An open-label, phase 2 study of personalized approach with perioperative immunotherapy for bladder preservation in muscle-invasive urothelial bladder carcinoma (MIBC).
Authors: Necchi Andrea , Raggi Daniele , Marandino Laura , Martini Alberto , Cereda Stefano , Malena Greta , Moschini Marco , Briganti Alberto , Salonia Andrea , Lucianò Roberta , Colecchia Maurizio , Montorsi Francesco 
Published: February 2022

TPS590 Background: Radical cystectomy (RC) without neoadjuvant chemotherapy is standard-of-care for cisplatin (cis)-ineligible pts (and those refusing cisplatin) with MIBC. Checkpoint inhibitors (CPIs) are being actively explored in the perioperative setting. CPIs documented a 42% pathologic complete response-rate (ypT0N0) in our previous trial (PURE-01, NCT02736266). In this trial, programmed cell-death ligand-1 (PD-L1) expression was associated with ypT0N0 response ( Necchi A, et al. Eur Urol. 2019), and a cohort of PD-L1+ pts who refused RC are still alive at long-term follow-up ( Bandini, Ann Oncol 2020). Initial data from trials aimed at delivering a systemic therapy while sparing any local therapy on the bladder tumor in highly-selected pts are promising ( Galsky, 2021, Geynisman, 2021). Sasanlimab (SASI) is a humanized, hinge region–stabilized (21) IgG4 mAb directed against human PD-1. Sasanlimab is currently being tested subcutaneously (SQ) in a phase III study in non-MIBC. Our hypothesis is that SASI can be offered in PD-L1+ pts as an exclusive therapeutic option instead of any additional treatment, after a clinical complete response (cCR) with an induction phase. Methods: This is a Phase 2, open-label, non-randomized, single-cohort study in pts with MIBC who are ineligible or unwilling to receive cisplatin-based neoadjuvant chemotherapy. The study will include pts with a PD-L1 CPS≥10% in tumor biopsy.Other key inclusion criteria: UC histology, an ECOG PS 0−1. Cis-ineligibility is defined as one of the following: glomerular filtration rate ≥30 but < 60 mL/min, or CTCAE v5 ≥grade 2 hearing loss or peripheral neuropathy. Key exclusion criteria: clinical evidence of ≥N1 or metastatic disease or UC in upper urinary tract; prior systemic therapy, radiation therapy, or prior RC. Pts will undergo a transurethral resection of the bladder (TURBT), a CT scan, and a 18FDG-PET/CT scan. SASI will be administered SQ at the recommended dose of 300mg for a total of 3 cycles every 4 weeks prior to redo-TURBT. Pts who will achieve a cCR (i.e., no evidence of residual viable tumor at re-TURBT sample, urinary cytology and imaging tests) will receive additional SASI treatment for a total period of 12 months, every 4 weeks. Pts with non-CR will be excluded from the study and start treatment according to guidelines or investigator preference. Primary endpoint: event-free survival (EFS). Secondary endpoint: proportion of cCR. According to Simon's 2-stage MinMax design, a total of 55 pts will be included, and we anticipate the need for enrolling 110 pts for the neoadjuvant phase of the study. This assumption will correspond to the need for screening approximatively 220 pts onto this trial. Exploratory analyses will include: artificial intelligence through multiparametric bladder MRI/PET, and ctDNA analyses pre-post neoadjuvant period. Clinical trial information: 2021-001649-10.