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Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis

BMJ 2018; 360 doi: (Published 14 March 2018) Cite this as: BMJ 2018;360:k793
  1. Shrujal Baxi, assistant attending123,
  2. Annie Yang, data assistant2,
  3. Renee L Gennarelli, assistant research biostatistician2,
  4. Niloufer Khan, fellow1,
  5. Ziwei Wang, resident4,
  6. Lindsay Boyce, research informationist5,
  7. Deborah Korenstein, chief attending12
  1. 1Department of Medicine, Memorial Sloan Kettering Cancer Center, 485 Lexington Avenue, 2nd Floor, New York, NY, USA
  2. 2Center for Health Policy and Outcomes, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  3. 3Department of Medicine, Weill Cornell Medicine, New York, NY, USA
  4. 4Department of Medicine, University of Cailfornia Los Angeles, Los Angeles, CA, USA
  5. 5Medical Library, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  1. Correspondence to: D Korenstein korenstd{at}
  • Accepted 30 January 2018


Objective To evaluate rates of serious organ specific immune-related adverse events, general adverse events related to immune activation, and adverse events consistent with musculoskeletal problems for anti-programmed cell death 1 (PD-1) drugs overall and compared with control treatments.

Design Systematic review and meta-analysis.

Data sources Medline, Embase, Cochrane Library, Web of Science, and Scopus searched to 16 March 2017 and combined with data from

Study selection Eligible studies included primary clinical trial data on patients with cancer with recurrent or metastatic disease.

Data extraction Three independent investigators extracted data on adverse events from and the published studies. Risk of bias was assessed using the Cochrane tool by three independent investigators.

Results 13 relevant studies were included; adverse event data were available on for eight. Studies compared nivolumab (n=6), pembrolizumab (5), or atezolizumab (2) with chemotherapy (11), targeted drugs (1), or both (1). Serious organ specific immune-related adverse events were rare, but compared with standard treatment, rates of hypothyroidism (odds ratio 7.56, 95% confidence interval 4.53 to 12.61), pneumonitis (5.37, 2.73 to 10.56), colitis (2.88, 1.30 to 6.37), and hypophysitis (3.38, 1.02 to 11.08) were increased with anti-PD-1 drugs. Of the general adverse events related to immune activation, only the rate of rash (2.34, 2.73 to 10.56) increased. Incidence of fatigue (32%) and diarrhea (19%) were high but similar to control. Reporting of adverse events consistent with musculoskeletal problems was inconsistent; rates varied but were over 20% in some studies for arthraligia and back pain.

Conclusions Organ specific immune-related adverse events are uncommon with anti-PD-1 drugs but the risk is increased compared with control treatments. General adverse events related to immune activation are largely similar. Adverse events consistent with musculoskeletal problems are inconsistently reported but adverse events may be common.


  • Contributors: 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. DK is the guarantor.

  • Funding: This study was supported in part by the National Institutes of Health and National Cancer Institute Cancer Center Support Grant (P30 CA008748). The funder had no role in the design of the study; the collection, analysis, and interpretation of the data; or approval of the finished manuscript.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare: no support from any organization 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 are available.

  • Transparency: The lead author (SB) 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, if relevant, registered) have been explained.

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