An Open-label, Randomized, Controlled Phase 3 Study of Disitamab Vedotin in Combination with Pembrolizumab Versus Chemotherapy in Subjects with Previously Untreated Locally Advanced or Metastatic Urothelial Carcinoma that Expresses HER2 (IHC 1+ and Greater)

Inclusion criteria for the pharmaceutical study and the performance study in 
the combined trial are the same:
-----------------------------
Participants must meet all of the following inclusion criteria to be eligible for enrollment into the study:

1. Age 18 years and older at the time of consent or considered an adult by local regulations.
2. Participants must have LA/mUC with histopathological confirmation (Stage IIIB-IV per American Joint Committee on Cancer, Cancer Staging Atlas 8th ed.), including UC originating from the renal pelvis, ureters, bladder, or urethra. Mixed-cell type tumors are eligible as long as urothelial (transitional cell histology) carcinoma is the predominant cell type. 

3. Participants must have measurable disease by investigator assessment according to RECIST v1.1. 

   Note: Participants with prior definitive radiation therapy must have measurable disease per RECIST v1.1 that is outside the radiation field or has demonstrated unequivocal progression since completion of radiation therapy. 

4. Participants must not have received prior systemic therapy for locally advanced or metastatic UC with the following exceptions: 
   1. Neoadjuvant or adjuvant therapy, including PD-(L)1 inhibitors, is acceptable, if disease recurrence/progression occurred more than 12 months after the last dose of therapy.  
5. Participants must be considered eligible to receive cisplatin- or carboplatin-containing chemotherapy, per the investigator’s evaluation. Participants meeting any of the following criteria should be considered cisplatin‑ineligible, and will receive carboplatin: 
   1. CrCl <60 mL/min but ≥30 mL/min within 7 days of randomization (measured by the Cockcroft-Gault formula).
   2. ECOG performance status of 2 within 7 days of randomization (refer to Inclusion Criterion 8 for additional criteria for ECOG 2 participants).
   3. NCI CTCAE Grade 2 or higher hearing loss.
6. Participants must be willing and able to provide archived formalin-fixed paraffin-embedded tumor tissue blocks (or, alternatively, freshly sectioned slides; see laboratory manual for details) from a muscle-invasive or metastatic UC lesion or a biopsy sample of metastatic UC. This must be obtained prior to study treatment initiation and will be sent to a sponsor‑designated central laboratory for biomarker analysis. If archival tissue is not available, then a newly obtained “fresh” baseline biopsy of an accessible tumor lesion is required within 28 days prior to Cycle 1 Day 1. Biopsy must provide adequate tissue for HER2 testing.
   1. Tumor tissue recommended to be collected within 12 months prior to enrollment or most recent sample. Tumor tissue obtained after completion of the most recent (neo) adjuvant systemic therapy is preferred.
7. HER2 expression of 1+ or greater on IHC determined by central laboratory.
8. An ECOG performance status score of 0, 1, or 2 within 7 days prior to randomization. 
   1. Participants with ECOG 2 must meet additional criteria: Hb ≥10 g/dL, CrCl ≥50 mL/min, and heart failure severity less than New York Heart Association (NYHA) Class III.
9. Adequate baseline cardiac parameters: 
   1. LVEF ≥50% 
   2. Fridericia’s corrected QT interval (QTcF) <470 ms 
10. The following baseline laboratory data, laboratory values collected within 7 days prior to randomization are acceptable: 
    1. Hb ≥9 g/dL without transfusion
    2. ANC ≥1.5 × 109/L
    3. Platelet count ≥100 × 109/L
    4. ALT and AST ≤2.5 × upper limit of normal (ULN) without liver metastases or ≤5 × ULN with liver metastases 
    5. Serum total bilirubin ≤1.5 × ULN or direct bilirubin ≤ ULN for participants with total bilirubin >1.5 × ULN; serum total bilirubin ≤3 × ULN for participants with Gilbert's syndrome 

Exclusion criteria for the pharmaceutical study and the performance study in 
the combined trial are the same:
-----------------------------
Participants meeting any of the following exclusion criteria are ineligible for enrollment into the study:

1. Known hypersensitivity to any excipient contained in the drug formulation of disitamab vedotin, cisplatin, carboplatin, gemcitabine, or pembrolizumab.
2. History of severe/life threatening IMAE with PD-(L)1 inhibitors are excluded. Please consult with medical monitor. 
   1. Grade ≥3 cardiomyopathy
   2. Grade 4 diarrhea/colitis IMAEs, hepatitis IMAEs, rash IMAEs
   3. Grade 3/4 adrenal insufficiency, hypophysitis, uveitis, hypothyroidism
3. CNS and/or leptomeningeal metastasis. 

   1. Participants with treated CNS metastases (by whole brain radiation therapy, surgery or radiosurgery, etc.) are permitted on study if all of the following are met:

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

      ii. Participant is on a stable dose of ≤10 mg/day of prednisone or equivalent for at least 2 weeks.

4. History of or active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). 
   1. Replacement therapy (eg, thyroxine, insulin, physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic disease-modifying treatment and is allowed, if disease is stable.
   2. Participants with vitiligo, psoriasis, type 1 diabetes mellitus, hypothyroidism, or resolved childhood asthma/atopy are allowed.
   3. Participants requiring intermittent use of bronchodilators, inhaled steroids, or local steroid injections are allowed.
   4. Participants with hypothyroidism that is stable with hormone replacement or Sjögren's syndrome are allowed.
5. Participants who have previously received any 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) are excluded. 
6. Participants with prior solid organ or bone marrow transplantation.
7. Pleural effusion or ascites with symptoms or requiring symptomatic treatment.
8. Participants with an estimated life expectancy <12 weeks.
9. Participants with ongoing clinically significant toxicity associated with prior treatment that has not resolved to ≤ Grade 1 or returned to baseline, except for Grade 2 alopecia.

10. Participant has received prior radiotherapy to a metastatic site without the use of chemotherapy radiosensitization within 3 weeks of the first dose of study intervention, with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks before the start of study intervention. Participants must have recovered from all radiation-related toxicities and must not require corticosteroids.

    Note: Ongoing hormonal/antihormonal treatment (eg, for breast cancer) is allowed, provided that the participant is eligible per exclusion criteria of prior malignancy.

11. Participants who previously received treatment with an MMAE agent or anti-HER2 therapy.
12. Ongoing sensory or motor neuropathy Grade 2 or higher.
13. Participants with acute, chronic, or symptomatic infections, including:
    1. Ongoing symptomatic severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2) infection except for participants who have recovered clinically but continue to have a detectable presence of SARS-CoV-2.
    2. History of human immunodeficiency virus (HIV) infection. Testing is not required unless mandated by local regulations. 
    3. History of hepatitis