Neoadjuvant combined chemotherapy and immunotherapy for upper tract urothelial carcinoma: Final results from a phase II study.

775 Background: Upper tract urothelial carcinoma (UTUC) carries a poor prognosis even after radical nephroureterectomy (RNU).The efficacy of neoadjuvant chemotherapy for UTUC remains uncertain due to limited and mainly retrospective evidence.This phase II study aims to investigate the efficacy and safety of combining chemotherapy (Gemcitabine/Cisplatin/ Carboplatin) with a PD-1 inhibitor (Toripalimab /Tislelizumab/Nivolumab/Pembrolizumab) as neoadjuvant treatment (NT) in UTUC. Methods: This single-arm, phase II trial enrolled 33 patients with high-grade cT1N0M0 or cT2–3N0M0 UTUC, confirmed by ureterorenoscopic biopsy and cross-sectional imaging. Patients received 2–4 cycles of neoadjuvant therapy consisting of gemcitabine (800 mg/m² , days 1 and 8), cisplatin or carboplatin (60 mg/m² on day 1), and a PD-1 inhibitor (240 mg on day 1) every 21 days, followed by RNU with pelvic lymphadenectomy. The primary endpoint was pathological complete response (pCR) rate; secondary endpoints included safety, compliance, and surgical feasibility. Results: All 33 patients completed treatment and were included in the analysis.The median age was 65.0 years; 54.5 % were male.Most had unifocal tumors, with a median maximum diameter of 3.0 cm (0.7-7.5). All patients experienced obstructed hydronephrosis. Clinical T staging was confirmed by multi-parameter MRI, indicating nine T2 and twenty-four T3 patients. Ureterorenoscopy biopsy revealed thirty high-grade and three low-grade urothelial carcinoma patients. All patients were classified as high-risk UTUC. Twenty-four patients completed 4 cycles, seven underwent 3 cycles and two underwent 2 cycles. The median interval time from initiation of NT to RNU and from the end of NT to RNU was 18.3 (10-34) weeks and 6.7 (2.3-29) weeks respectively. Operative time was slightly longer than for patients undergoing upfront surgery. The pCR rate was 27.3% (9/33), the ≤pT1 rate was 69.7% (23/33), and the DCR was 100%. No grade 5 chemotherapy-related adverse events were recorded, but 39.4% (13/33) experienced grade 2 myelosuppression, 24.2% (8/33) grade 3, and 6% (2/33) grade 4. Five patients experienced immune-related adverse events after 4 cycles, including hypothyroidism (grade 2) and adrenal insufficiency (grade 2). No serious surgery-related complications or readmissions within one month were reported. With a median follow-up of 22.1 months, all patients remained alive and tumor-free. Conclusions: The combination of chemotherapy and a PD-1 inhibitor as neoadjuvant therapy showed promising efficacy with acceptable safety in high-risk UTUC. This approach may offer a new therapeutic option for improving pathological responses before surgery. Clinical trial information: NCT04099589 .