ASCO 2018: Preoperative Pembrolizumab Before Radical Cystectomy for Muscle-Invasive Urothelial Bladder Carcinoma: Interim Clinical and Biomarker Findings from the Phase 2 PURE-01 Study

Chicago, IL ( There is level 1 evidence suggesting a survival benefit among patients that receive cisplatin-based neoadjuvant chemotherapy for muscle-invasive bladder cancer (MIBC) prior to radical cystectomy compared to immediate radical cystectomy [1]. However, for a variety of reasons, neoadjuvant chemotherapy is only administered to a minority of patients (~20%). With the recent reporting of KEYNOTE-045 in 2017 [2], pembrolizumab was associated with significantly longer overall survival (by approximately 3 months) and a lower rate of treatment-related adverse events than chemotherapy as second-line therapy for platinum-refractory bladder cancer. As such, pembrolizumab use in the neoadjuvant setting is intriguing. Andrea Necchi, MD, and colleagues presented results of their phase 2 PURE-01 trial assessing pembrolizumab before radical cystectomy for MIBC.

The PURE-01 trial is an open-label, single-arm, phase 2 study in Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy to evaluate the activity, medical and surgical safety, and immune modulatory effects of pembrolizumab administered prior to radical cystectomy. Key inclusion criteria for this trial included patients with:

  • Predominantly urothelial carcinoma histology (>50%)
  • Clinical stage ≤3bN0M0 disease by CT, MRI or PET/CT within four weeks of randomization. 
  • Residual disease after TURBT
  • GFR ≥20 ml/min
  • ECOG performance status 0-1
Key exclusion criteria included patients previously treated with chemotherapy for bladder cancer, or malignancies within five years of bladder cancer diagnosis. Pembrolizumab was administered at the dose of 200mg, as a 30-minute IV infusion, every 3 weeks for a total of three cycles prior to radical cystectomy. The primary outcome was a pathologic complete response (pT0) at the time of radical cystectomy in the intention to treat (ITT) population. Secondary outcomes include (i) adverse events, (ii) percentage of treatment-related delay in surgery, and (iii) Frequency of treatment-related adverse events. Biomarker analyses included: IHC PD-L1 combined positive score (CPS) and genomic sequencing with hybrid-capture based comprehensive genomic profiling. Tumor mutational burden (TMB) is determined on 1.1 Mbp of sequenced DNA and reported as mutations per megabase and microsatellite instability was determined on 114 loci. 

The study started enrolling patients in February 2017, and at a data cutoff of May 10, 2018 the median follow-up for PURE-01 was 8 months. The first stage of enrollment included 43 patients, the results of which are discussed herein. Among these patients were 35 males/7 females, with 37.2% of patients with cT2N0 disease, 58.1% with cT3N0, and 4.7% of patients with T2-3N1. At the time of this analysis, there were 17/43 patients that were pT0 (39.5%, 95%CI: 26.3-54.4) and 5 <pT2 (total <pT2 rate: 51.2%). Treatment failures were categorized as follows:

  • ypT2-4 ypN0: n=7, 16.3%
  • ypTany ypN+: n=9, 20.9%
  • Clinical failure (additional neoadjuvant chemotherapy): n=5, 11.6%
There were 59% of patients with tumor mutation burden > 10 mut/mb and 9% > 20 mut/mb. All tumors were microsatellite stable. In TURBT samples, the mean CPS score for pT0 patients was 30% vs 10% for non-pT0 patients, whereas mean tumor mutation burden was 13.16 mut/mb for pT0 patients vs 11.41 mut/mb for non-pT0 patients. DDR and/or RB1 genomic alterations were seen in 25/43 patients (58.1%), whereas DDR and/or RB1 genomic alterations and PD-L1 CPS ≥20% occurred in 10/43 patients (23.3%). The most common grade 1-2 AE was hypothyroidism (11%), and one patient had a grade 3 treatment-related AE (ALT increase) and suspended pembrolizumab; 6 patients (13.9%) had reversible grade 2 AEs. All 43 patients underwent radical cystectomy, with 20.9% of patients having a Clavien-Dindo Grade IIIa complication, 11.6% with IIIb, and 2.3% with grade IV.

Necchi concluded with several important messages:

  1. Neoadjuvant pembrolizumab was associated with few side effects, did not delay surgery, and induced a complete pathological response in nearly 40% of patients
  2. Immune genomic features and their modulation were disclosed in the non-metastatic setting
  3. DDR, RB1 genomic alterations and PD-L1 CPS may constitute the algorithm for selecting which patients deserve a bladder-sparing approach after response assessment: ie. TURBT pembrolizumab re-TURB  maintenance pembrolizumab.
Clinical trial information: NCT02736266

1. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349(9):859-866.
2. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 2017;376(11):1015-1026.

Presented by: Andrea Necchi, MD, Istituto Nazionale dei Tumori, Milan, Italy
Co-Authors: Alberto Briganti, Marco Bianchi, Daniele Raggi, Patrizia Giannatempo, Roberta Luciano', Maurizio Colecchia, Simona Massa, Marco Bandini, Nicola Fossati, Giorgio Gandaglia, Renzo Colombo, Andrea Gallina, Andrea Salonia, Roberto Salvioni, Siraj Mahamed Ali, Jeffrey S. Ross, Jon Chung, Francesco Montorsi; Vita-Salute San Raffaele University, Urological Research Institute, IRCCS San Raffaele Hospital, Milan, Italy; Vita Salute San Raffaele University and Urological Research Institute (URI), IRCCS San Raffaele Hospital, Milano, Italy; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; IRCCS San Raffaele Hospital, Milano, Italy; Vita-Salute San Raffaele University, Milan, Italy; IRCCS Ospedale San Raffaele, Milan, Italy; Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy; Vita-Salute San Raffaele University, Urological Research Institute, IRCCS San Raffaele Hospital, Milano, Italy; Foundation Medicine, Inc., Cambridge, MA; SUNY Upstate Medical University, Syracuse, NY; Universita Vita Salute San Raffaele, Milan, Italy

Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA