CG0070 Plus Pembrolizumab Produces Durable Responses in BCG-Unresponsive NMIBC

The cancer-selective oncolytic adenovirus cretostimogene grenadenorepvec (CG0070) plus pembrolizumab (Keytruda) elicited synergistic activity leading to durable responses and could provide an effective treatment alternative for patients with Bacillus Calmette-Guérin (BCG)–unresponsive, carcinoma in situ (CIS)–containing non–muscle invasive bladder cancer (NMIBC) who cannot undergo radical cystectomy, according to Roger Li, MD.

The phase 2, single-arm CORE-001 trial (NCT04387461) evaluated CG0070 and pembrolizumab in this population. Updated results presented at the2023 American Urological Association (AUA) Annual Meetingshowed that the combination elicited an overall complete response (CR) rate of 85% (n=29/34). By the 12-month time point, the CR rate was maintained in 68% (n = 17/25) of patients with available response data.¹ In comparison, the 12-month CR rate with CG0070 monotherapy was 28% (n = 13/46) in the phase 2 BOND-002 trial (NCT02365818).²

The regimen’s adverse effect (AE) profile was generally consistent with prior studies of each agent alone. Moreover, there was no clear evidence of synergistic toxicity.¹

These results support ongoing and future studies of CG0070 in non–muscle and muscle-invasive bladder cancer, including the single-arm phase 3 BOND-003 trial (NCT04452591) of CG0070 monotherapy, the phase 1/2 CORE-002 trial (NCT04610671) of CG0070 plus nivolumab (Opdivo), and the planned phase 3 PIVOT-001 trial of CG0070 plus immune checkpoint inhibitors.

“We’re excited to launch that trial soon, show the synergistic efficacy from the combination, and hopefully be able to bring this combination to patients soon,” Li said, regarding the planned phase 3 trial for CG0070 plus pembrolizumab.

In an interview with OncLive^®, Li, who is a genitourinary oncologist at Moffitt Cancer Center in Tampa, Florida, discussed how the synergistic mechanism of pembrolizumab plus CG0070 could address unmet needs in BCG-unresponsive NMIBC, safety and efficacy data for the combination from CORE-001, and how those data support planned research efforts for CG0070 in NMIBC.

OncLive: Could you discuss the rationale for investigating CG0070 plus pembrolizumab in patients with BCG-unresponsive NMIBC?

Li: In the BCG-unresponsive setting, there are very limited therapeutic options. The standard of care remains radical cystectomy. Unfortunately, a lot of patients that are elderly and frail are unable to undergo that procedure. Hence the [need] for more efficacious treatment options that will enable patients to preserve their bladder. In the past, CG0070 has demonstrated efficacy in this setting as did pembrolizumab. We hypothesized that there could be a synergistic mechanism between the 2 agents and launched this study to see whether that holds true.

Please describe the mechanism of action of CG0070. What made this agent a good candidate to evaluate in combination with pembrolizumab?

CG0070 is a cancer-selective oncolytic adenovirus that attaches to cancer cells specifically through its mechanism of action of having a human E2F promoter. [CG0070] only acts on the cancer cells that are defective in the retinoblastoma protein [Rb] pathway, which will increase the expression level of the E2F protein. In these cancer cells, the virus replicates and [causes] cell lysis. In doing that, [CG0070] also releases the cancer-specific neoantigens in the tumor microenvironment to attract the immune cells for an immunogenic attack. The reason to combine [CG0070] with pembrolizumab is that pembrolizumab has demonstrated efficacy in the BCG-unresponsive setting. It also reinvigorates lymphocytes that may become exhausted over time. The oncolytic virus and pembrolizumab creates a one-two punch to eliminate the cancer.

What updated findings from this study were presented at the 2023 AUA Meeting?

We reported the most up-to-date efficacy and safety data from the trial. All the patients have been accrued to the trial. [We enrolled a] total of 35 patients with BCG-unresponsive, CIS-containing NMIBC. We followed 25 patients out to the 12-month mark, which is the primary end point of the study, to assess for the CR rate as assessed by random bladder biopsies, cystoscopy, and urine cytology. Of these 25 patients, 68% achieved a durable CR at the 1-year timeframe. In addition, the toxicity of the combination does not seem to be synergistic at all. [There is] some added toxicity from both the intravesical treatment as well as pembrolizumab, but [there were] no surprises in that regard. Although there were a few cases of immune-related AEs those tended to be very transient and [were] eliminated after the patients came off therapy.

Why is the durability of the CR rate seen with this regimen notable?

In the past, pembrolizumab as well as nadofaragene firadenovec-vncg [Adstiladrin] have been approved for the BCG-unresponsive CIS-containing cohort. However, the CR rates for those therapies at 1 year range between 20% and 25%. Most patients [who receive these therapies] have recurrence and will require additional therapy for that. The durable response that we’re seeing in this combination trial is very encouraging and points to the fact that we can help patients keep their bladder for 1 year longer.

Are any next steps planned for this research?

We’re continuing to follow these patients beyond the primary end point of this study, [up] to 2, 3 and even 4 years after the first 2 years on trial at 6-month intervals to see what the long-term response rate is in this patient population.

In addition to the follow-up that we are planning for patients enrolled onto this trial, we’re also actively launching a randomized control trial comparing the combination of CG0070 and pembrolizumab vs pembrolizumab alone in this patient population.

What other studies were you looking forward to seeing presented at this year’s meeting?

There were a couple of different trials in the BCG-unresponsive setting that reported out [at the 2023 AUA Annual Meeting]. We know that cohort A of the [phase 2] KEYNOTE-057 trial [NCT02625961] has been reported out in the past. [In terms of] efficacy, the 1-year response rate was around 20%. I [was] interested in learning about cohort B, which included patients with papillary-only BCG-unresponsive [disease] and seeing the efficacy of pembrolizumab in that setting. The [investigators] also reported some of the data from cystectomy specimens obtained from those patients after coming off trial because of disease recurrence.

An additional study that I looked forward to hearing the results from [was] the [phase 2b] SunRISe-1 trial [NCT04640623], which tested the combination of TAR-200 and cetrelimab [JNJ-63723283] in the BCG-unresponsive setting, along with a few other arms testing the efficacy of TAR-200 monotherapy as well as cetrelimab by itself.

References

1. Li R, Steinberg G, Uchio EM, et al. CORE1: Phase 2 single arm study of CG0070 combined with pembrolizumab in patients with non muscle invasive bladder cancer unresponsive to Bacillus Calmette-Guerin (BCG). J Urol. 2023;209(4):e408. doi:10.1097/JU.0000000000003260.08
2. 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