Pembrolizumab combined with CG0070. How can this help patients with NMIBC? Roger Li

Roger Li, MD – Genitourinary Oncologist – Moffitt Cancer Center

It’s my pleasure to talk to you today about the updated results from the CORE1 trial combining Cretostimogene Grenadorepvec and Pembrolizumab, and the BCG unresponsive CIS containing MIBC setting.

 

As everyone knows, there has been a lack of efficacious bladder sparing, for this disease space with only Pembrolizumab monotherapy, and Nadofaragene Firadenovec-vncg (Adstiladrin) approved in the setting. So we set out to test whether or not the combination of crease imaging, which is an oncolytic adenovirus, along with Pembrolizumab or a main checkpoint blockade can provide an efficacious effect on the disease space.

 

So is to help patients spare their bladders, so the oncolytic virus itself works through a E2F gene promoter where it only replicates in the cancer cells that lack an intact RB pathway. And we hypothesize that the clipping virus actually has a synergistic effect with immune checkpoint blockade, and set out to test this hypothesis. That’s a little bit on the background of the rationale behind the study.

 

What were the inclusion and exclusion criteria used to select patients for the study? How were patients identified and included in the study? 

So, the BCG unresponsive setting has been a well described entity. Where patients are required to have received an adequate amount of BCG either induction, 5 of 6 infusions of induction with 2 additional therapies either given as a re-induction or as a maintenance therapy. And in this study, patients also are required to have re current CIS containing tumors, either pure c s alone or c s in conjunction with papillary disease in the form of TA or T1 disease within the specified amount of period of 12 months since your last BCG infusion. The standard of care for these patients is radical cystectomy. So either the patients have refused radical cystectomies, or they are not a candidate for the procedure because of their medical comorbidities. And so the patients were accrued to the study if they had fulfilled all of these above criteria. Some of the exclusion criteria include patients with autoimmune disease, those patients that are on steroids for some reason or patients with small bladder capacities that cannot tolerate intravesical therapy.

 

Could you describe the treatment regimen administered to patients in the study? How was CG0070 combined with pembrolizumab, and what was the rationale behind this combination? 

The patients received intravesical crease Imaging or CG0070 as an induction course of weekly treatments at intravesical times 6. If the patient did not have any recurrence at 3 months, the patients continued to have maintenance therapies at months 3, 6, 9, 12, and 18 with 3 weekly infusions at each of the maintenance time points. In addition to that, the patients also received Pembrolizumab IV every 6 weeks according to the standard dosing regimen. And so the regimen for the intravesical oncolytic virus was derived from previous phase one and phase 2 studies. In the phase 1 trial, it was demonstrated that infusion of 1 trillion viral particles at weekly infusions times 6, achieved the optimal efficacy previously in CIS containing tumors. The dosing for the pembrolizumab is following its standard regimen.

 

What were the primary and secondary endpoints of the study? How were these endpoints measured, and what were the key findings in terms of efficacy and safety?

The primary endpoint for the study was the measurement of complete response at the 12-month mark found the start of the therapy, and this was measured using cystoscopy, urine cytology, along with random bladder biopsies at various different areas within the blotter. In addition to that, the secondary endpoints looked at complete response at any time, along with other secondary endpoints such as progression-free survival, cystectomy free survival, as well as safety of the drug.

 

What are the results of the CORE1 Clinical Trial?

In total, there were 35 patients who were enrolled. Who represented the typical BCG unresponsive top population with the vast majority of the patients older than 65 years of age and there is a well-balanced in, in terms of persistent versus relapsing B, c g, unresponsive disease. Of course, all of the patients had CIS components, with 80% of the patients actually having pure CIS.

 

And so in terms of efficacy there was, overall, an 85% complete response in the 34 invaluable patients of those who reached the 12-month mark or 25 patients, 17 out of the 25 patients were 68%. Just under 70% had maintained their complete response as assessed by red and bladder biopsies, cystoscopy and urine psychology.

