Phase 2 Data Show Clinical Activity With CG0070 Plus Pembrolizumab in NMIBC

Roger Li, MD

Cretostimogene grenadenorepvec (CG0070) in combination with pembrolizumab (Keytruda) produced high complete response (CR) rates with a tolerable safety profile in patients with Bacillus Calmette-Guérin (BCG)–unresponsive non–muscle invasive bladder cancer (NMIBC), according to preliminary findings from the single-arm, phase 2 CORE-001 trial (NCT04387461), which were presented at the 2023 American Urological Association Annual Meeting.¹

Treatment with the combination led to an overall CR rate of 85% (n = 29/34). Additionally, the CR rates at 6 months, 9 months, and 12 months were 82% (n = 27/33), 81% (n = 25/31), and 68% (n = 17/25), respectively.

“Monotherapy CG0070 has demonstrated activity in the NMIBC setting, and the combination of CG0070 and pembrolizumab has demonstrated a lot of promise through the CORE-001 study,” Roger Li, MD, of Moffitt Cancer Center in Tampa, Florida, said in a presentation of the data.

CG0070 is a cancer-selective oncolytic adenovirus that is engineered to preferentially replicate within tumor cells. This virus infects tumor cells by triggering viral propagation and release of granulocyte-macrophage colony-stimulating factor (GM-CSF) and neoantigens in the tumor microenvironment. GM-CSF triggers APC differentiation and neoantigen uptake and deters myeloid-derived suppressor cells. Neoantigen recognition on the tumor’s dendritic cells activate cytotoxic T lymphocytes, which recognize and target the tumor. “We hypothesized that…as the lymphocytes become exhausted during this process, the implementation of immune checkpoint blockade then reinvigorates the lymphocytes to eliminate the cancer,” Li explained.

Previously, the phase 1, dose-escalation V-0046 trial (NCT00109655) investigated cretostimogene monotherapy in 35 patients with high-risk carcinoma in situ (CIS)–containing or papillary NMIBC who had progressed on BCG therapy. This open-label, multi-dose, and multi-schedule trial aimed to determine the safety, dose, and schedule determination of intravesical CG0070 monotherapy in this population.²

In V-0046, across all doses and schedules, the virus elicited a 3-month CR rate of 46% (n = 16). In total, 23% (n = 3/13), 46% (n = 6/13), and 78% (n = 7/9) of patients achieved a CR when receiving CG0070 as a single dose, every 28 days, and weekly for 6 weeks, respectively, with the total multi-dose CR rate (every 28 days + weekly for 6 weeks) being 59% (n = 13/22). The CR rates by dose were 62% (n = 8/13), 44% (n = 4/9), 40% (n = 4/10), and 0% (n = 0/3) at 1 x 1012 vp/mL, 3 x 1012 vp/mL, 1 x 1013 vp/mL, and 3 x 1013 vp/mL, respectively. The median duration of response (DOR) overall was 8.4 months, with ongoing responses at 17.0 months.

Subsequently, the single-arm, open-label, phase 2 BOND2 trial (NCT02365818) evaluated CG0070 monotherapy in 46 patients with high-risk NMIBC containing CIS who had progressed on BCG therapy, with CR rate as the primary end point. In total, 65% of patients (n = 30) achieved a CR at any time, 44% of patients (n = 20) had a CR at 6 months, and 28% of patients (n = 13) had a CR at 12 months. Findings from this trial also demonstrated a favorable safety profile with the agent. Most adverse effects (AEs) were transient, grade 1/2 local urinary tract symptoms, and no grade 4/5 AEs were observed.³

The open-label CORE-001 trial evaluated cretostimogene plus pembrolizumab in 35 patients with high-risk, BCG-unresponsive, CIS-containing NMIBC.1 Patients needed to have complete Ta/T1 resection at baseline and underwent urine cytology and cystoscopy at the time of enrollment. They then received weekly intravesical CG0070 induction at 1 x 1012 vp/mL, followed by a second weekly induction course of CG0070 at 1 x 1012vp/mL for 3 weeks in responders and 6 weeks in non-responders. Complete responders then received weekly maintenance courses of CG0070 at 1 x 1012 vp/mL for 3 weeks. Starting in cycle 1, patients also received intravenous pembrolizumab at 400 mg every 6 weeks for 2 years.

CORE-001 had a primary end point of CR at any time, with DOR, or CR at 12 months, as a key secondary end point.

Most patients were male (94.3%; n = 33), and the majority of patients were older than 65 years of age (77.1%; n = 27). At baseline, 77.1%, 20% (n = 7), and 2.9% (n = 1) patients had ECOG performance scores of 0, 1, and 2, respectively. Patients had received a median of 12 (range, 9-30) prior BCG instillations. In total, 60% (n = 21) and 40% (n = 14) of patients had persistent and recurrent high-risk NMIBC, respectively. At study entry, 8.55% (n = 3), 8.55% (n = 3), 2.9% (n = 1), and 80% (n = 28) of patients had CIS with T1, CIS with Ta HG, CIS with Ta HG and T1, and CIS, respectively. Most patients (85.7%; n = 30) were from the United States.

The AEs observed with the CG0070 plus pembrolizumab were predominantly transient, grade 1/2 local genitourinary AEs. The most common AEs were 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%).

Four patients experienced grade 3 AEs, including autoimmune hepatitis, reduced ejection fraction, decreased neutrophil counts, increased alkaline phosphatase, and adrenal insufficiency. No grade 4/5 AEs were observed.

“The toxicity profile is very much in line with previously reported monotherapy trials,” Li noted.

Currently, the ongoing, single-arm, open-label phase 3 BOND-003 trial (NCT04452591) is investigating CG0070 monotherapy in 110 patients with high-risk, BCG-unresponsive, CIS-containing NMIBC. The primary end point of this trial is CR at any time. Patients will receive CG0070 at 1 x 1012 vp/mL in a 6-week induction course followed by a second 6-week induction course in non-responders and a 3-week maintenance course in complete responders. At week 12, patients will undergo a mandatory biopsy.⁴

Disclosures: Dr Li reports research support from Predicine, Veracyte, CG Oncology, and Valar labs; and scientific advisor/consultant positions with BMS, Merck, Fergene, Arquer Diagnostics, Urogen Pharma, Lucence, and CG Oncology.

References

1. 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.
2. Burke JM, Lamm DL, Meng MV, et al. A first in human phase 1 study of CG0070, a GM-CSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer. J Urol. 2012;188(6):2391-2397. doi:10.1016/j.juro.2012.07.097
3. Packiam VT, Lamm DL, Barocas DA, et al. An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non-muscle-invasive bladder cancer: Interim results. Urol Oncol. 2018;36(10):440-447. doi:10.1016/j.urolonc.2017.07.005
4. Uchio EM, Lamm DL, Shore ND, et al. A phase 3, single-arm study of CG0070 in subjects with nonmuscle invasive bladder cancer (NMIBC) unresponsive to bacillus Calmette-Guerin (BCG). J Clin Oncol. Published online February 16, 2022. doi:10.1200/JCO.2022.40.6_TPS598