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Background Immune checkpoint inhibitors (ICIs) have become a standard of care for various types of cancer as a result of their demonstrated long-term survival benefit [1]. ICI therapy reinvigorates immune cells to achieve such treatment efficacy, but this mechanism of action can also give rise to autoimmune-like side effects known as immune-related adverse events (irAEs) [2]. The spectrum of irAEs is broad in that they can involve various organs, and, although they are usually mild or manageable, they can be lifethreatening [2]. However, of note, evidence has suggested that these irAEs may be an early sign of ICI treatment success [3]. Indeed, numerous studies have revealed a positive association of irAEs with tumor response or extended survival in patients receiving ICI treatment. The fact that not all studies have confirmed such an association, however, has left the nature of the relation between irAEs and ICI treatment efficacy unclear [3]. In an article published recently in this journal, Zhou et al. approached this important clinical question by undertaking a comprehensive systematic review and well-designed meta-analysis [4]. Systematic review identifies 30 articles for metaanalysis of PFS and OS For their meta-analysis, Zhou et al. considered only studies that reported hazard ratios for progression-free survival (PFS) or overall survival (OS) in patients with irAEs compared with those without irAEs, resulting in the inclusion of 30 original articles for the analysis. These 30 articles consisted mostly of studies that evaluated patients with non-small cell lung cancer or melanoma who were treated with inhibitors of programmed cell death-1 (PD-1) or its ligand PD-L1, although patients with other cancer types or those treated with ipilimumab, an antibody to cytotoxic T lymphocyte antigen-4 (CTLA-4), were also included. The metaanalysis evaluated potential publication bias by funnel plot-based analyses with Egger’s test and the trim-andfill method. It examined between-study heterogeneity by applying the χ test and I statistic, with a randomeffects model being adopted when significant heterogeneity was observed, and sensitivity analyses were also performed.

Association of immune-related adverse events with immune checkpoint inhibitor efficacy: real or imaginary?