Open-label, Randomized, Controlled Phase III Study of Disitamab Vedotin in Combination with Pembrolizumab Versus Chemotherapy in Subjects with Previously Untreated Locally Advanced or Metastatic Urothelial Carcinoma that Expresses HER2 (IHC 1+ and Greate

This is an open-label, randomized, controlled phase III study of Disitamab Vedotin in Combination with Pembrolizumab Versus Chemotherapy in Subjects with Previously Untreated Locally Advanced or Metastatic Urothelial Carcinoma that Expresses HER2 (IHC 1+ and Greater). Patients with locally advanced unresectable or metastatic urothelial carcinoma (LA/mUC) represent a population with a significant unmet medical need. 
Disitamab vedotin has shown encouraging single agent activity in late-line advanced urothelial carcinoma (UC). The initial experience with disitamab vedotin in combination with a programmed cell death protein 1 (PD-1) inhibitor suggests that the safety profile is manageable and tolerable. 

For more information, visit: https://clinicaltrials.gov/study/NCT05911295

Inova Schar Cancer Institute
A division of Inova Fairfax Hospital
8081 Innovation Park Drive 
Fairfax, VA 22031

1. Age 18 years and older at the time of consent
2. Subjects must have LA/mUC with histopathological confirmation (Stage IIIB-IV per American Joint Committee on Cancer, Cancer Staging Atlas 8th ed.), including UC originating from the renal pelvis, ureters, bladder, or urethra. Mixed-cell type tumors are eligible as long as urothelial (transitional cell histology) carcinoma is the predominant cell type.
3. Subjects must have measurable disease by investigator assessment according to RECIST v1.1.
4. Subjects must not have received prior systemic therapy for locally advanced or metastatic UC with the following exceptions:
   a. 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 therapy.
5. Subjects must be considered eligible to receive cisplatin- or carboplatin-containing chemotherapy, per the investigator's evaluation.
6. Subjects must be willing and able to provide archived formalin-fixed paraffin-embedded tumor tissue blocks (or, alternatively, freshly sectioned slides; see laboratory manual for details) from a muscle-invasive or metastatic UC lesion or a biopsy sample of metastatic UC.
7. HER2 expression of 1+ or greater on IHC determined by central laboratory.
8. An ECOG performance status score of 0, 1, or 2 within 7 days prior to randomization.

1. Known hypersensitivity to any excipient contained in the drug formulation of disitamab vedotin, cisplatin, carboplatin, gemcitabine, or pembrolizumab.
2. CNS and/or leptomeningeal metastasis.
3. History of or active autoimmune disease that has required systemic treatment in the past 2 years.
4. Subjects 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.
5. Subjects with prior solid organ or bone marrow transplantation.
6. Pleural effusion or ascites with symptoms or requiring symptomatic treatment.
7. Subjects who are pregnant or breastfeeding women.