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

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.