Adjuvant disitamab vedotin plus PD-1 blockade and gemcitabine/cisplatin in high-risk upper tract urothelial carcinoma: a two-stage real-world comparative study

Objectives: To evaluate real-world effectiveness and safety of adjuvant disitamab vedotin plus PD-1 blockade (ADC+ICI) versus gemcitabine/cisplatin (GC) in high-risk upper tract urothelial carcinoma after radical nephroureterectomy. Patients and methods: This single-center, two-stage observational study enrolled 421 patients with study-defined high-risk upper tract urothelial carcinoma. Cohort A evaluated adjuvant GC versus surgery alone using propensity score matching. Cohort B compared adjuvant GC with ADC+ICI using overlap weighting, with ECOG performance status and three-level HER2 IHC category included in covariate adjustment. Overall survival (OS), conventional disease-free survival (DFS), non-intravesical progression-free survival (PFS), intravesical recurrence-free survival (IVRFS), safety, and exploratory HER2-stratified outcomes were assessed. Results: In Cohort A, adjuvant GC was associated with improved OS after matching. In Cohort B, 48 patients received GC and 53 received ADC+ICI. After overlap weighting, baseline covariates were well balanced. ADC+ICI was not associated with a significant OS improvement versus GC (HR 0.47, 95% CI 0.12-1.89; P = 0.287; FDR-adjusted P = 0.403). Directionally favorable associations were observed for conventional DFS (HR 0.32, 95% CI 0.11-0.96; nominal P = 0.043; FDR-adjusted P = 0.172), non-intravesical PFS (HR 0.32, 95% CI 0.09-1.18; P = 0.086), and IVRFS (HR 0.21, 95% CI 0.04-1.09; P = 0.063). HER2 IHC 2+/3+ tumors showed exploratory favorable DFS/PFS signals. Grade ≥3 treatment-related adverse events were similar between groups. Conclusions: Adjuvant ADC+ICI showed comparable short-term OS and directionally favorable DFS/PFS trends versus GC, with a distinct toxicity profile. These findings are hypothesis-generating and require prospective validation.