Histological variant-specific significance of lymph node metastasis for the prognosis of metastatic urothelial carcinoma treated with pembrolizumab: A retrospective multicentric study (YUSHIMA study-04)

Background Histological variants (HV) are associated with aggressiveness in urothelial carcinoma (UC). Although immune checkpoint inhibitor (ICI) therapy has improved the prognosis of patients with metastatic UC with HV, the factors determining the prognosis of these patients following ICI therapy remains unclear. Methods The present, retrospective, multicentric study (YUSHIMA study-04) included patients with histologically confirmed mUC who received pembrolizumab as a second-line or later therapy between January 2018 and June 2023. The primary endpoint was the assessment of differences in prognostic factors of progression-free survival (PFS) and overall survival (OS) in patients with HV and those with pure UC (pUC). Results The study cohort consisted of 61 patients with HV and 331 with pUC. PFS and OS were comparable between the groups. The presence of lymph node metastasis (LNM) was independently associated with longer PFS (multivariate hazard ratio [mHR]: 0.35; P = 0.02) and OS (mHR: 0.25; P = 0.002) in the HV group but was not in the pUC group (univariate HR: 1.10; P = 0.54 and HR: 1.05; P = 0.76, respectively). When the prognosis of the groups was compared by LNM status, the HV group had significantly shorter PFS ( P = 0.003) and OS ( P = 0.008) in a subpopulation of patients without LNM. Conclusions The presence of LNM may be a HV-specific prognostic factor of a favorable outcome in patients with mUC receiving pembrolizumab as second-line or later therapy.