Radical cystectomy remains the standard curative-intent treatment for most patients with muscle-invasive bladder cancer, but it is associated with significant morbidity and long-term quality-of-life implications. Trimodality therapy is an accepted standard-of-care alternative for carefully selected patients who wish to preserve their bladder; however, optimal patient selection remains challenging.
The combination of enfortumab vedotin plus pembrolizumab (EV-P) has demonstrated remarkable activity in urothelial carcinoma, including in the perioperative setting, with pathologic complete response rates of approximately 50-60%. These results generate the hypothesis that a subset of patients may achieve sufficiently deep responses to allow selective deferral of cystectomy. Cohort A of this trial prospectively evaluates the use of multimodal response assessment (pelvic MRI and TURBT, ctDNA) to guide individualized decisions regarding cystectomy versus bladder preservation.
Radical nephroureterectomy (RNU) remains the standard curative-intent treatment for high-risk upper tract urothelial carcinoma (UTUC), but recurrence rates after surgery alone are high. Neoadjuvant cisplatin-based chemotherapy improves pathologic outcomes and is supported by phase II data, but its delivery is constrained by baseline renal dysfunction and the further decline in glomerular filtration that follows RNU - historically, only about 20% of patients remain cisplatin-eligible postoperatively, which is the principal rationale for delivering platinum in the neoadjuvant rather than adjuvant setting. A large fraction of patients with UTUC are cisplatin-ineligible at baseline, and no level 1 evidence supports a specific neoadjuvant regimen in this population.
EV-P is not constrained by renal function and has produced unprecedented activity in urothelial carcinoma. In the EV-302 upper tract subgroup, EV-P achieved an objective response rate of 67.7% and a complete response rate of 28.6%, with survival benefit preserved relative to platinum-based chemotherapy. In the perioperative bladder cancer setting, EV-P has yielded pathologic complete response rates of approximately 50-60%. However, available data on EV-P in UTUC are restricted to the metastatic setting, and prospective evaluation in the neoadjuvant setting is lacking. Cohort B of this trial addresses this gap by prospectively evaluating neoadjuvant EV-P followed by RNU in patients with high-risk UTUC, with pathologic complete response as the primary endpoint.
Adults ≥ 18 years of age.
ECOG Performance Status of 0-2
For Cohort A, a clinical or pathological diagnosis consistent with muscle-invasive urothelial carcinoma of the bladder (locoregional), with a clinical staging of T2 or higher, N0 to N2, and M0.
High-intermediate: High grade + Unifocal <1.5 cm
Eligible to receive enfortumab vedotin plus pembrolizumab (EV-P) in the opinion of the investigators.
Written informed consent obtained from the subject and the subject agrees to comply with all the study-related procedures.
Subjects must not have more than one active malignancy at the time of enrollment.
Amenorrhea that has lasted for ≥ 12 consecutive months without another cause, or
Parallel
enfortumab vedotin and pembrolizumab (EV/P)
DrugParticipants in both cohorts will first receive neoadjuvant enfortumab vedotin + pembrolizumab (EV-P) for 4 cycles. Each cycle is 21 days. Participants will be given 1.25 mg/kg enfortumab vedotin intravenously on days 1 and 8 and 200 mg pembrolizumab intravenously on day 1 of each cycle. Participants in Cohort A may then choose to receive 5 more cycles of EV-P followed by pembrolizumab alone to complete 1 year of study therapy if they have a composite complete clinical response. Participants in Cohort B will then receive 5 more cycles of EV-P followed by pembrolizumab alone to complete 1 year of study therapy following their definitive surgery.
Clinical complete response rate
Determine the percent of subjects in Cohort A that achieve a clinical complete response following completion of neoadjuvant EV-P. A clinical complete response is defined as having all three of the following: * A negative ctDNA result, * Imaging of the pelvis with negative lymph nodes and no distant metastasis on CT scans, AND * A TURBT showing T0 or low-grade Ta only, and a negative urinary cytology.
Pathologic complete response rate
Determine the percent of subjects in Cohort B who achieve a pathologic complete response at the time of surgery. A pathologic complete response is defined as having disease staging of pT0N0 at time of surgery.
Event-free survival
Determine the event-free survival of patients in Cohort A at 1 year from the start of EV-P
Event-free survival
Determine the event-free survival of patients in Cohort A at 2 years from the start of EV-P
Overall survival
Determine the overall survival of patients in Cohort A at 1 year from the start of EV-P
Overall survival
Determine the overall survival of patients in Cohort A at 2 years from the start of EV-P
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