Introduction & Objectives: Patients with MIBC who are ineligible for neoadjuvant cisplatin-based chemotherapy receive the standard of care treatment of radical cystectomy (RC) and pelvic lymph node dissection (PLND). This therapy alone is associated with high rates of recurrence and relatively poor overall survival (OS); novel perioperative systemic therapy regimens are needed. The PURE-01 single-arm study (NCT02736266) found that the PD-1 inhibitor pembrolizumab as single-agent neoadjuvant therapy in patients with MIBC had antitumor activity. The study also found that high PD-L1 expression was associated with a higher pathologic complete response rate (pCR). Materials & Methods: The KEYNOTE-905 (NCT03924895) randomized, multinational phase 3 study will assess efficacy and safety of perioperative pembrolizumab plus RC and perioperative EV with pembrolizumab plus RC vs RC alone for patients with MIBC. The patient population will comprise adults with histologically confirmed MIBC (T2-T4aN0M0 or T1-T4aN1M0) with predominant (≥50%) urothelial histology, confirmed by blinded independent central review. These patients must also be previously untreated with systemic therapies for MIBC, be cisplatin-ineligible, have Eastern Cooperative Oncology Group performance status of 0-2, and have tumor tissue for histology and PD-L1 analysis. Approximately 836 patients will be randomized 1:1:1 to 3 cycles of neoadjuvant pembrolizumab followed by RC plus PLND and 14 cycles of adjuvant pembrolizumab or 3 cycles of neoadjuvant EV and pembrolizumab followed by RC plus PLND and 6 cycles of adjuvant EV and 14 cycles of adjuvant pembrolizumab or RC plus PLND alone. Neoadjuvant or adjuvant pembrolizumab 200 mg will be administered intravenously every 3 weeks (Q3W). Neoadjuvant or adjuvant EV 1.25 mg/kg will be administered on days 1 and 8 Q3W. Stratification factors will be PD-L1 status (combined positive score [CPS] ≥10 vs <10), disease stage (T2N0 vs T3/T4N0 vs T1-T4aN1), and region (United States vs European Union vs Most of the World). Imaging (CT or MRI) will be performed 5 weeks or fewer precystectomy and at 6 weeks postcystectomy. Scans will then be performed Q12W up to week 96 postcystectomy and at discontinuation. Thereafter (ie, year 3 and beyond) imaging will be Q24W. The coprimary endpoints are pCR and event-free survival (EFS) (expressing PD-L1 [CPS ≥10] and all patients regardless of CPS). Secondary endpoints are OS, disease-free survival, and pathologic downstaging in populations described for pCR and EFS safety, and patient-reported outcomes. Adverse events (AEs) graded according to Common Terminology Criteria for Adverse Events v4.0 will be monitored from randomization through 30 days after last dose of study drug (90 days for serious AEs). Results: KEYNOTE-905 study is ongoing or planned in 25 countries across Asia, Australia, Europe, and North America. Conclusions: KEYNOTE-905 will provide further clarity on efficacy of perioperative pembrolizumab with or without EV in cisplatin-ineligible MIBC.
No datasets are available for this submission.