Selective bladder preservation after neoadjuvant zanidatamab combined with tislelizumab and chemotherapy in patients with HER2-positive muscle-invasive bladder cancer (HARBOR): A multicenter study.

TPS887 Background: Muscle-invasive bladder cancer (MIBC) is a highly aggressive malignancy commonly treated with radical cystectomy, which carries significant risks of complications and quality-of-life decline. Bladder-sparing strategies represent an important treatment approach, with neoadjuvant therapy playing a pivotal role in tumor downstaging, improving clinical complete response (cCR), and enabling selective bladder preservation. However, patients with HER2-positive MIBC generally have inferior outcomes, making the development of targeted approaches a pressing priority. Preclinical and early clinical studies have demonstrated that HER2-directed antibodies exert antitumor activity in urothelial carcinoma. Zanidatamab, a novel bispecific HER2 antibody, provides dual epitope binding, enhanced effector function including unique antibody-dependent cellular cytotoxicity (ADCC), and has shown robust activity in HER2-positive solid tumors. Combined with the PD-1 inhibitor tislelizumab and platinum-based chemotherapy, it may enable superior bladder-sparing efficacy in patients with HER2-positive MIBC. Methods: The ongoing HARBOR trial is a multicenter, open-label, single-arm, phase II study designed to evaluate the efficacy and safety of a selective bladder-preservation strategy following neoadjuvant zanidatamab plus tislelizumab and gemcitabine-cisplatin (GC) in patients with HER2-positive (immunohistochemistry 2+ or 3+) MIBC (cT2-4aN0-1M0). Twenty-five patients will receive four cycles of zanidatamab (1800 mg for weight < 70 kg or 2400 mg for weight ≥70 kg, IV, d1) + tislelizumab (200 mg, IV, d1) + gemcitabine (1,000 mg/m², IV, d1, d8) + cisplatin (70 mg/m², IV, d2). Post-treatment clinical reassessment determines subsequent management: patients achieving cCR undergo bladder-sparing treatment with zanidatamab plus tislelizumab; those without cCR may receive radiotherapy or partial cystectomy followed by zanidatamab plus tislelizumab, or proceed to radical cystectomy with adjuvant tislelizumab. The primary endpoint is cCR rate after neoadjuvant therapy. Key secondary endpoints include 1- and 2-year bladder-intact disease-free survival (BI-DFS), locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS), overall survival (OS), safety, and patient-reported quality of life (QoL). Registration number: ChiCTR2500110562.