Preoperative Pembrolizumab (pembro) before Radical Cystectomy (RC) for Muscle-invasive Urothelial Bladder Carcinoma (MIUC): Interim Clinical and Biomarker Findings from the Phase 2 PURE-01 study.
METHODS: PURE-01 (NCT02736266) is an open-label, single-arm, phase 2 study. Pts have predominant UC histology and cT≤3bN0 stage. Pts are enrolled regardless of cisplatin eligibility. Disease assessment is made via CT, PET/CT, and multiparametric bladder MRI (mpMRI). Pts receive 3 cycles of pembro 200mg q3w before RC. Pathologic complete response (pT0) in ITT population is the primary endpoint. The H1 is pT0 ≥25% and H0 pT0≤15%. 71 pts will be enrolled, with 43 pts at first stage according to MinMax design. ≥7pT0 are required at first stage. Biomarker analyses include: IHC PD-L1 combined positive score (CPS, Dako 22C3) 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 (mut) per megabase (Mb) and microsatellite instability is determined on 114 loci.
RESULTS: From 02/17-02/18, the first stage of 43 pts was completed (36M, 7F). 27 had cT3, 16 cT2; 59% had TMB > 10 mut/mb; 9% TMB > 20 mut/mb. All tumors were microsatellite stable. All pts had evident disease at mpMRI before pembro. One pt (2.3%) had G3 irAE (ALT increase) and suspended pembro; 6 (13.9%) had reversible G2 irAE. At the time of this analysis, 25 pts are evaluable for the primary endpoint. There were 8/25 pT0 (32%, 95%CI: 16.7-47.6) and 3 pTa/is (total pT < 2 rate: 44%). In TURB samples, mean CPS score for pT0 pts was 44.8% vs 17.4% non-pT0 pts (p < 0.001), mean TMB was 11.2 mut/mb vs 11.2 mut/mb, respectively. On 9 evaluable pts, substantial differences were found in pre- vs post-pembro genomic alterations (GA). Mean pre-pembro GA/tumor was 8.7; mean post-pembro GA/tumor was 7 (mean 47.5% overlapping GA).
CONCLUSIONS: Pembro is safe and has already exceeded the pT0 responses required at first stage. PD-L1 CPS may be predictive of pT0 response, and full translational findings at first stage will be presented. Clinical trial information: NCT02736266.
Journal of Clinical Oncology. 2018 June 01 [Epub]
Andrea Necchi, 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
Istituto Nazionale dei Tumori, Milan, Italy; 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
Journal of Clinical Oncology 36, no. 15_suppl (May 2018) 4507-4507; DOI: 10.1200/JCO.2018.36.15_suppl.4507