Neoadjuvant zanidatamab and tislelizumab with chemotherapy to try to preserve the bladder in HER2-positive muscle-invasive bladder cancer

Selective Bladder Preservation After Neoadjuvant Zanidatamab Combined With Tislelizumab and Chemotherapy in Patients With HER2-Positive Muscle-Invasive Bladder Cancer: A Multicenter Study

This study tests whether giving zanidatamab and tislelizumab with chemotherapy before surgery can allow people with HER2-positive muscle-invasive bladder cancer to keep their bladder.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 25 (estimated)
• Ages: 18 Years to 85 Years
• Sex: All
• Sponsor: Fujian Medical University Union Hospital (other)
• Drugs / interventions: zanidatamab, tislelizumab, chemotherapy
• Locations: 12 sites (Fuzhou, Fujian and 11 other locations)
• Trial ID: NCT07296705 on ClinicalTrials.gov

What this trial studies

This is a multicenter, open-label, single-arm phase II study enrolling patients with HER2-positive (IHC 2+ or 3+) muscle-invasive bladder cancer staged cT2-4aN0-1M0. Participants receive neoadjuvant zanidatamab plus tislelizumab together with platinum-based chemotherapy, followed by clinical reassessment for response. Patients who achieve a clinical complete response continue maintenance zanidatamab and tislelizumab, while those without complete response may receive radiotherapy or partial cystectomy plus maintenance or proceed to radical cystectomy with adjuvant tislelizumab. The trial excludes patients with prior anti-HER2 or PD-(L)1 therapy and requires submission of TURBT tumor tissue for HER2 testing.

Who should consider this trial

Good fit: Adults 18–85 with histologically confirmed urothelial muscle-invasive bladder cancer (cT2-4aN0-1M0), HER2-positive by IHC (2+ or 3+), ECOG 0–2, no prior anti-HER2 or PD-(L)1 therapy, and able to provide TURBT tissue are ideal candidates.

Not a fit: Patients who are HER2-negative, have metastatic (M1) disease, have received prior HER2- or PD-(L)1-directed therapy, or have poor performance status or inadequate organ function are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, this approach could allow more patients with HER2-positive MIBC to avoid radical cystectomy and preserve their bladder while maintaining cancer control.

How similar studies have performed: Neoadjuvant immunotherapy combined with chemotherapy has shown promising bladder-preserving responses in MIBC, and HER2-targeted agents like zanidatamab are emerging, but this specific combination and bladder-preservation strategy is relatively novel.

Eligibility criteria

Inclusion Criteria:

1. Willing to participate, able to provide written informed consent, and able to understand and comply with study requirements and the assessment schedule.
2. Age 18 to 85 years on the date of informed consent.
3. Residual disease after TURBT; histologically confirmed urothelial carcinoma of the bladder staged cT2-T4aN0-1M0 per AJCC 8th edition by histology and imaging. For mixed histology, urothelial carcinoma must be predominant (≥50%).
4. Availability of TURBT tumor tissue and corresponding pathology report; either fresh surgical tissue or unstained slides may be submitted.
5. HER2-positive: IHC 2+ or 3+.
6. No prior anti-HER2-directed therapy (including but not limited to HER2 antibodies, HER2-targeting ADCs, or HER2-targeted TKIs) and no prior PD-(L)1 therapy.
7. ECOG performance status 0-2.
8. Adequate organ function based on screening labs obtained ≤14 days before enrollment:

   a. For the following counts, no growth-factor support within 14 days prior to sample collection: i. Absolute neutrophil count ≥ 1.5 × 10\^9/L ii. Platelets ≥ 100 × 10\^9/L iii. Hemoglobin ≥ 90 g/L b. INR or aPTT ≤ 1.5 × upper limit of normal (ULN) c. Total bilirubin ≤ 1.5 × ULN (≤ 3 × ULN for Gilbert syndrome or isolated indirect hyperbilirubinemia) d. AST, ALT, and alkaline phosphatase ≤ 2.5 × ULN
9. Women of childbearing potential must have a negative urine or serum pregnancy test within ≤7 days before enrollment and agree to use highly effective contraception during the study and for ≥120 days after the last dose of zanidatamab, tislelizumab, or chemotherapy (whichever occurs later).
10. Non-sterilized men must agree to use highly effective contraception during the study and for ≥120 days after the last dose of zanidatamab, tislelizumab, or chemotherapy (whichever occurs later).

