Cohort A

Population and HER2 Status: 
Previously treated LA/mUC HER2-positive: IHC 3+, or IHC 2+ and ISH-positive

Open label study treatment, IV every 2 weeks: 
Disitamab vedotin (monotherapy)

Cohort C

Population and HER2 Status: 
Treatment-naïve  LA/mUC HER2 expressing (HER2 IHC ≥1+)

Combination therapy:
Drug: Disitamab vedotin
Given into the vein (IV; intravenous) every 2 weeks.

Drug:  Pembrolizumab
Given by IV on Day 1 of each 6-week cycle.

Cohort A

• Histopathologically-confirmed, locally-advanced, unresectable or metastatic urothelial cancer (LA/mUC), including UC originating from the renal pelvis, ureters, bladder, or urethra.
• Participants must have received only 1 or 2 lines of prior systemic treatment for LA/mUC, including 1 line of platinum-containing chemotherapy.
• At least one measureable lesion by investigator assessment based on RECIST version 1.1
• HER2-expression status determined by the central laboratory to be IHC 3+, or IHC 2+ and ISH-positive, in the provided tumor sample.
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.

Cohort C

• Histopathologically-confirmed LA/mUC, including UC originating from the renal pelvis, ureters, bladder, or urethra
• At least one measureable lesion by investigator assessment based on RECIST v1.1.
• Participant is eligible to receive cisplatin -or carboplatin- containing chemotherapy per investigator evaluation
• HER2-expression status determined by the central laboratory to be IHC 3+, or IHC 2+ and ISH-positive, in the provided tumor sample.
• ECOG performance status of 0, 1, or 2
• No prior systemic therapy for LA/mUC
  • Neoadjuvant therapy, including PD-(L)1 inhibitors, is acceptable, if disease recurrence/progression occurred more than 12 months after the last dose of systemic therapy.

Cohort A

• Known hypersensitivity to disitamab vedotin or any of their components
• Prior antitumor treatment (including chemotherapy, radiotherapy, targeted therapy, immunotherapy etc.) within 2 weeks of start of study (defined as Cycle 1 Day 1 for Cohorts A and B)
• Toxicity from a previous treatment has not returned to Grades 0 or 1 (except for Grade 2 alopecia)
• Prior MMAE-based ADCs (eg, enfortumab vedotin) or HER2-directed therapy
• Major surgery that has not fully recovered within 4 weeks prior to dose administration

Cohort C

• Known hypersensitivity to disitamab vedotin, pembrolizumab, or any of their components
• Prior antitumor treatment (including chemotherapy, radiotherapy, targeted therapy, immunotherapy etc.) within 2 weeks of start of study defined as Cycle 1 Day 1 for the single-arm part of Cohort C and as randomization date for the randomized part of Cohort C
• Toxicity from a previous treatment has not returned to Grades 0 or 1 (except for Grade 2 alopecia)
• Prior MMAE-based ADCs (eg, enfortumab vedotin) or HER2-directed therapy
• Major surgery that has not fully recovered within 4 weeks prior to dose administration
• Peripheral sensory or motor nueropathy > Grade 2 at baseline
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of a study drug
• 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.

Primary outcomes

• Confirmed objective response rate (cORR) per response evaluation criteria in solid tumors (RECIST) version 1.1 (v1.1) by blinded independent central review (BICR) (Cohorts A and C

Secondary outcomes

• cORR per RECIST v1.1 by investigator assessment (Cohorts A and C)
• Confirmed duration of response (DOR) per RECIST v1.1 by BICR (Cohorts A and C)
• Confirmed DOR per RECIST v1.1 by investigator assessment (Cohorts A and C)
• Progression-free survival (PFS) per RECIST v1.1 by BICR (Cohorts A and C)
• PFS per RECIST v1.1 by investigator assessment (Cohorts A and C)
• Disease control rate (DCR) per RECIST v1.1 by BICR (Cohorts A and C)
• DCR per RECIST v1.1 by investigator (Cohorts A and C)
• Overall survival (OS) (Cohorts A and C)
• Incidence of dose alterations (Cohorts A and C)
• Incidence of laboratory abnormalities (Cohorts A and C)
• Incidence of ECG abnormalities (Cohorts A and C)
• Change from baseline of LVEF (Cohorts A and C)
• PK parameter - AUC (Cohorts A and C)
• PK parameter - Cmax (Cohorts A and C)
• PK parameter - Tmax (cohorts A and C)
• PK parameter - Ctrough (Cohorts A and C)
• Incidence of anti-drug antibodies (ADAs)) against disitamab vedotin (Cohorts A and C)
• Incidence of anti-drug antibodies (ADAs) against pembrolizumab (Cohort C)
• Incidence of neutralizing antibodies (NABs) against disitamab vedotin (Cohorts A and C)