CG0070 Provides Durable Responses in Certain Patients with Non-Muscle Invasive Bladder Cancer

The combination of CG0070 plus pembrolizumab (Keytruda) was well tolerated and showed encouraging early efficacy data in patients with non-muscle invasive bladder cancer that are unresponsive to Bacillus Calmette-Guerin (BCG), according to results from the phase 2 CORE1 trial (NCT04387461).¹

During a presentation given at the 2022 American Urological Association Annual Meeting, Roger Li, MD, reported data of the combination of CG0070 and pembrolizumab in this patient population.

These results were found to be similar to preliminary findings of the phase 1 CORE2 trial (NCT04610671) which examined CG0070 plus nivolumab (Opdivo) in cisplatin ineligible patients with muscle invasive bladder cancer. These data showed promise of durable responses for patients on CG0070 combined with nivolumab.

According to Li, these results show a promising path forward for patients who previously did not have many treatment options.

In an interview with Targeted Oncology^TM, Li, genitourinary oncologist at the Moffitt Cancer Center, discussed the use of the selective oncolytic adenovirus, CG0070, in combination with immunotherapy treatments pembrolizumab and nivolumab for patients with non-muscle invasive bladder cancer who are unresponsive to BCG.

What is the mechanism of action for CG0070?

CG0070 is an adenovirus vector, an oncolytic virus, that acts through a 2-pronged attack by first [targeting] lice in the cancer cells. In doing that, it then releases the cancer associated antigens to elicit an immune response.

Can you discuss the design of the phase 2 CORE1 trial? What are the key outcomes?

Previously, CG0070 had been tested as a monotherapy in a phase 1 trial and a phase 2 trial that demonstrated the 12-month CR [complete response] rate of the monotherapy agents was around just under 30%. As we know, immunotherapy has also overtaken the treatment of BCG unresponsive disease, in that pembrolizumab was recently approved for that setting.

We hypothesized that the 2 agents can be placed together for synergistic efficacy. What we've seen in our preliminary results from the CORE2 trial reflects exactly that in the first 22 patients who were treated on trial, 20 patients had obtained a complete response. Moreover, 8 patients reached the 12-month response mark and 6 of those 8 patients continued to have a durable response.

What are the most recent results that you plan on sharing with fellow clinicians?

[At the AUA conference there were] 2 different presentations, 1 focusing on the results from the CORE1 trial and another that discussed the role of oncolytic virus in general and our portfolio of different clinical trials. [I discussed], mainly the correlative science that have been conducted on the CORE2 trial, which is a phase 1 trial conducted using a similar combination with CG0070 and nivolumab in the neoadjuvant setting for patients with muscle invasive bladder cancer who are cisplatin ineligible. We're focusing in more on the lymphocytic infiltrate that were seen prior to and after treatment, and the formation of tertiary lymphoid structures.

What was the rationale for your phase 2 study of durvalumab [Imfinzi] for patients with BCG unresponsive bladder cancer?

That trial [NCT02901548] was designed a while back, essentially following the same rationale for using immune checkpoint blockade in the BCG unresponsive setting.² That was an investigator-initiated trial that we conducted at Moffitt Cancer Center, acquiring 17 patients with CIS [carcinoma in situ] containing BCG unresponsive disease, who then underwent treatment with durvalumab until disease progression.

The primary end point for that study was a 6-month CR rate as demonstrated by not only cystoscopy, cytology, but also random bladder biopsy. Unfortunately, we didn't see a great result from that study. In the first 17 patients, we saw only an 11% complete response at 6 months. The 3 months CR rate was comparable to [patients on pembrolizumab]. The toxicity profile for durvalumab was very comparable to pembrolizumab, but because of the modest efficacy I don't know if there's going to be a next step for that agent.

Were there any signals in the study that can be applied to for future research?

We've looked at the PD-L1 status of the tumors that were taken at baseline and found that there were very few patients who were PD-L1 positive at baseline. That contrasted with what's been found described in the muscle invasive setting and in the metastatic setting. In addition, we also looked at the 12 chemokine [CK] score, which is a score that we've developed at Moffitt to look at immunogenic response for various tumors. Although the global 12 CK score did not increase with treatment, we did see that the amount of CXCL13, which also predicts for germinal center activity, was increased after treatment.

What are some unmet needs in this patient population that you would like to see addressed in research?

There are certainly a couple of agents that are approved in this setting, such as valrubicin [Valstar] originally and pembrolizumab, but I think the efficacy for both of those drugs are modest at best.

I think with those drugs, what we've learned is that although it's safe for us to continue to treat these patients with endovascular therapy and bladder sparing strategies, they're not necessarily going to progress on to muscle invasive disease. If we were to expedite them to radical cystectomy after failure for salvage treatment, there still needs to be an efficacious bladder sparing strategy. Therefore, I think the preliminary results that we're seeing from the combination trial with CG0070 and pembrolizumab really provides such a good strategy and I think it's going to really be a game changer for patients.

What currently excites you in the field of treatment for patients with bladder cancer?

I'm very excited about the direction that we're heading in using oncolytic viral therapy [to treat patients with] bladder cancer. I think bladder cancer being uniquely located in a very accessible organ lends itself very well to this type of local treatments combined with systemic immune checkpoint blockade. I'm very excited to see what the future holds for this strategy.

References

1. Li R, Steinberg G, Shah P, et al. CORE1: phase 2, single arm study of CG0070 combined with pembrolizumab in patients with non-muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guerin (BCG). Presented at: AACR Annual Meeting 2022; April 8-13, 2022; New Orleans, Louisiana. Abstract CT036.

2. Kim HS, Seo HK. Emerging treatments for bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer. Investig Clin Urol. 2021;62(4):361-377. doi:10.4111/icu.20200602