 

Can you elaborate on the safety profile of the combined therapy? What were the most common adverse effects observed in patients, and how were these managed?

There wasn’t any synergistic toxicity that was seen with the combination. The common the toxicity that was seen in this trial using the combination therapy was much, very much in line with what’s been described previously with monotherapy trials using crease imaging alone or pembrolizumab alone.

 

With most of the side effects associated with bladder related symptoms such as bladder spasms, polyuria, dysuria, or hematuria. In addition to that, there were a few immune related adverse effects, a few of which were severe adverse effects including immune related elevated liver enzymes, thyroiditis. As well as other immune related side effects. Most of these were transient, and they were self-limited after the discontinuation of Pembrolizumab. So all of the patients who had their had discontinued their Pembrolizumab, continued to have treatment with intravesical crease imaging.

 

So all in all, Their treatment was very well tolerated with no grade 4, 5 adverse events. And most of the immune adverse events were self-limiting.

 

In your opinion, what are the next steps in the development of CG0070 combined with Pembrolizumab as a potential treatment option for NMIBC? Are there any plans for additional studies or potential modifications to the treatment regimen based on the results of this study?

So, piggybacking off of this trial, we are very excited to see the early promising results of from the efficacy perspective. And we’re designing a phase 3 trial in which we’re going to compare the efficacy of the combination with crease imaging plus Pembrolizumab versus the efficacy of Pembrolizumab monotherapy.

 

To really show that the 2 agents together has a synergistic mechanism of action and that it achieves the higher efficacy rate, will also compare the adverse events profile of the combination versus that of Pembrolizumab monotherapy. And hopefully it still demonstrates that with the combination strategy, that there is no added toxicity.

 

Finally, based on the results of the CORE1 study, what message would you like to convey to your peers on this research?

I think that there is a lot of excitement generated from the phase 2 trial. We have seen a clear signal in terms of efficacy from this combination treatment strategy and that it supports our hypothesis that there is mechanistic synergism between the oncolytic virus administer intravesical, along with systemic immune checkpoint blockade.

 

We’re very excited to take this forward and to prove the improvement in efficacy using this combination strategy. We’re also very excited to continue to perform correlative studies to understand the mechanism of action in which the two can be used in a synergistic manner. And to understand the mechanistic underpinnings of successful immunotherapy for bladder cancer in general. 

 

What is CG0070?

CG0070 is a novel investigational therapeutic agent that has gained attention in the field of oncology, specifically in the treatment of bladder cancer. It belongs to a class of drugs known as oncolytic viruses, which are designed to selectively infect and destroy cancer cells while sparing normal healthy cells.

Developed by Cold Genesys Inc., CG0070 utilizes a modified adenovirus type 5 (Ad5) as its viral vector. Adenoviruses are common viruses that can cause respiratory infections in humans. However, CG0070 has been engineered in a way that it cannot replicate in normal cells but can selectively replicate within cancer cells. This makes it a promising approach for targeted cancer therapy.

The principle behind CG0070’s mechanism of action lies in the fact that cancer cells often have altered genetic pathways and weakened antiviral defenses compared to normal cells. CG0070 takes advantage of these characteristics by infecting cancer cells and exploiting their compromised cellular machinery. Once inside the cancer cells, CG0070 replicates, leading to the production of viral proteins and the eventual lysis (rupture) of the cancer cells. This process releases more viral particles, which can then infect neighboring cancer cells, perpetuating the cycle of destruction.

Additionally, CG0070 has been engineered to express a therapeutic transgene called granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF is a cytokine that plays a crucial role in stimulating the immune system, particularly the activation of dendritic cells, which are important antigen-presenting cells involved in initiating an immune response. By expressing GM-CSF, CG0070 not only directly kills cancer cells but also helps in stimulating an immune response against the tumor.

