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.

Study Overview

• Status: Not yet recruiting
• Conditions: Muscle-Invasive Bladder Cancer (MIBC)
• Intervention / Treatment: Drug: Trastuzumab Rezetecan Combined with Adebelizumab

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 58
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Yangyang Xu, M.D.; Phone Number: +8617703600131; Email: 602037@hrbmu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Experimental Group; Trastuzumab Rezetecan Combined with Adebelizumab

Drug: Trastuzumab Rezetecan Combined with Adebelizumab; Trastuzumab Rezetecan 3.2 mg/kg, Q3W, in combination with Adebrelimab 1200 mg, Q3W, for a total of 3 cycles. Subjects will undergo preoperative imaging and surgical eligibility assessment at 3-4 weeks after the last dose of neoadjuvant therapy. Those who meet the surgical criteria will receive either transurethral resection or radical resection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological Complete Response	Assessed by pathological evaluation of resected bladder cancer specimens after neoadjuvant therapy, defined as the proportion of patients with no residual tumor (pT0N0).	Assessed post-surgery (radical cystectomy or TURBT) on resected tumor specimens after neoadjuvant therapy. Measured postoperatively, up to approximately 4 months after treatment start.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Complete Response Rate	Assessed by preoperative imaging (CT/MRI) and urine cytology after neoadjuvant therapy, defined as the proportion of patients with no residual tumor on imaging, negative urine cytology, and no evidence of nodal or distant metastasis.	Assessed by preoperative imaging and surgical evaluation at 3-4 weeks after the last neoadjuvant dose. Up to approximately 4 months after treatment start.
Pathological Downstaging Rate	Assessed by postoperative pathological staging, defined as the proportion of patients with ypT < T2 and ypN = N0 after neoadjuvant therapy.	Assessed simultaneously with pCR on postoperative pathological staging. Up to approximately 4 months after treatment start.
Event-Free Survival	Time from first dose to first occurrence of disease progression, recurrence, second primary tumor, or death from any cause.	Time from treatment start to first occurrence of disease progression, recurrence, second primary tumor, or death. Continuously assessed during follow-up, maximum follow-up of 36 months.
Overall Survival	Time from first dose to death from any cause.	Time from treatment start to death from any cause. Continuously assessed, maximum follow-up of 36 months.
QoL Score	Assessed using the EORTC QLQ-C30 V3.0 patient-reported questionnaire at screening, each treatment cycle, end of treatment, and follow-up visits.	Assessed by EORTC QLQ-C30 V3.0 at screening, Day 1 of each 21-day cycle (3 cycles), pre-surgery, post-surgery q30d ×3, then q3m (Year 1) and q6m (Years 2-3), up to 36 months.
Adverse event incidence	AEs and laboratory abnormalities graded by NCI CTCAE v6.0; SAEs recorded separately; surgical endpoints (feasibility, delay/cancellation rate, procedure change, operation duration) collected from postoperative clinical records and surgical logs.	AEs/SAEs/lab abnormalities collected from informed consent to 30 days post-last dose (safety follow-up). Surgical endpoints assessed postoperatively. Only treatment-related SAEs collected during survival follow-up, up to 36 months.
Exploratory Biomarkers	Blood and tumor tissue samples collected at baseline, during treatment, and at end of treatment to assess PD-L1, HER2, and other markers for correlation with efficacy (e.g., pCR, EFS).	Blood and tumor samples at baseline, C2D1, C3D1 (21-day cycles), at progression, and at EOT (after 3 cycles/pre-surgery). Max collection ~4 months; no routine survival follow-up sampling.

Collaborators and Investigators

• Sponsor: Harbin Medical University
• Collaborators: Jilin Provincial Tumor Hospital; First Hospital of China Medical University; Tianjin Medical University Second Hospital; The Fourth Affiliated Hospital of China Medical University

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2029

Study Registration Dates

• First Submitted: May 21, 2026
• First Submitted That Met QC Criteria: May 31, 2026
• First Posted (Actual): June 3, 2026

Study Record Updates

• Last Update Posted (Actual): June 3, 2026
• Last Update Submitted That Met QC Criteria: May 31, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Other Study ID Numbers: SHR-A1811-1316-BC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No