756 Background: Standard of care treatment for HR NIMBC includes TURBT followed by intravesical BCG. However, high recurrence rates and BCG shortages highlight the need for effective, well-tolerated, and readily available treatment options. Cretostimogene grenadenorepvec is an oncolytic immunotherapy with dual mechanisms of action. It replicates in and lyses cancer cells with Retinoblastoma (Rb)-E2F pathway alterations, while simultaneously amplifying anti-tumor immune response, further mediated by the GM-CSF transgene. CORE-008 (NCT06567743) is a Phase 2, multi-arm, multi-cohort trial evaluating the efficacy and safety of intravesical cretostimogene in patients with HR NMIBC. Methods: Cohort A includes patients age ≥18 years, ECOG PS of 0-2, with pathologically confirmed HR NMIBC with CIS and who are BCG-naïve (no prior BCG, BCG administered > 24 months ago, or receipt of only 1-2 BCG doses within the past 24 months). Patients receive intravesical cretostimogene 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 Month 3, if persistent HG Ta and/or CIS is noted at biopsy. Response assessments included urine cytology, serial cystoscopy with directed biopsy, and axial imaging (as indicated). The primary endpoint is Complete Response (CR) at any time. Enrollment is complete. Results: As of the September 1, 2025 data cut off, 54 patients in Cohort A received treatment with intravesical cretostimogene. 88.8% of participants were 65 years of age or older, 9.3% are female, and 18.5% have an ECOG PS of 1. Baseline disease characteristics demonstrate CIS alone in 44.4%, CIS + HGTa in 31.5%, and CIS + T1 in 24.1%. 53 (98.1%) patients completed induction with 49 assessed for efficacy. Median exposure of the cohort is 15.3 weeks (range 1.1, 41.0 weeks). The CR rate at any time in evaluable patients is 83.7% (41/49) (95% CI 70.3-92.7%). No patients progressed to MIBC or metastatic disease. The safety and tolerability profile of cretostimogene is consistent with prior clinical trials with this agent. The most common adverse events are low grade and localized to the bladder. There are no related Serious Adverse Events, Grade 3+ adverse events or treatment related discontinuations. To date, only 3.7% (2/54) of patients required a dosing delay due to a related adverse event; however, none of these delays resulted in missed doses. Further, updated data will be presented. Conclusions: Cretostimogene has promising clinical efficacy and safety in patients with high-risk, BCG-naïve NMIBC. These findings support the further development of cretostimogene in other early, HR NMIBC disease states. Currently, additional treatment arms are planned for patients with BCG-naïve NMIBC. Clinical trial information: NCT06567743 .
Gary et al. (Sun,) studied this question.