Editor's Note: For patients with muscle-invasive bladder cancer (MIBC), when the tumor is large, deeply invasive, or has local lymph node metastasis, the radicality of whole bladder surgery can be affected. Neoadjuvant therapy can enhance the rate of radical resection by downstaging the tumor, and it has become a current research hotspot. At this year's ASCO Annual Meeting in Chicago, USA, a study led by Professor Hongqian Guo's team from Nanjing Drum Tower Hospital was selected, exploring a new neoadjuvant treatment strategy with toripalimab combined with chemotherapy for MIBC patients. "Oncology Frontier" invited Professor Shun Zhang from Nanjing Drum Tower Hospital to share the relevant content on-site.

Abstract No: 4596

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

Background: Recent clinical trials such as BLASST-1 and SAKK06/17 have shown that an immunotherapy combined with chemotherapy strategy may have synergistic effects as a neoadjuvant treatment for muscle-invasive bladder cancer (MIBC), with good patient tolerance. Toripalimab, a PD-1 inhibitor, has shown favorable outcomes in advanced urothelial carcinoma. This clinical study aims to evaluate the safety and efficacy of toripalimab combined with gemcitabine-cisplatin (GC) as neoadjuvant treatment for MIBC.

Methods: This prospective, single-arm, open-label, single-center phase II clinical trial (ChiCTR2100051298) from China enrolled 30 patients with clinical stage T2-3b N0 M0 MIBC who were scheduled to undergo radical cystectomy (RC). The treatment regimen was: Day 1 toripalimab 240 mg + gemcitabine 1000 mg/m2 + cisplatin 70 mg/m2, Day 8 gemcitabine 1000 mg/m2, every 21 days for four cycles. RC was performed one month after the last treatment. The primary endpoint was pathological complete response (pCR), with secondary endpoints including safety, overall survival (OS), and progression-free survival (PFS). Tumor regression after neoadjuvant therapy was assessed by comparing postoperative pathological results with preoperative radiological findings. The relationship between genomic changes/tumor mutation burden (TMB) and pCR rate was analyzed using Fisher’s exact test. This study was approved by the ethics committee of Nanjing Drum Tower Hospital.

Results: From January 2020 to December 2021, 30 patients were enrolled and received at least one treatment cycle, with 3 withdrawing before RC. Among 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 were 85.2% and 77.6%, respectively; the 1-year and 3-year OS rates were 96.2% and 84.6%, respectively. In patients with PD-L1 expression ≥5% (n=16), the pCR and PaR rates were 43.8% (7/16) and 68.8% (11/16), respectively. In patients with PD-L1 expression <5% (n=11), the pCR and PaR rates were 36.4% (4/11) and 63.6% (7/11), respectively. PD-L1 expression status and TMB were not significantly associated with the pCR rate. Further biomarker analysis indicated that the presence of KMT2D/ERBB2/EPHA2 co-mutations was associated with a lower pCR rate.

Among the 30 patients, 24 (80%) experienced treatment-related adverse events (AEs), with no grade 4 or higher AEs. Two patients experienced grade 3 AEs, including thrombocytopenia (1 case) and proteinuria (1 case). The most common AEs were nausea (63.3%), pruritus (33.3%), and fatigue (26.7%).

Conclusion: Toripalimab combined with GC chemotherapy demonstrated good efficacy and tolerability as a neoadjuvant treatment option for MIBC.

Expert Commentary: Today at the ASCO conference, I shared a new neoadjuvant treatment study for bladder cancer. This study included patients with T2-T3b bladder cancer treated with toripalimab combined with chemotherapy, followed by surgery after four cycles. As we know, neoadjuvant treatment for bladder cancer has been a research hotspot in recent years, with combined strategies involving PD-1 inhibitors and chemotherapy or ADCs actively being investigated.

This study, conducted over more than three years, showed that among patients who received RC, the PaR rate was 63% and the pCR rate was 40.7%. Notably, in patients who had previously undergone transurethral bladder tumor resection (9 cases), the pCR rate was as high as 66.7%. The study also found no significant correlation between PD-L1 or HER2 expression status and TMB or pCR rate. This study has the longest follow-up period among similar domestic studies; it indicates that toripalimab combined with chemotherapy can provide better survival benefits for high-risk MIBC patients.