A phase II study evaluating the efficacy and safety of perioperative enfortumab vedotin plus toripalimab combined with endoscope-based kidney-sparing surgery for patients with high-risk upper tract urothelial carcinoma (WUTSUP-04-EV-JS001).

TPS905 Background: Radical nephroureterectomy (RNU) for high-risk upper tract urothelial carcinoma (UTUC) often compromises renal function and eligibility for adjuvant therapy, while kidney-sparing surgery (KSS) carries high recurrence risks. Given the efficacy of enfortumab vedotin (EV) plus PD-1 inhibitors in advanced disease, the phase II WUTSUP-04 trial investigates whether this combination can downstage high-risk UTUC, enabling successful KSS while preserving the kidney, as well as offering long-term disease control. Methods: Study Design and population: This is a prospective single-center phase II trial conducted at West China Hospital, Sichuan University (CTEC : 2025-763). Key eligibility criteria include adults with histologically confirmed, high-risk, non-metastatic UTUC (cTa-2N0M0) with tumor size ≤20 mm or deemed endoscopically resectable, and an imperative or relative indication for nephron preservation (e.g., solitary kidney, bilateral UTUC, chronic kidney disease, strong preference for KSS with informed consent). Additionally, a prospective collection of data from contemporaneous patients who underwent RNU by the same lead surgeon and met comparable eligibility criteria will be conducted to compare the long-term oncological outcomes between the two treatment strategies. The treatment regimen is delivered sequentially across distinct phases: In the induction phase, patients receive 3 cycles of systemic EV (1.25 mg/kg IV, Days 1 & 8) plus Toripalimab (240 mg IV, Day 1) every 3 weeks. After response assessment and subsequent local tumor ablation, patients enter the consolidation phase, which consists of 6 cycles of adjuvant EV plus Toripalimab, followed by Toripalimab monotherapy to complete one year of total therapy. Endpoints: The primary endpoint is conversion-free survival (CFS), defined as the time from inclusion to the date of RNU performed for any UTUC-related indication, or death. Secondary endpoints include clinical complete response rate after induction, disease-free survival, metastasis-free survival, overall survival, renal function preservation, and safety. Sample size: The study includes an initial safety run-in phase (n=6). A sample size of 55 participants (including safety run-in) is planned to estimate the 12-month CFS rate with a precision (95% CI width) of approximately 0.087, assuming an exponential survival model. The study is approved by the Clinical Trial Ethics Committee of West China Hospital, Sichuan University and is initiating patient recruitment. Clinical trial information: CTEC: 2025-763.