Exploring Promising Therapies and Genomic Insights in Bladder Cancer Research - Laura Bukavina

January 8, 2024

Ashish Kamat welcomes Laura Bukavina to discuss highlights from the SUO 2023 meeting, focusing on bladder cancer research. Dr. Bukavina emphasizes the BOND-003 study on cretostimogene (creto), an adenovirus targeting bladder cancer cells with defective retinoblastoma genes. Creto shows a 75.7% complete response rate, with 74.4% lasting over six months. Another key topic is the ENVISION trial, examining UGN-102, a mitomycin gel for recurrent low-grade bladder cancer. This gel, adhering to the urothelium for extended periods, showed a 79.2% complete response at three months. Dr. Bukavina also highlights Dr. Faltas's work on the genomic landscape of upper tract urothelial carcinoma, revealing distinct differences from bladder cancer, including FGFR3 mutations and luminal papillary subtypes. These findings suggest tailored treatment approaches for metastatic disease. Dr. Bukavina concludes by discussing the importance of therapy availability, financial toxicity, and unique side effects in selecting treatments for patients.


Laura Bukavina, MD, Urologic Oncologist, University Hospitals Cleveland Medical Center, Cleveland, OH

Ashish Kamat, MD, MBBS, Professor of Urology and Wayne B. Duddleston Professor of Cancer Research, University of Texas, MD Anderson Cancer Center, Houston, TX

Read the Full Video Transcript

Ashish Kamat: Hello and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, professor of Urologic Oncology at MD Anderson Cancer Center, and it's a distinct pleasure to welcome, once again, to this forum Dr. Laura Bukavina, who is an assistant professor of Urologic Oncology at Case Western School of Medicine. Laura, you've done a lot of social media activity and you follow all the meetings and you send out your tweets and your excerpts from the various meetings that you attend, which I think the audience loves. And I thought it'd be great to have you spend a few moments with us today at this platform telling us what you thought were the highlights from SUO this year, 2023. So, thank you for joining us and take it away.

Laura Bukavina: Thank you so much, Ashish, and thank you for UroToday for having me. I certainly love going to meetings and seeing data firsthand. There's so much delight in seeing what other people and my colleagues are doing in research and having the ability to give other people a chance to be at the meeting even when they're not. And especially now, to present the new and ongoing research in bladder cancer is a great opportunity. So, thank you again.

I wanted to go over a couple of things that I thought were incredibly well done and I think really applicable to much of our clinical data and a lot of our patients that we see on a daily basis. The first thing I thought we should discuss is the BOND-003 study, which was presented by Mark Tyson, and I wanted to thank Mark for giving us the ability to use some of the slides and some of the data. So, this was cretostimogene, which was previously CG0070, previously utilized in combination with pembrolizumab. Now, this is a trial of a phase 3 trial, looking at monotherapy in BCG unresponsive high-grade with CIS plus or minus disease. So, those are the patients that are BCG refractory, we will call them.

What is creto? Creto is an adenovirus that specifically attaches to the CAR, which is the Coxsackie adenovirus receptor. As you can tell in this figure A, it's present in the majority of the normal cells, but as well as in some of the Tis, T1, and T2 cancer cells. Now, it's going to infect your normal cells equally as it does your cancer cells, however, it's reliant because it's a type of replicating adenovirus on the absence of the retinoblastoma gene or a defective retinoblastoma gene. And really, only in cancer, most of the cancer cells, is this retinoblastoma gene defective or deficient. Thus, while this Credo gene adenovirus can infect normal cells, it really will not cause additional lysis. And that's essentially how this works, is that while normal cells will get infected, they will not lyse the cells. Unlike the target cancer cells, which lack the retinoblastoma gene, what's going to happen is it's going to kill the cancer cells, causing a release of neoantigens into circulation.

