Steinberg, Gary D.

741 Background: A significant treatment gap exists for efficacious, well-tolerated bladder-sparing options for patients with HR BCG-UR NMIBC with CIS. Cretostimogene is an oncolytic immunotherapy with dual mechanisms of action. It replicates in and lyses cancer cells with Rb-E2F pathway alterations, while simultaneously amplifying an anti-tumor immune response, further mediated by the GM-CSF transgene. BOND-003 (NCT04452591) is a phase-3 study evaluating the efficacy and safety of cretostimogene in patients with HR BCG-UR NMIBC with CIS +/- HG Ta/T1 (Cohort C) and HG Ta/T1 only (Cohort P). We report data on radical cystectomy performed post-recurrence or progression on Cohort C. Methods: 112 patients were enrolled. Participants had previously received adequate BCG and were considered BCG-UR by the FDA definition. Cretostimogene treatment consisted of a 6 weekly induction course, followed by 3 weekly maintenance cycles every 3 months at year one and every 6 months during years 2-3. Repeat induction was permitted at Month 3, if persistent HG Ta or CIS. Response assessments included serial cystoscopy, urine cytology, and mandatory mapping biopsy at 12 mo, with centralized review of all pathology. The primary endpoint was Complete Response (CR) at any time. Cystectomy-Free Survival (CFS) and Progression-Free Survival (PFS) were key secondary endpoints. Results: As of the June 23, 2025 data cutoff (median follow-up of 25.8 months), the CR rate at any time is 75.5% (83/110) (95% CI 66.3-83.2%). Kaplan-Meier estimates of 12- and 24-month DoR are 64.2% (95% CI 52.5-73.8%) and 60.1% (95% CI 48.2-70.0%), respectively, with a median DoR of 27.9 months (95% CI 14.3-NE%) and ongoing. The 12- and 24- month CR rate is 46.4% (51/110) (95% CI 36.8-56.1%) and 41.8% (46/110) (95% CI 32.5-51.6%), respectively. The 12- and 24-month CFS rates are 89.2 (95% CI 81.3-93.9) and 81.3% (71.8-87.8), respectively, with median CFS not reached. Among 18 patients who underwent radical cystectomy post-disease recurrence or progression; 15 (83.3%) had NMIBC or pT0 on final pathology. At 12- and 24- months, 96.6% are free from ≥T2 progression. Cretostimogene has a well-tolerated safety profile, with no grade ≥3 treatment-related adverse events. Conclusions: Cretostimogene offers distinct advantages with its mechanism of action, efficacy, durability and safety profile for the treatment of HR BCG-UR NMIBC. Furthermore, a significant proportion of patients receiving cretostimogene remained progression-free and avoided radical cystectomy. Most patients who underwent radical cystectomy had NMIBC or pT0 on final pathology maintaining a window of opportunity. Ongoing and future investigations of cretostimogene, as monotherapy and in rational combinations, may address the considerable unmet need for patients with bladder cancer. Clinical trial information: NCT04452591 .

686 Background: Blue-light cystoscopy (BLC) is an established procedure for use in the diagnosis and surveillance of patients with non-muscle-invasive bladder cancer (NMIBC). It is associated with improved detection rates compared to white light cystoscopy (WLC); however, limited data is available regarding its role in upstaging and/or upgrading when used alongside WLC. The aim of this study is to assess the incidence and features of patients undergoing upstaging and/or risk-group migration with the implementation of BLC. Methods: Using data from the prospective multi-institutional Cysview Registry (2014-2024), patients with NMIBC who underwent transurethral resection or biopsy of bladder tumors were identified. The patients in whom malignant lesions were exclusively detected by BLC, as well as those experiencing an upward change in risk category (as defined by the American Urological Association [AUA] classification) based on BLC findings, were documented. The clinical features of these patients were subsequently reviewed. Results: In this study, 2,854 patients were enrolled, who collectively underwent 4,158 resections and provided 6,432 separate pathology samples. A total of 201 (7%) patients had at least one malignant lesion detected exclusively by BLC while having negative WLC. These lesions (total 335) included carcinoma in-situ (CIS) in 145 (43%), low-grade Ta in 53 (16%), high-grade Ta in 95 (28%), high-grade T1 in 37 (11%), and high-grade T2 in 5 (1%). In patients with multifocal disease, BLC resulted in AUA risk-group upward migration in 66 (2.3%) patients.Theclinical features of these two groups are presented in the table. Taken together, the total rate of upgrading or upstaging using BLC was 9.3%, including migration to low-risk in 1.2%, intermediate-risk in 2.1%, and high-risk in 6%. Conclusions: Using BLC during transurethral resection or biopsy of bladder tumors results in risk group migration in over 9% of patients with NMIBC. This impacts patient management, including the administration of intravesical therapy when it was not initially planned, an extension in the duration of therapy, or the decision to proceed with radical cystectomy. Clinical features of patients with malignant lesions detected by BLC only (A) and those with risk group migration (B). Clinical features A B Age, median (IQR), year 71 (63-76) 71 (61-77) Gender, n (%) Male Female 140 (74)49 (26) 54 (82)12 (18) History of smoking, n (%) 117 (62) 40 (61) Primary occurrence, n (%) 65 (34) 14 (21) History on intravesical therapy, n (%) 92 (49) 40 (61) Urine cytology * , n (%) Positive Suspicious Atypical Negative/NA 33 (17)21 (10)41 (20)106 (53) 13 (20)7 (11)10 (15)36 (54) IQR: interquartile range; NA: not available. *Detected by either voided urine or bladder wash.

