A systematic review of immune-related adverse event reporting in clinical trials of immune checkpoint inhibitors

Ann Oncol. 2015 Sep;26(9):1824-1829. doi: 10.1093/annonc/mdv182. Epub 2015 Apr 17.


Background: There are limited data about the quality of immune-related adverse event (irAE) reporting in immune checkpoint inhibitor (ICI) clinical trial publications.

Methods: A systematic search of citations from Medline, EMBASE and Cochrane databases identified prospective clinical trials involving ICIs in advanced solid tumors from 2003 to 2013. A 21-point quality score (QS) was adapted from the CONSORT harms extension statement. Linear regression was used to identify factors associated with quality reporting.

Results: After a review of 2628 articles, 50 trial reports were included, with ICIs as either monotherapy (54%) or part of a combination regimen (46%). The mean QS was 11.21 points (range 3.50-17.50 points). The median grade 3/4 AE rate reported was 21% (range 0%-66%) and 29/50 (58%) trials concluded that irAEs were tolerable. Multivariate regression analysis revealed that year of publication (within last 5 years, P = 0.01) and journal impact factor >15 (P = 0.004) were associated with higher QS. Complete reporting of specific characteristics of irAEs including onset, management and reversibility were reported by 14%, 8% and 6% of studies, respectively. The incidence of grade 3/4 adverse events was higher for inhibitors against CTLA-4 compared with other immune checkpoints (P < 0.001).

Conclusions: The reporting of irAEs is suboptimal. A standardized reporting method of irAEs that accounts for tolerability, management and reversibility is needed and would enable a more precise evaluation of the therapeutic risk benefit ratio of ICIs.

Keywords: adverse event; immune checkpoint inhibitors; quality control; systematic review.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Adverse Drug Reaction Reporting Systems / statistics & numerical data*
  • Clinical Trials as Topic / methods*
  • Humans
  • Immunotherapy / adverse effects*
  • Neoplasms / drug therapy*
  • Quality Control