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Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis

BMJ 2018; 363 doi: (Published 08 November 2018) Cite this as: BMJ 2018;363:k4226
  1. Cheng Xu, resident physician1,
  2. Yu-Pei Chen, resident physician1,
  3. Xiao-Jing Du, associate professor1,
  4. Jin-Qi Liu, postgraduate1,
  5. Cheng-Long Huang, postgraduate1,
  6. Lei Chen, associate professor1,
  7. Guan-Qun Zhou, fellow1,
  8. Wen-Fei Li, associate professor1,
  9. Yan-Ping Mao, associate professor1,
  10. Chiun Hsu, professor2,
  11. Qing Liu, statistician3,
  12. Ai-Hua Lin, statistician3,
  13. Ling-Long Tang, associate professor1,
  14. Ying Sun, professor1,
  15. Jun Ma
  1. 1Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou 510060, China
  2. 2Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
  3. 3Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, China
  1. Correspondence to: J Ma majun2{at}
  • Accepted 4 October 2018


Objective To provide a complete toxicity profile, toxicity spectrum, and a safety ranking of immune checkpoint inhibitor (ICI) drugs for treatment of cancer.

Design Systematic review and network meta-analysis.

Data sources Electronic databases (PubMed, Embase, Cochrane Library, and Web of Science) were systematically searched to include relevant studies published in English between January 2007 and February 2018.

Review methods Only head-to-head phase II and III randomised controlled trials comparing any two or three of the following treatments or different doses of the same ICI drug were included: nivolumab, pembrolizumab, ipilimumab, tremelimumab, atezolizumab, conventional therapy (chemotherapy, targeted therapy, and their combinations), two ICI drugs, or one ICI drug with conventional therapy. Eligible studies must have reported site, organ, or system level data on treatment related adverse events. High quality, single arm trials and placebo controlled trials on ICI drugs were selected to establish a validation group.

Results 36 head-to-head phase II and III randomised trials (n=15 370) were included. The general safety of ICI drugs ranked from high to low for all adverse events was as follows: atezolizumab (probability 76%, pooled incidence 66.4%), nivolumab (56%, 71.8%), pembrolizumab (55%, 75.1%), ipilimumab (55%, 86.8%), and tremelimumab (54%, not applicable). The general safety of ICI drugs ranked from high to low for severe or life threatening adverse events was as follows: atezolizumab (49%, 15.1%), nivolumab (46%, 14.1%), pembrolizumab (72%, 19.8%), ipilimumab (51%, 28.6%), and tremelimumab (28%, not applicable). Compared with conventional therapy, treatment-related adverse events for ICI drugs occurred mainly in the skin, endocrine, hepatic, and pulmonary systems. Taking one ICI drug was generally safer than taking two ICI drugs or one ICI drug with conventional therapy. Among the five ICI drugs, atezolizumab had the highest risk of hypothyroidism, nausea, and vomiting. The predominant treatment-related adverse events for pembrolizumab were arthralgia, pneumonitis, and hepatic toxicities. The main treatment-related adverse events for ipilimumab were skin, gastrointestinal, and renal toxicities. Nivolumab had a narrow and mild toxicity spectrum, mainly causing endocrine toxicities. Integrated evidence from the pooled incidences, subgroup, and sensitivity analyses implied that nivolumab is the best option in terms of safety, especially for the treatment of lung cancer.

Conclusions Compared with other ICI drugs used to treat cancer, atezolizumab had the best safety profile in general, and nivolumab had the best safety profile in lung cancer when taking an integrated approach. The safety ranking of treatments based on ICI drugs is modulated by specific treatment-related adverse events.

Systematic review registration PROSPERO CRD42017082553.


  • Contributors: The first four authors (CX, Y-PC, X-JD, and J-QL) contributed equally to this work. JM conceived, designed, and supervised the project. JM performed the quality assessment, review, and approval of the manuscript. CX, X-JD, Y-PC, and J-QL contributed to the design of the study, writing the protocol, data preparation, analysis and interpretation, and writing and final approval of the report. CX and X-JD identified eligible trials, extracted the data, and assessed the quality of included trials. CX, J-QL, C-LH, L-LT, LC, G-QZ, W-FL, and Y-PM processed the data and generated the tables and figures. CX, A-HL, and QL were responsible for statistical analysis and interpretation. CX, Y-PC, L-LT, and LC contributed to the interpretation of the data. CX, X-JD, and J-QL drafted the manuscript. CX, Y-PC, YS, and CH revised the manuscript before submission. CX, Y-PC, and J-QL participated in the formal revision, including statistical analysis, data processing, production of figures and tables, and text modification. All authors had full access to the data in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis. JM is the guarantor. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

  • Funding: This work was supported by grants from the Natural Science Foundation of Guang Dong Province (No 2017A030312003), Health and Medical Collaborative Innovation Project of Guangzhou City (No 201803040003), Innovation Team Development Plan of the Ministry of Education (No IRT_17R110), and Overseas Expertise Introduction Project for Discipline Innovation (111 Project, No B14035). The sponsors or funders had no involvement in any parts of this study. All authors confirmed the independence of researchers from funding sources.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare: support from the Natural Science Foundation of Guang Dong Province, Health and Medical Collaborative Innovation Project of Guangzhou City, Innovation Team Development Plan of the Ministry of Education, and Overseas Expertise Introduction Project for Discipline Innovation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: Not required.

  • Data sharing: No additional data available.

  • The manuscript’s guarantor (JM) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned and registered have been explained.

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