Trastuzumab Rezetecan and Adebrelimab as Neoadjuvant Therapy for HER2-Positive Muscle-Invasive Bladder Cancer

Neoadjuvant Trastuzumab Rezetecan and Adebrelimab for HER2-positive Muscle-invasive Bladder Cancer: a Phase II, Prospective, Single-arm, Multicenter Trial

This study aims to evaluate the efficacy and safety of neoadjuvant trastuzumab rezetecan combined with adebrelimab for the treatment of HER2-positive muscle-invasive bladder cancer.

Bladder cancer is an aggressive malignancy with a poor prognosis, ranking 13th globally in cancer incidence and first among urological tumors in China, with an increasing trend observed in urban cancer surveillance. Traditional treatments, including radical cystectomy and platinum-based chemotherapy, have limitations such as chemotherapy resistance and reduced postoperative quality of life. Recently, immune checkpoint inhibitors and antibody-drug conjugates (ADCs) have become research hotspots. This prospective, single-arm, multicenter clinical study aims to preliminarily evaluate the efficacy and safety of Trastuzumab Rezetecan combined with Adebrelimab as neoadjuvant therapy for HER2-expressing muscle-invasive bladder cancer (MIBC). A total of 58 eligible patients will be enrolled. The study includes screening, neoadjuvant treatment, and follow-up periods. During screening, untreated HER2-expressing MIBC patients eligible for radical surgery will be enrolled, with the period from informed consent to first dose not exceeding 28 days. The neoadjuvant treatment consists of Trastuzumab Rezetecan 3.2 mg/kg Q3W and Adebrelimab 1200 mg Q3W for three cycles. Patients will undergo imaging and surgical assessment 3-4 weeks after the last neoadjuvant treatment; those meeting surgical criteria will receive either transurethral resection or radical cystectomy. In the follow-up period, patients who proceed to surgery after neoadjuvant treatment will undergo postoperative safety monitoring and long-term survival follow-up.

Inclusion Criteria:

1. Age ≥18 years.

2. ECOG performance status of 0 or 1.

3. Histopathologically diagnosed muscle-invasive bladder cancer (MIBC) (cT2-T4a, N0-1, M0).

4. Tumor tissue with HER2 expression (IHC 2+ or 3+) and suitable for radical cystectomy (RC) and transurethral resection of bladder tumor (TURBT).

5. No prior systemic chemotherapy.

6. At least one measurable lesion per RECIST v1.1 (spiral CT long diameter ≥10 mm or short diameter of enlarged lymph node ≥15 mm) before diagnostic surgery.

7. Adequate organ function (no transfusion or hematopoietic growth factor within 2 weeks before blood count screening):

   ANC ≥1.5×10⁹/L

   PLT ≥100×10⁹/L

   Hb ≥90 g/L

   TBIL ≤1.5×ULN (except subjects with Gilbert's syndrome)

   ALT and AST ≤2.5×ULN

   Cr ≤1.5×ULN

   LVEF ≥50%

   QTcF ≤450 ms

8. Females of childbearing potential must agree to abstain from heterosexual intercourse or use reliable, effective contraception from signing informed consent until at least 120 days after the last dose of study drug; serum HCG must be negative within 7 days before starting study treatment; and must be non-lactating.

9. A female is considered of childbearing potential if she has reached menarche, is not postmenopausal (≥12 consecutive months of amenorrhea without other cause), and has not undergone sterilization surgery (e.g., hysterectomy, bilateral tubal ligation, or bilateral oophorectomy).

10. Male patients with partners of childbearing potential must agree to abstain from heterosexual intercourse or use reliable, effective contraception from signing informed consent until at least 120 days after the last dose of study drug. During the same period, male subjects must also agree not to donate sperm. Male subjects with pregnant partners must use a condom and no additional contraception is required.

11. Subjects voluntarily join the study, sign written informed consent, and are expected to have good compliance with the study protocol.

