First-line tislelizumab plus gemcitabine produced durable responses in platinum-ineligible locally advanced or metastatic urothelial carcinoma.
First-line tislelizumab (Tevimbra) plus gemcitabine produced a confirmed objective response rate (ORR) of 46.7% and a disease control rate (DCR) of 76.7% in patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma, according to data from a single-center, single-arm phase 2 trial (ChiCTR2200061631) published in Frontiers in Immunology.¹
At a data cutoff of September 1, 2025, the median progression-free survival (PFS) was 13.9 months (95% CI, 11.4-16.3) and the median overall survival (OS) was 23.3 months (95% CI, 18.2-28.3) among evaluable patients (n = 30). Two patients (6.7%) achieved a complete response (CR) and 12 (40.0%) achieved a partial response (PR), with a median time to response of 1.92 months (range, 1.51-3.12) and a median duration of response of 12.22 months (95% CI, 4.93-19.22).
Between July 2, 2022, and December 1, 2024, 41 patients were screened and 30 were enrolled after meeting eligibility criteria, including histologically confirmed urothelial carcinoma with measurable disease per RECIST 1.1 criteria and an ECOG performance status of 2 or less.¹ Platinum intolerance was defined by at least one of: ECOG performance status of 2, creatinine clearance of 30 to 60 mL/min, grade 2 or higher sensorineural hearing loss or peripheral neuropathy, or New York Heart Association class II heart failure.¹
Patients received tislelizumab at 200 mg intravenously on day 0 plus gemcitabine at 1.0 g/m² on days 1 and 8 of each 21-day cycle; tislelizumab dose reduction was not permitted, while gemcitabine dosing could be adjusted for toxicity. Patients with CR, PR, or stable disease (SD) after 4 to 6 cycles could transition to tislelizumab maintenance; 23 patients (CR, 2; PR, 12; SD, 9) entered maintenance therapy.
The median patient age was 67 years (range, 40-79), 70.0% were male, and 90.0% had urothelial carcinoma as the sole histology; 60.0% had PD-L1 expression of 1% or higher and 26.7% had upper tract disease.
Any-grade TRAEs occurred in 73.3% of patients, most commonly leukopenia (43.3%) and neutropenia (40.0%). Grade 3/4 TRAEs occurred in 4 patients (13.3%), including fatigue, decreased appetite, nausea, elevated alanine aminotransferase, and myelosuppression; 2 patients required gemcitabine dose reduction for grade 3/4 myelosuppression, and 1 patient discontinued treatment after 4 cycles because of grade 3 fatigue. No treatment-related deaths were reported.
In an exploratory biomarker analysis of tumor-associated TLS conducted in 26 of the 30 patients, the ORR was 66.7% (n = 9) in the TLS-positive group vs 35.3% (n = 17) in the TLS-negative group, a difference that did not reach statistical significance (P = .218).¹ Subgroup analyses also showed numerically higher ORR in female patients (67%) vs male patients (38%) and in patients without liver metastasis (52%) vs those with liver metastasis (29%).
Investigators noted that the single-center, single-arm design precluded comparative analysis, and that TLS testing was feasible in only 86.7% of the cohort because of limited sample size. Multivariable analyses were not performed to avoid overfitting given the modest sample size, and post-progression treatment data were not systematically quantified, limiting interpretation of the OS findings. The authors concluded that the tislelizumab-gemcitabine combination displayed a preliminary efficacy signal with a manageable safety profile in cisplatin-ineligible la/mUC and stated that confirmation in larger randomized trials is required.
