Background: Trimodality therapy (TMT) is a standard treatment option for MIUC. We previously reported an early analysis of a phase II study of pembro added to standard TMT with maximal transurethral resection of bladder tumor (TURBT), hypofractionated RT and twice weekly gem (ASCO 2021). Herein we present updated follow up safety and efficacy results. Methods: In this multicenter phase 2 trial, patients (pts) with clinical T2-T4aN0M0 MIUC who were ineligible fpr or declined radical cystectomy, had ECOG PS 0/1 and eGFR≥30 cc/min were enrolled. Pts received pembro 200 mg IV x 1 followed by maximal TURBT and then whole bladder RT (52 Gy/20 fx) with twice weekly gem 27 mg/m² and pembro Q3 wks x 3 treatments. Response was assessed every 12 weeks post-RT with CT/MRI, tumor bed biopsy and cytology. The primary endpoint was 2-yr bladder-intact disease-free survival (BIDFS; first of MIUC, regional or distant metastases, cystectomy or death). Our study had 85% power to detect a 20% absolute improvement in 2-yr BIDFS rate over 60% historical rate (Mak JCO 2014). Key secondary endpoints included safety, 12-week pathologic complete response (CR) rate, metastases-free survival (MFS) and overall survival (OS). Results: Between 5/2016 and 6/2022, 54 pts (median age 74 years, 72% male, 83% Caucasian; clinical stage: 74% T2, 22% T3 and 4% T4) were enrolled at 5 institutions. PD-L1 status was available in 43 pts, and 21 pts (49%) had modified proportion score≥10. Forty-six (88%) pts completed all therapy. 1/54 (2%), 3/54 (6%), and 4/54 (7%) discontinued RT/Gem, Gem or Pembro, respectively, most commonly due to toxicity. 6 pts (11%) underwent salvage cystectomies. As of 6/2022, with a median FU of 23 months (1.6- 62.7) there were 12 (22%) tumor recurrences (3 MIUC, 5 locoregional, 4 distant). 4 pts (7%) had non-muscle invasive only recurrences. The efficacy outcomes are shown. 10 pts died during the study period (18%; 3 from disease progression, 1 from treatment toxicity and 6 from unrelated/unknown causes). There were no new safety signals in our updated analysis: 13 pts (24%) experienced 17 AEs that were Grade 3 or greater (cytopenias [n=7], colitis [n=5], cystitis [n=2], polyneuropathy, fatigue, hypokalemia [n=1, each]). Grade 3 or greater immune-related AEs included 2 pts with colitis, 1 pt with polyneuropathy and 1 pt with Grade 5 colonic perforation. Conclusions: TMT combined with pembro was well tolerated and continues to show promising early outcomes data. A large phase 3 trial is underway to further explore this treatment. Clinical trial information: NCT02621151.

CI, confidence interval; ITT, intention to treat; NA, not applicable; NR, not reached.