KEYNOTE-D78: This study is testing whether a targeted therapy (called disitamab vedotin) alone, or when given with immunotherapy, works to treat HER2 expressing urothelial cancerA 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

Exclusion

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)
• 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.