Dinney, Colin P N

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 .

Purpose Many patients with high-risk non–muscle-invasive bladder cancer (NMIBC) are either refractory to bacillus Calmette-Guerin (BCG) treatment or may experience disease relapse. We assessed the efficacy and safety of recombinant adenovirus interferon alfa with Syn3 (rAd–IFNα/Syn3), a replication-deficient recombinant adenovirus gene transfer vector, for patients with high-grade (HG) BCG-refractory or relapsed NMIBC. Methods In this open-label, multicenter (n = 13), parallel-arm, phase II study ( ClinicalTrials.gov identifier: NCT01687244), 43 patients with HG BCG-refractory or relapsed NMIBC received intravesical rAd–IFNα/Syn3 (randomly assigned 1:1 to 1 × 10 11 viral particles (vp)/mL or 3 × 10 11 vp/mL). Patients who responded at months 3, 6, and 9 were retreated at months 4, 7, and 10. The primary end point was 12-month HG recurrence-free survival (RFS). All patients who received at least one dose were included in efficacy and safety analyses. Results Forty patients received rAd–IFNα/Syn3 (1 × 10 11 vp/mL, n = 21; 3 × 10 11 vp/mL, n = 19) between November 5, 2012, and April 8, 2015. Fourteen patients (35.0%; 90% CI, 22.6% to 49.2%) remained free of HG recurrence 12 months after initial treatment. Comparable 12-month HG RFS was noted for both doses. Of these 14 patients, two experienced recurrence at 21 and 28 months, respectively, after treatment initiation, and one died as a result of an upper tract tumor at 17 months without a recurrence. rAd–IFNα/Syn3 was well tolerated; no grade four or five adverse events (AEs) occurred, and no patient discontinued treatment because of an adverse event. The most frequently reported drug-related AEs were micturition urgency (n = 16; 40%), dysuria (n = 16; 40%), fatigue (n = 13; 32.5%), pollakiuria (n = 11; 28%), and hematuria and nocturia (n = 10 each; 25%). Conclusion rAd—IFNα/Syn3 was well tolerated. It demonstrated promising efficacy for patients with HG NMIBC after BCG therapy who were unable or unwilling to undergo radical cystectomy.