Introduction:

A significant treatment gap exists for efficacious, well-tolerated bladder-sparing options for patients with High-Risk BCG-Unresponsive Non-Muscle Invasive Bladder Cancer with Carcinoma in Situ +/- HG Ta/T1 (BCG-UR HR NMIBC with CIS). Cretostimogene grenadenorepvec 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 leading to tumor antigen release and anti-tumor immune response, further amplified 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). Here, we report updated 24-month outcomes from Cohort C. Notably, cretostimogene has received Fast Track and Breakthrough Therapy Designations for BCG-UR NMIBC with CIS. 

Methods:

A total of 112 adults with confirmed HR BCG-UR NMIBC with CIS were enrolled, with efficacy data from 110 patients. Participants had previously received adequate BCG and were considered BCG-UR by the US FDA guidance. Cretostimogene treatment consisted of 6 weekly doses during induction, followed by 3 weekly maintenance cycles at Months 3, 6, 9, 12 and 18. Participants were eligible for repeat induction therapy at Month 3, if persistent HG Ta or CIS was noted at biopsy. Response assessment included serial cystoscopy, urine cytology, and mandatory mapping biopsy, with centralized review of all pathology. The primary endpoint was Complete Response (CR) at any time. Secondary endpoints included Duration of Response (DoR), Recurrence-Free Survival (RFS), Progression-Free Survival (PFS), Cystectomy-Free Survival (CFS), safety, and tolerability. 

Results:

As of the June 23, 2025 data cutoff, with a median follow-up time 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 an ongoing median DoR of 27.9 months (95% CI 14.3-NE%). The 12-month CR rate is 46.4% (51/110) (95% CI 36.8-56.1%). Updated results include landmark and K-M estimated 24-month CR rates of 41.8% (46/110) (95% CI 32.5-51.6%) and 42.4% (95% CI: 32.7–51.7%), respectively. Therefore, 90% of 12-month responders maintained durable outcomes at Year 2. CRs are consistent across all patient subgroups. At 24 months, 97.3% (107/110) are free from ≥T2 progression during the treatment phase and 83.6.% (92/110) have avoided a radical cystectomy for bladder cancer. 83.3% (15/18) of patients who underwent RC were T0 or NMIBC. Cretostimogene has a very well-tolerated safety profile, with no grade ≥3 treatment-related adverse events. Grade 1 and 2 related adverse events are transient, with a median resolution time of 1 day.

Conclusion:

Cretostimogene offers distinct advantages with its efficacy, durability and safety profile for the treatment of HR BCG-UR NMIBC. Ongoing and future investigations of this promising therapy, as monotherapy and in rational combinations, may address the considerable unmet need for patients with bladder cancer. 

Funding: CG Oncology, Inc