Probiotics Combined With Targeted Therapy Plus Immunotherapy in Bladder-Preserving Setting for Patients With MIBC

• Probiotic (Drug), also known as Clostridium butyricum CBM 588 Probiotic Strain: 80 mg orally twice daily during induction and intensive treatment periods; 80 mg orally twice daily, 3 weeks on / 3 weeks off dosing schedule during maintenance treatment period
• Disitamab Vedotin (Drug), also known as RC48-ADC: 2.0 mg/kg IV every 2 weeks during the induction treatment period and intensive treatment period
• Toripalimab (Drug), also known as JS001: 3.0 mg/kg IV every 2 weeks during the induction and intensive treatment periods; followed by 240 mg IV every 3 weeks during the maintenance treatment period.

Primary outcomes

• bladder-intact event free survival (BI-EFS), evaluated by independent review committee [Up to approximately 3 years]: Bladder intact event-free survival (BIEFS) refers to the time from the date of randomization to the first occurrence of any bladder preservation failure event through tumor control, whichever occurs first. Bladder preservation failure events include: 1. Rapid progression: progressive disease (PD) assessed by imaging at the mid-induction evaluation; 2. Tumor recurrence: ≥T2 stage, high-grade urothelial carcinoma (per the WHO 2016 Classification of Tumours of the Urinary System), or non-urothelial carcinoma histology; 3. Tumor metastasis: including lymph node metastasis and distant organ metastasis; 4. Death from any cause; 5. Receipt of radical cystectomy for any other reason.

Secondary outcomes

• clinical complete response (cCR) [Up to approximately 3 years]: Clinical complete response rate (cCR) refers to the proportion of participants who achieve all of the following criteria after completion of induction treatment: first, negative urine cytology; second, no new lymph node metastasis or distant metastatic lesions identified on imaging examinations; third, no malignant tumor identified on cystoscopy biopsy, or only low-grade Ta/T1 urothelial carcinoma present.
• Metastasis-free survival (MFS) [Up to approximately 3 years]: Metastasis-free survival (MFS) refers to the time from the date of randomization to the first occurrence of lymph node metastasis or distant organ metastasis, whichever occurs first.
• Overall survival (OS) [Up to approximately 3 years]: Overall survival (OS) refers to the time from the date of randomization to the date of death of the subject.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Patients have histologically confirmed, radiologically staged cT2-3N0M0 urothelial carcinoma of the bladder, in which urothelial carcinoma is the predominant component (>50%).
* Serum butyrate level <46 μg/L as determined by quantitative mass spectrometry.
* HER2 expression is assessed by immunohistochemistry (IHC) on pretreatment tumor specimens, with confirmed IHC ≥1+.
* Patients are deemed ineligible for radical cystectomy based on laboratory evaluation and patient preference.
* Patients considered ineligible for cisplatin therapy and meeting at least one of the following criteria: ECOG performance status >1 or Karnofsky performance status of 60-70%; Creatinine clearance <60 mL/min; Hearing loss ≥ Grade 2 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0; Peripheral neuropathy ≥ Grade 2 (NCI-CTCAE v5.0); New York Heart Association (NYHA) Class III or higher heart failure.
* ECOG performance status of 0-2.
* Adequate cardiac, bone marrow, hepatic, renal, and coagulation functions.

Exclusion Criteria:

* Prior ADCs or PD-1/PD-L1 inhibitor therapy.
* Known hypersensitivity to microbiota-related preparations (microecological products), RC48-ADC or Toripalimab or any of its components.
* Receipt of other approved systemic anticancer therapy or systemic immunomodulatory agents (including but not limited to interferon, interleukin-2, and tumour necrosis factor) within 28 days prior to enrolment.
* Prior radiotherapy for bladder cancer.
* Prior antitumour drug therapy, except for the following: a. For patients who previously received systemic chemotherapy, a treatment-free interval of at least 3 months between the last dose and the start of induction therapy is required; b. Local intravesical chemotherapy or immunotherapy (including BCG) must be completed at least 1 week before initiation of study neoadjuvant treatment.
* Surgery or significant trauma within 28 days prior to enrolment (implantation of vascular access devices and TURBT are not considered).
* Severe chronic or active infection requiring systemic antibacterial, antifungal, or antiviral therapy within 14 days prior to enrolment.
* Receipt of live vaccines within 28 days prior to enrolment.
* Active autoimmune disease requiring systemic treatment and considered by the investigator to potentially interfere with the study treatment.
* Requirement for long-term high-dose corticosteroids or other immunosuppressive agents.
* Clinically significant abnormalities that may affect treatment, including electrolyte disturbances, hypoalbuminaemia, interstitial lung disease, non-infectious pneumonitis, or other uncontrolled systemic diseases. These include uncontrolled diabetes, hypertension, or cardiovascular disease, such as active cardiac conditions within 6 months prior to enrolment.
* Untreated chronic hepatitis B with HBV DNA ≥500 IU/mL (2,500 copies/mL) or known HBV carriers with active disease.
* Active hepatitis C infection.
* History of immunodeficiency, including positive human immunodeficiency virus (HIV) test, other acquired or congenital immunodeficiency disorders, or a history of allogeneic stem cell transplantation or solid organ transplantation.
* Toxicities from prior therapies that have not recovered to baseline or stabilised.
* Presence of other concomitant malignancies.