Melanie Cole, MS (Host): Welcome to AHN Med Talks, an informative resource for physicians across various specialties as we delve into the latest medical insights and best practices, ensuring you stay at the forefront of your field. I'm Melanie Cole. And we have a panel for you today highlighting bladder cancer treatments and exciting advancements at AHN.

Joining me is Dr. Goutham Vemana, he's a urologist with the Allegheny Health Network; and Dr. Alex Helfand, he's a medical oncologist hematologist with the AHN Cancer Institute. Doctors, thank you so much for joining us today. And Dr. Vemana, I'd like to start with you in how has our understanding of the landscape of bladder cancer evolved over the past decade or so? How is this influencing clinical decision-making today? Speak a little bit about the prevalence and what you're seeing in the trends

Goutham Vemana, MD: The bladder cancer is a fairly prevalent diagnosis of cancer in the United States. There are about 80,000 new cases per year that we see. Typically, we're finding these patients by screening them for hematuria, so blood in the urine. And patients either have microscopic blood in the urine that we're seeing on a urine screen, or they're coming in with visible blood in the urine, gross hematuria.

Previously, we were diagnosing these patients by getting samples from their biopsy, a transurethral resection. There wasn't a lot of sophistication in terms of how we would target their treatments. We are kind of cycling through various things, either just bladder resections. And then, based on the type of cancer that we see in the bladder, we're funneling them to different types of intravesical treatments, so treatments that we put in the patient's bladder to try to prevent progression and recurrences. These were not necessarily selected based on any particular molecular specifications or genetic specifications. We're basing these decisions on tumor characteristics, what type of cancer it was, how deep is it in the bladder. And then, just like the variant of histology, most bladder cancers are something called urothelial cancers, and we stage them based on how deep they're growing into the bladder. And so, the treatments are tailored to that. And so, there are basically two broad categories. There's muscle-invasive bladder cancer, and non-muscle-invasive bladder cancer. Most cancers that we diagnose are non-muscle-invasive bladder cancer. And about a quarter of them are muscle-invasive bladder cancer. And these are essentially two separate entities. So, we urologists have a lot of experiences dealing with these non-muscle-invasive bladder cancers.

Coming into the modern era, like most patients were just getting bladder resections. And then, there were two, really one agent that we were offering patients called BCG. BCG is actually a vaccine for tuberculosis. It essentially tricks the body into attacking bladder cancer cells, and we are using that for certain high risk patients with bladder cancer who don't have muscle invasion.

Now, there's been a pretty big change in the recent options that we have, but we have many more options we ever had to select patients for treatments. Again, like they're not necessarily based on any kind of underlying genetic features. There are some on the horizon. But now, we tend to select patients who are not responding to BCG treatments, and there are a lot more options we have for those patients.

Melanie Cole, MS: Thank you so much. It's really an exciting time in your field. And Dr. Helfand, tell us about some of the current treatment offerings for non-muscle-invasive bladder cancer. How are you approaching that balance between bladder preservation and radical cystectomy in your treatment? As Dr. Vemana was just speaking about, that used to be mainly what was done, but now there are so many new tools in your toolbox as it were.

Alex Helfand, MD: That's an excellent question. I think that the sort of mainstay of management of non-muscle-invasive urothelial carcinoma, certainly from the patient perspective, is that most patients would like to try to preserve their bladder as long as possible. And the goal on our end is obviously to try to help them to do that while also preserving the likelihood of cure and longer term survival.

So, as Dr. Vemana was speaking about, BCG has certainly been the mainstay of management, particularly of high risk bladder cancer for the past 30 to 40 years. But what is particularly exciting now is that we have a number of agents which have shown significant promise in patients who do not respond or have recurred despite having received BCG. And so, among the options for treatment include re-treatment with BCG, along with a newer drug called ANKTIVA, which we do here at AHN. There's also an option for BCG plus another drug, which is an immunostimulant called Adstiladrin, which uses a viral vector. There is also data for the combination of BCG re-exposure along with immunotherapy. In addition to that, data using a different type of device, which Dr. Vemana can speak about in more detail, but that's called TAR-200 and that has also been shown to have excellent complete response rates in the BCG refractory setting, which is particularly exciting because a large percentage of those patients will be able to avoid cystectomy.

One thing that I would just highlight is that, even just in the past few weeks, we have data looking at patients who have never received BCG before for high risk non-muscle-invasive urothelial carcinoma. And we now have data from both the CREST trial and from the POTOMAC trial showing improved event-free survival in patients who received BCG along with immunotherapy upfront, meaning the first time they ever received BCG. And that's particularly exciting to try to move the needle so that we can try to maximize the number of patients who can avoid cystectomy and avoid progression to muscle-invasive bladder cancer.

Goutham Vemana, MD: This is a great summary of the new novel agents that we have on the horizon here, some of which that we have at Allegheny Health Network. I've been using BCG and ANKTIVA in select patients and have had fairly good results with it and good tolerability.

The one that we're very excited about is TAR-200, and this is a device that gets implanted or kind of free floating in the bladder and you insert it with a special catheter and it pushes this pretzel basically that has gemcitabine tablets. So, gemcitabine is a chemotherapy drug. And we previously were using this by just squirting it in patient's bladders, and they would hold in their bladder for about 60 minutes and then they would urinate it out.

