High CR Rate in BCG-Unresponsive NMIBC With Cretostimogene Grenadenorepvec/Pembro

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A high complete response rate was achieved in patients with BCG–unresponsive NMIBC using the combination of cretostimogene grenadenorepvec and pembrolizumab, according to final phase 2 CORE-001 trial results.

Roger Li, MD

Roger Li, MD

According to the final results of the phase 2 CORE-001 trial (NCT04387461), cretostimogene grenadenorepvec, an oncolytic immunotherapy, given with pembrolizumab (Keytruda) generated a high complete response (CR) rate when used for the treatment of patients with BCG–unresponsive non–muscle-invasive bladder cancer (NMIBC). Updated results were presented at the 2024 ASCO Annual Meeting.1,2

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://tinyurl.com/3psrrz8n
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://tinyurl.com/4tcckx2v
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.
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