4601 Background: Cretostimogene grenadenorepvec is a type-5 oncolytic adenovirus designed to selectively replicate in bladder cancer cells with alterations in the retinoblastoma pathway. Additionally, the virus is engineered to express the GM-CSF transgene, resulting in a potent oncolytic immunotherapy mode of action. Cretostimogene monotherapy recently received Food and Drug Administration (FDA) Fast Track and Breakthrough Therapy Designations (BTD) in the BCG-Unresponsive, High-Risk, non-Muscle Invasive Bladder Cancer with Carcinoma in Situ (BCG-UR HR NMIBC with CIS) indication with a Complete Response (CR) at any time rate of 76%. This phase-2 study assessed the potential synergy between intravesical cretostimogene and pembrolizumab in patients with BCG-UR, HR NMIBC, with CIS, with or without Ta/T1 tumors. This combination has also received BTD from the FDA. Methods: 35 pts were treated with cretostimogene (1x1012 viral particles) in combination with pembrolizumab at a dose of 400 mg IV q6 weeks. Cretostimogene induction was given as 6 weekly intravesical instillations followed by 3 weekly maintenance doses at months 3, 6, 9, 12, and 18. Pts with persistent CIS or high-grade Ta tumors at the 3mo assessment were eligible for re-induction. Pembrolizumab was administered for up to 24mo. Response assessments included cystoscopy, urine cytology, cross-sectional imaging, and mandatory bladder mapping biopsies at 12mo. The primary endpoint was CR at 12mo. Secondary endpoints included CR at any time, duration of response (DOR), CR at 24mo, cystectomy-free survival, and safety. Exploratory endpoints included analyses of baseline viral receptor expression, free E2F levels, PD-L1 status, urinary cytokine panels and measures of viral replication. Results: 30/35 pts are evaluable per protocol for the primary endpoint. Five pts discontinued prior to the 12mo time point. The CR rate in the Intention to Treat (ITT) population at 12mo and any time, was 57% (20/35) (95% CI 40-73%) and 83% (29/35) (95% CI 66-93%), respectively. Median DOR has not been reached but exceeds 21mo. The current CR rate in the ITT population at 24mo is 46% (16/35) (95% CI 29-63%). Three pts have yet to reach the 24mo time point. Cystectomy-free survival at 21mo is 80%. Complete data on the ITT and evaluable patient cohorts will be presented. Analyses of treatment-related adverse events (AE) are consistent with the individual agents and demonstrate no synergistic toxicity. Conclusions: The efficacy and safety of cretostimogene plus pembrolizumab for treatment of BCG-UR, HR NMIBC with CIS demonstrates best-in-class CR and DOR compared to current FDA-approved therapies, with an acceptable AE profile. Further investigation of this promising combination therapy is warranted and may serve to address a considerable unmet need. Clinical trial information: NCT04387461 .

The use of blue light cystoscopy (BLC) has been shown to improve bladder tumor detection. However, data demonstrating the efficacy of BLC across different races are limited. Herein, we aim to evaluate heterogeneity in the characteristics of BLC for the detection of malignant lesions among various races. Clinicopathologic information was collected from patients enrolled in the multi-institutional Cysview® registry (2014–2021) who underwent transurethral resection or biopsy of bladder tumors. Outcome variables included sensitivity and negative and positive predictive values of BLC and white light cystoscopy (WLC) for the detection of malignant lesions among various races. Overall, 2379 separate lesions/tumors were identified from 1292 patients, of whom 1095 (85%) were Caucasian, 96 (7%) were African American, 51 (4%) were Asian, and 50 (4%) were Hispanic. The sensitivity of BLC was higher than that of WLC in the total cohort, as well as in the Caucasian and Asian subgroups. The addition of BLC to WLC increased the detection rate by 10% for any malignant lesion in the total cohort, with the greatest increase in Asian patients (18%). Additionally, the positive predictive value of BLC was highest in Asian patients (94%), while Hispanic patients had the highest negative predictive value (86%). Our study showed that regardless of race, BLC increases the detection of bladder cancer when combined with WLC.

