The PIVOT-006 trial is currently underway, evaluating the efficacy and safety of cretostimogene versus active surveillance in patients with intermediate-risk non-muscle invasive bladder cancer (NMIBC). This Phase 3 randomized study aims to address the knowledge gap and unmet medical need for improved adjuvant therapies in this patient population, where recurrence rates remain high despite guideline recommendations for intravesical therapy or surveillance.
Mechanism of Action and Prior Success
Cretostimogene grenadenorepvec is an oncolytic immunotherapy that selectively replicates in bladder cancer cells with alterations in the Rb-E2F pathway. This mechanism is designed to target and kill cancer cells while sparing normal tissue. Additionally, cretostimogene expresses GM-CSF, a cytokine that primes tumor-specific immunity following cancer cell lysis. Cretostimogene has received FDA Fast Track and Breakthrough Therapy designations for high-risk, BCG-unresponsive NMIBC, demonstrating a favorable safety profile.
Trial Design and Endpoints
The PIVOT-006 trial includes patients with histologically confirmed intermediate-risk NMIBC, as defined by AUA/SUO guidelines, within 90 days of randomization. Key criteria include age ≥18 years, ECOG performance status of 0-2, and absence of nodal or metastatic disease. Patients are stratified by receipt of single-dose perioperative chemotherapy and tumor grade.
Approximately 364 patients will be randomized 1:1 to receive either intravesical cretostimogene adjuvant to TURBT (Cohort 1) or surveillance (Cohort 2). Patients in the surveillance arm have the option to cross over to the cretostimogene arm upon recurrence if their tumor remains appropriate for treatment. The cretostimogene regimen involves six weekly induction doses, followed by maintenance cycles at months 3 and 6, and single doses at months 9 and 12.
The primary endpoint is recurrence-free survival. Secondary endpoints 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 is powered to detect a 10% absolute improvement in recurrence-free survival at 12 months in the treatment group with 90% power.
Clinical Significance and Enrollment
Dr. Mark Tyson, a urologic oncologist at Mayo Clinic, emphasized the potential of cretostimogene to provide an alternative for patients seeking options beyond frequent surgical interventions, particularly given the burden of recurring tumors and potential BCG shortages. Enrollment is progressing well, with over 90 clinical sites participating, supported by collaborations with organizations like SUO-CTC and BCAN.
Dr. Zachary Klaassen, a urologic oncologist at the Georgia Cancer Center, noted the paucity of trials in the intermediate-risk disease space and the importance of partnerships with SUO-CTC and BCAN in supporting patient-centered research and trial enrollment.
Potential Impact
The PIVOT-006 trial is poised to provide valuable insights into the efficacy of cretostimogene in intermediate-risk NMIBC. The results could potentially expand the therapeutic options for this patient population, offering a novel oncolytic immunotherapy approach to reduce recurrence and improve patient outcomes.
