Introduction & Objectives: Despite aggressive local and systemic therapy, MIBC outcomes remain dismal, with high recurrence rates and poor survival outcomes. Standard-of-care therapy of neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy results in a modest 5-year survival benefit. A phase 2 trial of neoadjuvant chemotherapy plus pembrolizumab had promising antitumor activity in cisplatin-eligible patients with MIBC (HCRN GU14-188; NCT02365766). In this trial, the estimated 36-month overall survival (OS), relapse-free survival, and disease-specific survival rates were 82%, 63%, and 87%, respectively, and toxicity was manageable, thus warranting further study of perioperative pembrolizumab plus neoadjuvant chemotherapy in MIBC.

Materials & Methods: The KEYNOTE-866 (NCT03924856) randomized, multinational, phase 3 study will assess efficacy and safety of perioperative pembrolizumab plus chemotherapy (gemcitabine plus cisplatin) versus perioperative placebo plus chemotherapy for patients with MIBC. Enrolled patients are adults with histologically confirmed MIBC (T2-T4aN0M0) with predominant (≥50%) urothelial histology confirmed by blinded independent central pathology and imaging review. Patients must also be previously untreated, be cisplatin-eligible, have Eastern Community Oncology Group (ECOG) performance status 0 or 1, and have tumor tissue for histology and PD-L1 analysis. Approximately 790 patients will be randomly assigned in a 1:1 ratio to 4 cycles of neoadjuvant pembrolizumab or placebo plus chemotherapy followed by 13 cycles of adjuvant pembrolizumab or placebo after radical cystectomy plus pelvic lymph node dissection. Neoadjuvant or adjuvant pembrolizumab 200 mg or placebo will be administered intravenously every 3 weeks (Q3W); neoadjuvant chemotherapy consists of 4 cycles of gemcitabine 1000 mg/m2 plus cisplatin 70 mg/m2 Q3W. Stratification factors will be PD-L1 status (combined positive score [CPS] ≥10 vs <10), disease stage (T2 vs T3/4), and region (United States vs Europe vs rest of world). Imaging (CT or MRI) will be performed 5 weeks or less prior to cystectomy and at 6 weeks postcystectomy. Imaging will then be performed Q12W up to week 96 postcystectomy and at discontinuation. Thereafter—year 3 and beyond—imaging will be Q24W. The dual primary end points are pathologic complete response (pCR) and event-free survival (EFS) evaluated in patients whose tumors express PD-L1 (CPS ≥10) and in all patients irrespective of CPS score. Secondary end points are OS, disease-free survival, and pathologic downstaging in patients with CPS≥10 and in all patients irrespective of CPS score, as well as safety, and patient-reported outcomes. Adverse events (AEs) graded per Common Terminology Criteria for Adverse Events, version 4.0, will be monitored from randomization through 30 days after last dose of study drug (90 days for serious AEs).

Results: The KEYNOTE-866 study is underway in 22 countries across Asia, Australia, Europe, and North America.

Conclusions: KEYNOTE-866 will provide further clarity on the efficacy of perioperative pembrolizumab plus chemotherapy in MIBC.

Perioperative Pembrolizumab or Placebo and Neoadjuvant Chemotherapy in Patients With Muscle-Invasive Bladder Cancer (MIBC) Who Are Eligible for Cisplatin (KEYNOTE-866 phase 3 study)