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

812 Background: Upper Tract Urothelial Carcinoma (UTUC) presents a challenging prognosis even after Radical Nephroureterectomy (RNU). The efficacy of neoadjuvant chemotherapy for UTUC remains uncertain.This phase II study aims to investigate the efficacy and safety of a combination of chemotherapy (Gemcitabine/Cisplatin/Carboplatin) and PD-1 inhibitor (Toripalimab /Tislelizumab/Nivolumab) as neoadjuvant treatment (NT) in UTUC patients. Methods: We planned to enroll 34 UTUC patients with either cT1N0M0 (high grade) or cT2-3N0M0, confirmed by ureterorenoscopy biopsy and imaging. The treatment regimen included three or four cycles of NT (Gemcitabine, 800mg/m 2 , days 1 and 8/Cisplatin or Carboplatin, 60mg/m 2 , day 1/Toripalimab or Tislelizumab or Nivolumab, 240mg, day 1 of a 21-day cycle), followed by RNU and pelvic lymphadenectomy. The primary outcome was the pathological complete response (pCR) rate, with secondary outcomes including significant downstaging (≤pT1) rate, disease control rate (DCR), and safety. Results: To date, 30 patients have been accrued since August 1st, 2020, and recruitment is ongoing. Twenty-seven patients have completed treatments and were preliminarily analyzed, with three patients still undergoing treatment. The median age was 65.0 years, with 55.6% being male. The majority of patients had unifocal tumors, with a median maximum diameter of 3.3cm (0.7-7.5). All patients experienced obstructed hydronephrosis. Clinical T staging was confirmed by multi-parameter MRI, indicating four T2 and twenty-three T3 patients. Ureterorenoscopy biopsy revealed twenty-five high-grade and two low-grade urothelial carcinoma patients. All patients were classified as high-risk UTUC. Twenty patients completed 4 cycles, five 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 17.3 (11.4-28) weeks and 6.8 (2.3-22) weeks respectively. The pCR rate was 29.6% (8/27), the ≤pT1 rate was 63.0% (17/27), and the DCR was 100%. No grade 4-5 chemotherapy-related adverse events were recorded, but 41% (11/27) experienced grade 2 myelosuppression, 29.6% (8/27) grade 3, and 7.4% (2/27) grade 4. Four patients experienced immune-related adverse events after 4 cycles, including hypothyroidism (grade 2) and adrenal insufficiency (grade 2). No surgery-related complications or readmissions within one month were reported. With a median follow-up of 14.1months, all patients remained alive and tumor-free. Conclusions: Preliminary analyses suggest that the combination of chemotherapy and a PD-1 inhibitor as NT exhibits promising pCR rate for UTUC. The treatment was manageable in terms of safety, with immune-related adverse events potentially leading to prolonged treatment periods. Clinical trial information: NCT04099589 .