A Phase 2 Study of Tislelizumab as Neoadjuvant Treatment of Cisplatin-Ineligible High-Risk Upper Tract Urothelial Carcinoma.

PURPOSE: We investigated the efficacy and safety of tislelizumab as neoadjuvant therapy in patients with cisplatin-ineligible high-risk upper tract urothelial carcinoma (UTUC). MATERIALS AND METHODS: In this single-arm phase 2 trial (NCT04672330), 20 patients with high-risk UTUC were enrolled. Eligibility criteria included high-risk UTUC (defined as high-grade UTUC confirmed by endoscopic biopsy or urinary cytology, radiographic evidence of invasion [cT2-T4N0-2M0], and/or hydronephrosis), an Eastern Cooperative Oncology Group performance status of 0 to 2, no previous systemic therapy, and cisplatin ineligibility. Patients received neoadjuvant tislelizumab before radical surgery. Contrast-enhanced MRI was performed before the third dose and again before surgery. The primary end point was pathological complete response rate (ypT0N0). Secondary end points included pathological response rate (≤ypT1N0), objective response rate, disease-free survival, safety profile, and perioperative complications. Multiplex immunofluorescence assessed immune cell populations in the tumor microenvironment. RESULTS: Among the 20 patients, 13 underwent radical nephroureterectomy, 1 received endoscopic ablation, and 3 had segmental ureteral resection. Three patients declined surgery because of disease progression or adverse events. The pathological complete response rate was 20%, with 45% of patients restaged to ≤ pT1. Median disease-free survival and overall survival were not reached. Grade 3/4 treatment-related adverse event occurred in 15% of patients. MRI analysis revealed higher apparent diffusion coefficient entropy in patients with partial response. Exploratory analysis showed increased PD-L1(+)CD68(+) macrophages and PD-1(+)CD8(+) T cells in the tumor stroma of partial and complete responders. CONCLUSIONS: Neoadjuvant tislelizumab showed promising efficacy and manageable toxicity in patients with high-risk, cisplatin-ineligible UTUC. Increased apparent diffusion coefficient entropy on MRI and the presence of PD-L1(+)CD68(+) macrophages in the tumor stroma may serve as potential predictors of response to neoadjuvant tislelizumab.