Skip to main content
SpringerLink
Log in

Adverse Events Associated with Immune Checkpoint Inhibitors: Overview of Systematic Reviews

  • Systematic Review
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Background

Recognition and management of adverse events (AEs) associated with immune checkpoint inhibitor (ICI) use by cancer patients requires expertise from multiple disciplines. Greater awareness of potential AEs may result in earlier recognition, appropriate management, and better patient outcomes.

Objective

The primary objective of this overview of systematic reviews was to synthesize and consolidate systematic review evidence describing the incidence proportion and severity of AEs associated with various ICI therapies across different cancers.

Methods

A systematic literature search of four databases was conducted to identify systematic reviews that describe the incidence proportion and severity of AEs related to ICI therapy in cancer patients. A systematic review was eligible if it included adults with cancer; on ICI alone or in combination with another ICI, chemotherapy, or targeted therapy; severity (graded according to the Common Terminology Criteria for Adverse Events) and incidence proportion of AEs and whether it reported its eligibility criteria. AEs of interest were identified through an iterative ranking exercise by key stakeholders and knowledge users. Extraction of PICOTTS elements and quality indicators (AMSTAR-2) were used to manage overlap of primary studies across systematic reviews at the outcome level. Cancer subtypes were mapped to drug class and AE severity.

Results

Overall, 129 systematic reviews met the inclusion criteria for data mapping. Systematic reviews reported incidence proportions for more than 76 AEs, of which 34 were identified as AEs of interest. After overlap assessment, 65 systematic reviews were chosen for data extraction. The three AEs with the highest median incidence were fatigue (18.3%, interquartile range [IQR] 15.0–28.0%), diarrhea (15.3%, IQR 9.7–29.2%) and rash (14.4%, IQR 10.3–19.2%). The three AEs (high-grade) with the highest median incidence were diarrhea (1.5%, IQR 1.2–6.0%), colitis (1.3%, IQR 0.6–6.1%) and neutropenia (1.2%, IQR 0.4–3.3%). Incidence proportions of high-grade AEs were often considerably lower than all-grade AEs and combination therapy (ICI combinations or combinations of ICI with chemotherapy or targeted therapy) was responsible for some of the highest incidence proportions regardless of AE. Rare AEs and certain cancer subtypes were not well reported.

Conclusions

Early recognition of AEs associated with ICIs requires expertise from diverse specialists, not just oncologists. Greater awareness of potential AEs may result in earlier recognition, appropriate management, and better patient outcomes.

PROSPERO Registration

CRD42021231593.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Schirrmacher V. From chemotherapy to biological therapy: a review of novel concepts to reduce the side effects of systemic cancer treatment. Int J Oncol. 2019;54(2):407–19.

    CAS  PubMed  Google Scholar 

  2. Murciano-Goroff YR, Warner AB, Wolchok JD. The future of cancer immunotherapy: microenvironment-targeting combinations. Cell Res. 2020;30(6):507–19.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Hui E. Immune checkpoint inhibitors. J Cell Biol. 2019;218(3):740–1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Cancer Care Ontario. Immune Checkpoint Inhibitor Toxicity Management Clinical Practice Guideline. Updated March 2018 [cited 10 Dec 2020]. https://www.cancercareontario.ca/en/guidelines-advice/types-of-cancer/52976. Accessed 10 Dec 2020.

  5. Horrow JC, Digregorio GJ, Barbieri EJ, Rupp E. Intravenous infusions of nitroprusside, dobutamine, and nitroglycerin are compatible. Crit Care Med. 1990;18(8):858–61.

    Article  CAS  PubMed  Google Scholar 

  6. Khoja L, Day D, Wei-Wu Chen T, Siu LL, Hansen AR. Tumour- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review. Ann Oncol. 2017;28(10):2377–85.

    Article  CAS  PubMed  Google Scholar 

  7. Kirschenbaum HL, Aronoff W, Perentesis GP, Plitz GW, Cutie AJ. Stability and compatibility of lidocaine hydrochloride with selected large-volume parenterals and drug additives. Am J Hosp Pharm. 1982;39(6):1013–5.

    CAS  PubMed  Google Scholar 

  8. Martins F, Sofiya L, Sykiotis GP, Lamine F, Maillard M, Fraga M, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol. 2019;16(9):563–80.

