Cretostimogene Monotherapy Elicits Durable CRs in High-Risk NMIBC

Treatment with the novel investigational oncolytic immunotherapy cretostimogene grenadenorepvec elicited durable complete responses (CR) over 12 months in patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non–muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS), according to data from the phase 3 BOND-003 trial (NCT04452591) presented at the 2024 American Urological Association Annual Meeting.¹

Looking at the efficacy analysis, the overall CR rate at any time point for all patients was 75.2% (95% CI, 65%-83%).

Cretostimogene also demonstrated durable responses over time as 53.8% of patients who underwent repeat induction converted to CR. A duration of response (DOR) ≥ 6 months was maintained in 52 patients, a DOR ≥ 12 months in 29 patients, and a DOR ≥ 21 months in 14 patients. Eight, 22, and 36 complete responders are still pending.

“This speaks to the oncolytic immunotherapeutic mechanism of action, whereby the immune system switches from innate to adaptive, as seen with the second induction course of BCG,” said Mark D. Tyson, II, MD, MPH, a urologic oncologist at Mayo Clinic in Phoenix, Arizona, in an interview.

“Cretostimogene is a conditionally replicating oncolytic serotype 5 adenovirus that has been designed to preferentially replicate in and kill cancer cells. The E2F1 promoter drives the expression of essential viral genes while restricting replication to RB-pathway deficient tumor cells, thereby sparing normal tissue,” added Tyson.

BOND-003 is an open-label, single-arm, phase 3 trial which enrolled patients with BCG-unresponsive, high-risk NMIBC across North America and the Asia-Pacific region. Those eligible for enrollment were patients aged 18 years and older with pathologically confirmed high-risk NMIBC with CIS +/- Ta/T1 disease that is unresponsive to BCG treatment. Patients were also required to have an ECOG performance status of 0 to 2. A total of 112 patients were enrolled.

The primary end point being evaluated in the trial is the rate of CRs reached at any time. Investigators are also evaluating the secondary end points of CR rate at 12 months, DOR, progression-free survival (PFS), cystectomy-free survival (CFS), and safety.²

Of the 112 patients enrolled in BOND-003, and at the data cutoff date of April 1, 2024, most patients were White (61%), male (74%), and >65 years of age (83%).1 The median age of patients was 74 years (range, 43-90). The cohort was heavily pretreated with the median number of 12 (range, 7-66) prior BCG installations. Several other patients also were previously treated with pembrolizumab (Keytruda).

A total of 92.4% of patients had not required a cystectomy at the 1-year time point. None of the patients with a CR had undergone a radical cystectomy, and there was no nodal or metastatic progression observed. Further, the PFS at 12 months was 96.7%.

Looking at safety, cretostimogene has been generally well-tolerated with no grade 3 or greater treatment-related adverse events (TRAEs) seen and no deaths reported. Most AEs were grade 1 or 2. TRAEs occurred in 70 patients (62.5%) with the most common (>10%) being bladder spasm (23.2%), pollakiuria (19.6%), dysuria (15.2%), micturition urgency (15.2%), and hematuria (14.2%).

Two (1.8%) grade 2 serious AEs, cystitis and clot retention, were observed, and 1 patient discontinued the trial due to an unrelated AE. Moreover, 94.5% of patients completed all expected treatments.

While Tyson recognized the difficulty of comparing the results of studies due to underlying differences in the patient populations, cretostimogene appears to compare favorably to the current nonsurgical standards of care, including nogapendekin alfa inbakicept-pmln (N-803, Anktiva), nadofaragene firadenovec-vncg (Adstiladrin), and pembrolizumab.

“The 75% response rate observed for cretostimogene monotherapy compares favorably to the 62% observed for the [nogapendekin] combination therapy with BCG, to the 51% for nadofaragene, and to the 41% for pembrolizumab,” explained Tyson. “Similarly, the duration of complete response for cretostimogene monotherapy compares favorably with 83% of responders at a 12-month time point having a duration of response greater than 12 months vs 58% for [nogapendekin], and 46% [for both] for nadofaragene and pembrolizumab.”

These data led the FDA to grant both fast track and breakthrough designations for the development of cretostimogene grenadenorepvec for the treatment of BCG-unresponsive NMIBC in December 2023. CG Oncology and the FDA are continuing to work together to advance cretostimogene grenadenorepvec as a potential backbone therapy in bladder cancer.

References:

1. Tyson M, Uchio E, Nam J, et al. Pivotal results from BOND-003: A phase 3, single-arm study of intravesical cretostimogene grenadenorepvec for the treatment of high risk, BCG-unresponsive non-muscle invasive bladder cancer. Presented at: 2024 American Urological Association Meeting; May 3-May 6, 2022; San Antonio, TX.
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 May 3, 2024. https://www.clinicaltrials.gov/study/NCT04452591