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

• disitamab vedotin (Drug), also known as RC48, RC48-ADC: Given into the vein (IV; intravenous) every 2 weeks
• pembrolizumab (Drug), also known as KEYTRUDA®: 400mg given by IV every 6 weeks
• gemcitabine (Drug), also known as Gemzar: 1000 mg/m\^2 given by IV on days 1 and 8 of every 3-week cycle
• cisplatin (Drug): 70 mg\^2 given by IV on day 1 of every 3-week cycle
• carboplatin (Drug): Area under the plasma concentration-time curve (AUC) 4.5 or 5 given by IV on day 1 of every 3-week cycle

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) [Approximately 3 years]: The time from randomization to first documentation of disease progression per RECIST v1.1 by BICR, or to death due to any cause.
• Overall survival (OS) [Approximately 5 years]: The time from date of randomization to date of death due to any cause.

Secondary outcomes

• Objective response rate (ORR) per RECIST v1.1 by BICR [Approximately 3 years]: The proportion of participants with confirmed complete response (CR) or partial response (PR) according to RECIST v1.1.
• ORR per RECIST v1.1 by investigator assessment [Approximately 3 years]: The proportion of participants with confirmed CR or PR according to RECIST v1.1.
• Duration of Response (DOR) per RECIST v1.1 by BICR [Approximately 3 years]: The time from first documented response of CR or PR (that is subsequently confirmed) to the first documented disease progression per RECIST v1.1, or to death due to any cause.
• DOR per RECIST v1.1 by investigator assessment [Approximately 3 years]: The time from first documented response of CR or PR (that is subsequently confirmed) to the first documented disease progression per RECIST v1.1, or to death due to any cause.
• Control Rate (DCR) per RECIST v1.1 by BICR [Approximately 3 years]: The proportion of participants with confirmed CR, PR, or stable disease according to RECIST v1.1.
• DCR per RECIST v1.1 by investigator assessment [Approximately 3 years]: The proportion of participants with confirmed CR, PR, or stable disease according to RECIST v1.1.
• PFS per RECIST v1.1 by investigator assessment [Approximately 3 years]: The time from randomization to first documentation of disease progression per RECIST v1.1, or to death due to any cause.
• Number of participants with adverse events (AEs) [Through 30 days after the last study treatment; approximately 2 years]: Any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.
• Number of participants with laboratory abnormalities [Through 30 days after the last study treatment; approximately 2 years]
• Treatment discontinuation rate due to AEs [Approximately 2 years]
• Number of electrocardiogram (ECG) abnormalities [Through 30 days after the last study treatment; approximately 2 years]
• Change from baseline of left ventricular ejection fraction (LVEF) [Through 2 years after last study treatment; approximately 4 years]
• 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 [Approximately 2 years]: The EORTC QLQ-C30 is used to evaluate health-related quality of life, functioning, disease symptoms, and treatment-related side effects. Scores range from 0-100. For GHS/QoL and functional scales, higher scores represent higher QoL or functioning. For symptom scales, higher scores represent more symptoms/worse status.
• Time to Deterioration in EORTC QLQ-C30 GHS/QoL Score [Approximately 2 years]: The time from the date of randomization to the date of first deterioration (change from baseline ≥10) in GHS/QoL score with no subsequent recovery. The EORTC QLQ-C30 is used to evaluate health-related quality of life, functioning, disease symptoms, and treatment-related side effects. Scores range from 0-100. For GHS/QoL and functional scales, higher scores represent higher QoL or functioning. For symptom scales, higher scores represent more symptoms/worse status.
• Time to pain progression [Approximately 2 years]: The time from the date of randomization to whichever of the following occurs earlier: * an increase in Numeric Rating Scale (NRS) for pain intensity of 2 points or more from baseline at 2 consecutive visits, * an increase in number of opioid or analgesic use from baseline, * or initiation of opioid or analgesic use. NRS for pain intensity asks participants to best describe their pain at its worst in the last 24 hours from 0 to 10. On the NRS, 0 means no pain and 10 means pain as bad as you can imagine.

Sex: All, ages: 18 Years to any

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

168 more sites not listed.

• Pfizer CT.gov Call Center, Study director, Pfizer