Impact of immune-related adverse events on the therapeutic efficacy of pembrolizumab in urothelial carcinoma: a multicenter retrospective study using time-dependent analysis

BACKGROUND: Several studies have reported the incidence of immune-related adverse events (irAEs) as a predictor of the efficacy of anti-programmed cell death protein 1 antibodies in patients with cancer. However, immortal time bias has not always been fully addressed in these studies. In this retrospective multicenter study, we assessed the association between the incidence of irAEs and the efficacy of pembrolizumab in urothelial carcinoma (UC) using time-dependent analysis, an established statistical method to minimize immortal time bias. METHODS: The study included 176 patients with advanced UC who underwent pembrolizumab treatment at seven affiliated institutions between January 2018 and July 2020. Patients with irAEs were compared with those without irAEs in terms of overall survival (OS) and cancer-specific survival (CSS). Immortal time bias was eliminated by using time-dependent analysis. RESULTS: Of the 176 patients, irAEs occurred in 77 patients (43.8%), with a median of 60 days. The irAEs (+) cohort showed significantly favorable OS and CSS compared with the irAEs (−) cohort (p=0.018 and p=0.005, respectively), especially in the cohort with grade 1–2 irAEs (OS and CSS; p=0.003 and p=0.002, respectively). Multivariate analyses identified any irAEs and grade 1–2 irAEs as independent favorable prognostic factors for OS and CSS. CONCLUSION: Even after minimizing immortal time bias by time-dependent analysis, the incidence of irAEs, especially grade 1–2 irAEs, could be a significant predictor of favorable prognoses in patients with UC who have undergone pembrolizumab treatment.