Overview

The purpose of this Phase II, open-label, multicenter, randomized controlled study is to evaluate the efficacy and safety of Enfortumab Vedotin in combination with Toripalimab compared to Gemcitabine plus Cisplatin. This regimen is evaluated as a neoadjuvant treatment for patients with locally advanced or high-risk muscle-invasive bladder cancer. Participants will be randomly assigned in a 1:1 ratio to one of two cohorts. Cohort A will receive Enfortumab Vedotin and Toripalimab for 3 treatment cycles. Cohort B will receive Gemcitabine and Cisplatin for 3 treatment cycles. Following the neoadjuvant treatment phase, patients will undergo radical cystectomy and pelvic lymph node dissection. The primary endpoint of the study is the 1-year Event-Free Survival (EFS) rate. Secondary endpoints include pathological downstaging rate (pDR), pathological complete response (pCR), Disease-Free Survival (DFS), Overall Survival (OS), and the assessment of adverse events. Additionally, the study will evaluate the relationship between treatment efficacy and the expression of PD-L1 and Nectin-4 in tumor tissues.

Eligibility

Inclusion Criteria:

• Voluntarily agree to participate in the study and sign the informed consent form (ICF).
• Age ≥ 18 and ≤ 80 years at the time of signing the ICF.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Histologically confirmed muscle-invasive urothelial carcinoma of the bladder, with variant histology components comprising \< 50%.
• Radiographically confirmed non-metastatic urothelial carcinoma (M0). Clinical stage must be locally advanced or possess high-risk features, including at least one of the following: clinical stage cT3-T4aNxM0, or definitive high-risk cT2 (e.g., accompanied by tumor-related hydronephrosis, lymphovascular invasion).
• Participants must be evaluated as fit for and scheduled to undergo radical surgery, and clinically fit to tolerate cisplatin-based chemotherapy.
• Able to provide tumor tissue samples (at least 5 unstained slides, or paraffin scrolls/blocks).
• Expected life expectancy of at least 12 weeks.
• Adequate organ function, defined by the following laboratory values (obtained without blood transfusion within 14 days or growth factor support within 7 days prior to testing): Absolute neutrophil count (ANC) ≥ 1.5 × 10\^9/L; Platelet count (PLT) ≥ 100 × 10\^9/L; Hemoglobin (Hb) ≥ 90 g/L; Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × Upper Limit of Normal (ULN); Total bilirubin (TBIL) ≤ 1.5 × ULN; International Normalized Ratio (INR) ≤ 1.5 × ULN; Creatinine clearance ≥ 60 mL/min (calculated using the Cockcroft-Gault formula); Left ventricular ejection fraction (LVEF) ≥ 50%; QTcF interval ≤ 480 ms.
• Female participants of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose of study treatment and must be willing to use highly effective contraception during the study and for 180 days after the last dose.
• Male participants with female partners of childbearing potential must be surgically sterile or willing to use highly effective contraception during the study and for 180 days after the last dose.
• Able to understand and comply with study visits, treatment plans, laboratory tests, and other study procedures.

Exclusion Criteria:

• Prior systemic anti-tumor therapy for urothelial carcinoma, including radiotherapy, chemotherapy, targeted therapy, or biological therapy (except for intravesical instillation therapy).
• Prior treatment with PD-1/PD-L1 inhibitors or antibody-drug conjugates (ADCs).
• Active malignancies other than urothelial carcinoma within 3 years prior to the first dose, except for curatively treated malignancies (e.g., basal or squamous cell skin cancer, localized low-risk prostate cancer, papillary thyroid cancer, carcinoma in situ of the cervix, ductal carcinoma in situ of the breast).
• Active autoimmune disease requiring systemic treatment (e.g., use of disease-modifying agents, corticosteroids, or immunosuppressants) within 2 years prior to the first dose; or received high-dose steroids (\>10 mg/day prednisone equivalent) or other immunosuppressive medications within 14 days prior to the first dose. (Physiological replacement therapies are permitted).
• Severe thromboembolic events or severe cardiovascular/cerebrovascular diseases within 1 year prior to the first dose, including but not limited to myocardial infarction, unstable angina, pulmonary embolism, cerebral hemorrhage, cerebral infarction, and deep vein thrombosis.
• Major surgical procedure within 28 days prior to the first dose; or cystoscopy/ureteroscopy biopsy or intravesical therapy within 7 days prior to the first dose.
• Peripheral neuropathy ≥ Grade 2.
• Severe dry eye syndrome, active keratitis, corneal ulcers, or conditions assessed by the investigator as increasing the risk of corneal disease and unsuitable for participation.
• Active infections, including: Positive HBsAg with HBV-DNA copy number ≥ 500 IU/mL; Positive HCV antibody with positive HCV-RNA; Positive HIV antibody; Active tuberculosis infection; Other active infections requiring systemic therapy within 7 days prior to the first dose.
• Other severe or uncontrolled diseases, including but not limited to: Severe respiratory diseases (e.g., moderate-to-severe interstitial or obstructive pulmonary disease, severe asthma); New York Heart Association (NYHA) Class III or IV heart failure; HbA1c ≥ 8% (except for participants whose fasting blood glucose is stably controlled at ≤ 10 mmol/L with medication); Poorly controlled hypertension (systolic BP ≥ 160 mmHg and/or diastolic BP ≥ 100 mmHg); Large pleural effusion or ascites requiring symptomatic treatment within 14 days prior to the first dose.
• Receipt of live vaccines within 28 days prior to the first dose or plans to receive live vaccines during the study.
• Prior allogeneic hematopoietic stem cell transplantation or solid organ transplantation.
• Use of strong CYP3A4 inhibitors or inducers within 14 days prior to the first dose.
• Known severe hypersensitivity or intolerance to the study drugs or any of their excipients.
• Substance abuse or psychiatric disorders that may interfere with study compliance.
• Any other condition that, in the opinion of the investigator, makes the participant unsuitable for the study.