Daneshmand, S.

TPS913 Background: A subset of patients with MIBC who receive neoadjuvant therapy (NAT) prior to radical cystectomy (RC) have a pathologic complete response (pCR) at the time of RC. With pCR rates of 22-42% in patients with MIBC following NAT (+/- ICI), whether a subset of patients with good clinical response to NAT can avoid RC is an important unanswered question, especially with the development of more active systemic therapies. HCRN 16-257 evaluated maintenance nivolumab in lieu of cystectomy in patients with MIBC who experienced clinical complete response (cCR) following neoadjuvant GC and nivolumab. The cCR rate was 48%, but 8/33 (24%) patients who elected bladder preservation subsequently underwent cystectomy for local disease recurrence. The RETAIN trial also evaluated omission of local therapy following neoadjuvant therapy with a 2-year bladder preservation rate in patients with ≤T1 disease following NAC of 54% (22/41). Of the 9/25 (36%) patients on that trial developed metastatic disease, 8/9 developed localized disease before metastasizing. These data illustrate the critical role that local therapy plays in patients with MIBC. For this reason, we believe that radiotherapy to the bladder combined with ICI will improve bladder intact event-free survival (BI-EFS). This trial also allows for patients to opt for bladder preservation based on a good clinical response to NAT. Methods: This is a single arm, phase 2 trial (NCT07061964) evaluating risk-adapted bladder preservation therapy for patients with MIBC following NAT. NAT consists of any NCCN guideline concordant therapy for MIBC. Patients with cT2-T4aN0M0 MIBC who complete NAT will be eligible if they have ≤T1 disease on post-NAT TURBT, confirmed by biopsies of prior tumor sites and systematic sampling (left/right lateral walls, dome, posterior wall, trigone). Patients will receive 55 Gray (Gy) in 20 fractions of radiotherapy (RT) to the bladder with 1 year of pembrolizumab. The primary objective is to evaluate whether 3-year BI-EFS is at least 70% in participants with < = T1 (without multifocal CIS) following NAT and RT with 1 year of pembrolizumab. Secondary objectives include local muscle invasive recurrence-free survival, metastasis-free survival (MFS), overall survival (OS), the rate of salvage cystectomy, and evaluation of the frequency and severity of toxicities in participants who receive RT and pembrolizumab. Plasma and urine will be banked for future correlative studies. S2427 was activated in September 2025 with an accrual goal of 111 patients. Clinical trial information: NCT07061964 .

LBA629 Background: Whether BCG strain influences clinical efficacy is unclear. BCG shortages and a reliance on a single strain may impact disease outcomes. Evidence also suggests that priming with intradermal (ID) BCG vaccination prior to intravesical (IVe) BCG enhances anti-tumor immunity and cancer clearance. Co-primary objectives address these issues. Methods: The trial design calls for 924 eligible patients with BCG naïve non-muscle invasive bladder cancer (NMIBC) (HG Ta/T1 +/- CIS or CIS alone) with negative purified protein derivative (PPD) to be randomized in a 1:1:1 ratio, to IVe TICE (Arm 1), IVe Tokyo-172 (Arm 2), or ID + IVe Tokyo-172 (Arm 3) BCG, stratifying on age group and clinical stage. IVe BCG included 6 weekly instillations (induction) and three weekly instillations (maintenance) at 3 and 6 months (mo), then every 6 mo for 3 years. Objective 1 tests whether Tokyo-172 BCG is non-inferior (NI) to TICE BCG, specifying a NI hazard ratio=1.34 (84% power). Objective 2 tests whether priming with ID prior to IVe Tokyo-172 is superior to IVe Tokyo-172 (HR=0.71, 83% power). The primary endpoint is high-grade recurrence-free survival (HG-RFS) censored at last cystoscopy, using a one-sided α=0.021 for each test. A Cox model adjusting for the stratification factors is used. Secondary endpoints include adverse events, 6-mo biopsy-proven complete response (CR) in patients with CIS +/- Ta, T1, duration of CR, PPD conversion and HG-RFS, progression-free survival (PFS) and quality of life. Max follow-up is 5 years. Results: 1000 (984 eligible) patients were enrolled from 2/17-12/20. Median (IQR) follow up is 4.6 (3.6, 5.0) yrs. Median age (range) is 70 yrs (26, 99), 17% are female, 9% are non-white, and 34% had CIS at entry. HG-RFS, CR, duration of CR at 4 yrs, and PFS were similar among arms (Table). PPD conversion occurred in 29% and was not correlated with HG-RFS. Gr 1-2 AE rate was similar (67%, 71%, and 67%) and Gr 3-4 (no Gr 5s) rate was 6%, 11%, and 14% for Arms 1,2, and 3, respectively. Conclusions: Tokyo-172 is non-inferior to TICE BCG in terms of HG RFS and CIS CR and is similar for PFS. Gr 3-4 AE rate is higher with Tokyo-172. Priming with Tokyo-172 BCG does not improve HG RFS. PPD conversion is not prognostic. Clinical trial information: NCT #03091660 . CIS Component N (eligible) 5-yr HG RFS HG RFSHR (95.8% CI) @ 5-yrPFS PFS HR(95% CI) @ CR %(95% CI) 4 yr CR duration Tice Ive 333 (330) 58% 79% 62%; 71/114(53%, 71%) 80% Tokyo Ive 332 (327) 64% *0.82(0.63, 1.08) 79% *0.99(0.70, 1.39) 60%; 66/110(50%, 69%) 83% Tokyo ID + Ive 335 (327) 63% **1.00(0.76, 1.33) 77% **1.07(0.76, 1.51) 63%; 69/109(54%, 72%) 80% 3 mo. PPD + conversionY vs. N 782 evaluable225 (29%)557 (71%) 69%67% ^HR=0.91(0.68, 1.22) * Tokyo-172 vs. Tice, ** Tokyo Priming vs. Tokyo no priming. ^conversion to PPD + vs. – @ adjusted for 2 strat factors (and arms for PPD model). PFS event = MIBC, metastasis, or death.

