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:
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1. Age 18 years and older at the time of consent or considered an adult by
local regulations.
2. Subjects must have LA/mUC with histopathological confirmation, 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. Subjects must have measurable disease by investigator assessment according
to RECIST v1.1.
4. Subjects must not have received prior systemic therapy for locally advanced
or metastatic UC with the following exceptions:
a. 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. Subjects must be considered eligible to receive cisplatin- or
carboplatin-containing chemotherapy, per the investigator*s evaluation.
6. Subjects must be willing and able to provide archived formalin-fixed
paraffin-embedded tumor tissue blocks 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 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.
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.
9. Adequate baseline cardiac parameters
10. Acceptable baseline laboratory data, laboratory values collected within 7
days prior to randomization
11. Subjects of childbearing potential under conditions
12. Subjects who can get someone pregnant under conditions
13. The subject must provide documented informed consent.
14. Subject must be willing and able to comply with the trial procedures and
the follow-up schedule

Exclusion criteria for the pharmaceutical study and the performance study in
the combined trial are the same:
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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 irAE with PD-(L)1 inhibitors are excluded.
3. CNS and/or leptomeningeal metastasis.
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).
5. Subjects 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. Subjects with prior solid organ or bone marrow transplantation.
7. Pleural effusion or ascites with symptoms or requiring symptomatic treatment.
8. Subjects with an estimated life expectancy <12 weeks.
9. Subjects 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. Subject 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. Subjects must have
recovered
from all radiation-related toxicities and must not require corticosteroids.
11. Subjects who previously received treatment with an MMAE agent or anti-HER2
therapy.
12. Ongoing sensory or motor neuropathy Grade 2 or higher.
13. Subjects with acute, chronic, or symptomatic infections
14. Has a diagnosis of immunodeficiency condition/disorder (ie, immunoglobulin
A [IgA] deficiency, etc.) or is receiving chronic systemic steroid therapy
(dose >10 mg daily of prednisone or equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of study drug.
15. Subjects with history of idiopathic pulmonary fibrosis, organizing
pneumonia, drug-induced pneumonitis, noninfectious pneumonitis, interstitial
lung disease, or idiopathic pneumonitis are excluded. Subjects with current
pneumonitis or interstitial lung disease are also excluded.
16. Subjects with a history of another invasive malignancy within 3 years
before the first dose of study intervention, or any evidence of residual
disease from a previously
diagnosed malignancy.
17. Uncontrolled cardiac disease
18. Subjects who have received radiotherapy within 2 weeks prior to
randomization.
19. Subjects who have received major surgery within 4 weeks prior to
randomization. Subject must have recovered adequately from complications from
the study intervention prior to randomization.
20. Subjects requiring chronic oxygen therapy or have Grade >=3 pulmonary
disease unrelated to underlying malignancy.
21. Subjects who have received a live or live-attenuated vaccine within 30 days
prior to randomization.
22. Subjects who are pregnant or breastfeeding women.
23. Other serious underlying medical condition, psychiatric or substance abuse
disorder that, in the opinion of the investigator, would impair the subject*s
ability to receive or tolerate the planned treatment, or comply with the
requirements of the study and follow-up.
24. Other serious, uncontrolled concomitant diseases that may affect protocol
compliance or interpretation of outcomes, including active opportunistic
infections or advanced (severe) infections, or uncontrolled diabetes.