Introduction:

Patients with High-Risk BCG-Unresponsive Non-Muscle Invasive Bladder Cancer (HR BCG-UR NMIBC) have limited treatment options. The US FDA has approved treatments for BCG-UR patients with CIS, but additional bladder-sparing therapies are needed, especially for the BCG-UR papillary-only population. Cretostimogene grenadenorepvec is a tumor-selective oncolytic immunotherapy with dual mechanism of action. It replicates in and lyses cancer cells with Retinoblastoma (Rb)-E2F pathway alterations. This releases tumor-specific antigens, initiating anti-tumor immune response, further amplified by the GM-CSF transgene. Cretostimogene received US FDA Fast Track and Breakthrough Therapy Designations for BCG-UR HR NMIBC with CIS. The BOND-003 Cohort P study (NCT04452591) is a multi-national, 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 performance status 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 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 after the first disease assessment at 3 months for patients with persistent HG Ta and/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 High-Grade Recurrence-Free Survival (HG-RFS), Progression-Free Survival (PFS), and safety. Over 35 clinical sites were selected in the United States and Japan. The study has completed enrollment.

Results:

A total of 56 patients who received treatment with cretostimogene were evaluated for HG-RFS and safety. As of the July 30, 2025 data cut off, 76.8% of patients were 65 or older and 21.4% were female. 66.1% of participants had HG Ta papillary NMIBC at baseline. Kaplan-Meier estimates of HG-RFS at 3- and 9-months are 94.9% (95% CI 87.9-100.0%) and 73.1% (95% CI 57.8-88.5%), respectively. There were no progression events to MIBC or metastatic disease. Cretostimogene demonstrated a favorable safety profile, with most adverse events localized to low grade bladder symptoms. There were no serious treatment-related adverse events and no discontinuations related to cretostimogene.

Conclusion:

Results from the BOND-003 Cohort P clinical trial of cretostimogene monotherapy in patients with BCG-UR papillary-only NMIBC demonstrate encouraging HG-RFS and a consistent, 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 in High-Risk papillary-only BCG-UR NMIBC.

Funding: CG Oncology, Inc