TPS582 Background: The majority of patients with bladder cancer present with non-muscle invasive disease (Chang 2016; Woldu 2017; Kates 2020; Li 2020). The standard of care for treatment of high risk NMIBC involves transurethral resection of the bladder tumor (TURBT) followed by intravesical Bacillus Calmette-Guerin (BCG) or chemotherapy. Although the response rate to BCG therapy is high, many patients recur within 1–5 years (Matulay JU 2021). For patients who have BCG unresponsive disease after adequate course of BCG, there are limited options. While radical cystectomy (RC) is still considered the standard of care, most patients are reluctant to undergo RC and their options are limited to intravesical chemotherapy or pembrolizumab. Enfortumab vedotin (EV) is an antibody-drug conjugate directed to Nectin-4, which is highly expressed in bladder tumors. In EV-301, a phase 3 study, EV showed an OS benefit vs chemotherapy in patients with locally advanced or metastatic urothelial carcinoma (la/mUC) who had previously received platinum-based therapy and a PD-1 or PD-L1 inhibitor (Powles NEJM 2021). Based on its demonstrated benefit in la/mUC, EV is currently being evaluated in earlier UC settings. The purpose of this study is to investigate the intravesical administration of EV for patients with NMIBC. Methods: EV-104 (NCT05014139) is a phase 1, open-label, multicenter, dose-escalation and dose-expansion study designed to evaluate the safety, tolerability, PK, and antitumor activity of intravesical EV in adults with high-risk BCG-unresponsive NMIBC (carcinoma in situ with or without papillary disease) who are ineligible for or refuse RC. The dose escalation part of the trial aims to identify the maximum tolerated dose (MTD) and/or recommended dose of intravesical EV. The dose expansion part will evaluate patients at the MTD or recommended dose and further characterize safety and antitumor activity of intravesical EV. The study treatment regimen will include an induction phase, where patients will receive intravesical EV weekly for 6 weeks followed by monthly maintenance for a total of 9 additional EV doses. Patients will be assessed for response every 3 months by cystoscopy and urine cytology, while on study. Safety and antitumor activity endpoints will be summarized using descriptive statistics. The study is currently enrolling in the US with additional sites planned in Canada and the EU. Clinical trial information: NCT05014139 .

Abstract Introduction: CG0070, is an Ad5-based oncolytic vaccine engineered to express GM-CSF and replicate selectively in tumor cells with mutated or deficient RB. The CG0070 mechanism of action includes cell lysis and immunogenic cell death which is enhanced in the presence of GM-CSF. In an open label ph. 2 study, an overall CR rate of 62% and a CR at 12 months (m) of 29% have been observed in patients with high risk NMIBC previously treated with BCG. IV pembrolizumab, was recently approved by the FDA for patients with BCG-unresponsive CIS (with or without papillary tumors) with an overall complete RR of 41% and a 12 m CR rate of ~20%.This ph. 2 study will assess the potential synergy of the two agents in the treatment of BCG-unresponsive NMIBC. Methods:35 pts with BCG-unresponsive CIS with or without concurrent Ta or T1 disease will be treated with intravescical CG0070 (1x1012 vp) in combination with pembrolizumab at a dose of 400 mg IV q6 weeks. CG0070 will be administered weekly x 6 as induction followed by weekly x 3 maintenance instillations at months 3, 6, 9, 12, and 18. Pts with persistent CIS or HG Ta at 3 m may receive re-induction with weekly x 6 of CG0070. Pembrolizumab will be administered up to 24 m. Assessment of response will include q 3 m cystoscopy with biopsy of areas suspicious for disease, urine cytology, CTU/MRU, and mandatory bladder mapping biopsies at 12 m. Recurrence of HG disease will be enumerated as disease recurrence. The primary endpoint of the study is CR at 12 m. Secondary endpoints will include CR at any time, progression free survival, duration of response, cystectomy free survival and the safety of the combination. Correlate assessments will include changes in the tumor immune microenvironment, systemic immune induction, viral replication and transgene expression. Baseline expression of PD-L1, coxsackie adenovirus receptor, E2F transcription factor as well as anti-Ad5 Ab titer will be correlated with tumor response. Results: Thus far, 10 patients are evaluable at the 3 m timepoint for efficacy. Assessment of these 10 pts demonstrates 100% CR at 3 mos. Six of the 10 pts have also reached the 6 m hallmark in a CR as well as 2 at the 12 mos timepoint. Treatment related AE have been limited to transient grade 1-2 local-regional genitourinary adverse events with no grade 3 or 4 treatment related AE reported date. Conclusions: This initial data on the efficacy and safety of CG0070 plus pembrolizumab for the treatment of BCG unresponsive NMIBC is encouraging. An update on the study will be provided at the time of presentation. Citation Format: Roger Li, Gary Steinberg, Paras Shah, Ed Uchio, Donald Lamm, Trinity Bivalacqua, Vignesh Packiam, Ashish Kamat, Michael Chisamore, John McAdory, Paola Grandi, Jee-Hyun Kim, James Burke. CORE1: Phase 2, single arm study of CG0070 combined with pembrolizumab in patients with non-muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guerin (BCG) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT036.

