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

This study was 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.

Written By: Andrea Necchi1, Andrea Anichini1, Daniele Raggi1, Simona Massa1, Maurizio Colecchia1, Patrizia Giannatempo1, Roberta Mortarini1, Elena Farè1, Francesco Monopoli1, Antonella Messina1, Roberto Salvioni1, Luigi Mariani1, Alberto Briganti2, Roberta Lucianò2, Marco Bianchi2, Renzo Colombo2, Andrea Gallina2, Andrea Salonia2, Francesco Montorsi2, Siraj M. Ali3, Russell Madison3, Jeffrey S. Ross3, Jon H. Chung3

Authors Affiliations:
1: Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori.
2: Vita Salute San Raffaele University and Urological Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Hospital, Milan, Italy.
3: Foundation Medicine, Cambridge, MA; and Jeffrey S. Ross, Upstate Medical University, Syracuse, NY.

J Clin Oncol. 2018 Oct 20:JCO1801148. doi: 10.1200/JCO.18.01148. 

Read the Expert Commentary by Bishoy M. Faltas, MD