High CR Rate in NMIBC Is Maintained by Cretostimogene Grenadenorepvec Plus Pembrolizumab

Final results from the phase 2 CORE-001 trial (NCT04387461), presented at the 2024 ASCO Annual Meeting, showed that the pairing of cretostimogene grenadenorepvec with pembrolizumab (Keytruda) maintained a high complete response (CR) rate in patients with BCG-unresponsive, high-risk non–muscle-invasive bladder cancer (NMIBC) with carcinoma in situ, suggesting the potential for a novel bladder-sparing therapy in this patient population.

In the 35-patient intention-to-treat (ITT) population, the 12-month CR rate was 57% (n = 20; 95% CI, 40%-73%) and the any-time CR rate was 83% (95% CI, 70%-95%). Over half (54.3%; 95% CI, 36.9%-70.8%) of compete responders maintained their response at 24 months.

At a median follow-up of 26.5 months, the median duration of response (DOR) was not yet reached, but exceeded 21 months. No patients had disease progression, with a progression-free survival (PFS) rate of 100%.

“Very importantly, no patient progressed to muscle-invasive bladder cancer or metastatic urothelial carcinoma on our trial. This compares very favorably with other trials that have been conducted in this space, including with nadofaragene firadenovec (94%), pembrolizumab (91%), or N-803 plus BCG (90%),” Roger Li, MD, of Moffitt Cancer Center in Tampa, Florida, said in a presentation at the ASCO meeting.

Summarizing the overall results, Li added, “CORE-001’s excellent efficacy, long-term durability of response, and favorable benefit-to-risk-ratio profile seen with combination cretostimogene and pembrolizumab suggest the potential for a novel bladder-sparing therapy in the BCG-unresponsive NMIBC setting.”

The open-label CORE-001 trial evaluated cretostimogene plus pembrolizumab in 35 patients with high-risk, BCG-unresponsive, CIS-containing NMIBC, with or without papillary disease.

Patients received induction therapy as 6 weekly intravesical instillations of cretostimogene. Those with persistent high-grade disease at week 12 were eligible to receive re-induction with another cycle of 6 weekly treatments. Patients achieving a CR (no disease present) at week 12 were then administered 3 weekly maintenance treatments. Then, starting at week 24, patients received 3 weekly maintenance treatments every 3 months up to week 48 and then every 24 weeks after that. Concurrent pembrolizumab was administered intravenously beginning on day 1 and continuing every 6 weeks for a maximum of 24 months.

The primary end point was CR at 12 months, with DOR, PFS, and safety as key secondary end points.

Previously reported baseline characteristics for CORE-001 showed that 94.3% of patients were male and the majority of patients were older than 65 years (77.1%).3 ECOG performance status at baseline was 0 (77.1%), 1 (20%), or 2 (2.9%). The median number of prior BCG instillations was 12 (range, 9-30).

Regarding safety, treatment-related adverse events (TRAEs) were similar to previous studies of single-agent use of the 2 treatments, and no additional toxicity was observed from combining the agents.^1,2 TRAEs specifically related to cretostimogene were all grade 1/2 and self-limited. No treatment-related deaths occurred.

“Future clinical trials will evaluate cretostimogene monotherapy and rational combinations as a backbone therapy for patients with high-risk NMIBC,” said Li.

In December 2023 the FDA granted cretostimogene Breakthrough Therapy and Fast Track Designations for the treatment of patients with high-risk BCG-unresponsive NMIBC with CIS with or without Ta or T1 (papillary) tumors.⁴ The designations, which will expedite the development and regulatory review of cretostimogene in this setting, are supported by results from the phase 3 BOND-003 trial. BOND-003 is an open-label, single-arm trial in which the CR rate at any time point for patients receiving cretostimogene plus pembrolizumab was 75.2%.⁵

CG Oncology, the company developing cretostimogene, reported in a news release that topline data from BOND-003 are anticipated by the end of the year.²

References

1. Li R, Shah PH, Stewart TF, et al. Final results of CORE-001: A phase-2, single arm study of cretostimogene grenadenorepvec in combination with pembrolizumab in patients with BCG-unresponsive, non-muscle invasive bladder cancer with carcinoma in situ. J Clin Oncol 42, 2024 (suppl 16; abstr 4601). doi: 10.1200/JCO.2024.42.16_suppl.4601
2. CG Oncology to Present Positive Final Results from Phase 2 CORE-001 Study of Cretostimogene Grenadenorepvec in Combination with Pembrolizumab in BCG-Unresponsive High-Risk NMIBC at ASCO 2024 Annual Meeting. Published online May 24, 2024. Accessed June 5, 2024. https://ir.cgoncology.com/news-releases/news-release-details/cg-oncology-present-positive-final-results-phase-2-core-001
3. Li R, Steinberg G, Uchio EM, et al. Phase 2 single arm study of CG0070 combined with pembrolizumab in patients with non muscle invasive bladder cancer unresponsive to bacillus Calmette-Guerin (BCG). Presented at: 2023 AUA Annual Meeting; April 28-May 1, 2023; Chicago, IL. Abstract PD13-08.
4. CG Oncology. CG Oncology Receives Both FDA Fast Track and Breakthrough Therapy Designation for Cretostimogene Grenadenorepvec in High-Risk BCG-Unresponsive Non-Muscle Invasive Bladder Cancer. Published online and accessed December 5, 2023. https://cgoncology.com/cg-oncology-receives-both-fda-fast-track-and-breakthrough-therapy-designation-for-cretostimogene-grenadenorepvec-in-high-risk-bcg-unresponsive-non-muscle-invasive-bladder-cancer/
5. Tyson M, Uchio E, Nam J, et al. Pivotal results from BOND-003:A phase 3, single-arm study of intravesical cretostimogene grenadenorepvec for the treatment of high risk, BCG-unresponsive non-muscle invasive bladder cancer. Presented at: 2024 American Urological Association Meeting; May 3-May 6, 2022; San Antonio, TX.