Now, in addition to lysing the cells, there's also DNA that's within the adenovirus that codes for GMCSF, which we now know primes dendritic cells for antigen presentation. So, it's almost like a dual approach. You kill the cancer cells, and then you prime the dendritic cells to present these neoantigens from the lysed cancer cells to T cells, which causes further cytotoxic T cell activation. And that's how it works from innate to adaptive. And that's the hypothesis currently, really, that it really works by multiple weeks of therapy and causing switching from the innate response to an adaptive response, causing memory T cells and additional therapeutic response against cancer. So, just in terms of the trial design, as we mentioned, these are your BCG refractory patients. So, these patients have gotten BCG therapy as defined by the FDA 2018 guidelines with adequate therapy and have recurrence of Ta/T1 high grade, no urethral involvement, or prosthetic involvement.

Now, these patients received weekly, just as we did with BCG, weekly induction through the catheter for six weeks, and then they were able to get a second induction if they did not respond to the initial induction. And then the maintenance course was weekly times three. Now, there were mandatory biopsies, five biopsies, that were done at 12 months, in addition to cytology and cystoscopy. And the primary outcome really looked at a complete response as defined by no disease on biopsies, or cytology, or cystoscopy. In addition, cystectomy-free survival, recurrence-free survival, were some of the secondary outcomes that they were looking at. Overall, when they looked at the complete response, this was 75.7% at any time. And when you looked at patients who lasted with a complete response over six months, this was 74.4%. Now, an important thing to point out is that the patients who did not respond during the initial induction course and received the second induction course, an additional 30% of those patients were able to generate a complete response.

And that really points to the hypothesis that there is an innate to adaptive switching of your immune cell response, which potentially propagates that additional complete response in those patients. Now, since the space within non-muscle invasive bladder cancer is getting incredibly hot with so many different therapies, it's always important to point out the adverse events in these patients. And only two patients had grade two toxicity, and no patients reported any grade three toxicity. So, it's a well-tolerated drug, and when you compare it to some of the other things that are in the pipeline or currently have been released, it compares very favorably. Now, if you look at pembro, it actually outperformed pembro, and it certainly outperformed the nadofaragene. And had a similar response in terms of a complete response to the IL-15 superagonist. Overall, I think this is a very promising therapy, which certainly got the FDA fast track for approval, and I think more data in terms of combination therapy with pembrolizumab is ongoing.

Now, the second thing I wanted to look at, and this is to switch gears. We talked about the BCG-refractory disease. Now, let's switch to those patients that we find to be challenging in a different setting, are those patients who have recurrent low-grade disease, who we continuously see in the office, never really have the presence of high-grade disease, but just have high-burden, frequent recurrences, which require multiple TURBTs. Now, this data was presented by Sandip Prasad, and I think this is very clinically relevant to a lot of our patients that we see in the clinic. So, what is UGN? UGN is a mitomycin gel. So, unlike the aqueous solution of mitomycin or gemcitabine that we instill, the gel itself has the ability to stick to the urothelium and can last up to six hours within the bladder. So, patients can actually avoid urinating multiple times without this gel actually being excreted, which is important because the contact surface area of mitomycin and the duration of the treatment, we know, is important in terms of our ability to chemoablate, which means to kill the cancer cells on contact surface.

So, the ENVISION trial really focused on a different population. It focused on the patients who we consider to be intermediate risk, but low-grade. So, those patients who had frequent recurrences of low-grade disease. Now, the TURBTs alone have high mortality and high morbidity. So, this trial really tried to minimize the morbidity associated with frequent TURBTs. This was a single-arm, open-label study that was able to enroll 240 patients with the primary endpoint at three months of a complete response. And similar to our other trial that we just talked about, BOND-003, this also required cystoscopic evaluation, cytology, as well as biopsy at three months. So, if you look at the patients overall and look at the three-month recurrence, those patients upon instillation of the mitomycin gel, had a 79.2% complete response. So, if you look at the confidence interval, it's a pretty tight confidence interval, so between 73% and 84%. So, almost 80% of the patients with the presence of low-grade disease were able to have a complete response without additional TURBT.

So, what that means to you, if you see a patient with frequent low-grade disease and you see a recurrence, the instillation of the mitomycin gel, means 80% of those patients, so four out of five patients, were able to have no presence of the recurrent disease at three months. Now, the 20% of patients that did have to undergo TURBT, only 2.3% of them had actually upstaged into high-grade disease. So, certainly, we will consider that that to be clinically safe among our patients. Similarly, in terms of adverse events, there were low adverse events, no patients with grade group three, and only one patient who developed a urethral stricture. As we know with mitomycin gel, it's something that we always consider, and only one patient out of 190 had a stricture after this.