    Article  CAS  PubMed  Google Scholar 

  9. Xing P, Zhang F, Wang G, Xu Y, Li C, Wang S, et al. Incidence rates of immune-related adverse events and their correlation with response in advanced solid tumours treated with NIVO or NIVO+IPI: a systematic review and meta-analysis. J Immunother Cancer. 2019;7(1):341.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Reynolds KL, Cohen JV, Ryan DP, Hochberg EP, Dougan M, Thomas M, et al. Severe immune-related adverse effects (irAE) requring hospital admission in patients treated with immune checkpoint inhibitors for advanced malignancy: Temporal trends and clinical significance. J Clin Oncol. 2018;36(15):3096.

    Article  Google Scholar 

  11. Pollock M FR, Becker LA, Pieper D, Hartling L. Chapter V: Overviews of Reviews: Cochrane; 2020 [updated September 2020. http://www.training.cochrane.org/handbook. Accessed 10 Dec 2020.

  12. Lunny C, Brennan SE, Reid J, McDonald S, McKenzie JE. Overviews of reviews incompletely report methods for handling overlapping, discordant, and problematic data. J Clin Epidemiol. 2020;118:69–85.

    Article  PubMed  Google Scholar 

  13. Gates M, Gates A, Guitard S, Pollock M, Hartling L. Guidance for overviews of reviews continues to accumulate, but important challenges remain: a scoping review. Syst Rev. 2020;9(1):254.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097.

  15. McGowan J, Sampson M, Salzwedel DM, Cogo E, Foerster V, Lefebvre C. PRESS peer review of electronic search strategies: 2015 guideline statement. J Clin Epidemiol. 2016;75:40–6.

    Article  PubMed  Google Scholar 

  16. CADTH. Grey Matters: a practical tool for searching health-related grey literature. 2014. https://www.cadth.ca/resources/finding-evidence/grey-matters. Accessed 10 Dec 2020.

  17. Lunny C, Brennan SE, McDonald S, McKenzie JE. Toward a comprehensive evidence map of overview of systematic review methods: paper 2-risk of bias assessment; synthesis, presentation and summary of the findings; and assessment of the certainty of the evidence. Syst Rev. 2018;7(1):159.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Lunny C, Pieper D, Thabet P, Kanji S. Managing overlap of primary study results across systematic reviews: practical considerations for authors of overviews of reviews. BMC Med Res Methodol. 2021;21(1):140.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017;358:j4008.

  20. Pollock M, Fernandes RM, Newton AS, Scott SD, Hartling L. The impact of different inclusion decisions on the comprehensiveness and complexity of overviews of reviews of healthcare interventions. Syst Rev. 2019;8(1):18.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Bougioukas KI, Liakos A, Tsapas A, Ntzani E, Haidich AB. Preferred reporting items for overviews of systematic reviews including harms checklist: a pilot tool to be used for balanced reporting of benefits and harms. J Clin Epidemiol. 2018;93:9–24.

    Article  PubMed  Google Scholar 

  22. Abdel-Rahman O. Toxicity patterns associated with chemotherapy/immune checkpoint inhibitor combinations: a meta-analysis. Immunotherapy. 2019;11(6):543–54.

    Article  CAS  PubMed  Google Scholar 

  23. Almutairi AR, McBride A, Slack M, Erstad BL, Abraham I. Potential immune-related adverse events associated with monotherapy and combination therapy of ipilimumab, nivolumab, and pembrolizumab for advanced melanoma: a systematic review and meta-analysis. Front Oncol. 2020;10:91.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Arnaud-Coffin P, Maillet D, Gan HK, Stelmes J-J, You B, Dalle S, et al. A systematic review of adverse events in randomized trials assessing immune checkpoint inhibitors. Int J Cancer. 2019;145(3):639–48.

    Article  CAS  PubMed  Google Scholar 

  25. Balasubramanian A, Onggo J, Gunjur A, John T, Parakh S. Immune checkpoint inhibition with chemoradiotherapy in stage III non-small-cell lung cancer: a systematic review and meta-analysis of safety results. Clin Lung Cancer. 2021;22(2):74–82.

    Article  CAS  PubMed  Google Scholar 

  26. Barroso-Sousa R, Barry WT, Garrido-Castro AC, Hodi FS, Min L, Krop IE, 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.

