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J Clin Oncol. 2018 Oct 20:JCO1801148. doi: 10.1200/JCO.18.01148. [Epub ahead of print]

Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study.

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Andrea Necchi, Andrea Anichini, Daniele Raggi, Simona Massa, Maurizio Colecchia, Patrizia Giannatempo, Roberta Mortarini, Elena Farè, Francesco Monopoli, Antonella Messina, Roberto Salvioni, and Luigi Mariani, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori; Alberto Briganti, Roberta Lucianò, Marco Bianchi, Renzo Colombo, Andrea Gallina, Andrea Salonia, and Francesco Montorsi, Vita Salute San Raffaele University and Urological Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Hospital, Milan, Italy; Siraj M. Ali, Russell Madison, Jeffrey S. Ross, and Jon H. Chung, Foundation Medicine, Cambridge, MA; and Jeffrey S. Ross, Upstate Medical University, Syracuse, NY.



To determine the activity of pembrolizumab as neoadjuvant immunotherapy before radical cystectomy (RC) for muscle-invasive bladder carcinoma (MIBC) for which standard cisplatin-based chemotherapy is poorly used.


In the PURE-01 study, patients had a predominant urothelial carcinoma histology and clinical (c)T≤3bN0 stage tumor. They received three cycles of pembrolizumab 200 mg every 3 weeks before RC. The primary end point in the intention-to-treat population was pathologic complete response (pT0). Biomarker analyses included programmed death-ligand 1 (PD-L1) expression using the combined positive score (CPS; Dako 22C3 pharmDx assay), genomic sequencing (FoundationONE assay), and an immune gene expression assay.


Fifty patients were enrolled from February 2017 to March 2018. Twenty-seven patients (54%) had cT3 tumor, 21 (42%) cT2 tumor, and two (4%) cT2-3N1 tumor. One patient (2%) experienced a grade 3 transaminase increase and discontinued pembrolizumab. All patients underwent RC; there were 21 patients with pT0 (42%; 95% CI, 28.2% to 56.8%). As a secondary end point, downstaging to pT<2 was achieved in 27 patients (54%; 95% CI, 39.3% to 68.2%). In 54.3% of patients with PD-L1 CPS ≥ 10% (n = 35), RC indicated pT0, whereas RC indicated pT0 in only 13.3% of those with CPS < 10% (n = 15). A significant nonlinear association between tumor mutation burden (TMB) and pT0 was observed, with a cutoff at 15 mutations/Mb. Expression of several genes in pretherapy 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.


Neoadjuvant pembrolizumab resulted in 42% of patients with pT0 and was safely administered in patients with MIBC. This study indicates that pembrolizumab could be a worthwhile neoadjuvant therapy for the treatment of MIBC when limited to patients with PD-L1-positive or high-TMB tumors.


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