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

Inclusion Criteria:

• Histopathological confirmation of locally advanced unresectable or metastaticurothelial 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 willbe made for neoadjuvant or adjuvant therapy, if disease recurrence/progressionoccurred 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 amuscle-invasive or metastatic UC lesion or biopsy of metastatic UC prior totreatment initiation. If archival tissue is not available a newly obtained baselinebiopsy 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 7days prior to randomization.

Exclusion Criteria:

• Known hypersensitivity to disitamab vedotin, cisplatin, carboplatin, gemcitabine, orpembrolizumab or any of their components.

• History of severe/life threatening immune-related adverse event (irAE) with PD-(L)1inhibitors are excluded.

• Central nervous system (CNS) and/or leptomeningeal metastasis. Participants withtreated CNS metastases are permitted if all of the following are met.

• CNS metastases have been clinically stable for at least 4 weeks and baselinescans show no evidence of new or worsening CNS metastasis.

• Participant is on a stable dose of ≤ 10 mg/day of prednisone or equivalent forat least 2 weeks.

• History of or active autoimmune disease that has required systemic treatment in thepast 2 years.

• Prior treatment with an agent directed to another stimulatory or co-inhibitory Tcell 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