    Article  PubMed  Google Scholar 

  27. Baxi S, Yang A, Gennarelli RL, Khan N, Wang Z, Boyce L, et al. Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis. BMJ. 2018;360:k793.

  28. Bishay K, Tandon P, Bourassa-Blanchette S, Laurie SA, McCurdy JD. The risk of diarrhea and colitis in patients with lung cancer treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Curr Oncol. 2020;27(5):e486–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chen K, Wang X, Yang L, Chen Z. The anti-PD-1/PD-L1 immunotherapy for gastric esophageal cancer: a systematic review and meta-analysis and literature review. Cancer Control. 2021;28:1073274821997430.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Da L, Teng Y, Wang N, Zaguirre K, Liu Y, Qi Y, et al. Organ-specific immune-related adverse events associated with immune checkpoint inhibitor monotherapy versus combination therapy in cancer: a meta-analysis of randomized controlled trials. Front Pharmacol. 2019;10:1671.

    Article  CAS  PubMed  Google Scholar 

  31. de Filette J, Andreescu CE, Cools F, Bravenboer B, Velkeniers B. A systematic review and meta-analysis of endocrine-related adverse events associated with immune checkpoint inhibitors. Horm Metab Res. 2019;51(3):145–56.

    Article  PubMed  CAS  Google Scholar 

  32. El Osta B, Hu F, Sadek R, Chintalapally R, Tang SC. Not all immune-checkpoint inhibitors are created equal: Meta-analysis and systematic review of immune-related adverse events in cancer trials. Crit Rev Oncol Hematol. 2017;119:1–12.

    Article  PubMed  Google Scholar 

  33. Facchinetti F, Di Maio M, Tiseo M. Adding PD-1/PD-L1 inhibitors to chemotherapy for the first-line treatment of extensive stage small cell lung cancer (SCLC): a meta-analysis of randomized trials. Cancers. 2020;12(9):2645.

    Article  CAS  PubMed Central  Google Scholar 

  34. Fu J, Li W-Z, McGrath NA, Lai CW, Brar G, Xiang Y-Q, et al. Immune checkpoint inhibitor associated hepatotoxicity in primary liver cancer versus other cancers: a systematic review and meta-analysis. Front Oncol. 2021;11:650292.

  35. Grunwald V, Voss MH, Rini BI, Powles T, Albiges L, Giles RH, et al. Axitinib plus immune checkpoint inhibitor: evidence- and expert-based consensus recommendation for treatment optimisation and management of related adverse events. Br J Cancer. 2020;123(6):898–904.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Gu Y, Zhang H, Liu Z, Xia Y, Liang B, Liang L. Different patterns of treatment-related adverse events of programmed cell death-1 and its ligand-1 inhibitors in different cancer types: a meta-analysis and systemic review of clinical trials. Asia Pac J Clin Oncol. 2020;16(5):e160–78.

    Article  PubMed  Google Scholar 

  37. Guo X, Li W, Hu J, Zhu EC, Su Q. Hepatotoxicity in patients with solid tumors treated with PD-1/PD-L1 inhibitors alone, PD-1/PD-L1 inhibitors plus chemotherapy, or chemotherapy alone: systematic review and meta-analysis. Eur J Clin Pharmacol. 2020;76(10):1345–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Huang Y-F, Xie W-J, Fan H-Y, Du J. Comparative risks of high-grade adverse events among FDA-approved systemic therapies in advanced melanoma: systematic review and network meta-analysis. Front Oncol. 2020;10:571135.

  39. Khan M, Lin J, Liao G, Tian Y, Liang Y, Li R, et al. Comparative analysis of immune checkpoint inhibitors and chemotherapy in the treatment of advanced non-small cell lung cancer: a meta-analysis of randomized controlled trials. Medicine. 2018;97(33):e11936.

  40. Li H, Xu J, Bai Y, Zhang S, Cheng M, Jin J. Nephrotoxicity in patients with solid tumors treated with anti-PD-1/PD-L1 monoclonal antibodies: a systematic review and meta-analysis. Invest New Drugs. 2021;39(3):860–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Li L, Xu F, Chen Y, Ren X, Liu Y, Chen Y, et al. Indirect comparison between immunotherapy alone and immunotherapy plus chemotherapy as first-line treatment for advanced non-small cell lung cancer: a systematic review. BMJ Open. 2020;10(11):e034010.

