Pembrolizumab as Neoadjuvant Therapy Preceding Radical Cystectomy in Patients with Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Group, Phase 2 Study

Abstract

Background: Cisplatin-based neoadjuvant chemotherapy prior to radical cystectomy (RC) is the standard of care for muscle-invasive bladder carcinoma (MIBC), but it is administered in few patients. Methods:In the PURE-01 study, pembrolizumab was administered prior to RC. The patients had a predominant urothelial carcinoma histology and clinical (c)T≤3bN0 stage. They received 3 cycles of 200 mg pembrolizumab every 3 weeks prior to RC. Pathologic complete response (pT0) in intention-to-treat population was the primary endpoint. The biomarker analyses included PD-L1 expression using the combined positive score (CPS) (Dako 22C3), genomic sequencing (FoundationOne assay) and an immune gene expression assay. Findings: From 02/17 to 03/18, 50 patients were enrolled. Twenty-seven (54%) had cT3, 21 (42%) had cT2, and 2 (4%) had cT2-3N1. One patient (2%) had a grade 3 transaminase increase and discontinued pembrolizumab. All patients underwent RC: there were 21 pT0 (42%, 95% CI: 29*4-55*8%). As a secondary endpoint, the downstaging to pT<2 was obtained in 27 patients (54%, 95% CI: 40*4-67%). In 54.3% of the patients with PD-L1 CPS≥10% (n=35), RC indicated pT0, whereas RC indicated pT0 in only 13*3% of those with a CPS<10% (n=15). All 5 patients with a tumor mutation burden (TMB) in the 90th percentile achieved pT0. The expression of several genes in pre-therapy lesions was significantly different between pT0 and non-pT0 cohorts. Significant post-therapy changes in the TMB and evidence of adaptive mechanisms of immune-resistance were observed in residual tumors. Interpretation: Neoadjuvant pembrolizumab resulted in 42% pT0 and was safely administered in MIBC patients. This study supports that pembrolizumab could be a worthwhile neoadjuvant therapy for MIBC when limited to patients with PD-L1-positive or high-TMB tumors. Clinical Trial Number: ClinicalTrials.gov, number NCT02736266 Funding Statement: Merck & Co., Inc., Kenilworth, NJ, USA; Associazione Italiana per la Ricerca sul Cancro (AIRC). Declaration of Interests: Necchi A: consultant for Merck, Astra Zeneca, Janssen, Incyte, Roche, BioclinTherapeutics, Clovis Oncology, Bayer, and Astellas/Seattle Genetics. Grant/Research support from: Merck and Astra Zeneca. Travel expenses/Honoraria from: Roche, Merck, Astra Zeneca, and Janssen. Ali SM, Madison R, Ross JS, and Chung JH: employees of Foundation Medicine Inc. Raggi D, Anichini A, Giannatempo P, Briganti A, Massa S, Luciano R, Colecchia M, Mortarini R, Bianchi M, Colombo R, Gallina A, Salonia A, Messina A, Salvioni R, and Montorsi F: no disclosures. Ethics Approval Statement: The study protocol and all amendments were approved by the ethics committee of the sponsor institution. The study was conducted in accordance with the protocol and its amendments, the Good Clinical Practice guidelines, and the provisions of the Declaration of Helsinki. All patients provided written informed consent before enrollment.