Antibody-Drug Conjugate Plus Immunotherapy Versus Immunotherapy Plus Chemotherapy for Extensive Transurethrally Unresectable Very-High-Risk Non-Muscle-Invasive Bladder Cancer

Patients with very-high-risk non-muscle-invasive bladder cancer (VHR NMIBC) and extensive tumors that cannot be completely resected transurethrally represent a challenging population with limited bladder-preserving treatment options. Although radical cystectomy is generally recommended for these patients, some are medically unfit for or unwilling to undergo radical surgery. Systemic combination therapies may offer an alternative approach to achieving disease control and preserving the bladder.

Previous studies have demonstrated promising antitumor activity with immunotherapy combined with chemotherapy in this population. Antibody-drug conjugates (ADCs), which enable targeted delivery of cytotoxic agents, have also shown encouraging efficacy in urothelial carcinoma. However, whether ADC plus immunotherapy provides improved antitumor activity compared with immunotherapy plus chemotherapy remains uncertain.

TRUCE-06 is a prospective, multicenter, randomized, open-label, phase II screening trial comparing ADC plus immunotherapy with immunotherapy plus chemotherapy in patients with HER2-expressing, extensive transurethrally unresectable VHR NMIBC. Eligible patients will be randomly assigned in a 1:1 ratio to the two treatment groups.

The primary objective is to compare the complete response rate of high-risk disease between the two treatment strategies. Complete response of high-risk disease is defined as the absence of high-grade Ta, T1, or CIS, without progression to muscle-invasive disease, lymph node or distant metastasis, or death. Treatment response will be evaluated through transurethral resection of bladder tumor (TURBT), imaging, and urine cytology.

In addition to the primary efficacy assessment, the study will evaluate overall complete response, duration of response, progression-free survival, overall survival, safety, patient-reported outcomes, and exploratory biomarkers. The findings may inform the development of future bladder-preserving treatment strategies for patients with extensive VHR NMIBC.

• Disitamab Vedotin and Toripalimab (Drug): Disitamab vedotin is a HER2-targeted antibody-drug conjugate. Toripalimab is a monoclonal antibody targeting programmed cell death protein 1 (PD-1). They are administered intravenously every 3 weeks.
• Toripalimab and Nab-Paclitaxel (Drug): Toripalimab is a monoclonal antibody targeting programmed cell death protein 1 (PD-1). Nab-paclitaxel is an albumin-bound formulation of paclitaxel. They are administered intravenously every 3 weeks.

Primary outcomes

• Complete Response Rate of High-Risk Disease [At the initial response assessment after 4 treatment cycles (approximately 12 weeks)]: The proportion of patients achieving complete response of high-risk disease, defined as the absence of high-grade Ta, T1, or carcinoma in situ (CIS), without progression to muscle-invasive bladder cancer, lymph node or distant metastasis, or death. Treatment response will be assessed using transurethral resection of bladder tumor (TURBT), imaging, and urine cytology.

Secondary outcomes

• Progression-Free Survival (PFS) [From randomization, assessed up to 2 years]: Time from randomization to disease progression or death from any cause.
• Duration of Response (DOR) [From first documented CR, assessed up to 2 years]: Time from the first documented complete response to disease recurrence, progression, or death, as defined in the protocol.
• Overall Complete Response Rate [At initial response assessment, approximately 12 weeks]: Proportion of patients achieving complete disappearance of all bladder tumors, including both high-grade and low-grade disease.
• Overall Survival (OS) [From randomization, assessed up to 2 years]: Time from randomization to death from any cause

Other outcomes

• Patient-reported health-related quality of life measured by EQ-5D-5L [Up to 24 months from randomization.]: Health-related quality of life (HRQoL) directly reported by patients without clinician interpretation, measured using the EQ-5D-5L questionnaire.
• Patient-reported health-related quality of life measured by EORTC QLQ-C30 [Up to 24 months from randomization.]: Health-related quality of life directly reported by patients without clinician interpretation, assessed using the EORTC QLQ-C30 questionnaire.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Patients aged 18 years or older.
2. Histologically confirmed urothelial carcinoma of the bladder, classified as very-high-risk non-muscle-invasive bladder cancer (VHR NMIBC) according to the European Association of Urology (EAU) risk classification.
3. Extensive bladder tumors that cannot be completely resected transurethrally, defined by at least one of the following criteria:

   * A solitary or confluent tumor with a maximum diameter greater than 5 cm;
   * Multifocal tumors involving more than 30% of the bladder mucosal surface.
   * Transurethral unresectability must be independently confirmed by at least two experienced urologists.
4. HER2 expression confirmed by immunohistochemistry (IHC 1+, 2+, or 3+).
5. No prior systemic anticancer therapy for cancer.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
7. Adequate hematologic, hepatic, and renal function to receive the study treatments.
8. Ability to understand the study requirements and willingness to provide written informed consent.

Exclusion Criteria:

1. Histologically confirmed muscle-invasive bladder cancer (≥T2), lymph node metastasis, or distant metastasis.
2. Predominantly non-urothelial histology, including pure squamous cell carcinoma, adenocarcinoma, or neuroendocrine carcinoma.
3. Previous treatment with antibody-drug conjugates, immune checkpoint inhibitors, or systemic chemotherapy for bladder cancer.
4. Active autoimmune disease requiring systemic immunosuppressive treatment, or other contraindications to immune checkpoint inhibitor therapy.
5. Active or uncontrolled infection, or other clinically significant uncontrolled medical conditions that may compromise patient safety.
6. Clinically significant peripheral neuropathy or other conditions that would preclude treatment with the study medications.
7. Known severe hypersensitivity to any study medication or its components.
8. Pregnancy or breastfeeding.
9. Concurrent participation in another interventional clinical trial involving investigational anticancer treatment.
10. Any other condition that, in the investigator's judgment, would make participation inappropriate or interfere with the assessment of study outcomes.