Efficacy of Cretostimogene Grenadenorepvec and Pembrolizumab in BCG-Resistant NMIBC

The standard treatment for patients with high-risk non-muscle invasive bladder cancer (NMIBC) includes transurethral resection of bladder tumor (TURBT) followed by intravesical bacillus Calmette-Guérin (BCG). Radical cystectomy (RC) is recommended in patients with BCG-unresponsive NMIBC. However, due to the high morbidity and risk associated with RC, identifying alternative treatment options for this subgroup of patients is crucial. Cretostimogene grenadenorepvec (CG0070), an oncolytic adenovirus, has been investigated for its potential efficacy in patients unresponsive to BCG. Li et al. recently reported the results of the CORE-001 trial testing cretostimogene in combination with the PD-1 inhibitor pembrolizumab.

The intention-to-treat cohort consisted of 35 patients. All patients were ineligible for or had refused RC. The median age was 72 years, and the median number of intravesical BCG instillations before enrollment was 12. At the 12-month timepoint, 57.1% (95% CI, 40.7 – 73.5) of patients had complete response (CR). At 3 months, 82.9% (95% CI, 70.4 – 95.3) of patients had a CR. The median follow-up period was 26.5 months and median duration of response was not reached but exceeded 21 months. Approximately 29% of patients developed high-grade recurrences but none progressed to MIBC or metastatic disease. One patient died of a non-cancer related cause. The median high-grade recurrence free survival (RFS) was not reached. RC was subsequently performed in 20% of patients for recurrent disease.

The median number of cretostimogene and pembrolizumab doses were 18.0 and 8.0, respectively. Treatment-related adverse events (TRAEs) associated with cretostimogene were low-grade and included bladder spasm (45.7%), dysuria (25.7%), pollakiuria (25.7%), micturition urgency (17.1%), hematuria (14.2%), and nocturia (11.4%). The most common TRAEs associated with pembrolizumab were fatigue (31.4%), diarrhea (14.3%), and hypothyroidism (11.4%). Five patients experienced grade 3 TRAEs due to pembrolizumab.

This landmark study demonstrates the efficacy and safety of cretostimogene and pembrolizumab combination as a promising bladder-sparing strategy. The distinct mechanisms of action of the two agents potentially drive the synergistic effect of the combination. Intravesical delivery of the oncolytic virus allows direct access to the disease site, while systemic immune checkpoint blockade promotes systemic and local anti-tumor immune activity.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine

References:

Li R, Shah PH, Stewart TF, et al. Oncolytic adenoviral therapy plus pembrolizumab in BCG-unresponsive non-muscle-invasive bladder cancer: the phase 2 CORE-001 trial. Nat Med. Published online June 6, 2024. doi:10.1038/s41591-024-03025-3

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