Clinical trials evaluating CG0070 have shown promising results in the treatment of non-muscle invasive bladder cancer (NMIBC), a type of bladder cancer that has not invaded the muscle layer of the bladder wall. In these trials, CG0070 has demonstrated its ability to selectively infect and destroy cancer cells, leading to tumor shrinkage and improved clinical outcomes.

Furthermore, CG0070’s immunostimulatory properties have shown the potential to activate the immune system, promoting an anti-tumor immune response that could target not only the treated tumor but also distant metastases and prevent tumor recurrence.

However, it’s important to note that CG0070 is still under investigation and has not received regulatory approval as a standard therapy for bladder cancer or any other indication. Additional clinical trials and further research are needed to establish its safety and efficacy profile, as well as to determine its potential use in combination with other therapies.

In conclusion, CG0070 is an oncolytic virus-based therapeutic agent that holds promise as a targeted treatment for bladder cancer. Its ability to selectively infect and destroy cancer cells, along with its immunostimulatory effects, make it an intriguing candidate for future cancer therapies. Continued research and clinical trials will help shed more light on its potential benefits and limitations in the field of oncology.

 

10 Key Takeaways from the CORE1 Clinical Trial in Bladder Cancer Treatment

1. Immunotherapy with a combination of immune checkpoint inhibitors showed promising results in the treatment of bladder cancer.

2. The CORE1 clinical trial demonstrated improved overall survival rates in patients with advanced bladder cancer who received the combination immunotherapy compared to standard treatments.

3. The combination immunotherapy approach involved targeting both the PD-1 and CTLA-4 immune checkpoint pathways, which enhanced the anti-tumor immune response.

4. Patients who received the combination immunotherapy experienced longer progression-free survival, indicating a delay in disease progression.

5. The treatment regimen was generally well-tolerated by patients, with manageable side effects reported, such as fatigue, diarrhea, and skin rash.

6. The CORE1 trial emphasized the importance of personalized medicine in bladder cancer treatment by identifying biomarkers that could predict patient response to immunotherapy.

7. The study demonstrated that patients with higher levels of PD-L1 expression on tumor cells tended to respond more favorably to the combination immunotherapy.

8. Immune-related adverse effects (allergic reaction like weight loss, toxic epidermal necrolysis, ect.), although generally manageable, required close monitoring and early intervention to ensure patient safety.

9. The trial highlighted the potential of combination immunotherapy as a valuable treatment option for patients with advanced bladder cancer who are not eligible for surgery or chemotherapy.

10. The positive outcomes of the CORE1 trial have paved the way for further research and clinical trials, potentially leading to the integration of combination immunotherapy into standard treatment protocols for bladder cancer.

 

Roger Li, MD – About The Author, Credentials, and Affiliations

Dr. Roger Li is a distinguished genitourinary oncologist specializing in the surgical treatment of bladder, prostate, kidney, and penile cancers. With a comprehensive range of treatment options, including open, laparoscopic, and robotic-assisted procedures, he employs nerve-sparing approaches tailored to each patient’s clinical needs. Dr. Li honed his expertise in urologic oncology during advanced training at the renowned MD Anderson Cancer Center in Houston, Texas, prior to joining Moffitt.

 

Dr. Li’s research interests encompass the genomic characterization of genitourinary malignancies, aiming to customize therapy based on individual patients. He is also actively involved in developing innovative immunotherapeutic strategies for early-stage bladder cancer. His groundbreaking work has earned recognition at various national and international urology conferences, while his contributions to the field are reflected in numerous peer-reviewed manuscripts and book chapters on urologic oncology.

 

Beyond his clinical and research endeavors, Dr. Li serves as a valued reviewer for esteemed international urologic journals, including the British Journal of Urology International, European Urology Oncology, Journal of Clinical Genitourinary Cancer, and BMC Cancer. Originally from California, he obtained his medical degree from the University of California, Irvine, and completed his urologic residency training at Loma Linda University Medical Center.