4597 Background: CG0070, is an Ad5-based oncolytic vaccine engineered to express GM-CSF and replicate selectively in tumor cells with mutated or deficient RB. The CG0070 mechanism of action includes cell lysis and immunogenic cell death which is enhanced in the presence of GM-CSF. In an open label ph. 2 study, an overall CR rate of 62% and a CR at 12 months (m) of 29% have been observed in patients with high risk NMIBC previously treated with BCG. IV pembrolizumab, was recently approved by the FDA for patients with BCG-unresponsive CIS (with or without papillary tumors) with an overall complete RR of 41% and a 12 m CR rate of ̃20%. This ph. 2 study will assess the potential synergy of the two agents in the treatment of BCG-unresponsive NMIBC. Methods: 35 pts with BCG-unresponsive CIS with or without concurrent Ta or T1 disease will be treated with intravescical CG0070 (1x1012 vp) in combination with pembrolizumab at a dose of 400 mg IV q6 weeks. CG0070 will be administered weekly x 6 as induction followed by weekly x 3 maintenance instillations at months 3, 6, 9, 12, and 18. Pts with persistent CIS or HG Ta at 3 m may receive re-induction with weekly x 6 of CG0070. Pembrolizumab will be administered up to 24 m. Assessment of response will include q 3 m cystoscopy with biopsy of areas suspicious for disease, urine cytology, CTU/MRU, and mandatory bladder mapping biopsies at 12 m. Recurrence of HG disease will be enumerated as disease recurrence. The primary endpoint of the study is CR at 12 m. Secondary endpoints will include CR at any time, progression free survival, duration of response, cystectomy free survival and the safety. Correlate assessments will include changes in the tumor immune microenvironment, systemic immune induction,viral replication and transgene expression. Baseline expression of PD-L1, coxsackie adenovirus receptor, E2F transcription factor as well as anti-Ad5 Ab titer will be correlated with tumor response. Results: A CR rate of 87.5% (14/16) at the 3 m assessment timepoint has been observed thus far. All patients in CR at 3 m remain in CR at downstream timepoints including: 9/9 at 6 m, 6/6 at 9 m, and 3/3 at 12 m. Treatment related AE have been generally limited to transient grade 1-2 local-regional genitourinary adverse events with no reports of grade 3, 4 or SAE attributed to treatment with CG0070/Pembroluzimab. Conclusions: This initial data on the efficacy and safety of CG0070 plus pembrolizumab for the treatment of BCG unresponsive NMIBC is encouraging. Additional data on efficacy as well as safety and biomarker (CAR, E2F, and PDL1) assessment will be presented for at least 25 of the projected 35 patients at the time of the conference. Clinical trial information: NCT04387461.

Objectives To evaluate the role of blue‐light cystoscopy (BLC) in detecting invasive tumours that were not visible on white‐light cystoscopy (WLC). Patients and Methods Using the multi‐institutional Cysview registry database, patients who had at least one white‐light negative (WL–)/blue‐light positive (BL+) lesion with invasive pathology (≥T1) as highest stage tumour were identified. All WL–/BL+ lesions and all invasive tumours in the database were used as denominators. Relevant baseline and outcome data were collected. Results Of the 3514 lesions (1257 unique patients), 818 (23.2%) lesions were WL−/BL+, of those, 55 (7%) lesions were invasive (48 T1, seven T2; 47 unique patients) including 28/55 (51%) de novo invasive lesions (26 unique patients). In all, 21/47 (45%) patients had WL−/BL+ concommitant carcinoma in situ and/or another T1 lesions. Of 22 patients with a WL−/BL+ lesion who underwent radical cystectomy (RC), high‐risk pathological features leading to RC was only visible on BLC in 18 (82%) patients. At time of RC, 11/22 (50%) patients had pathological upstaging including four (18%) with node‐positive disease. Conclusions A considerable proportion of invasive lesions are only detectable by BLC and the rate of pathological upstaging is significant. Our present findings suggest an additional benefit of BLC in the detection of invasive bladder tumours that has implications for treatment approach.