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 unresponsive to Bacillus Calmette-Guerin (BCG), according to the results of the phase 2 CORE1 study (NCT04387461).1

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

These results appeared to be similar to preliminary findings from the phase 1 CORE2 study (NCT04610671) investigating CG0070 plus nivolumab (Opdivo) in patients ineligible for cisplatin and with muscle-invasive bladder cancer. These data showed promise of sustained responses for patients to CG0070 in combination 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 OncologyTMLi, a 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 do not respond to BCG.

What is the mechanism of action of CG0070?

CG0070 is an adenovirus vector, an oncolytic virus, which acts through a two-pronged attack by first [targeting] lice in the cancer cells. By doing so, it then releases the cancer-associated antigens to mount an immune response.

Can you discuss the design of the phase 2 CORE1 study? What are the main outcomes?

Previously, CG0070 had been tested as monotherapy in a Phase 1 study and a Phase 2 study demonstrating the CR of 12 months [complete response] percentage of monotherapy agents was about just under 30%. As we know, immunotherapy has also overtaken the treatment of unresponsive BCG disease as pembrolizumab was recently approved for that setting.

We hypothesized that the 2 agents can be placed together for synergistic efficacy. What we saw in our preliminary results from the CORE2 study exactly reflects that in the first 22 patients treated during the study, 20 patients had achieved a complete response. In addition, 8 patients achieved the 12-month response and 6 of those 8 patients maintained a durable response.

What are the most recent results that you plan to share with other clinicians?

[At the AUA conference there were] 2 different presentations, 1 focusing on the results of the CORE1 study and another discussing the role of oncolytic virus in general and our portfolio of different clinical studies. [I discussed], primarily the correlative science conducted on the CORE2 trial, a phase 1 trial conducted with a similar combination with CG0070 and nivolumab in the neoadjuvant setting for patients with muscle-invasive bladder cancer who are ineligible for cisplatin. We focus more on the lymphocytic infiltrate observed before and after treatment, and the formation of tertiary lymphoid structures.

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

that process [NCT02901548] was designed a while ago, essentially following the same rationale for using immune checkpoint blockade in the unresponsive BCG environment.2 That was an investigator-initiated study we conducted at the Moffitt Cancer Center that recruited 17 patients with CIS [carcinoma in situ] with BCG unresponsive disease, who subsequently received durvalumab treatment until disease progression.

The primary endpoint 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 research. In the first 17 patients we only saw a complete response of 11% after 6 months. The 3-month CR rate was comparable to: [patients on pembrolizumab]† The toxicity profile for durvalumab was very similar to pembrolizumab, but due to its modest efficacy, I don’t know if there will be a next step for that drug.

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

We looked at the PD-L1 status of the tumors taken at baseline and found that there were very few patients who were PD-L1 positive at baseline. This contrasted with what has been found in the muscle-invasive setting and in the metastatic setting. In addition, we also looked at the 12 chemokines [CK] score, a score we developed at Moffitt to look at the immunogenic response for different tumors. Although the global 12 CK score did not increase with treatment, we did see that the amount of CXCL13, which also predicts germinal center activity, 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 number of drugs that are approved in this setting, such as valrubicin [Valstar] originally and pembrolizumab, but I think the efficacy of both drugs is modest at best.

I think with those drugs we’ve learned that while it’s safe for us to continue treating these patients with endovascular therapy and bladder-sparing strategies, they won’t necessarily evolve into a muscle-invasive disease. If we were to rush them to radical cystectomy after salvage treatment failure, there must still be an effective bladder-sparing strategy. That’s why I think the preliminary results that we’re seeing from the combination trial with CG0070 and pembrolizumab really provide such a good strategy and I think it will really be a game changer for patients.

What is your current interest in treating patients with bladder cancer?

I am very excited about the direction we are going with oncolytic viral therapy [to treat patients with] bladder cancer. I think bladder cancer, which is uniquely localized in a very accessible organ, lends itself very well to this kind of topical treatment in combination with systemic blockade of the immune system. I am very curious what the future holds for this strategy.

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; Apr 8-13, 2022; New Orleans, Louisiana. Summary CT036.
2. Kim HS, Seo HK. Emerging treatments for bacillus Calmette-Guérin unresponsive non-muscle invasive bladder cancer. Research Clin Urol† 2021;62(4):361-377. doi: 10.4111/icu.2020602

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