Abstract CT003: Preoperative pembrolizumab (pembro) before radical cystectomy (RC) for muscle-invasive urothelial bladder carcinoma (MIUC): Interim clinical and biomarker findings from the phase II PURE-01 study
Authors: Necchi Andrea , Briganti Alberto , Bianchi Marco , Raggi Daniele , Giannatempo Patrizia , Freschi Massimo , Colecchia Maurizio , Fossati Nicola , Gandaglia Giorgio , Colombo Renzo , Gallina Andrea , Salonia Andrea , Salvioni Roberto , Ali Siraj M. , Chung Jon H. , Montorsi Francesco 
Published: August 2018

Abstract
Introduction:
MIUC is an aggressive and cisplatin-based neoadjuvant chemotherapy (CT) is recommended, but it is administered in a minority of pts. Pembro is an EMA and FDA-approved therapy for metastatic UC after platinum failure or for cisplatin-ineligible pts.
Methods:
PURE-01 (NCT02736266) is an open-label, single-arm, phase 2 study to evaluate pembro before RC. Inclusion criteria: predominant UC histology, ≤T3bN0 stage, and eligibility to cisplatin or carboplatin CT. Pts were staged with PET/CT scan and multiparametric bladder MRI (mpMRI), and received 3 cycles of pembro 200mg 3 weekly before RC. No additional anti PD-1/PD-L1 therapy is allowed post-operatively. Pathologic complete response (pT0) is the primary endpoint (with ITT principle for analyses). The H1 is pT0 ≥20% and H0 pT0≤10%. Stopping rules based on Bayesian predictive probability will be applied over the planned total sample size of 90 pts (a0=0.5, b0=0.5, θT=0.90, θL=0.10, θU=0.90, p=0.20).
Biomarker analyses on pre- (TURB) and post-therapy (RC) lesions include: IHC PD-L1 combined positive score (CPS, Dako 22C3) and genomic sequencing with FoundationOne assay (Foundation Medicine Inc., Cambridge, MA, USA), with tumor mutational burden (TMB) quantification. A first interim analysis is presented.
Results:
From 02/17-01/18, 34 pts were enrolled (28M, 6F). 21 had cT3, 13 cT2, 6 had hydronephrosis.
All pts had evident disease at mpMRI before starting pembro. One pt (2.9%) had G3 irAE (ALT increase) and suspended pembro; 5 (14.7%) had reversible G2 irAE. At the time of interim analysis, 22 pts are evaluable for the primary endpoint. There were 7/22 pT0 (31.8%) and 3 pTa/is (total pT≤2 rate: 45.4%). In TURB samples, 100% pT0 pts had PD-L1 CPS&gt;20%, versus all non-pT0 pts who had CPS≤10%. Median TMB in pts with pT≤2 response was 12.28 mut/mb versus 7.02 mut/mb in non-responding pts.
On 6 evaluable pts, substantial differences were found in pre- versus post-therapy mutation profile (mean: 44.5% overlapping mutations), including FGFR alterations.
Conclusion:
Pembro is safe and endowed with a potent antitumor and biological activity in MIUC. Signals toward a strong association between CPS&gt;20% and pT0 response, coupled with higher TMB and pT≤2 response, yield the potential for practice changing, pending full translational findings in this cohort that will be presented at the meeting.
Citation Format: Andrea Necchi, Alberto Briganti, Marco Bianchi, Daniele Raggi, Patrizia Giannatempo, Massimo Freschi, Maurizio Colecchia, Nicola Fossati, Giorgio Gandaglia, Renzo Colombo, Andrea Gallina, Andrea Salonia, Roberto Salvioni, Siraj M. Ali, Jon H. Chung, Francesco Montorsi. Preoperative pembrolizumab (pembro) before radical cystectomy (RC) for muscle-invasive urothelial bladder carcinoma (MIUC): Interim clinical and biomarker findings from the phase II PURE-01 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT003.