  42. Li Z-Q, Yan H-C, Gu J-J, Yang Y-L, Zhang M-K, Fang X-J. Comparative efficacy and safety of PD-1/PD-L1 Inhibitors versus platinum-based chemotherapy for the first-line treatment of advanced non-small cell lung cancer: a meta analysis of randomized controlled trials. Pharmacol Res. 2020;160:105194.

  43. Lin L-L, Lin G-F, Yang F, Chen X-Q. A systematic review and meta-analysis of immune-mediated liver dysfunction in non-small cell lung cancer. Int Immunopharmacol. 2020;83:106537.

  44. Liu H, Xu D, Wang W, Sun F, Zhang S, Yang X, et al. Systematic assessment of risk of fever in solid tumor patients treated with PD-1/PD-L1 inhibitors: a systematic review and meta-analysis. Front Oncol. 2020;10:570080.

  45. Liu Q, Fang Z, Liu M, Xu R, Yi F, Wei Y, et al. The benefits and risks of CTLA4 inhibitor plus PD1/PDL1 inhibitor in stage IIIB/IV non-small cell lung cancer: a systematic analysis and meta-analysis based on randomized controlled trials. J Clin Pharm Ther. 2021;46(6):1519–30.

    Article  CAS  PubMed  Google Scholar 

  46. Lu J, Li L, Lan Y, Liang Y, Meng H. Immune checkpoint inhibitor-associated pituitary-adrenal dysfunction: a systematic review and meta-analysis. Cancer Med. 2019;8(18):7503–15.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Lu J, Yang J, Liang Y, Meng H, Zhao J, Zhang X. Incidence of immune checkpoint inhibitor-associated diabetes: a meta-analysis of randomized controlled studies. Front Pharmacol. 2019;10:1453.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Luo W, Wang Z, Tian P, Li W. Safety and tolerability of PD-1/PD-L1 inhibitors in the treatment of non-small cell lung cancer: a meta-analysis of randomized controlled trials. J Cancer Res Clin Oncol. 2018;144(10):1851–9.

    Article  CAS  PubMed  Google Scholar 

  49. Miyashita H, Mikami T, Satoi S, Cruz C, Galsky MD. Incidence and risk of colitis with programmed death 1 versus programmed death ligand 1 inhibitors for the treatment of cancer. J Immunother. 2020;43(9):291–8.

    Article  CAS  PubMed  Google Scholar 

  50. Narayan V, Kahlmeyer A, Dahm P, Skoetz N, Risk MC, Bongiorno C, et al. Pembrolizumab monotherapy versus chemotherapy for treatment of advanced urothelial carcinoma with disease progression during or following platinum-containing chemotherapy. A Cochrane Rapid Review. Cochrane Database Syst Rev. 2018;7(7):CD012838.

  51. Ni X, Xing Y, Sun X, Suo J. The safety and efficacy of anti-PD-1/anti-PD-L1 antibody therapy in the treatment of previously treated, advanced gastric or gastro-oesophageal junction cancer: a meta-analysis of prospective clinical trials. Clin Res Hepatol Gastroenterol. 2020;44(2):211–22.

    Article  CAS  PubMed  Google Scholar 

  52. Ornstein MC, Garcia JA. Toxicity of checkpoint inhibition in advanced RCC: a systematic review. Kidney cancer. 2017;1(2):133–41.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Park R, Lopes L, Cristancho CR, Riano IM, Saeed A. Treatment-related adverse events of combination immune checkpoint inhibitors: systematic review and meta-analysis. Front Oncol. 2020;10:258.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Petrelli F, Ardito R, Borgonovo K, Lonati V, Cabiddu M, Ghilardi M, et al. Haematological toxicities with immunotherapy in patients with cancer: a systematic review and meta-analysis. Eur J Cancer. 2018;103:7–16.

    Article  CAS  PubMed  Google Scholar 

  55. Shi Y, Duan J, Guan Q, Xue P, Zheng Y. Effectivity and safety of PD-1/PD-L1 inhibitors for different level of PD-L1-positive, advanced NSCLC: a meta-analysis of 4939 patients from randomized controlled trials. International immunopharmacology. 2020;84:106452.

  56. Si Z, Zhang S, Yang X, Ding N, Xiang M, Zhu Q, et al. The association between the incidence risk of peripheral neuropathy and PD-1/PD-L1 inhibitors in the treatment for solid tumor patients: a systematic review and meta-analysis. Front Oncol. 2019;9:866.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Sonpavde GP, Grivas P, Lin Y, Hennessy D, Hunt JD. Immune-related adverse events with PD-1 versus PD-L1 inhibitors: a meta-analysis of 8730 patients from clinical trials. Future Oncol. 2021;17(19):2545–58.

    Article  CAS  PubMed  Google Scholar 

  58. Su Q, Sun Z, Zhang C, Hou Y, Cao B. PD-1/PD-L1 antibodies efficacy and safety versus docetaxel monotherapy in advanced NSCLC patients after first-line treatment option: systems assessment. Oncotarget. 2017;8(35):59677–89.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Su Q, Zhu EC, Wu J-B, Li T, Hou Y-L, Wang D-Y, et al. Risk of pneumonitis and pneumonia associated with immune checkpoint inhibitors for solid tumors: a systematic review and meta-analysis. Front Immunol. 2019;10:108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Tandon P, Bourassa-Blanchette S, Bishay K, Parlow S, Laurie SA, McCurdy JD. The risk of diarrhea and colitis in patients with advanced melanoma undergoing immune checkpoint inhibitor therapy: a systematic review and meta-analysis. J Immunother. 2018;41(3):101–8.

    Article  PubMed  Google Scholar 

  61. Tian Y, Zhang Z, Yang X, Li D, Zhang L, Li Z, et al. The risk ratio of immune-related colitis, hepatitis, and pancreatitis in patients with solid tumors caused by PD-1/PD-L1 inhibitors: a systematic review and meta-analysis. Front Oncol. 2020;10:261.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Tong Z-Q, Wu D-Y, Liu D, Dong M. Incidence risk of PD-1/PD-L1-related pneumonia and diarrhea in non-small cell lung cancer (NSCLC) patients: a systematic review and meta-analysis of randomized controlled trials. Eur J Clin Pharmacol. 2021;77(8):1079–88.

    Article  CAS  PubMed  Google Scholar 

  63. Tun AM, Thein KZ, Thein WL, Guevara E. Checkpoint inhibitors plus chemotherapy for first-line treatment of advanced non-small cell lung cancer: a systematic review and meta-analysis of randomized controlled trials. Future Sci OA. 2019;5(9):FSO421.

  64. Voutsadakis IA. PD-1 inhibitors monotherapy in hepatocellular carcinoma: meta-analysis and systematic review. Hepatobil Pancreat Dis Int. 2019;18(6):505–10.

    Article  Google Scholar 

  65. Voutsadakis IA. A systematic review and meta-analysis of PD-1 and PD-L1 inhibitors monotherapy in metastatic gastric and gastroesophageal junction adenocarcinoma. Euroasian J Hepato-gastroenterol. 2020;10(2):56–63.

    Article  Google Scholar 

  66. Wang B-C, Cao R-B, Li P-D, Fu C. The effects and safety of PD-1/PD-L1 inhibitors on head and neck cancer: a systematic review and meta-analysis. Cancer Med. 2019;8(13):5969–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Wang P-F, Chen Y, Song S-Y, Wang T-J, Ji W-J, Li S-W, et al. Immune-related adverse events associated with anti-PD-1/PD-L1 treatment for malignancies: a meta-analysis. Front Pharmacol. 2017;8:730.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Wang Y, Zhou S, Yang F, Qi X, Wang X, Guan X, et al. Treatment-related adverse events of PD-1 and PD-L1 inhibitors in clinical trials: a systematic review and meta-analysis. JAMA Oncol. 2019;5(7):1008–19.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Xiao BY, Lin GH, Zhao YX, Wang BC. The efficacy and safety of PD-1/PD-L1 inhibitors in breast cancer: a systematic review and meta-analysis. Transl Cancer Res. 2020;9(6):3804–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Xu D, Liu H, Xiang M, Feng A, Tian M, Li D, et al. The relationship between pneumonitis and programmed cell death-1/programmed cell death ligand 1 inhibitors among cancer patients: a systematic review and meta-analysis. Medicine. 2020;99(41):e22567.

