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

Inclusion Criteria:

Cohorts A and B

• Histopathologically-confirmed, locally-advanced, unresectable or metastaticurothelial 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 forLA/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 renalpelvis, 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 lastdose of systemic therapy

• At least one measurable lesion by investigator assessment based on RECIST v1.1.

• Participant is eligible to receive cisplatin- or carboplatin- containingchemotherapy 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 renalpelvis, ureters, bladder, or urethra

• Based on a participant's eligibility to receive treatment with standard of caretherapies in Japan, participants must have received all of the following lines oftherapy for LA/mUC:

• a. One prior line of platinum-containing chemotherapy.

• b. Prior therapy with PD-(L)1 inhibitors as (neo)adjuvant therapy, first-linemaintenance 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 renalpelvis, 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 lastdose of systemic therapy.

• At least one measurable lesion by investigator assessment based on RECIST v1.1.

• Participant is eligible to receive cisplatin- or carboplatin- containingchemotherapy 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

Cohort G

• Histopathologically-confirmed, locally-advanced, unresectable or metastaticurothelial 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 forLA/mUC, including 1 line of therapy containing enfortumab vedotin as monotherapy orin combination with pembrolizumab

• The last administration of enfortumab vedotin must be 90 days from the start ofstudy treatment. Intervening therapies are allowed between the final dose ofenfortumab vedotin and the start of disitamab vedotin.

• 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

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 forCohorts A and B)

• Toxicity from a previous treatment has not returned to Grades 0 or 1 (except forGrade 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 doseadministration

• Peripheral sensory or motor neuropathy ≥ Grade 2 at baseline

Cohort C

• Known hypersensitivity to disitamab vedotin, pembrolizumab, or any of theircomponents

• Prior antitumor treatment (including chemotherapy, radiotherapy, targeted therapy,immunotherapy etc.) within 2 weeks of start of study defined as Cycle 1 Day 1 forthe single-arm part of Cohort C and as randomization date for the randomized part ofCohort C)

• Toxicity from a previous treatment has not returned to Grades 0 or 1 (except forGrade 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 doseadministration

• 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 ofimmunosuppressive therapy within 7 days prior the first dose of study drug

• Participants who have previously received any prior treatment with an agent directedto another stimulatory or co-inhibitory T cell receptor (including but not limitedto CD137 agonists, CAR-T cell therapy, CTLA-4 inhibitors, or OX-40 agonists) areexcluded.

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 forCohort D)

• Toxicity from a previous treatment has not returned to Grades 0 or 1 (except forGrade 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 doseadministration

• Peripheral sensory or motor neuropathy ≥ Grade 1 at baseline

Cohort E

• Known hypersensitivity to disitamab vedotin, pembrolizumab, or any of theirurothelial 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 therapy containing enfortumab vedotin as monotherapy or
in combination with pembrolizumab
 

• The last administration of enfortumab vedotin must be 90 days from the start of
study treatment. Intervening therapies are allowed between the final dose of
enfortumab vedotin and the start of disitamab vedotin.
 

• 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
 
 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 forCohort E)

• Toxicity from a previous treatment has not returned to Grades 0 or 1 (except forGrade 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 doseadministration

• 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 ofimmunosuppressive therapy within 7 days prior the first dose of study drug

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 of start of study (defined as Cycle 1 Day 1 forCohort G)

• Toxicity from a previous treatment has not returned to Grades 0 or 1 (except forGrade 2 alopecia)

• Prior HER2-directed therapy

• Major surgery that has not fully recovered within 4 weeks prior to doseadministration

• Peripheral sensory or motor neuropathy ≥ Grade 2 at baseline

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