SUO 2024: Topline Results from BOND-003: A Phase-3 Study of Intravesical Cretostimogene Grenadenorepvec for the Treatment of High-Risk BCG-Unresponsive NMIBC with CIS

(UroToday.com) The 2024 Society of Urologic Oncology (SUO) annual meeting held in Dallas, TX between December 3^rd – 6^th, 2024 was host to a bladder cancer session. Dr. Mark Tyson presented the late-breaking abstract results of BOND-003, a phase III study of intravesical Cretostimogene Grenadenorepvec for the treatment of high-risk BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) with CIS.

Cretostimogene Grenadenorepvec is a conditionally replicating, highly immunogenic adenovirus that inserts into the human E2F-1 promoter, leading to selective RB-E2F pathway alterations, and encodes the GM-CSF transgene. It binds to Coxsackie Adenovirus Receptor (CAR), which is expressed in all stages of bladder cancer. It falls under the umbrella of oncolytic immunotherapy, with viral replication resulting in tumor lysis and stimulation of an immune response.^1,2

In the phase III BOND-003 trial, 112 patients with high-risk, BCG-unresponsive NMIBC with CIS +/- high-grade papillary disease (all papillary disease resected) received intravesical Cretostimogene Grenadenorepvec, administered weekly x 6 weeks in the induction phase. A maintenance course was given to responders once weekly for 3 weeks every 3 months for the 1^st year, followed by once weekly for 3 weeks every 6 months in the 2^nd year. A second induction course was allowed for non-responders. The primary endpoint was complete response at any time, with additional endpoints including:

Complete response at 12 months
Duration of response
Recurrence-free survival
Progression-free survival
Safety

BOND-003 trial
The patient demographics and baseline characteristics are summarized below. 74% of patients were male, and median patient age was 74 years. 63% of patients were treated in the United States. The median number of prior BCG instillations was 12. 80% of patients had CIS-only disease, and 20% had both CIS and high-grade papillary disease.
BOND-003 trial patient demographics
The overall complete response rate at any time was 74.5% (95% CI: 65.4–82.4%). At 12 months, the complete response rate was 46–50%, and 41% at 24 months.

The overall complete response rate at any time was 74.5% (95% CI: 65.4–82.4%). At 12 months, the complete response rate was 46–50%, and 41% at 24 months
97.3% of patients remained free of disease progression to muscle-invasive disease at 12 months, and the 12-month cystectomy-free survival rate was 90%. The complete responses rates, which were centrally confirmed, were consistent across patient subgroups.

Among patients who achieved a complete response, 64% and 57% of patients maintained a complete response at 12 and 24 months, respectively. The median duration of response has not yet been reached but exceeds 27 months.

Among patients who achieved a complete response, 64% and 57% of patients maintained a complete response at 12 and 24 months, respectively. The median duration of response has not yet been reached, but exceeds 27 months
Notably, 50% of patients re-induced with oncolytic immunotherapy converted to a complete response, with 64.3% maintaining a durable response after the conversion.

otably, 50% of patients re-induced with oncolytic immunotherapy converted to a complete response, with 64.3% maintaining a durable response after the conversion.
From a safety standpoint, there were no grade ≥3 treatment-related adverse events or deaths report. Most adverse events were grade 1–2 in nature. There were no treatment-related discontinuations. 97.3% completed all protocol-defined treatment. Two patients (1.8%) had serious treatment-related adverse events (both Grade 2).
From a safety standpoint, there were no grade ≥3 treatment-related adverse events or deaths report. Most adverse events were grade 1–2 in nature. There were no treatment-related discontinuations. 97.3% completed all protocol-defined treatment. Two patients (1.8%) had serious treatment-related adverse events (both Grade 2)
Dr. Tyson concluded his presentation of the BOND-003 trial as follows:

Cretostimogene grenadenorepvec provides compelling complete response rates (74.5%), with durable responses:
- The median duration of response was not reached but exceeds 27 months
- 64% of responders maintain their response at 12 months
It is a very well-tolerated regimen
- No grade ≥3 treatment-related adverse events or discontinuations
- 97.3% completed all protocol-defined treatments
This drug easily fits and is scalable within existing clinic workflow
- Can be administered by medical assistants and registered nurses
Future and ongoing clinical trials evaluating cretostimogene monotherapy, and rational combinations, will serve as the backbone of therapy

Presented by: Mark Tyson, II MD, MPH, Associate Professor of Urology, Mayo Clinic Arizona, Scottsdale, AZ

Written by: Rashid K. Sayyid, MD, MSc – Robotic Urologic Oncology Fellow at The University of Southern California, @rksayyid on Twitter during the 2024 Society of Urologic Oncology (SUO) annual meeting held in Dallas, TX between December 3^rd and 6^th, 2024

References:

Burke JM, Lamm DL, Meng MV, et al. A first in human phase 1 study of CG0070, a GM-CSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer. J Urol. 2012; 188(6):2391-7.
Sachs MD, Rauen KA, Ramamurthy M, et al. Integrin αv and coxsackie adenovirus receptor expression in clinical bladder cancer. Urology. 2002; 60(3):531-6.

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