Cretostimogene grenadenorepvec plus nivolumab shows promise in cisplatin-ineligible MIBC

The combination of neoadjuvant cretostimogene grenadenorepvec plus nivolumab was safe and efficacious in patients with cisplatin-ineligible muscle-invasive bladder cancer (MIBC), according to data from the phase 1b CORE-002 trial (NCT04610671) published in Nature Medicine.¹

Final completion of the CORE-002 trial is anticipated for February 2025.

The data were concurrently presented at the 39th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) in Houston, Texas.²

According to the authors, this combination may offer a potential alternative to cisplatin-based chemotherapy for these patients.

“The recent Nature Medicine publication underscores cretostimogene’s compelling safety profile and provide preliminary evidence supporting the potential use as a combination therapy for patients with different types of bladder cancer,” said Vijay Kasturi, MD, chief medical officer of CG Oncology, in a news release on the data.³ “Cretostimogene’s dual mechanism of action positions it to potentially work well as either a monotherapy or in combination because it selectively replicates and destroys cancer cells while simultaneously amplifying the immune response against bladder tumors. Cretostimogene targets bladder cancer cells, without harming normal cells in the bladder.”

Overall, safety data from the trial showed no instances of dose limiting toxicities. There was 1 patient who discontinued treatment following an adverse event (AE), although the AE was not thought to be due to treatment.

Grade 3 or higher treatment-emergent AEs occurred in 57% of patients. The majority of these, according to the authors, were due to complications from RC-PLND. The most frequent treatment-related AEs attributed to cretostimogene included grade 1/2 catheter leakage (24%), bladder spasms (14%), and dysuria (14%).

Data also showed a pathological complete response (pT0N0) rate of 42.1%, which the authors note is similar to the response rate seen with standard-of-care cisplatin-based chemotherapy and significantly higher than what has been reported with nivolumab monotherapy. Pathologic response was found to be associated with baseline free E2F activity as well as tumor mutational burden. A link was not observed between pathologic response and PD-L1 status.

No patients achieved a partial response (<pT2N0) in the study. Disease downstaging within the bladder occurred in 2 patients, however these patients did harbor pelvic nodal metastases. Additionally, at 1 year, the recurrence-free survival rate was 70.4%.

The authors also observed, “Although T cell infiltration was broadly induced following intravesical oncolytic virotherapy, the formation and maturation of tertiary lymphoid structures were specifically associated with complete response, emphasizing the importance of adaptive humoral immune responses.”

In total, the study enrolled and treated 21 adult patients with cT2-4aN0-1M0 MIBC who were ineligible for or refused cisplatin-based chemotherapy. For the study, patients received 6 weekly intravesical instillations of cretostimogene (1 × 1012 viral particles) plus 480 mg intravenous nivolumab at weeks 2 and 6.

The median follow-up was 27.3 months.

The primary outcome measure for the study was safety. The secondary outcome measure was anti-tumor efficacy of the combination, as measured by the pathologic complete response rate and 1-year recurrence-free survival.

Final completion of the CORE-002 trial is anticipated for February 2025.⁴

“The CORE-002 study lent us insights towards the safety, efficacy, and mechanism of action of intravesical oncolytic immunotherapy—cretostimogene with nivolumab. We learned that this combination was not only well tolerated, but also able to provide 42% pathologic complete response, on par with standard-of-care cisplatin chemotherapy in healthier patients,” said lead author Roger Li, MD, a genitourinary oncologist at Moffitt Cancer Center, in correspondence with Urology Times®. “We also learned about potential biomarkers that can be used to select for patients more likely to respond to therapy—those with higher baseline tumor mutational burden, and E2F target expression. In addition, there were exciting insights we found as far as the tumor specific T- and B-cell activities that may be leveraged in future immunotherapeutic trials. Together, the data point to the exciting potential for this combination regimen to be used to treat patients with muscle-invasive bladder cancer.”

In addition to CORE-002, cretostimogene grenadenorepvec is also being assessed in the phase 3 BOND-003 trial (NCT04452591) for patients with high-risk non-muscle invasive bladder cancer (NMIBC) who are unresponsive to BCG. Results from this trial are expected by the end of 2024. The therapy is also being assessed in the phase 3 PIVOT-006 trial (NCT06111235) for patients with intermediate-risk NMIBC.

Cretostimogene was previously granted fast track and breakthrough therapy designations by the FDA in December 2023 for patients with high-risk NMIBC.

References

1. Li R, Villa NY, Yu X, et al. Oncolytic immunotherapy with nivolumab in muscle-invasive bladder cancer: a phase 1b trial. Nat Med. 2024. doi:10.1038/s41591-024-03324-9

2. Li R, Li T, Villa NY, et al. Oncolytic virotherapy combined with nivolumab elicits complete responses in muscle-invasive bladder cancer in association with the formation of tertiary lymphoid structures. Presented at: 39th Annual Meeting of the Society for Immunotherapy of Cancer (SITC). November 6-10, 2024. Houston, Texas. Abstract 596

3. CG Oncology announces Nature Medicine publication of phase 1b study results evaluating cretostimogene grenadenorepvec in combination with nivolumab in muscle-invasive bladder cancer. News release. CG Oncology Inc. Published online and accessed November 11, 2024. https://ir.cgoncology.com/news-releases/news-release-details/cg-oncology-announces-nature-medicine-publication-phase-1b-study

4. Study of CG0070 combined with nivolumab in cisplatin ineligible patients with MIBC. ClinicalTrials.gov. Last updated July 10, 2024. Accessed November 11, 2024. https://clinicaltrials.gov/study/NCT04610671