And then the last thing I wanted to talk about is really some of the study in the translational world that Dr. Faltas talked about within the upper tract. He gave a fantastic talk, talking about how upper tract disease, while we previously considered it to be not just anatomically different, but now we are also finding information on how it's also genetically different to our bladder cancer. And I wanted to highlight some of the things that he talked about, not only coming out from his group, but also from the group from MD Anderson, MSK, being able to look at the genomic landscape of upper tracts. So, some of the earlier data, coming from 2017 and in 2019, looked at the landscape of upper tract in terms of the mutations. And what was consistently being found is that many of them do have an FGFR3 mutation, which is overexpressed compared to your bladder cancer cell line.

Now, if you look at the data that's coming out of Bishoy Faltas's lab, which they also show that there is a higher FGFR, there's also a PPAR gamma signal within those upper tract diseases. Now, what does that mean in terms of subtyping? So, we know that many of our bladder cancer specimens, we have certain molecular classifications in response to immunotherapy and, similar to our bladder cancer patients, upper tract disease, surprisingly, was mostly found to be luminal. In fact, more luminal papillary, which has implications in T cell infiltration and response to therapy. One of the great things that I thought was pointed out is that initially, when the data was coming up in upper tract disease and FGFR3 mutation, one of the quotes was said that really the biology of upper tracts drives the therapy response.

So, in terms of FGFR activating and the molecular alterations, when we look at the upper tract disease overall, and we looked at the earlier study of erdafitinib in advanced urothelial carcinoma, when we look at the subgroup analysis within the lower tract compared to upper tract disease, based on these FGFR mutations, we found that, while there, this is a subgroup analysis, and really not primed, the study was not primed to evaluate upper versus lower tract, you clearly see a difference between the response. And this is really driven by that response, not just anatomically different groups, but also genomically different alterations between upper tract and lower tract, which is your bladder cancer.

The data that he presented further was really to look at the differences between metastatic and primary disease. Now, we know that an FGFR mutation is present within the primary upper tract disease, but what actually happens within metastatic disease, and this was beautifully done, looking at discordance in genomic and transcriptomic differences, and he pointed out that only 17.6% of mutations were shared between primary and metastatic samples. And what was interesting is that if you look at an FGFR3 mutation, it's really now underwhelmingly low in the metastatic world. So, what the goal of this research is to look at potentially precise treatment in patients with metastatic disease. Now, since we know that there are alternative transcriptomic differences between metastatic and primary upper tract, our therapy really should be oriented to the metastatic genomic differences and less so to the primary disease state. So, with that, I'd love to see if you have any discussion points, Ashish.

Ashish Kamat: Thanks so much, Laura, for taking the time and summarizing what you thought were the key points from SUO 2023. I think you hit the highlights because, on one stream, we have the low-grade, intermediate-risk bladder cancer patients that may seem like they're not going to be threatened by their cancer, but it's a nuisance factor when you have these tumors that recur, recur repeatedly, and we clearly need something for them. I think one of the good things about the ENVISION study is that they focused on the intermediate-risk bladder cancer patients, as defined by the IBCG, for example, and focused on the low-grade patients, so we can safely then get those patients on a chemoablation arm without worrying about a high-grade tumor potentially persisting and growing underneath the surface.

What do you think the implications are of the findings in the real world? Do you think that the UGN data will allow you, for example, to use this as chemoablation in a primary setting? Would you select certain groups of patients such as the sick, or older patients, or the ones on anticoagulation, for example? What's your sense as to how you might use this?

Laura Bukavina: I think, Ashish, that's a great question. I think patients who we consider to be at risk for anesthesia adverse events, so the older patients, the patients with severe comorbidities, whether it's pulmonary or cardiac, and with persistent low-grade disease, these are the great patients for mitomycin. Now, it doesn't mean that those patients will never undergo TURBT. Down the line, they potentially might need to have a TURBT, but if we can cut down the amount of TURBTs per year, or per every two years, that these patients require, and minimize the risk of anesthesia, I think that's the goal of this therapy. In terms of the low-grade disease but high volume, I'm not quite sure about those patients where you have high volume, low-grade disease, and we all have those patients, where they just recur, and there's tons of low-grade tumors everywhere. I'm not sure how this therapy will really do in those patients, but certainly, the ones with a few papillary tumors along the bladder, high comorbidity status, perhaps ECOG status that's two or above, those are the patients that I think will benefit highly.

