Immune checkpoint inhibitors (ICI) are the standard of care for tumors, including metastatic urothelial carcinoma (mUC). A recent phase III randomized controlled trial demonstrated better overall survival (OS) in patients with mUC treated with second-line pembrolizumab therapy than in those receiving platinum-based chemotherapy [1]. Pembrolizumab inhibits the interaction between programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1), thereby promoting an antitumor immune reaction.

ICIs occasionally induce immune-related adverse events (irAEs), which limit their use in certain cases [2,3]. Potential mechanisms of irAE development involve a cross-reactive immune response and an increase in preexisting autoantibodies and inflammatory cytokines [2]. The role of the gut microbiota in the antitumor activity of intestinal CD4+ and CD8+ T cells is currently garnering much attention for its potential effect on the activity of ICIs [4]. Most irAEs are self-limiting, but severe irAEs (grade ≥3) can be life-threatening [5].

IrAEs are reportedly associated with a favorable prognosis in various forms of cancer, including genitourinary cancer [[6], [7], [8], [9]]. Despite the association of irAE occurrence with improved outcomes of pembrolizumab therapy in patients with mUC [[10], [11], [12], [13]], the relationship between the severity of the irAEs and the treatment outcomes remains unclear. Previous studies demonstrated an improved prognosis in patients with relatively severe irAEs (≥grade [G] 3 or ≥G2) [10] while another study found an improvement in the prognosis associated with even milder irAEs (G1–2) [11,12]. However, as of yet, very few studies have assessed the relevance to the prognosis of the number of irAEs and the organs affected by them.

The present study comprehensively assessed the association of the number and types of organ affected by irAEs and the severity of the symptoms with the outcomes of pembrolizumab therapy in patients with mUC.