4824 - KEYNOTE-905: A Phase 3 Study of Cystectomy Plus Perioperative Pembrolizumab Versus Cystectomy Alone in Cisplatin (cis)-Ineligible Patients (pts) With Muscle-Invasive Bladder Cancer (MIBC)

Background

Current standard of care for pts with MIBC who are ineligible for neoadjuvant cis-based chemotherapy is radical cystectomy (RC) + pelvic lymph node dissection (PLND). Due to high rates of recurrence and relatively poor overall survival (OS) with RC + PLND alone, there is an urgent need for novel perioperative systemic therapy regimens. A recent single-arm study (PURE-01; NCT02736266) showed clinical activity of pembrolizumab as single-agent neoadjuvant therapy in pts with MIBC and that high PD-L1 expression was associated with a higher pathologic complete response rate.

Trial design

KEYNOTE-905 (NCT03924895) is a randomized, global, multicenter, phase 3 trial of perioperative pembrolizumab plus RC versus RC alone in cis-ineligible pts with MIBC. Approximately 610 adult (≥18 years) pts with histologically confirmed diagnosis of MIBC (T2-T4aN0M0) with predominant (≥50%) urothelial histology are eligible. Pts must be ineligible to receive cis, have an ECOG PS score of 0-2, and must not have previously received any systemic anticancer therapies for MIBC. Pts will be stratified by clinical T stage (T2 vs T3/4), PD-L1 combined positive score (CPS) (≥10 vs < 10), and geographic region. Pts will be randomly assigned 1:1 to receive either 3 cycles of neoadjuvant pembrolizumab followed by RC + PLND and then 14 cycles of adjuvant pembrolizumab or RC + PLND alone. Pembrolizumab 200 mg will be administered every 3 weeks. CT/MRI imaging will be performed before and after cystectomy. Pts who are disease-free at postcystectomy imaging will continue with serial imaging until progression/discontinuation; all imaging will be assessed by blinded independent central review. Coprimary end points are pathologic complete response (pT0N0) and event-free survival evaluated in pts whose tumors express PD-L1 CPS ≥10 and in all pts irrespective of CPS score. Secondary end points are OS, disease-free survival, and pathologic downstaging. Adverse events (AEs) will be monitored from randomization through 30 days after last dose of study drug (90 days for serious AEs). Patient-reported outcomes will also be measured.

Clinical trial identification

NCT03924895, April 23, 2019.

Editorial acknowledgement

Matthew Grzywacz, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA), funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

M. Galsky: Advisory / Consultancy: Janssen, Merck, Astellas, Genentech, BMS, Novartis, Pfizer, EMD Serono, AstraZeneca, Seattle Genetics, Incyte, Aileron, Dracen, Ionvio, NuMab, Dragonfly Therapeutics; Research grant / Funding (institution): Dendreon, Novartis, BMS, Merck, AstraZeneca, Genentech/Roche. A. Necchi: Honoraria (self): Merck, Roche, AstraZeneca, Janssen, Rainier Therapeutics, Bayer, BMS, Clovis; Advisory / Consultancy: Merck, Roche, AstraZeneca, Janssen, Rainier Therapeutics, Bayer, BMS, Clovis; Research grant / Funding (institution): Merck, AstraZeneca; Spouse / Financial dependant: Bayer. N.D. Shore: Advisory / Consultancy: Amgen, Astellas, AstraZeneca, Bayer, BMS, Dendreon, Ferring, Janssen, Merck, MDxHealth, Pfizer, Sanofi, Tolmar; Speaker Bureau / Expert testimony: Astellas, Janssen. F. Witjes: Advisory / Consultancy: Roche, MSD, BMS. K. Nam: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. J.L. Godwin: Full / Part-time employment: Merck & Co., Inc. T.L. Frenkl: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: MSD. E.R. Plimack: Advisory / Consultancy: BMS, Genentech, Incyte, Janssen, Merck; Research grant / Funding (institution): Astellas, BMS, Genentech, Merck, Peloton, Pfizer.