Cretostimogene grenadenorepvec continues to show favorable efficacy, safety in NMIBC

Updated data from the phase 3 BOND-003 trial (NCT04452591) continue to support the efficacy, safety, and tolerability of cretostimogene grenadenorepvec in patients with high-risk BCG-unresponsive non–muscle invasive bladder cancer (NMIBC).¹

The data were presented by Trinity J. Bivalacqua, MD, PhD, at the 40th Annual European Association of Urology Congress in Madrid, Spain.

Trinity J. Bivalacqua, MD, PhD

Overall, updated efficacy data showed a complete response (CR) rate at any time point of 75.5% (95% CI, 66.3-83.2%). The 12-month landmark CR rate was 46% (95% CI, 36.9-56.1). There are also 30 confirmed CRs that have reached the 24-month timepoint. Per Kaplan-Meier estimate, the 12- and 24-month CR rates are 50% (95% CI, 39.6-58.9%) and 41% (95% CI, 30.4-50.8%), respectively. The CR rate was consistent across patient subgroups.

Additionally, at 12 months, 97.3% of patients were free from progression to muscle-invasive bladder cancer, and the cystectomy-free survival was 90.0%.

Data also showed a sustained duration of response (DOR) in these patients. The estimated DOR was 63.7% (95% CI, 51.8-73.3%) at 12 months and 58.7% (95% CI, 46.4-69.0%) at 24 months. The median DOR has not been reached but exceeds 28 months (95% CI, 14.3-NE). The median follow-up is 22.3 months.

Bivalacqua noted during the presentation, “What this demonstrates very clearly is that patients that have a durable response at 12 months continue with a durable response at [24] months. We can hypothesize that this may relate to the innate to adaptive switching with immunogenic memory. However, this has never been proven.”

Cretostimogene was also generally well-tolerated, with the majority of adverse events (AEs) being grade 1 or 2. In total, 64.3% of patients experienced any grade treatment-related AE (TRAE). The most common TRAEs (reported in more than 10% of patients) included bladder spasms (25%), pollakiuria (20.5%), urgency (19.6%), dysuria (15.2%), and hematuria (13.4%). The median time to TRAE resolution was 1 day. There were no grade 3 or higher TRAEs, treatment-related discontinuations, nor deaths.

Bivalacqua then outlined translational data on cretostimogene. Data collected in the induction period showed that levels of creto titer and GM-CSF in the urine both peaked following instillation and were sustained locally for 4 to 5 days. According to Bivalacqua, these data suggest that there is effective payload delivery.

In the maintenance phase, Bivalacqua noted, “We see similar pharmacokinetics with a peak and trough pattern as previously showed. And the titers are present through throughout the maintenance period.”

Cretostimogene also demonstrate stable and robust antibody and anti-tumor response. Antibody response was shown to be associated with clinical outcomes.

There were no creto levels detected systemically, with concentration remaining in the bladder even with repeat dosing. Based on these findings, the investigators concluded that post-cretostimogene close contact precautions are not needed.

In total, cohort C of the BOND-003 study included 112 patients with high-risk BCG-unresponsive NMIBC with CIS. Patients enrolled in the study received an induction course of weekly cretostimogene for 6 weeks. For non-responders, a second 6-week induction course was given. Patients then received a maintenance course of 3 weekly treatments ever 12 weeks for year 1 and then every 6 months for years 2 and 3.²

Bivalacqua noted, “Another important point to delineate between multiple trials in this disease space is the fact that this trial had mandatory biopsy at 12 months, which allows us to better detect the effectiveness of any therapeutic agent.”

Among those enrolled in the study, the majority of patients were male (74%), White (62%), and over 65 years of age (83%). This was also a heavily pre-treated population; the median number of prior BCG instillations was 12 (range, 7 to 66).

The primary end point for the trial was CR rate at any time point. Secondary end points include CR at 12 months, DOR, recurrence-free survival, progression-free survival, cystectomy-free survival, and safety.

Cretostimogene currently has FDA breakthrough therapy and fast track designations for high-risk BCG-unresponsive NMIBC with CIS with or without papillary tumors.³ These designations were awarded in December 2023 based on initial findings from BOND-003.

“Cretostimogene’s strong safety and efficacy profile, combined with its best-in-class durability, address an unmet need for my non-muscle invasive bladder cancer patients,” concluded Bivalacqua, a professor of urology and oncology at the Perelman Center for Advanced Medicine at the University of Pennsylvania, in a news release on the findings.⁴ “Now with the new translational data indicating that post-treatment close contact precautions are unnecessary, I am confident that cretostimogene will represent a breakthrough in bladder cancer treatment, if approved by the FDA.”

REFERENCES

1. Bivalacqua T, Tyson MD, Uchio EM, et al. Updated clinical & translational results: BOND-003 Cohort C- A phase 3, single-arm study of intravesical cretostimogene grenadenorepvec for high-risk BCG-unresponsive non-muscle invasive bladder cancer with carcinoma in situ. Presented at: 40^th Annual European Association of Urology Congress. Madrid, Spain. March 21-24, 2025. Abstract LB12

2. Study of cretostimogene given in patients with non-muscle invasive bladder cancer ,unresponsive to Bacillus-Calmette-Guerin (BOND-003). ClinicalTrials.gov. Last updated January 6, 2025. Accessed March 25, 2025. https://clinicaltrials.gov/study/NCT04452591

3. CG Oncology receives both FDA Fast Track and Breakthrough Therapy Designation for cretostimogene grenadenorepvec in high-risk BCG-unresponsive non-muscle invasive bladder cancer. News release. CG Oncology. December 5, 2023. Accessed March 25, 2025. https://cgoncology.com/cg-oncology-receives-both-fda-fast-track-and-breakthrough-therapy-designation-for-cretostimogene-grenadenorepvec-in-high-risk-bcg-unresponsive-non-muscle-invasive-bladder-cancer/

4. Cretostimogene Grenadenorepvec data continues to demonstrate best-in-class durability of response as well as consistent and compelling safety and efficacy. News release. GC Oncology, Inc. March 24, 2025. Accessed March 25, 2025. https://ir.cgoncology.com/news-releases/news-release-details/cretostimogene-grenadenorepvec-data-continues-demonstrate-best