Neoadjuvant combined chemotherapy and immunotherapy for upper tract urothelial carcinoma: Preliminary results from a phase II study.
Authors: Bi Xin-Gang , Zhang Wen , Xie Yaoyu , Wu Jie , Cui Honglei , Cao Chuanzhen , Lu Li , Wen Li , Guan Youyan , Shi Hongzhe , Xiao Zhendong , Jiang Zhichao , Sun Yongkun , Zheng Shan , Zhang Jin , Zhou Aiping , Shou Jianzhong 
Published: January 2024

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Background: Upper Tract Urothelial Carcinoma (UTUC) presents a challenging prognosis even after Radical Nephroureterectomy (RNU), and postoperative renal insufficiency further limits the options for adjuvant therapy. The efficacy of neoadjuvant chemotherapy for UTUC remains uncertain as past studies have not shown satisfactory results and have mostly been retrospective. There is an urgent need for a more promising regimen. This phase II study aims to investigate the efficacy and safety of a combination of chemotherapy (Gemcitabine/Cisplatin) and PD-1 inhibitor (Toripalimab) 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/m2, days 1 and 8/Cisplatin, 60mg/m2, day 1/Toripalimab, 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, 17 patients have been accrued since August 1st, 2020, and recruitment is ongoing. Fifteen patients have completed treatments and were preliminarily analyzed, with two patients still undergoing treatment. The median age was 66.0 years, with 53.3% being male. The majority of patients had unifocal tumors, with a median maximum diameter of 2.8cm (0.4-5.8). All patients experienced obstructed hydronephrosis. Clinical T staging was confirmed by multi-parameter MRI, indicating two T2 and thirteen T3 patients. Ureterorenoscopy biopsy revealed 13 high-grade and two low-grade urothelial carcinoma patients. All patients were classified as high-risk UTUC. Twelve patients completed 4 cycles, and three underwent 3 cycles. The median interval time from initiation of NT to RNU and from the end of NT to RNU was 18.3 (11.4-22.7) weeks and 6.3 (0.1-11.6) weeks respectively. The pCR rate was 20.0% (3/15), the ≤pT1 rate was 53.3% (8/15), and the DCR was 100%. No grade 4-5 chemotherapy-related adverse events were recorded, but 26.7% (4/15) experienced grade 2 myelosuppression, 20% (3/15) grade 3, and 6.7% (1/15) grade 4. Two 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 25.6 months, 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 .