Disitamab Vedotin With Pembrolizumab vs Chemotherapy in Previously Untreated Urothelial Cancer Expressing HER2

Inclusion Criteria: Histopathological confirmation of locally advanced unresectable or metastatic urothelial carcinoma (LA/mUC), including UC originating from the renal pelvis, ureters, bladder, or urethra. Measurable disease by investigator assessment per RECIST v1.1. Participant must not have received prior systemic therapy for LA/mUC. Exception will be made for neoadjuvant or adjuvant therapy, if disease recurrence/progression occurred more than 12 months after the last dose of therapy. Eligible to receive cisplatin- or carboplatin-containing chemotherapy. Able to provide archived formalin-fixed paraffin-embedded tumor tissue blocks from a muscle-invasive or metastatic UC lesion or biopsy of metastatic UC prior to treatment initiation. If archival tissue is not available a newly obtained baseline biopsy of an accessible tumor lesion is required within 28 days of cycle 1 day 1. HER2 expression of 1+ or greater on immunohistochemistry (IHC). Eastern Cooperative Oncology Group (ECOG) performance score of 0, 1, or 2 within 7 days prior to randomization. Exclusion Criteria: Known hypersensitivity to disitamab vedotin, cisplatin, carboplatin, gemcitabine, or pembrolizumab or any of their components. History of severe/life threatening immune-related adverse event (irAE) with PD-(L)1 inhibitors are excluded. Central nervous system (CNS) and/or leptomeningeal metastasis. Participants with treated CNS metastases are permitted if all of the following are met. CNS metastases have been clinically stable for at least 4 weeks and baseline scans show no evidence of new or worsening CNS metastasis. Participant is on a stable dose of ≤ 10 mg/day of prednisone or equivalent for at least 2 weeks. History of or active autoimmune disease that has required systemic treatment in the past 2 years. Prior treatment with an agent directed to another stimulatory or co-inhibitory T cell receptor (including but not limited to CD137 agonists, CAR-T cell therapy, CTLA-4 inhibitors, or OX-40 agonists). Prior solid organ or bone marrow transplantation. Pleural effusion or ascites with symptoms or requiring symptomatic treatment. Estimated life expectancy <12 week Prior treatment with an MMAE agent or anti-HER2 therapy