Cretostimogene Grenadenorepvec With Pembrolizumab Offers Best-in-Class CR, DOR, for NMIBC

The CORE-001 trial began in 2020 to study the breakthrough therapy cretostimogene grenadenorepvec (cretostimogene) in combination with pembrolizumab for the treatment of high-risk non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) in patients who are unresponsive to bacillus Calmette-Guérin (BCG) therapy.

At the 2024 American Society of Clinical Oncology Annual Meeting, Roger Li, MD, presented the final results of this phase 2 trial.

Cretostimogene is a type-5 oncolytic adenovirus that selectively replicates bladder cells with alterations in the retinoblastoma pathway. With a complete response rate at any time of 76% for patients in the BCG-unresponsive high-risk NMBIC with CIS population, the therapy recently received Fast Track and Breakthrough Therapy designation from the US Food and Drug Administration (FDA).

A combination of cretostimogene (1×10¹² viral particles) and pembrolizumab 400 mg was administered to 35 patients intravenously every 6 weeks. Cretostimogene was administered as 6 weekly intravesical instillations followed by 3 weekly maintenance doses at months 3, 6, 9, 12, and 18. Patients with persistent CIS or high-grade Ta tumors at the 3-month assessment were eligible for re-induction. Pembrolizumab was administered for up to 24 months.

Response assessments included cystoscopy, urine cytology, cross-sectional imaging, and mandatory bladder mapping biopsies at 12 months. The primary end point was complete response (CR) at 12 months, and secondary end points included CR at any time, duration of response (DOR), CR at 24 months, cystectomy-free survival (CFS), and safety.

A total of 30 patients were evaluable for the primary end point; 5 patients discontinued treatment prior to the 12-month time point. In the intention-to-treat (ITT) population at 12 months and any time, the CR rate was 57% (20 patients; 95% CI, 40%-73%) and 83% (29 patients; 95% CI, 66%-93%), respectively.

The median DOR has not been reached but exceeds 21 months. The current CR rate in the ITT group at 24 months is 46% (16 patients; 95% CI, 29%-63%), and 3 patients have not yet reached the 24-month time point. The CFS at 21 months is 80%. Treatment-related adverse events (AEs) are consistent with what has been seen in the individual therapies and show no synergistic toxicity.

Cretostimogene with pembrolizumab has demonstrated best-in-class CR and DOR compared with current FDA-approved therapies for BCG-unresponsive patients with high-risk NMIBC with CIS. The combination has an acceptable AE profile, and further research of this combination is highly encouraged.