  71. Xu H, Tan P, Ai J, Zhang S, Zheng X, Liao X, et al. Antitumor activity and treatment-related toxicity associated with nivolumab plus ipilimumab in advanced malignancies: a systematic review and meta-analysis. Front Pharmacol. 2019;10:1300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Xu H, Tan P, Zheng X, Huang Y, Lin T, Wei Q, et al. Immune-related adverse events following administration of anti-cytotoxic T-lymphocyte-associated protein-4 drugs: a comprehensive systematic review and meta-analysis. Drug Des Dev Ther. 2019;13:2215–34.

    Article  CAS  Google Scholar 

  73. Xu M, Nie Y, Yang Y, Lu Y-T, Su Q. Risk of neurological toxicities following the use of different immune checkpoint inhibitor regimens in solid tumors: a systematic review and meta-analysis. Neurologist. 2019;24(3):75–83.

    Article  PubMed  Google Scholar 

  74. Yang L, Dong X-Z, Xing X-X, Cui X-H, Li L, Zhang L. Efficacy and safety of anti-PD-1/anti-PD-L1 antibody therapy in treatment of advanced gastric cancer or gastroesophageal junction cancer: a meta-analysis. World J Gastrointest Oncol. 2020;12(11):1346–63.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Yang Y, Pang P, Xie Z, Wang N, Liang H, Zhao L. The safety of first and subsequent lines of PD-1/PD-L1 inhibitors monotherapy in non-small cell lung cancer patients: a meta-analysis. Transl Cancer Res. 2020;9(5):3231–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Zhang B, Wu Q, Zhou YL, Guo X, Ge J, Fu J. Immune-related adverse events from combination immunotherapy in cancer patients: a comprehensive meta-analysis of randomized controlled trials. Int Immunopharmacol. 2018;63:292–8.

    Article  CAS  PubMed  Google Scholar 

  77. Zhang B, Zhou YL, Chen X, Wang Z, Wang Q, Ju F, et al. Efficacy and safety of CTLA-4 inhibitors combined with PD-1 inhibitors or chemotherapy in patients with advanced melanoma. Int Immunopharmacol. 2019;68:131–6.

    Article  CAS  PubMed  Google Scholar 

  78. Zhang C, Zhang S, Xu D, Liu R, Zhu Q, Zhao Y, et al. Incidence risk of PD-1/PD-L1 related diarrhea in non-small cell lung cancer (NSCLC) patients: a systematic review and meta-analysis. Cancer Manag Res. 2019;11:3957–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Zhang H, Shen J, Yi L, Zhang W, Luo P, Zhang J. Efficacy and safety of ipilimumab plus chemotherapy for advanced lung cancer: a systematic review and meta-analysis. J Cancer. 2018;9(23):4556–67.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Zhang Q, Huo G-W, Zhang H-Z, Song Y. Efficacy of pembrolizumab for advanced/metastatic melanoma: a meta-analysis. Open Med. 2020;15(1):447–56.

    Article  CAS  Google Scholar 

  81. Zhang S, Zhou Z, Wang L, Li M, Zhang F, Zeng X. Rheumatic immune-related adverse events associated with immune checkpoint inhibitors compared with placebo in oncologic patients: a systemic review and meta-analysis. Therap Adv Chron Dis. 2021;12:2040622320976996.

    CAS  Google Scholar 

  82. Zhang X, Chen L, Zhao Y, Yin H, Ma H, He M. Safety and efficacy in relapsed or refractory classic hodgkin’s lymphoma treated with PD-1 inhibitors: a meta-analysis of 9 prospective clinical trials. Biomed Res Int. 2019;2019:9283860.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Zhao L, Yu J, Wang J, Li H, Che J, Cao B. Risk of immune-related diarrhea with PD-1/PD-L1 inhibitors in different cancer types and treatment regimens. J Cancer. 2020;11(1):41–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Zhou H, Fu X, Li Q, Niu T. Safety and efficacy of anti-PD-1 monoclonal antibodies in patients with relapsed or refractory lymphoma: a meta-analysis of prospective clinic trails. Front Pharmacol. 2019;10:387.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Ziogas IA, Evangeliou AP, Giannis D, Hayat MH, Mylonas KS, Tohme S, et al. The role of immunotherapy in hepatocellular carcinoma: a systematic review and pooled analysis of 2,402 patients. Oncologist. 2021;26(6):E1036–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Xin YuJ, Hubbard-Lucey VM, Tang J. Immuno-oncology drug development goes global. Nat Rev Drug Discov. 2019;18(12):899–900.