Ashish Kamat: Yeah, I think this is a great agent to have. Again, it's not approved yet, but once it's approved, hopefully, for our patients, where we can use it in selected patients. And then that brings me to the selection, obviously, of the patients that have BCG-unresponsive disease and the BOND study. Again, the CORE study using CG with pembro has excellent results, and now, of course, we're seeing a single-agent, which is even better because you avoid systemic toxicity. As you pointed out, there's a plethora of agents that are moving along the fast track, and some of them, or most of the more current ones, seem to be beating pembro and nado as far as efficacy rates are concerned, which is great because we've learned from the prior errors and trial design and re-inducing the patients, as you mentioned.

In your mind, assuming that these agents all get approved, what would you think would be your selection criteria? Would it be the frequency of dosing, cost, toxicity, all of the above? How would you envision, and I know it's a broad question, but what do you think are some of the points you would be considering when you're trying to select which drug for which patient?

Laura Bukavina: I think the ability to actually be able to provide the medication. We've had a lot of issues in the past with some of the therapy being available, approved, but not available to the patients. So that's number one. So, are you able to get the medication to a patient, and do you have someone who can actually do the therapy in terms of nursing, because some of it is complex in terms of follow-up. That would be my number one goal. Can I get it to the patient? The second thing will be the financial toxicity. A lot of these therapies are becoming fairly equivalent in terms of complete response, whether it's six months or 12 months. Am I able to provide this with minimal financial toxicity to the patients? Perhaps if someone is incredibly resistant to having a cystectomy and is a candidate for these types of therapy, but is not able to afford it, that becomes a very difficult question, just because we can't provide the therapy, but the patient will have financial toxicity that's going to affect not only them, but also their family members down the line for multiple years to come. That's going to be a tough choice for many of us.

And the last thing I would like to evaluate in those patients is also, what is the toxicity for these patients? A lot of the therapies, pembro aside, but a lot of the intravesical therapies that we currently have, they have low-grade group three toxicity. However, there are some differences in terms of unique side effects. So, someone who has significant LUTS symptoms, and some of the therapies that we consider today have significant lower urinary tract symptoms, those potential therapies might not be an option for them. Mito gel, for example, for someone who has a history of stricture disease. Perhaps that's not the best therapy for them because there is that low, but still persistent, ability to get stricture disease down the line. So those are the big three that I would consider, I think. A, is it available, B, toxicity to the patient?

Ashish Kamat: Yeah, these are important points. And again, the sequencing of BCG-unresponsive therapies was the focus of our IBCG retreat that we had this year. And that was one of the questions that everyone found hard to figure out, is, "How am I going to select these drugs and sequence them in patients?" Talking about sequencing, you mentioned Bishoy Faltas's work. He's doing some excellent work. I think that the FGFR story over the last almost two and a half, three decades that people have been working on FGFR from Maggie Knowles in the UK, now here, Bishoy, and others looking at it, I think we're recognizing that it's one of those alterations that is irrelevant when it comes to bladder cancer in the lower-risk patients, but when it comes to upper tract and metastatic disease, if you can find it in the bad actors, so to speak, you can then target the appropriate patient, and you summarized the data really well.

And I think moving forward, exactly like you said, focusing on the differences between the primary and the metastatic, and then trying to figure out which patients would actually benefit from it and how the toxicity plays in. For example, the THOR study with systemic erda is too toxic for patients with localized disease. But for example, the TAR-210 intravesical delivery with the erda that's given in the bladder, might be more palatable to patients. Same thing with the upper tract. Can you deliver it locally? Do you need it for localized disease? How do you do it for metastatic disease? All of these things are clearly what the community is going to be looking forward to. And again, thank you for summarizing that data. So, Laura, I want to thank you once again for taking the time and joining us today. It was great having you on, and thanks again.

Laura Bukavina: Thank you so much for having me.