A Study of Disitamab Vedotin Alone and With Pembrolizumab in Urothelial Cancer That Expresses HER2

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 2 or 3 prior lines of systemic therapy for LA/mUC, including the following:

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.
Participants with available tissue should provide archived or freshly sectioned slides
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

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)
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

There are additional inclusion and exclusion criteria. The study center will determine if criteria for participation are met.