    Article  CAS  Google Scholar 

  87. Wang DY, Salem JE, Cohen JV, Chandra S, Menzer C, Ye F, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. 2018;4(12):1721–8.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Robert C. A decade of immune-checkpoint inhibitors in cancer therapy. Nat Commun. 2020;11(1):3801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Raschi E, Mazzarella A, Ippazio CA, Bendinelli N, Forcesi E, Tuccori M, et al. Toxicities with immune checkpoint inhibitors: emerging priorities from disproportionality analysis of the FDA adverse event reporting system. Targ Oncol. 2019;14:205–21.

    Article  Google Scholar 

  90. Raschi E, Gatti M, Gelsomino F, Ardizzoni A, Poluzzi E, De Ponti F. Lessons to be learnt from real-world studies on immune-related adverse events with checkpoint inhibitors: a clinical perspective from pharmacovigilance. Target Oncol. 2020;15:449–66. https://doi.org/10.1007/s11523-020-00738-6.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Brahmer JR, Abu-Sbeih H, Ascierto PA, Brufsky J, Cappelli LC, Cortazar FB, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother Cancer. 2021;9(6): e002435. https://doi.org/10.1136/jitc-2021-002435.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Schneider BJ, Naidoo J, Santomasso BD, Lacchetti C, Adkins S, Anadkat M, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol. 2021;39(36):4073–126. https://doi.org/10.1200/JCO.21.01440.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge Risa Shorr, MLS, for her assistance and expertise in developing their search strategy and conducting the literature search.

Author information

Author notes

  1. Salmaan Kanji and Sydney Morin are acknowledged as co-first authors on this work.

Authors and Affiliations

  1. The Ottawa Hospital, 501 Smyth Rd, Ottawa, ON, K1H 8L6, Canada

    Salmaan Kanji, Dominick Bosse & Xiang Wang

  2. Montfort Hospital, Ottawa, ON, Canada

    Sydney Morin & Pierre Thabet

  3. University of Waterloo, Waterloo, ON, Canada

    Kyla Agtarap & Debanjali Purkayastha

  4. St. Michaels Hospital, Unity Health Toronto, Toronto, ON, Canada

    Carole Lunny

  5. University of British Columbia, Vancouver, BC, Canada

    Carole Lunny

  6. Ottawa Hospital Research Institute, Ottawa, ON, Canada

    Salmaan Kanji & Brian Hutton

Authors
  1. Salmaan Kanji
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sydney Morin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kyla Agtarap
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Debanjali Purkayastha
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pierre Thabet
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dominick Bosse
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Carole Lunny
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Brian Hutton
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conception and design of the study: SK, PT, BH, CL, DB, XW. Abstract screening: SM, DP, KA, PT and SK. Data collection: SM, DP and KA. Overlap management, data synthesis and interpretation: SK, PT, SM, DP, KA. Drafting the article: SM and SK. Critical revision of the article: All authors. Final approval of the version to be published: All authors.

Corresponding author

Correspondence to Salmaan Kanji.

Ethics declarations

Funding

No external funding was used in the preparation of this manuscript

Conflicts of interest/competing interests

Brian Hutton has received honoraria from Eversana for the provision of scientific advice on methods for evidence synthesis. Dominick Bosse has received honoraria for consultations or presentations from Pfizer, BMS, AstraZeneca, AMGEN, IPSEN, Bayer, AbbVie, Eisai and Merck. Salmaan Kanji, Sydney Morin, Kyla Agtarap, Debanjali Purkayastha, Pierre Thabet, Xiang Wang and Carole Lunny declare they have no conflicts of interest that might be relevant to the contents of this manuscript.

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and material

Not applicable.

Code availability

Not applicable.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 2049 KB)

Supplementary file2 (PDF 4735 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kanji, S., Morin, S., Agtarap, K. et al. Adverse Events Associated with Immune Checkpoint Inhibitors: Overview of Systematic Reviews. Drugs 82, 793–809 (2022). https://doi.org/10.1007/s40265-022-01707-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40265-022-01707-1

Search

Navigation