Risk of Bias and Heterogeneity—Reply

In Reply We appreciate the interest and comments by Matsumoto et al regarding our article, which assessed the incidence of programmed cell death 1 (PD-1) inhibitor–related pneumonitis in a systematic review and meta-analysis of published trial reports. Risk of bias is certainly an important concept. Indeed, we have assessed publication bias using Begg's and Egger's tests with funnel plots, heterogeneity using Cochrane's Q statistics, and inconsistency by I² statistics, as presented in the Results section. In terms of the risk of bias for individual studies, it should be noted that we have included the original articles that have published the results of the prospective trials of PD-1 inhibitors, to date. These trial studies were conducted according to the detailed trial protocols that were approved by the institutional review boards and were designed to address the important domains of risk of bias assessment described in the established tool. In addition, the trials used National Cancer Institute Common Terminology Criteria for Adverse Events as a unified guideline to assess and grade pneumonitis during therapy. However, we also recognize that trials with small sample sizes may be less trustworthy sources compared with large observational studies with broad eligibility criteria involving typical patient populations. Although inclusion of such observational studies may contribute to evaluation of the incidence of pneumonitis in the real-world setting, such data were not available at the time of the study because PD-1 inhibitors are a novel group of agents that have only recently been approved for treatment of patients with cancer in the clinical setting. The systematic review part of the article was intended to provide the summary of the data of PD-1 inhibitor–related pneumonitis that were available in the early trial publications, to meet the increasing needs in the immuno-oncology community in a timely manner.

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