755 Background: Patients with High-Risk BCG-Unresponsive Non-Muscle Invasive Bladder Cancer have limited treatment options. The US FDA approved treatments for BCG-UR patients with CIS, but additional bladder-sparing therapies are needed, especially for the BCG-UR papillary-only population. Cretostimogene is an oncolytic immunotherapy with dual mechanisms of action. It replicates in and lyses cancer cells with Rb-E2F pathway alterations. This releases tumor-specific antigens, initiating an anti-tumor immune response, further amplified by the GM-CSF transgene. The BOND-003 Cohort P study (NCT04452591) is a single-arm clinical trial assessing the efficacy and safety of intravesical cretostimogene in HR, papillary-only, BCG-UR NMIBC patients. Methods: Eligibility criteria include age ≥18 years, ECOG PS of 0-2, and histologically confirmed BCG-UR HG Ta/T1 papillary disease without CIS within 90 days of study enrollment as verified per central pathology review. Patients had no visible evidence of residual bladder cancer before treatment. Intravesical cretostimogene is instilled for six weekly doses during the induction phase, followed by three weekly maintenance cycles quarterly through Month 12, then every six months through Month 36. Re-induction is permitted at 3 months for patients with HG Ta or CIS. Primary disease assessments include serial cystoscopy, urine cytology, axial imaging, and mandatory biopsy directed at prior tumor locations at Month 12, with centralized review of pathologic samples. Endpoints include HG-RFS, HG-EFS, PFS, and safety. The study has completed enrollment. Results: A total of 56 patients who received treatment with cretostimogene are evaluated based on data from September 1, 2025 cut off. At baseline, 76.7% of patients are 65 years or older, 21.4% are female, 64.3% have HG Ta, and 35.7% have HG T1 papillary NMIBC. Kaplan-Meier estimates of HG-RFS at 6- and 9-months are 84.6% (95% CI 73.1 - 96.1%) and 80.4% (95% CI 66.8-94.0%), respectively. No patients have undergone a radical cystectomy. One patient progressed to metastatic disease despite a clinical complete response in the bladder. Cretostimogene demonstrates a favorable safety profile, with most adverse events localized to low grade bladder symptoms. There are no serious treatment-related adverse events and no discontinuations related to cretostimogene. To date, no patients have required a dose delay or missed a dose due to a related adverse event. There have been no deaths related to study treatment. Further, updated data will be presented. Conclusions: These results demonstrate consistent efficacy and a well-tolerated safety profile. Mature data with longer term follow-up will build upon these promising findings and will inform future treatment approaches with cretostimogene. Clinical trial information: NCT04452591 .