This is a single-arm, open-label, non-randomized Phase II trial evaluating the efficacy of induction therapy with enfortumab vedotin (EV) plus pembrolizumab (P) for 18 weeks (6 cycles), followed by maintenance pembrolizumab in treatment-naïve patients with metastatic urothelial carcinoma (mUC). Approximately 97 patients will be enrolled. Induction consists of EV (1.25 mg/kg IV on Days 1 and 8 of each 21-day cycle; starting dose of 1 mg/kg allowed) and P (200 mg IV on Day 1 of each cycle). Radiographic assessments occur after 3 and 6 cycles. Patients achieving complete or partial response transition to maintenance P (400 mg IV every 6 weeks or 200 mg IV every 3 weeks) for up to 2 years. Dose modifications for EV are permitted per protocol; no dose adjustments for P. Treatment continues until disease progression, unacceptable toxicity, or completion of maintenance therapy. Patients will enter long-term or survival follow-up as applicable.
Patients must have histologically and radiographically confirmed locally advanced, unresectable urothelial carcinoma.
Patients should not have received prior systemic therapy for metastatic disease.
Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension in accordance with RECIST criteria v1.1
Patients may have received prior neoadjuvant or adjuvant immune checkpoint inhibitor therapy for localized disease and are eligible if they completed the treatment ≥12 months prior to initiating treatment on this clinical trial.
Patients who have received prior monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs) for urothelial cancer.
Grade 2 or higher baseline sensory or motor neuropathy.
Uncontrolled diabetes (HbA1c >8%)
Patients with uncontrolled and untreated central nervous system (CNS) metastases.
Single group
Enfortumab vedotin
DrugEV will be administered at 1.25 mg/kg IV on Days 1 and 8 of each 21-day cycle
Pembrolizumab
DrugPembrolizumab will be administered at 200 mg IV on Day 1 of each 21-day cycle
18-month progression-free survival (PFS)
radiographic progression or death from any cause within 18 months of initiating treatment
Overall Survival (OS)
Time from initiating treatment to death from any cause, to capture long-term survival benefits
Duration of Response (DoR)
Time from first objective response (CR/PR) to radiographic progression or death, providing insight into the sustained efficacy of the treatment
PFS 2 after EV rechallenge
Since patients progressing after completing induction EV/P will be able to receive EV re-challenge, we will measure PFS with EV rechallenge measured from the start of EV rechallenge to the next progression defined by RECIST 1.1 or death
Treatment-free interval
Time from the completion of induction EV/P to either EV re-initiation or the start of another therapy, measuring how long patients remain off treatment
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Fox Chase Cancer Center
Lead sponsor
United States Department of Defense
Collaborator
