Expanded Access Program to provide real-world data on cretostimogene grenadenorepvec

The methodology for the Cretostimogene Grenadenorepvec Expanded Access Program (EAP; NCT06443944) was shared during a poster presentation at the Society of Urologic Oncology (SUO) 25th Annual Meeting in Dallas, Texas.¹

Sarah P. Psutka, MD, MSc

According to Sarah P. Psutka, MD, MSc, who presented the poster at the meeting, the EAP is “trying to take a creative approach to generating needed real-world data on how the drug performs in a pragmatic cohort that is reflective of what we see in practice, as opposed to a curated clinical trial cohort. But [it’s] also offering [this treatment to] folks who may not actually be able to access the FDA approved options that are available right now due to either financial constraints or access to physicians who have access to the drug.”

Cretostimogene grenadenorepvec is an investigational oncolytic immunotherapy for patients with BCG-unresponsive high-risk non–muscle-invasive bladder cancer (NMIBC). The therapy was granted Fast Track and Breakthrough Therapy Designations by the FDA in December 2023 for BCG-unresponsive NMIBC with carcinoma in situ (CIS) based on preliminary data from the ongoing BOND-003 trial (NCT04452591).

Topline data from the BOND-003 trial were also shared at the SUO meeting, showing that cretostimogene was efficacious and well tolerated.

“But if you look at the generalizability of data, the BOND-003 cohort was very reflective of what we see in most clinical trial cohorts for patients with bladder cancer: overwhelmingly Caucasian [and] overwhelmingly male,” explained Psutka, who is an associate professor of urology at the University of Washington and Fred Hutchinson Cancer Center in Seattle, Washington. “Obviously there are strict eligibility criteria for those trials, so you end up seeing efficacy data and safety data in a cohort that doesn't necessarily generalize to the greater population. With the extended access program, it is an opportunity for patients to receive the drug in real-world practice. The company is working to recruit sites that are likely to have a fairly diverse patient population—academic centers, but also community practices and even VAs, with the goal of being able to offer patients who might not be able to access FDA approved treatments in this disease space a drug that has good oncologic efficacy, a great safety profile, and a good tolerability profile.”

Patients enrolled in the open-label EAP will first receive an induction course of intravesical cretostimogene in combination with DDM, a transduction agent, for 6 weekly doses. This will be followed by a maintenance phase beginning with 3 weekly cycles quarterly through month 12, and then every 6 months after that, through month 24.

To be eligible for enrollment, patients need to have an ECOG performance score of 0 to 3 and pathologically confirmed BCG-unresponsive CIS +/- high-grade Ta or high-grade T1 disease following the completion of adequate BCG treatment. Patients are excluded from the study if they have muscle invasive, locally advanced, or metastatic bladder cancer or active autoimmune disease requiring systemic treatment. Additionally, patients cannot be pregnant or have received systemic anti-cancer therapy within 4 weeks of study start.²

The primary objective for the study is safety. Secondary outcomes include complete response at any time point and at 12 months, duration of response, high-grade recurrence-free survival, progression-free survival, and radical cystectomy-free survival.

“There are also important data points that are being collected that I think are going to be very helpful in thinking about how to make decisions around cretostimogene use in the future, because they are prospectively collecting quality-of-life and [patient-report outcome] data as well,” Psutka added. “At the end of the day, when we start trying to figure out and unpack the treatment selection question with the data that are largely coming from non-comparative trials, that patient reported data is going to be really important.”

This first patients have already been enrolled in the EAP.

Findings from BOND-003

Initial findings from cohort C of the BOND-003 trial were presented during a late-breaking abstract session at the SUO meeting.³ In total, the study included 112 patients with pathologically confirmed high-risk, BCG-unresponsive NMIBC with CIS +/- high-grade Ta/T1 disease.

Data showed an overall CR rate of 74.5% (95% CI, 65.4%-82.4%). At 12 months, the CR rate was 46% (95% CI, 36.9-56.1) and 50% (95% CI, 39.6-58.9%) by Kaplan-Meier estimate. According to the presentation, there were “25 confirmed CRs that have reached 24-month timepoint and beyond,” with a 24-month CR rate of 41% (95% CI, 30.4-50.8) by Kaplan-Meier estimate.

In addition, Tyson reported that 97.3% of patients were free from progression to muscle-invasive bladder cancer at 12 months. The 12-month cystectomy-free survival rate was 90.0%.

At the time of data report, the median duration of response (DOR) was not yet reached but exceeded 27 months. The estimated DOR probability was 63.5% (95% CI, 51.2-73.4) at 12 months and 56.6% (95% CI, 43.3-67.8) at 24 months.

Treatment with cretostimogene was also well tolerated. There was a 0% rate of grade 3 or higher treatment-related adverse events (TRAEs) or deaths. The majority of AEs were grade 1-2, and no treatment-related discontinuations were reported. A total of 72 (64/3%) patients had at least 1 TRAE of any grade. Any-grade TRAEs that were observed in more than 10% of patients included bladder spasm, pollakiuria, urgency, dysuria, and hematuria.

Assessment in Cohort C of the trial remains ongoing. Additionally, enrollment is open in Cohort P of the trial, which was added on to assess cretostimogene in up to 70 patients with high-grade Ta/T1 papillary bladder cancer.

Primary completion of the trial is expected in December 2027.⁴

References

1. Psutka SP, Porten SP, Scarpato KR, et al. The Cretostimogene Grenadenorepvec Expanded Access Program in Patients with Non-Muscle Invasive Bladder Cancer Unresponsive to Bacillus Calmette-Guerin. Presented at: Society of Urologic Oncology 25th Annual Meeting. December 4-6, 2024. Dallas, Texas. Abstract 236. https://suo-abstracts.secure-platform.com/a/gallery/rounds/21/details/4056

2. An Expanded Access Program of Cretostimogene Grenadenorepvec for Treatment of NMIBC for Patients Unresponsive to BCG. ClinicalTrials.gov. Last updated June 5, 2024. Accessed December 10, 2024. https://clinicaltrials.gov/study/NCT06443944

3. Tyson M, Uchio E, Nam J-K, et al. Topline results from BOND-003: a phase-3 study of intravesical cretostimogene grenadenorepvec for the treatment of high-risk BCG-unresponsive NMIBC with CIS. Presented at: Society of Urologic Oncology 25th Annual Meeting. December 4-6, 2024. Dallas, Texas. Late-breaking abstract

4. Study of Cretostimogene Given in Patients With Non-Muscle Invasive Bladder Cancer ,Unresponsive to Bacillus-Calmette-Guerin (BOND-003). ClinicalTrials.gov. Last updated December 2, 2024. Accessed December 10, 2024. https://clinicaltrials.gov/study/NCT04452591