A Phase 2 Multi-Cohort, Open-Label, Multi-Center Clinical Study Evaluating the Efficacy and Safety of Disitamab Vedotin (RC48-ADC) Alone or in Combination with Pembrolizumab in Subjects with Locally Advanced Unresectable or Metastatic Urothelial Carcinoma That Expresses HER2

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

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