Dr Li on the Rationale for Evaluating CG0070 Plus Pembrolizumab in BCG-Unresponsive NMIBC

Roger Li, MD, genitourinary oncologist, Moffitt Cancer Center, expands on the mechanism of action for the combination of CG0070 (cretostimogene grenadenorepvec) and pembrolizumab (Keytruda), detailing the rationale for investigating the regimen's synergy in patients with Bacillus Calmette-Guérin (BCG)–unresponsive, carcinoma in situ-containing non–muscle invasive bladder cancer (NMIBC).

There is currently a substantial lack of effective treatment options for patients with BCG-unresponsive NMIBC that allow patients to preserve their bladder function, Li begins. Although radical cystectomy remains the standard-of-care in this setting, many patients that are elderly and frail are not good candidates for this procedure, he adds.

CG0070 contains a human E2F promoter that allows it to specifically attach to cancer cells that are defective in the retinoblastoma protein pathway, Li explains. This pathway is responsible for increases in E2F expression. The virus replicates in these cancer cells, and leads to cell lysis, Li says. During lysis, CG0070 also releases cancer-specific neoantigens into the tumor microenvironment. These neoantigens recruit immune cells to the tumor site to mount an immunogenic attack, Li details.

Prior studies have shown the efficacy of the cancer-selective oncolytic adenovirus CG0070 and pembrolizumab as single agents in BCG-unresponsive MIBC, Li continues. Additionally, pembrolizumab has been shown to reinvigorate lymphocytes that may become exhausted over time, he notes.

Accordingly, it was hypothesized that administering these treatments incombination could be synergistic, thereby producing more durable responses, Li states. Therefore the phase 2 CORE-001 trial (NCT04387461) was created to evaluate this hypothesis. Demonstrating that the combination elicited a high overall response rate that was maintained at the 12-month time point. Although the regimen did show synergistic activity, no clear evidence of synergistic toxicity was observed, and the regimen’s adverse effect profile was generally consistent with prior studies of each agent alone.