Review of Cretostimogene Grenadenorepvec (CG) Clinical Trials in High-risk BCG-unresponsive NMIBC


This episode provides an in-depth discussion on Cretostimogene Grenadenorepvec (CG), an investigational agent for high-risk BCG-unresponsive NMIBC, including the mechanism of action, its efficacy and safety data from clinical trial trials like CORE01 and BOND-003 (NCT04452591), and the rationale behind combining CG with anti-PD-1/PD-L1 antibodies. Experts also provide their insights on future directions in clinical development and application of CG in various NMIBC treatment scenarios, such as a monotherapy and in combination with IO, including its potential use in intermediate-risk disease.

This is a synopsis of the Viewpoints video series featuring moderator, Sam S. Chang, MD, MBA, from Vanderbilt University School of Medicine, and panelists Gary Steinberg, MD, FACS, from Rush University Medical Center, Mark Tyson, MD, of Mayo Clinic Phoenix, Roger Li, MD, from Moffitt Cancer Center, and Sandip M. Prasad, MD, MPhil, of Morristown Medical Center.

Episode 8 provides an insightful exploration of ongoing clinical trials and research on cretostimogene grenadenorepvec (CG), particularly for high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC). The panelists provide a comprehensive overview of CG, also known as CG0070, which is a intravesically-delivered oncolytic immunotherapy. It is a conditionally replicating adenovirus that targets cancer cells with defective RB pathways. The unique aspect of CG is its E2F1 promoter, which allows the virus to replicate and cause cytolysis in tumor cells, while releasing tumor-associated antigens into the microenvironment. This dual approach not only eliminates tumor cells, but also potentially stimulates both adaptive cell-mediated and humoral immune responses. Pivotal trials such as CORE01 and BOND-003 (NCT04452591) are discussed. The BOND-003 study, a phase 3 trial of CG monotherapy in BCG-unresponsive CIS showed a 75.7% complete response rate at any time point, with a durable response rate of 64% at six months and 74.4% at nine months. These encouraging results, coupled with minimal side effects and no grade 3 treatment-related adverse events, underscore CG's potential as an effective treatment option. The discussion extends to the strategic rationale behind combining CG with anti-programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) antibodies, and the potential application of CG in various NMIBC treatment scenarios. The panelists discuss the promising results of combining CG with pembrolizumab, a checkpoint inhibitor, in BCG-unresponsive CIS-containing patients. The combination therapy demonstrated an impressive complete response rate of 86% at three months, significantly higher than pembrolizumab alone. These findings emphasize the importance of looking beyond short-term efficacy to longer-term response rates, as patients seek durable bladder-sparing therapies. Furthermore, the treatment schedules of these combinations are highlighted, with pembrolizumab administered every 6 weeks and CG given in a similar manner to its monotherapy administration in the BOND-003 trial. This includes an induction course followed by maintenance treatments over an extended period, mirroring SWOG's schedule but with the added benefit of immune modulation.

In conclusion, this episode of Urology Times® Viewpoints provides a comprehensive overview of the evolving landscape of CG in high-risk BCG-unresponsive NMIBC. The discussion underscores the significance of these investigational therapies, offering new hope and direction for patients grappling with challenging NMIBC cases.

*Video synopsis is AI-generated and reviewed by Urology Times® editorial staff.

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