(UroToday.com) The 2024 American Urological Association (AUA) annual meeting featured a plenary session, and a presentation by Dr. Mark Tyson discussing results from BOND-003, a phase 3, single-arm study assessing intravesical cretostimogene grenadenorepvec for the treatment of high risk, BCG-unresponsive non-muscle invasive bladder cancer. Cretostimogene Grenadenorepvec is a highly immunogenic conditionally replication adenovirus, and its oncolytic immunotherapy mechanism is that it encodes GM-CSF with insertion of the human EF2-1 promoter:
It binds to the Coxsackie Adenovirus Receptor (CAR) leading to robust expression in all stages of bladder cancer, and subsequent viral replication results in tumor lysis.
Dr. Tyson notes that oncolytic immunotherapy is selective oncolysis and potent antitumor response, with the following steps:
- Targeting and destroying cancer cells
- Stimulation of anti-tumor response
BOND-003 is a phase 3 trial of cretostimogene monotherapy for BCG-unresponsive high-risk NMIBC with CIS. The trial is a single-arm, open-label, intravesical administration of cretostimogene monotherapy for patients with pathologically confirmed BCG-unresponsive high-risk NMIBC with CIS +/- Ta/T1. Patients had all Ta/T1 disease resected prior to treatment, with mandatory biopsies at the 12-month assessment. The dosing regimen is an induction course of six weekly treatments, with the option for a second induction of six weekly treatments for non-responders. The maintenance course is weekly x 3 every 3 months for year 1 and then weekly x 3 every 6 months for year 2. The endpoints for the trial are complete response at any time, complete response at 12 months, duration of response, progression free survival, and recurrence free survival.
Among 112 patients evaluable (April 1, 2024), the majority of patients are male (74.1%) with a median age of 74.0 years (range: 43-90). Of note, this was a very heavily pretreated cohort with 12 median number of BCG instillations (range: 7-66). The complete baseline characteristics are as follows:
These updated results from BOND-003 (n = 105) included a 75.2% (95% CI 65% - 83%) complete response rate at any time based on central review. This in the context of all patients having active disease at baseline prior to enrollment and having received adequate BCG therapy as per FDA 2018 Guidance on BCG-unresponsive NMIBC. Cretostimogene also showed durable response over time:
- 53.8% of repeat induction patients converted to a complete response
- 52 patients have a duration of response >= 6 months
- 29 patients have a duration of response >= 12 months
- 14 patients have a duration of response >=21 months
- 92.4% cystectomy free survival, with none of the patients with a complete response having undergone radical cystectomy, and none having nodal or metastatic progression
- 96.7% progression free survival at 12 months
The Swimmer’s plot for the updated results is as follows:
Cretostimogene has been generally well tolerated, with most adverse events being grade 1-2, with 2 patients (1.8%) having serious treatment-related adverse events (grade 2). There were no grade >= 3 treatment-related adverse events reported, one patient with a treatment discontinuation due to an unrelated adverse event, and 94.5% of patients completing all treatments:
Dr. Tyson noted that cretostimogene has a familiar and convenient installation process/schedule for practices, with a thaw time in up to 10 minutes. It can be administered by allied healthcare professionals, and is generally well tolerated. 100% of patients in BOND-003 had a successful instillation, which will streamline use for future cohorts and studies.
Dr. Tyson also emphasized that cretostimogene has the potential to become the backbone therapy in the NMIBC treatment landscape:
Based on these and the initial results of BOND-003, the FDA has granted fast track designation for cretostimogene monotherapy in BCG-unresponsive CIS with or without Ta/T1 papillary disease.
The next phase of the BOND-003 trial includes two important aspects:
- Treatment extension
- Maintenance extension – complete responders are eligible for maintenance through year 3
- Maintenance dosing – weekly x 3 every 3 months in year 1, and weekly x 3 every 6 months in year 2 and year 3
- Addition of a BCG-unresponsive papillary cohort (n = 70) – Cohort P (n ~ 75)
- Dosing schedule: standard cretostimogene induction and maintenance schedule
- Summary of changes: patients will have the option for repeat induction, if in non-response at 3 months
The cretostimogene expanded access program is now up and running aiming to be available for a broader range of patients with CIS-containing BCG unresponsive NMIBC, prioritizing geographically and ethnically diverse populations of real world patients. CG Oncology will provide the supply of cretostimogene. Additionally, the SUO-CTC has two additional trials ongoing. PIVOT-006, is a phase 3 trial of adjuvant cretostimogene versus TURBT alone in intermediate risk NMIBC, with over 90 North American sites participating in the study. CORE-008 is a phase 2 multi-arm, multi-cohort trial of cretostimogene in high-risk NMIBC, with cohort A enrolling BCG-naïve patients, cohort B enrolling BCG exposed patients, and with additional cohorts under design.
Presented by: Mark Tyson II, MD, MPH, Urologic Oncologist, Mayo Clinic Arizona, Scottsdale, AZ
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 American Urological Association (AUA) Annual Meeting, San Antonio, TX, Fri, May 3 – Mon, May 6, 2024.
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Breaking Paradigms: BOND-003's Cretostimogene Monotherapy for High-Risk, BCG-Unresponsive Non-Muscle Invasive Bladder Cancer - Mark Tyson