Tislelizumab combined with gemcitabine as first-line treatment in cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma: a single center, single-arm phase 2 trial.

Introduction: Patients with la/mUC have an unfavorable prognosis and limited treatment options, particularly those who were considered ineligible for cisplatin-containing therapeutic schedule. ICIs have played a significant therapeutic role among this group of patients. Ongoing clinical investigations continue to explore the utility of ICIs, both used alone or in combination with other treatment methods. Methods: The purpose of this clinical trial is to explore the efficacy and safety of gemcitabine combined with tislelizumab as initial treatment for the la/mUC patients who are intolerant to platinum-based drugs. Primary endpoints were ORR and DCR. Secondary endpoints comprised PFS and OS. Results: At the data cutoff (September 1, 2025), 30 patients were enrolled. As the results display, the mPFS was 13.9 months (95% CI: 11.4-16.3), and the mOS was 23.3 months ([IQR]: 14.4-33.1; 95% CI: 18.2-28.3).The confirmed ORR was 46.7% (14/30; 95% CI: 28.3-65.7), DCR was 76.7%. The most frequent TRAEs were hematological toxicities, including leukopenia (43.3%) and neutropenia (40.0%). We also explored the predictive potential of tumor-associated TLS as an innovative analysis. There was a quantitative difference in ORR according to the results of TLS analysis, with response rates of 66.7% (n=9) in TLS positive group and 35.3% (n=17) in negative group. However, this observed change did not reach statistical significance (P = 0.218). Discussion: In conclusion, the combination of tislelizumab and gemcitabine demonstrated manageable tolerability and a promising preliminary efficacy signal as first-line therapeutic strategy for la/mUC patients who cannot receive cisplatin-containing regimen and warrants further investigation. Clinical Trial Registration: https://www.chictr.org.cn/index.html, identifier ChiCTR2200061631.