The Inconsistent and Inadequate Reporting of Immune-Related Adverse Events in PD-1/PD-L1 Inhibitors: A Systematic Review of Randomized Controlled Clinical Trials
Authors: Xie Tong , Zhang Zhening , Qi Changsong , Lu Ming , Zhang Xiaotian , Li Jian , Shen Lin , Peng Zhi 
Published: August 2021

Abstract

Background
Immune-related adverse events (irAEs) are of great interest and importance in clinical practice, and many deficiencies and controversies have been noted in the reporting of irAEs. Herein, we aimed to evaluate the current status of irAE reporting in randomized controlled clinical trials (RCTs) of PD-1/PD-L1 inhibitors and to attempt to explain and solve the current pitfalls associated with this reporting.

Materials and Methods
We conducted a systematic review across multiple databases, including PubMed, Web of Science, Embase, and the Cochrane Library. The RCTs that compared PD-1/PD-L1 inhibitors with standard treatments were included. The Harms extension of the Consolidated Standards of Reporting Trials (CONSORT) was used to evaluate the completeness of irAE reporting.

Results
A total of 44 articles and 23,759 patients were included in the analysis. The terminology of the irAEs changed over time (p = .01) and was different among immune checkpoint inhibitors (ICIs) (p = .005). Twenty-two of the studies provided a definition of irAE, but only four of them concretely addressed this definition. The incidence of any grade of irAEs ranged from 16.9% to 96%, whereas grade 3–4 irAE ranged from 2% to 23%. The RCTs with combined therapy exhibited a higher incidence of grade 3–4 irAEs (p = .012). Thirty-two studies reported irAEs in the control arms, whereas seven studies reported irAEs only in the experimental arms. Respiratory, endocrine, and gastrointestinal disorders were the most commonly reported irAEs. IrAEs were generally neglected in the introduction or conclusion sections in all of the study reviews and were never subjected to subgroup analyses. Moreover, withdrawals due to severe irAEs, as well as clarifications of the irAE collection methods, were also poorly reported. RCTs using combination therapies in the experimental arms were associated with a higher reporting quality (p = .032). However, the completeness of the reporting did not improve over the last 5 years (p = .076).

Conclusion
The reporting of irAEs was inadequate, and there are still inconsistencies and controversies in the reporting of irAEs. In the future, authors should be encouraged to adhere to the Harms extension of the CONSORT statement.

Implications for Practice
PD-1/PD-L1 inhibitors profoundly changed the landscape of cancer treatment, and thousands of randomized controlled clinical trials (RCTs) were active or completed over the past decade. However, different from chemotherapy or targeted therapy, the profile of immune-related adverse effects (irAE) was unique. An understanding of irAEs is developed mainly from clinical trials; however, inconsistencies and controversies between trials were noted. This study primarily reviewed the evolution of irAE terminology and definitions and evaluated the reporting quality of each RCT. It was found that RCTs using combined immunotherapy were associated with higher quality of irAE reporting. This article identifies the controversies and deficiencies in current irAE reporting and provides possible explanations and suggestions for these inadequacies.