Introduction:

American Urologic Association (AUA) and National Comprehensive Cancer Network (NCCN) Bladder Cancer Guidelines recommend adjuvant intravesical therapy or surveillance for patients diagnosed with Intermediate-Risk Non-Muscle Invasive Bladder Cancer (IR NMIBC). Despite this, up to 60% of patients will recur and there is a general lack of level-1 evidence in the management of IR NMIBC. As a result, there is both a knowledge gap and an unmet medical need for improved therapies in the adjuvant setting of IR NMIBC. Cretostimogene grenadenorepvec is an oncolytic immunotherapy designed to selectively replicate in bladder cancer cells with Retinoblastoma (Rb)-E2F pathway alterations, commonly found in high-risk BCG-UR NMIBC. In addition, cretostimogene also expresses GM-CSF adding to local and systemic cancer control. Cretostimogene received both US FDA Fast Track and Breakthrough Therapy Designations in the HR, BCG-unresponsive NMIBC indication and has demonstrated a consistently favorable tolerability and safety profile. Based on the strength of those data, PIVOT-006 has been designed as a multi-national, randomized Phase 3 study to assess the efficacy and safety of adjuvant cretostimogene versus surveillance in patients with IR NMIBC.

Methods:

Eligibility criteria include: histologically confirmed IR NMIBC diagnosis within 90 days of randomization, as defined by AUA/SUO Guidelines, age ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, absence of nodal or metastatic disease at screening. Stratification factors include receipt of single-dose perioperative chemotherapy and tumor grade. Patients (N~364) will be randomized 1:1 to receive intravesical cretostimogene (Cohort 1) adjuvant to TURBT or surveillance (Cohort 2). Participants in Cohort 2 will be eligible to receive intravesical cretostimogene if recurrence with IR NMIBC is noted. Intravesical cretostimogene will be instilled in combination with DDM, a transduction agent, for 6 weekly doses during the induction phase, followed by 3 weekly maintenance cycles at months 3 and 6, and culminating in single intravesical doses at months 9 and 12.  Primary disease assessments include serial cystoscopy, urine cytology, axial imaging, and centralized review of pathologic samples. The primary outcome measure is Recurrence-Free Survival. Secondary outcome measures include safety, tolerability, Progression-Free Survival, and time to next intervention. Exploratory outcome measures include Health-Related Quality of Life and biomarker analyses. The study tests the hypothesis of 10% absolute improvement in RFS at 12 months in the treatment group with 90% power.  The trial has received Society of Urologic Oncology-Clinical Trials Consortium (SUO-CTC) and Bladder Cancer Advocacy Network (BCAN) support. 90+ clinical sites have been selected. Screening and enrollment are ongoing. NCT06111235

Results:

Conclusion:

Funding: CG Oncology