a single centre experience and review of the literature. Ann Oncol. 2017;28(2):377–85.PubMedGoogle Scholar
  33. 33.
    Cuzzubbo S, Javeri F, Tissier M, et al. Neurological adverse events associated with immune checkpoint inhibitors: review of the literature. Eur J Cancer. 2017;73:1–8.CrossRefGoogle Scholar
  34. 34.
    Cortes J, Mauro M, Steegmann JL, et al. Cardiovascular and pulmonary adverse events in patients treated with BCR-ABL inhibitors: data from the FDA adverse event reporting system. Am J Hematol. 2015;90(4):E66–72.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of PharmacyChildren’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 PediatricChongqingChina
  2. 2.School of PharmacyChongqing Medical UniversityChongqingChina

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