Exclusion Criteria:

1. Patients with any active autoimmune disease or history of autoimmune disease (including but not limited to: autoimmune hepatitis, interstitial pneumonia, uveitis, etc.); patients with vitiligo; patients with childhood asthma that has completely resolved and requires no intervention in adulthood may be included; patients with asthma requiring bronchodilators for medical intervention are excluded.
2. Patients currently using immunosuppressants or systemic corticosteroids for immunosuppressive purposes (dose >10 mg/day prednisone or equivalent) and continuing use within 2 weeks before the first dose.
3. History of severe allergic reactions to other monoclonal antibodies.
4. Subjects with untreated central nervous system (CNS) metastases; subjects who have received prior systemic, radical treatment for brain or leptomeningeal metastases (radiotherapy or surgery) may be included if imaging confirms stability for at least 1 month, systemic corticosteroid therapy (dose >10 mg/day prednisone or equivalent) has been discontinued for more than 2 weeks, and they are asymptomatic.
5. Hypertension that cannot be well controlled with antihypertensive medication (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg).
6. Poorly controlled cardiac clinical symptoms or diseases, including: 1) NYHA class ≥2 heart failure; 2) unstable angina; 3) myocardial infarction within 1 year; 4) clinically significant supraventricular or ventricular arrhythmias requiring treatment or intervention; 5) QTc >450 ms (male) or QTc >470 ms (female); 6) Left ventricular ejection fraction (LVEF) ≤50% (i.e., EF >50% is required for inclusion).
7. Abnormal coagulation function (INR >2.0, PT >16 s), bleeding tendency, or currently receiving thrombolytic or anticoagulant therapy; prophylactic use of low-dose aspirin or low molecular weight heparin is permitted.
8. Bleeding events of grade ≥2 per CTCAE v6.0 within 4 weeks before the first dose.
9. Imaging shows tumor invasion into major blood vessels, or the investigator judges that the tumor has a very high possibility of invading major blood vessels during treatment, leading to fatal massive hemorrhage.
10. Arterial/venous thrombotic events within 6 months before the first dose, such as cerebrovascular accident (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism.
11. Patients who received prior chemotherapy (including platinum-based chemotherapy) or surgery less than 4 weeks before study drug administration; palliative radiotherapy less than 2 weeks before study drug administration; molecular targeted therapy (including other oral targeted drugs in clinical trials) within less than 5 half-lives before the first study drug dose, or prior treatment-related adverse events (excluding alopecia) not recovered to ≤CTCAE grade 1.
12. Patients with radiation enteritis caused by pelvic radiotherapy within 12 months before study drug administration.
13. Active infection, unexplained fever ≥38.5°C within 7 days before dosing, or baseline white blood cell count >15×10⁹/L.
14. Known history or evidence of interstitial lung disease or non-infectious pneumonitis that has required corticosteroid therapy; or patients who may interfere with the detection or management of suspected drug-related pulmonary toxicity.
15. History of immunodeficiency, including positive HIV serology, or other acquired or congenital immunodeficiency diseases, or known active tuberculosis.
16. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (HBV reference: HBsAg positive and HBV DNA ≥500 IU/ml; HCV reference: HCV antibody positive and HCV viral load > upper limit of normal).
17. Patients with another malignancy within the past 5 years or concurrently (excluding cured basal cell carcinoma of the skin and carcinoma in situ of the cervix; for patients with recurrent ovarian cancer with prior history of breast cancer, those with no recurrence for >3 years after radical breast cancer surgery are excluded).
18. Prior treatment with anti-PD-1, anti-PD-L1, anti-CTLA-4 antibodies (or any other antibodies targeting T-cell co-stimulatory or checkpoint pathways).
19. Receipt of live vaccine within 4 weeks before the first dose or possible receipt during the study period.
20. Pregnant or breastfeeding female patients.
21. Patients judged by the investigator to have other conditions that may affect the conduct of the clinical study, inability to comply with the protocol, or lack of cooperation, or patients at risk of study participation.