FDA Grants Fast Track, Breakthrough Therapy Designations to Cretostimogene Grenadenorepvec for NMIBC

The FDA has granted fast track and breakthrough therapy designations to cretostimogene grenadenorepvec (CG0070) for use as a potential therapeutic option in patients with high-risk Bacillus Calmette-Guérin (BCG)–unresponsive non–muscle invasive bladder cancer (NMIBC) with carcinoma in situ with or without Ta or T1 tumors.¹

The decision is supported by findings from ongoing clinical trials, including the phase 3 BOND-003 trial (NCT04452591), which showed that treatment with the intravesically delivered oncolytic immunotherapy provided clinical benefit in the form of complete responses (CRs) with acceptable tolerability.

“Receiving both FDA fast track and breakthrough therapy designation is an important milestone in the development of cretostimogene grenadenorepvec and for patients with bladder cancer who urgently need more therapeutic options,” Ambaw Bellete, president & chief operating officer of CG Oncology, stated in a press release.

The open-label, single-arm BOND-003 study enrolled 116 patients with high-risk NMIBC with carcinoma in situ with or without Ta/T1 disease who were BCG unresponsive.² These patients had persistent or recurrent disease within 1 year of BCG therapy completion. They were required to have an ECOG performance status of 0 to 2 and have acceptable organ function. They could not be candidates for or must have refused radical cystectomy. Exclusion criteria included having upper tract or prostatic urethra malignancy, prior receipt of adenovirus-based cancer treatment, and/or muscle-invasive or locally advanced metastatic bladder cancer.

Study participants were administered cretostimogene grenadenorepvec intravesically followed by a sequence of bladder washes with 5% DDM and normal saline. The agent was given weekly for weeks 1 through 6.³ Those who had persistent high-grade disease at week 13 received another cycle of 6 weekly treatments, and patients with no disease at that time point received 3 weekly treatments. At week 25, patients received 3 weekly treatments every 12 weeks through week 49 and every 24 weeks thereafter.

CR at any time served as the trial’s primary end point, and key secondary end points comprised duration of response (DOR), progression-free survival, time to progression, and safety.

Early data from the trial were presented at the 24th Annual Meeting of the Society of Urological Oncology. At a data cutoff date of October 5, 2023, cretostimogene grenadenorepvec elicited an anytime CR rate of 75.7% among 66 patients who were evaluable for efficacy.² The CR rates at 3 and 6 months were 68.2% and 63.6%, respectively.

Regarding safety, the most common treatment-related adverse effects (TRAEs) reported with single-agent cretostimogene grenadenorepvec were transient grade 1 or 2 genitourinary symptoms. No grade 3 or higher TRAEs were reported, and no patients had discontinued treatment with the agent due to toxicity.

“We are encouraged by this momentum following our recent announcement of first results from our phase 3 BOND-003 study for patients with high-risk BCG-unresponsive NMIBC,” Bellete added in the press release.¹ “CG Oncology looks forward to working with the FDA to advance cretostimogene grenadenorepvec as a potential backbone therapy in bladder cancer. We would like to thank the patients, caregivers, investigators, and their staff who have participated in the clinical trials.”

Cretostimogene grenadenorepvec is also being explored in combination with pembrolizumab (Keytruda) in patients with BCG-unresponsive, high-risk NMIBC and carcinoma in situ as part of the phase 2 CORE-001 trial (NCT04387461).⁴ To enroll, patients were required to have complete Ta/T1 resection at baseline and to have undergone urine cytology and cystoscopy at enrollment.

Participants were given induction treatment with cretostimogene grenadenorepvec at 1 x 10¹² vp/mL weekly, followed by a second weekly induction course of the agent at 1 x 10¹² vp/mL for 3 weeks in responders and 6 weeks in those who did not respond. Those who achieved a CR were then administered weekly maintenance courses of the agent at 1 x 10¹² vp/mL for 3 weeks. Beginning in cycle 1, they were given pembrolizumab intravenously at a dose of 400 mg every 6 weeks for the duration of 2 years.

CR at any time represented the trial’s primary end point. Secondary end points included DOR and 12-month CR rate.

Data presented at the 2023 American Urological Association Annual Meeting showed that the doublet elicited an overall CR rate of 85% in 34 evaluable patients. The 6-, 9-, and 12-month CR rates were 82%, 81%, and 68%, respectively.

The AEs reported with the combination were predominantly transient, grade 1 or 2 local genitourinary toxicities. The most frequently experienced AEs included bladder spasm (grade 1, 31.4%; grade 2, 11.4%), fatigue (31.4%; 5.7%), pollakiuria (25.7%; 2.9%), dysuria (20.0%; 2.9%), hematuria (11.4%; 2.9%), micturition urgency (5.6%; 5.7%), diarrhea (11.4%; 0%), hypothyroidism (2.9%; 8.6%), nocturia (8.6%; 2.9%), urinary tract infection (8.6%; 2.9%), abdominal pain (8.6%; 0%), increased alanine aminotransferase (5.7%; 2.9%), increased aspartate aminotransferase (5.7%; 2.9%), headache (8.6%; 0%), pruritus (5.7%; 2.9%), arthralgia (2.9%; 2.9%), asthenia (2.9%; 2.9%), bladder discomfort (5.7%; 0%), increased blood glucose (5.7%; 0%), chills (5.7%; 0%), myalgia (5.7%; 0%), polyuria (5.7%; 0%), urinary incontinence (5.7%; 0%), urinary retention (2.9%; 2.9%), and urinary tract pain (5.7%; 0%).

Grade 3 AEs were experienced by 4 patients and included autoimmune hepatitis, reduced ejection fraction, decreased neutrophil counts, increased alkaline phosphatase, and adrenal insufficiency. No grade 4 or 5 AEs were reported.

Cretostimogene grenadenorepvec is also being evaluated in combination with nivolumab (Opdivo) in patients with high-risk, cisplatin-ineligible muscle-invasive bladder cancer as a part of the phase 1b/2 CORE-002 trial (NCT04610671), and as a single agent in those with intermediate-risk NMIBC or high-risk BCG-naive and -exposed NMIBC, as part of the phase 3 PIVOT-006 (NCT06111235) and phase 2 CORE-008 trials, respectively.⁵

References

1. CG Oncology receives both FDA fast track and breakthrough therapy designation for cretostimogene grenadenorepvec in high-risk BCG-unresponsive non-muscle invasive bladder cancer. News release. CG Oncology, Inc. December 5, 2023. Accessed January 3, 2024. 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/
2. Cretostimogene grenadenorepvec monotherapy first results show 75.7% complete response rate at any time in patients with high-risk BCG-unresponsive non-muscle-invasive bladder cancer. News release. CG Oncology, Inc. November 30, 2023. Accessed January 3, 2024. https://cgoncology.com/cretostimogene-grenadenorepvec-monotherapy-first-results-show-75-7-complete-response-rate-at-any-time-in-patients-with-highrisk-bcg-unresponsive-non-muscle-invasive-bladder-cancer/
3. Study of CG0070 given in patients with non-muscle invasive bladder cancer, unresponsive to Bacillus-Calmette-Guerin (BOND-003). ClinicalTrials.gov. Updated May 12, 2023. Accessed January 3, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT04452591
4. 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.
5. Cretostimogene grenadenorepvec clinical studies. CG Oncology, Inc. Accessed January 3, 2024. https://cgoncology.com/pipeline/