Cohort C

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

Open-Label Study Treatment:
Disitamab vedotin ± pembrolizumab

Cohort G

Population and HER2 Status:
LA/mUC previously treated with EV HER2-expressing (HER2 IHC ≥1+)

Open-Label Study Treatment:
Disitamab vedotin monotherapy

Cohort C

• Histopathologically-confirmed LA/mUC, including UC originating from the renal pelvis, ureters, bladder, or urethra
• 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 final dose of systemic therapy
• At least one measurable 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 1+, 2+ or 3+, on the provided tumor tissue sample
• ECOG performance status of 0, 1, or 2 (2 is only allowed if certain criteria are met)

Cohort G

• Histopathologically-confirmed LA/mUC, including UC originating from the renal pelvis, ureters, bladder, or urethra
• Prior therapy:
  • Received only 1 or 2 lines of prior systemic therapy for LA/mUC, including 1 line of therapy containing enfortumab vedotin, as monotherapy or in combination with pembrolizumab
• At least one measurable lesion by investigator assessment based on RECIST v1.1.
• HER2-expression status determined by the central laboratory to be IHC 1+, 2+ or 3+, on the provided tumor tissue sample
• ECOG performance status of 0 or 1

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 prior to the start of the 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 neuropathy ≥ 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 intervention
• 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.

Cohort G:

• Known hypersensitivity to disitamab vedotin or any of their components
• Prior antitumor treatment (including chemotherapy, radiotherapy, targeted therapy, immunotherapy etc.) within 2 weeks prior to the start of the study defined as Cycle 1 Day 1 for Cohort G
• Prior HER2-direct therapy
• Major surgery that has not fully recovered within 4 weeks prior to dose administration
• Peripheral sensory or motor neuropathy ≥ Grade 2 at baseline
• Uncontrolled cardiac disease including cardiac failure, cardiac arrhythmia Grade ≥ 2, cardiac ischemia, or uncontrolled hypertension
• History of, or active, autoimmune disease that has required systemic therapy in the past 2 years

Primary outcomes

Cohort C:

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

Cohort G:

• Objective response rate (ORR) per response evaluation criteria in solid tumors (RECIST) version 1.1 (v1.1) by blinded independent central review (BICR)

Secondary outcomes

• cORR per RECIST v1.1 by investigator assessment (Cohort C)
• Confirmed duration of response (DOR) per RECIST v1.1 by BICR (Cohort C)
• Confirmed DOR per RECIST v1.1 by investigator assessment (Cohort C)
• ORR per RECIST v1.1 by investigator assessment (Cohort G)
• DOR per RECIST v1.1, as assessed by BICR (Cohort G)
• DOR per RECIST v1.1, as assessed by investigator (Cohort G)
• Progression-free survival (PFS) per RECIST v1.1 by BICR (Cohorts C & G)
• PFS per RECIST v1.1 by investigator assessment (Cohorts C & G)
• Disease control rate (DCR) per RECIST v1.1 by BICR (Cohorts C & G)
• DCR per RECIST v1.1 by investigator (Cohorts C & G)
• Overall survival (OS) (Cohort C & G)
• Safety and tolerability (Cohorts C & G)
• PK parameters (Cohort C)
• Incidence of anti-drug antibodies (ADAs) (Cohort C)