Arm A

Population and HER2 Status : 
Untreated LA/mUC; HER2 expressing (HER2 IHC ≥1+)

Open-Label Study Treatment (Randomized 1:1) 
Disitamab vedotin (DV)+ pembrolizumab (combination therapy) until progression

Arm B

Population and HER2 Status : 
Untreated LA/mUC; HER2 expressing (HER2 IHC ≥1+)

Open-Label Study Treatment (Randomized 1:1)
Cisplatin/Carboplatin + Gemcitabine x 4-6 cycles, maintenance avelumab as clinically appropriate and available

• 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.

Notes: Adequate baseline cardiac and laboratory parameters

• 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

Primary outcomes

• Progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review (BICR)
• Overall survival (OS)

Secondary outcomes

• Objective response rate (ORR) per RECIST v1.1 by BICR
• ORR per RECIST v1.1 by investigator assessment
• Duration of Response (DOR) per RECIST v1.1 by BICR
• DOR per RECIST v1.1 by investigator assessment
• Disease control Rate (DCR) per RECIST v1.1 by BICR
• DCR per RECIST v1.1 by investigator assessment
• PFS per RECIST v1.1 by investigator assessment
• Number of participants with adverse events (AEs)
• Number of participants with laboratory abnormalities
• Treatment discontinuation rate due to AEs
• Number of electrocardiogram (ECG) abnormalities
• Change from baseline of left ventricular ejection fraction (LVEF)
• Change from baseline to Week 16 in European Organization for Research and Treatment of Cancer core Quality of Life questionnaire (EORTC QLQ-C30) Global Health Status (GHS)/QoL Score
• Time to Deterioration in EORTC QLQ-C30 GHS/QoL Score
• Time to pain progression