Cretostimogene Grenadenorepvec Confers High CR Rate in NMIBC

Trinity J. Bivalacqua, MD, PhD

Preliminary findings from the phase 3 BOND-003 trial (NCT04452591) showed that treatment with the investigational, intravesically delivered oncolytic immunotherapy cretostimogene grenadenorepvec led to sustained and durable complete responses (CRs) and a tolerable safety profile in patients with high-risk non-muscle invasive bladder cancer (NMIBC) who are unresponsive to Bacillus Calmette-Guerin (BCG). Data were presented on November 30, 2023, during the 24th Annual Meeting of the Society of Urological Oncology (SUO) in Washington, DC.¹

At the October 5, 2023, data cutoff, results from BOND-003 demonstrated that efficacy-evaluable patients (n = 66) achieved an anytime CR rate of 75.7%. The 3- and 6-month CR rates were 68.2% and 63.6%, respectively.¹

In terms of safety, adverse effects (AEs) observed with cretostimogene grenadenorepvec monotherapy were consistent with the known safety profile of the agent. The most common treatment-related AEs included transient grade 1 to 2 genitourinary symptoms. Study authors reported no grade 3 or higher AEs related to cretostimogene grenadenorepvec and no instances of discontinuation related to AEs were observed.¹

“The positive BOND-003 initial results demonstrate the impact of cretostimogene in BCG-unresponsive disease patients as a promising new monotherapy which may lead to profoundly meaningful non-surgical outcomes for those with recurrent bladder cancer,” Trinity J. Bivalacqua, MD, PhD, the director of urologic oncology and a professor of urology and oncology at the Perelman Center for Advanced Medicine of the University of Pennsylvania in Philadelphia, said in a press release. “NMIBC has been a difficult disease to treat, and patients have often had no options except surgical removal of the bladder.”¹

BOND-003 was an open-label, single-arm trial that fully enrolled patients with tissue pathology confirmed, high-risk NMIBC with carcinoma in situ with or without Ta/T1 disease who are unresponsive to BCG (n = 116). BCG failure was defined as persistent or recurrent disease within 12 months of completion of adequate BCG therapy.²

To be eligible for enrollment, patients needed to have adequate organ function, an ECOG performance status of 2 or less, and be ineligible for or refused radical cystectomy. Those with upper tract or prostatic urethra malignancy, prior treatment with adenovirus-based cancer therapy, and/or muscle invasive or locally advanced metastatic bladder cancer were excluded.²

Following enrollment, patients received CG0070 intravesically followed by a sequence of bladder washes with 5% DDM and normal saline. CG0070 was given weekly on weeks 1 through 6. Patients with persistent high-grade disease at week 13 received another cycle of 6 weekly treatments; those with no disease at week 13 received 3 subsequent weekly treatments. At week 25, patients were given 3 weekly treatments every 12 weeks through week 49 then every 24 weeks thereafter.²

The primary end point was CR at any time. Secondary end points included duration of response, progression-free survival, time to progression, and safety.²

Cretostimogene grenadenorepvec is also under investigation in combination with the PD-1 inhibitor pembrolizumab (Keytruda) in the phase 2 CORE-001 study (NCT04387461) for the treatment of patients with NMIBC who are unresponsive to BCG.¹ Findings presented during the American Urological Association 2023 Annual Meeting, which took place in April 2023 in Chicago, Illinois, showed that efficacy-evaluable patients who received the combination (n = 34) achieved an overall CR rate of 85%, including 6-, 9-, and 12-month CR rates of 82%, 81%, and 68%, respectively, among 33, 31, and 25 respective patients evaluable for efficacy at those time points. Additionally, no grade 4 or 5 AEs were reported.³

“We are thrilled to present this data [from BOND-003] at SUO, and we look forward to further discussions with the FDA on advancing cretostimogene grenadenorepvec as a potential new therapy for bladder cancer patients at significant risk of disease recurrence and progression,” Arthur Kuan, chief executive officer, CG Oncology, said in the release. “Our goal is to transform the treatment landscape for patients with bladder cancer, and these results reinforce our commitment to developing bladder-sparing therapeutics to improve patient outcomes and quality of life.”¹

References

1. Cretostimogene grenadenorepvec monotherapy first results show 75.7% complete response rate at any time in patients with high-risk BCG-unresponsive non-muscle-invasive bladder cancer. News release. CG Oncology. November 30, 2023. Accessed December 1, 2023. https://www.businesswire.com/news/home/20231130351326/en
2. Study of CG0070 given in patients with non-muscle invasive bladder cancer, unresponsive to Bacillus-Calmette-Guerin (BOND-003). ClinicalTrials.gov. Updated May 12, 2023. Accessed December 1, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04452591
3. Li R, Steinber G, Uchio EM, et al. CORE1: phase 2 single arm study of CG0070 combined with pembrolizumab in patients with non muscle invasive bladder cancer unresponsive to Bacillus-Calmette-Guerin (BCG). J Urol. 2023;209(suppl 4):e408. doi:10.1097/JU.0000000000003260.08