Introduction:

Standard of care treatment for High Risk NIMBC includes TURBT followed by intravesical BCG. However, high recurrence rates and the persistent BCG shortage highlight the need for effective, well-tolerated, and readily available treatment options. Cretostimogene is a tumor-selective oncolytic immunotherapy with a dual mechanism of action. It replicates in and lyses cancer cells with Retinoblastoma (Rb)-E2F pathway alterations, releasing virus- and tumor-specific antigens that initiate an anti-tumor immune response, which is further enhanced by the GM-CSF transgene. Cretostimogene received Fast Track and Breakthrough Therapy Designations by FDA for HR BCG-Unresponsive NMIBC. 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 across the BCG-naïve, BCG-exposed, and BCG-unresponsive disease states. We report first results from Cohort A, focused on patients with BCG-naïve NMIBC.

Methods:

Cohort A includes patients with pathologically confirmed HR NMIBC with CIS and who are BCG-naive. Criteria for the BCG-Naïve cohort consists of no prior BCG treatment, BCG administered >24 months ago, or receipt of 1-2 BCG doses within the past 24 months. Patients receive intravesical cretostimogene in combination with DDM, an excipient that enhances adenoviral delivery, 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 or CIS is noted at biopsy. Response assessments included serial cystoscopy with directed biopsy (as indicated), urine cytology, and axial imaging. The primary endpoint is Complete Response (CR) at any time. Secondary endpoints include Duration of Response, all-cause Event-Free Survival, Bladder Cancer Specific Survival, Progression-Free Survival, Cystectomy-Free Survival, safety, and tolerability. Exploratory outcome measures are Health-Related Quality of Life, Overall Survival, and biomarker assessments. Enrollment is complete.

Results:

As of the July 14, 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 and 9.3% are female. Baseline disease characteristics demonstrate CIS alone in 44.4%, CIS + HGTa in 31.5%, and CIS + T1 in 24.1%. Median exposure of the cohort is 12.7 weeks (range 1.1, 30.3 weeks). The CR rate at any time in evaluable patients is 86.5% (32/37) (95% CI 71.2-95.5%). There were no progression events to MIBC or metastatic disease. The safety and tolerability profile of cretostimogene is consistent with prior clinical trials of cretostimogene. The most common adverse events are low grade and localized to the bladder. There are no related grade 3 or higher adverse events and no treatment related discontinuations.

Conclusion:

The first results from CORE-008 Cohort A demonstrate that cretostimogene has promising clinical efficacy and safety in patients with high-risk, BCG-naïve NMIBC. These findings support the further evaluation of cretostimogene in the early, HR NMIBC disease continuum. Additional analyses are planned in patients with high-grade BCG-naïve Ta/T1 papillary-only NMIBC, within CORE-008, Cohort A.

Funding: CG Oncology, Inc