A phase II clinical trial of toripalimab combined with cisplatin plus gemcitabine chemotherapy as neoadjuvant treatment for muscle-invasive bladder cancer.

4596 Background: Recently clinical trials like BLASST-1 and SAKK06/17 showed that immunotherapy combined with chemotherapy as neoadjuvant regimen of muscle-invasive bladder cancer (MIBC)may produce synergistic effects with good tolerability. Toripalimab, a PD-1 inhibitor, has achieved good therapeutic effects in advanced urothelial cancer. This clinical study was designed to verify the safety and efficacy of Toripalimab with gemcitabine-cisplatin (GC) as neoadjuvant therapy (NAT) for MIBC. Methods: It is a prospective, single-arm, open-label, single-center phase II clinical study from China (ChiCTR2100051298). Thirty patients with MIBC clinically staged as T 2-3b N 0 M 0 , who were scheduled for RC were enrolled. Patients received: Toripalimab 240 mg + Gemcitabine 1000 mg/m 2 + Cisplatin 70mg/m 2 on day 1, Gemcitabine 1000mg/m 2 on day 8 every 21 days (1 cycle), totally for 4 cycles. RC will be performed 1 month after last therapy. The primary endpoint is pathological complete response (pCR), and the secondary endpoints are safety, overall survival (OS), and progression-free survival (PFS). The tumor regression effect after NAT will be evaluated by comparing the postoperative pathological results with the preoperative radiological results. The FISHER's exact test was used to analyze the relationship between genomic changes / tumor mutation burden (TMB) and pCR rate. This study has been approved by the Ethics Committee of Gulou Hospital, Nanjing. Results: From Jan 2020 to Dec 2021, 30 individuals participated in the study and received at least 1 cycle therapy, and 3 dropped out before RC. Among the patients who underwent RC, the pathological response (PaR) rate was 63% (17/27) and the pCR rate was 40.7% (11/27). The 1-year and 3-year PFS rates are 85.2% and 77.6%, respectively; The 1-year and 3-year OS rates are 96.2% and 84.6%, respectively. In the patients with PD-L1 expression ≥5% (n = 16), pCR and PaR rates was 43.8% (7/16) and 68.8% (11/16), respectively. In the patients with PD-L1 expression < 5% (n = 11), the pCR rate was 36.4% (4/11) and the PaR rate was 63.6% (7/11). The status of PD-L1 expression and TMB were not associated with pCR rate. Further biomarker analysis indicated that patients with any dual co-mutation in KMT2D/ERBB2/EPHA2 were associated with a lower pCR rate. Among the 30 patients, 24 cases (80%) experienced treatment related adverse reactions (AEs), with no grade 4 AEs nor above. Two patients experienced grade 3 AEs, including thrombocytopenia (1) and proteinuria (1). The most common AEs were pruritus (33.3%), fatigue (26.7%), and nausea (23.3%). Nine cases (30%) experienced immune-related AEs, including rash, thyroid dysfunction, increased blood glucose, and pneumonia, with no grade 3-4 AEs. Conclusions: Toripalimab combined with GC chemotherapy demonstrates good efficacy and tolerability and is an alternative option for NAT of MIBC. Clinical trial information: ChiCTR2100051298.