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Clinical and Pharmacokinetic/Pharmacodynamic Insights From CORE-008 Cohort A-Phase 2 Study of Intravesical Cretostimogene Grenadenorepvecin Patients with High-Risk BCG-Naïve Non-Muscle Invasive Bladder Cancer
Matthew Mossanen, MD1, Colin P.N. Dinney, MD2, Shane M. Pearce, MD3, Laurence H. Belkoff, DO4, Brian C. Mazzarella, MD5, Christopher M. Pieczonka, MD6, Neal D. Shore, MD7, Jonathan Henderson, MD8, Siamak Daneshmand, MD9, Gary D. Steinberg, MD10, Trinity J. Bivalacqua, MD, PhD11.
1Dana Farber Cancer Institute/Brigham and Women's Hospital, Boston, MA, USA, 2University of Rochester Medical Center, Rochester, NY, USA, 3Spokane Urology, Spokane, WA, USA, 4MidLantic Urology, Bala Cynwyd, PA, USA, 5Urology Austin, Austin, TX, USA, 6Associated Medical Professionals of New York (an affiliate of US Urology Partners), Syracuse, NY, USA, 7START Carolinas/Carolina Urologic Research Center, Myrtle Beach, SC, USA, 8Arkansas Urology, Little Rock, AR, USA, 9University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA, 10Rush University Medical Center, Chicago, IL, USA, 11University of Pennsylvania, University of Pennsylvania, PA, USA.
Background: Cretostimogene, an oncolytic immunotherapy, selectively targets and lyses cancer cells with Retinoblastoma (Rb)-E2F pathway alterations, triggering anti-tumor immune activation which is further amplified by the GM-CSF transgene. CORE-008 (NCT06567743) is a phase 2, multi-arm, multi-cohort trial evaluating the efficacy and safety of intravesical cretostimogene in patients with HR NMIBC.
Methods: BCG-naïve included no prior BCG, BCG administered >24 months ago, or 1-2 BCG doses in the past 24 months. Patients receive six weekly cretostimogene induction doses, followed by three weekly maintenance instillations each quarter through Month 12, then once every six months through Month 36. Re-induction was permitted at Month 3. A validated qPCR assay was used to assess urine cretostimogene levels. Absolute concentration of urine GM-CSF was assessed by the Olink® Target 48 Cytokine Panel to evaluate transgene expression. The primary endpoint was Complete Response (CR) at any time.
Results: Fifty-four patients received treatment; 88.8% were ≥65 years or older, 9.3% were female, and 18.5% had an ECOG-PS of 1. Baseline disease characteristics demonstrated CIS alone in 44.4%, CIS + HGTa in 31.5%, and CIS + T1 in 24.1%. Fifty-three (98.1%) patients completed induction with 49 assessed for efficacy. As of September 01, the CR rate at any time in evaluable patients was 83.7% (41/49) (95% CI 70.3-92.7%). No patients progressed to MIBC or metastatic disease. There were no grade ≥3 adverse events. At baseline, there were no detectable cretostimogene levels and low levels of endogenous GM-CSF. Cretostimogene levels increased after the first instillation, suggesting active replication, and cleared within one week following each cycle's final instillation. GM-CSF levels increased after the first induction instillation and decreased to near-baseline within a week, suggesting successful transgene expression.
Conclusion: Cretostimogene demonstrates promise for patients with HR, BCG-naïve NMIBC. Pharmacokinetic/pharmacodynamic insights reinforce cretostimogene's mechanism of action, treatment schedule, and safety profile.
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