CLINICAL TRIAL / NCT04879329

Inclusion Criteria: Cohorts A and B - 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 measurable lesion by investigator assessment based on RECIST version 1.1. - HER2-expression status determined by the central laboratory to be IHC 1+, 2+ or 3+, 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 - No prior systemic therapy for LA/mUC - 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 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 Cohort D - Histopathologically-confirmed LA/mUC, including UC originating from the renal pelvis, ureters, bladder, or urethra - Based on a participant's eligibility to receive treatment with standard of care therapies in Japan, participants must have received all of the following lines of therapy for LA/mUC: - a. One prior line of platinum-containing chemotherapy. - b. Prior therapy with PD-(L)1 inhibitors as (neo)adjuvant therapy, first-line maintenance therapy or as second line treatment. - c. Prior enfortumab vedotin therapy. - At least one measurable lesion by investigator assessment based on RECIST v1.1. - ECOG performance status of 0 or 1 Cohort E - Histopathologically-confirmed LA/mUC, including UC originating from the renal pelvis, ureters, bladder, or urethra - No prior systemic therapy for LA/mUC - 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 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+, in the provided tumor sample - ECOG performance status of 0 or 1 Exclusion Criteria: Cohorts A and B - 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 - Peripheral sensory or motor neuropathy ≥ Grade 2 at baseline 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 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 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. Cohort D - 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 Cohort D) - Toxicity from a previous treatment has not returned to Grades 0 or 1 (except for Grade 2 alopecia) - Prior HER2-directed therapy - Any prior history of ≥ Grade 3 non-hematological AEs related to prior therapy - Major surgery that has not fully recovered within 4 weeks prior to dose administration - Peripheral sensory or motor neuropathy ≥ Grade 1 at baseline Cohort E - 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 Cohort E) - Toxicity from a previous treatment has not returned to Grades 0 or 1 (except for Grade 2 alopecia) - Any prior history of ≥ Grade 3 non-hematological AEs related to prior therapy - 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 1 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 study drug There are additional inclusion and exclusion criteria. The study center will determine if criteria for participation are met.