Response-Guided Bladder Preservation With Trastuzumab Rezetecan, Adebrelimab, and Concurrent Bladder Radiotherapy in HER2-Expressing Muscle-Invasive Bladder Cancer

Inclusion Criteria:

Inclusion Criteria:

1. Age ≥18 years, male or female; able to provide written informed consent; willing and able to comply with all protocol-required examinations and follow-up.
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
3. Histologically confirmed muscle-invasive urothelial carcinoma of the bladder. Minor squamous, glandular, or other mixed differentiation is permitted. Patients with pure non-urothelial carcinoma may be enrolled at the investigator's discretion.
4. Clinical stage cT2-T4a, N0, M0, based on pelvic/abdominal imaging with or without chest imaging.
5. HER2 expression of IHC 1+, 2+, or 3+ in tumor tissue, as determined by a central or designated laboratory.
6. Suitable for maximal transurethral resection of the bladder tumor (TURBT) and considered by a multidisciplinary team to be eligible for radical cystectomy if required.
7. Adequate organ function: absolute neutrophil count ≥1.5 × 10\^9/L; platelet count ≥100 × 10\^9/L; hemoglobin ≥90 g/L; ALT and AST ≤2.5 × upper limit of normal (ULN); total bilirubin ≤1.5 × ULN; eGFR ≥50 mL/min/1.73 m² or CrCl ≥50 mL/min; INR ≤1.5 × ULN if not receiving anticoagulant therapy; left ventricular ejection fraction ≥50% or the institutional lower limit of normal; and no uncontrolled clinically significant cardiovascular disease.
8. No active interstitial lung disease or pneumonitis on baseline pulmonary assessment, including chest CT.
9. Participants of childbearing potential must agree to use effective contraception during the study and for the protocol-specified period after the last dose. A negative pregnancy test is required when applicable.

Exclusion Criteria:

• 1. Distant metastasis (M1), clearly uncontrollable extra-regional metastatic disease, or an upper urinary tract tumor requiring priority treatment.

  2. Previous systemic anticancer treatment for the current bladder cancer, including chemotherapy, immunotherapy, anti-HER2 targeted therapy, or antibody-drug conjugates, or previous pelvic radiotherapy that could affect the delivery or safety of study radiotherapy.

  3. Unable to complete protocol-required local treatment, including inability to undergo maximal TURBT or the presence of a contraindication to radiotherapy, such as previous high-dose irradiation to the same region or active inflammatory bowel disease.

  4. Active autoimmune disease or a history requiring long-term systemic immunosuppressive treatment, including prednisone ≥10 mg/day or equivalent within 14 days before treatment. Physiologic replacement doses are permitted.

  5. Active pneumonitis or interstitial lung disease, or a history of severe drug-related pneumonitis.

  6. Uncontrolled infection, including active tuberculosis, or HBV, HCV, or HIV infection considered unsuitable for enrollment by the investigator. Patients with markedly elevated HBV DNA who are not receiving appropriate antiviral treatment are excluded.

  7. Another malignancy within the previous 5 years, except adequately treated low-risk malignancies such as basal cell carcinoma of the skin or carcinoma in situ of the cervix.

  8. Known active central nervous system metastases. Previously treated brain metastases may be permitted if radiographically stable for ≥4 weeks and systemic corticosteroids have been discontinued for >2 weeks.

  9. Uncontrolled hypertension despite antihypertensive treatment, defined as systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg.

  10. Abnormal coagulation, including INR >2.0 or prothrombin time >16 seconds, a bleeding tendency, or current thrombolytic or anticoagulant therapy. Prophylactic low-dose aspirin or low-molecular-weight heparin is permitted.

  11. Any bleeding event of CTCAE version 5.0 grade 2 or higher within 4 weeks before the first dose.

  12. Imaging evidence of tumor invasion of major blood vessels or, in the investigator's judgment, a very high risk of invasion of major blood vessels resulting in fatal hemorrhage during treatment.

  13. An arterial or venous thrombotic event within 6 months before the first dose, including cerebrovascular accident, transient ischemic attack, cerebral hemorrhage, cerebral infarction, deep-vein thrombosis, or pulmonary embolism.

  14. Radiation enteritis caused by pelvic radiotherapy received within 12 months before study treatment.

  15. Active infection, unexplained fever ≥38.5°C within 7 days before treatment, or baseline white blood cell count >15 × 10\^9/L.

  16. Known interstitial lung disease, evidence or history of noninfectious pneumonitis requiring corticosteroid treatment, or any condition that may interfere with the detection or management of suspected drug-related pulmonary toxicity.

  17. Clinically significant uncontrolled comorbidity, including New York Heart Association class III-IV heart failure, recent myocardial infarction or unstable angina, severe arrhythmia, or poorly controlled hypertension.

  18. History of severe hypersensitivity to adebrelimab, trastuzumab rezetecan, or any component or excipient of either study drug.

  19. Pregnant or breastfeeding women. 20. Any other condition that, in the investigator's judgment, may affect participant safety, efficacy assessment, or protocol compliance, such as severe psychiatric illness or inability to attend regular follow-up.