Exclusion Criteria:

1. Pregnant or breastfeeding women.
2. Uncontrolled infection requiring systemic therapy.
3. Diagnosis of another malignancy within the past 5 years.
4. Major surgery or significant trauma within 28 days prior to enrollment (placement of a vascular access device and TURBT are not considered major surgery).
5. Prior radiotherapy to the bladder for bladder cancer.
6. Active autoimmune disease requiring systemic treatment that, in the investigator's judgment, would affect study therapy.
7. Any of the following cardiovascular criteria:

   1. Cardiac chest pain within ≤28 days before first study dose, defined as moderate pain that limits activities of daily living.
   2. Symptomatic pulmonary embolism within ≤28 days before first study dose.
   3. Any acute myocardial infarction within ≤6 months before first study dose.
   4. Any history of heart failure of New York Heart Association (NYHA) Class III or IV within ≤6 months before first study dose.
   5. Any ventricular arrhythmia of severity ≥ Grade 2 within ≤6 months before first study dose.
   6. Any cerebrovascular accident within ≤6 months before first study dose.
   7. Corrected QT interval (QTc by Fridericia): ≥470 msec for women or ≥450 msec for men.

   i. Note: If the initial ECG shows QTc \>450 msec (men) or \>470 msec (women), a follow-up ECG should be performed to confirm.

   h) Left ventricular ejection fraction (LVEF) ≤50% by multigated acquisition (MUGA) scan or echocardiography (ECHO). The same modality used at baseline must be used for follow-up assessments.
8. History of acute myocardial infarction or ischemic stroke within 6 months.
9. Human immunodeficiency virus (HIV) infection (i.e., positive antibodies to HIV-1/2), active syphilis infection, or active tuberculosis infection.
10. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
11. History of interstitial lung disease, non-infectious pneumonitis, or uncontrolled pulmonary disease, including pulmonary fibrosis or acute lung disease.
12. Known hypersensitivity to any study drug.
13. Concurrent participation in another clinical study, unless observational (non-interventional) or in the follow-up phase of an interventional study.
14. Any other condition deemed by the investigator to render the patient ineligible.

Where this trial is running

Fuzhou, Fujian and 11 other locations

• Fujian Medical University Union Hospital — Fuzhou, Fujian, China (RECRUITING)
• Fujian Provincial Hospital Affiliated to Fuzhou University — Fuzhou, Fujian, China (RECRUITING)
• Affiliated Hospital of Putian University — Putian, Fujian, China (RECRUITING)
• Quanzhou First Hospital Affiliated to Fujian Medical University — Quanzhou, Fujian, China (RECRUITING)
• Sanming First Hospital — Sanming, Fujian, China (RECRUITING)
• The First Affi liated Hospital of Xiamen University — Xiamen, Fujian, China (RECRUITING)
• Zhangzhou Affiliated Hospital to Fujian Medical University — Zhangzhou, Fujian, China (RECRUITING)
• Jiangxi Cancer Hospital — Nanchang, Jiangxi, China (RECRUITING)
• Shandong Cancer Hospital — Jinan, Shandong, China (RECRUITING)
• Fudan University Shanghai Cancer Center — Shanghai, Shanghai Municipality, China (RECRUITING)
• Zhejiang Cancer Hospital — Hangzhou, Zhejiang, China (RECRUITING)
• The First Affiliated Hospital of Wenzhou Medical University — Wenzhou, Zhejiang, China (RECRUITING)

Study contacts

• Study coordinator: Shaoxing Zhu, MD

Conditions: Muscle Invasive Bladder Cancer