The novel part of TAR-200 is that it's a sustained release of gemcitabine. And this Implantable device remains free-floating in somebody's bladder for about three weeks at a time. And so, these drugs are being continuously emitted during that time. Most of the drug delivery is given within the first couple weeks, but the concept of this is that it's continuing to expose the bladder to this chemotherapy agent over a much longer period than just squirting it in their bladder for an hour at a time. And what the results have shown is that patients have had incredible results with this treatment, with significant amount of rates of complete response of up to 82%. And the nice thing is that they've had a fair amount of durability of response for over two years with about 50% of patients having a good durability response while on this treatment. So, it is a nice option for patients who have this high risk recurrent bladder cancer that has failed BCG previously.

Alex Helfand, MD: And I would just 100% second all of that. I think it's a really promising treatment and quite tolerable and certainly a nice option to try to control non-muscle-invasive disease. The other thing I would just add is we're still waiting for the results of the BRIDGE trial, which is a cooperative group trial recruiting just shy of a thousand patients comparing gemcitabine and docetaxel in the first line to BCG, and that will also be a really important addition to the options potentially for how we manage this disease and try to prevent progression to muscle invasion.

We're hoping to open up another trial using a new viral vector in combination with BCG in patients who are BCG refractory. And so, I mentioned this simply to try to reinforce that we, you know, certainly encourage everyone to always reach out to us. We're happy to see patients, happy to discuss patients, because we do have a lot of options for these patients. And we very much have quite a few cutting edge options as the research evolves and we find better and better options for patients with really good tolerability.

Goutham Vemana, MD: The nice thing about many of these treatments that we offer at AHN, specifically BCG and ANKTIVA, which we're doing currently, is these are being given at all of our cancer centers throughout AHN. So, patients have given access to getting these treatments in very good geographic regions across Pittsburgh and Western Pennsylvania.

Melanie Cole, MS: Well, it certainly is so interesting, and I want you both to come back. As you said, you're waiting for results of these trials. Well, we will wait with you and come back and tell us about those. But in the meantime, Dr. Helfand, what are some of the current options for neoadjuvant therapies and systemic therapy options? What role do these have in your current treatment protocols?

Alex Helfand, MD: So when we speak about neoadjuvant options, we're speaking about muscle-invasive urothelial carcinoma, meaning a disease that is staged as T2, and that is invading the muscle wall of the bladder. And for these patients, what we have known for a long time is that treatment with chemotherapy before surgery improves overall survival, meaning that patients who are treated before and then undergo cystectomy will live longer compared to patients who do not receive any systemic therapy prior to surgery.

The standard of care until about a year ago had been chemotherapy alone with either dose-dense MVAC or gemcitabine plus cisplatin. But the results of the NIAGARA trial, which added immunotherapy to chemotherapy, demonstrated that there were superior progression-free survival and overall survival by adding immunotherapy. And so, that is essentially now the standard of care for neoadjuvant therapy for muscle-invasive bladder cancer. It'd be the combination of gemcitabine plus cisplatin, plus durvalumab. And all three drugs are given before surgery and immunotherapy has then continued to complete a total year of treatment afterwards.

 Interestingly, we now have data that's been presented at the ESMO conference a couple weeks ago showing that the combination of enfortumab vedotin as well as pembrolizumab, which is the standard of care for metastatic disease improved outcomes compared to chemotherapy alone-- that was not eligible for chemotherapy. I apologize. So, basically showing excellent overall survival of about 75% in patients who received these two drugs, EV and pembro, both before and after surgery. And so, we will obviously await to see whether that gains FDA approval, but I suspect that will be added to the guidelines fairly soon for patients who are cisplatin-ineligible.

And we await the results of two trials, both the EV-304 trial as well as the VOLGA trial, which are also comparing EV pembro to patients who were receiving chemotherapy alone. So, again, it's really important that patients receive chemoimmunotherapy around the time of surgery if they're cisplatin-eligible. And if they're not, we, for the first time, have data showing a benefit to non-cisplatin-based treatment in this population.

Goutham Vemana, MD: Just from the surgeon perspective, we see a lot of excellent responses to these new treatments. I've now operated, I've done cystectomy for patients who've been on the new treatment with gemcitabine, cisplatin, and durvalumab. But also, patients with advanced disease had been put on EV pembro and had great responses that we've taken for radical cystectomy when their metastatic disease was resolved. And we've had a lot of durable responses. And it really has changed the game for us in urology and bladder cancer, even in the advanced bladder cancer stage. It's really opened up the avenue for better treatment for these patients.

Alex Helfand, MD: Response rates of up to 70% in the metastatic setting with EV and pembro, this is finally allowing for what we might call a consolidation cystectomy. And obviously, the data is quite limited. But certainly, we are rendering many more of these patients free of any disease than ever before, and that's particularly promising. Because with this regimen we've doubled overall survival compared to chemotherapy alone. And that's doubled from about 16 to 34 months. So, this has probably been the greatest revolution in bladder cancer in the past 20 some years. So, this is something that we do routinely here at AHN. And I think it just demonstrates that with continued research and progress that we continue to help patients live longer every day.

Melanie Cole, MS: Dr. Vemana, you represent two specialties here focused on treating bladder cancer. Can you tell us about your combined clinic, why this is relevant, and how AHN's multidisciplinary approach integrating urologic oncology, medical oncology, radiation pathology enhance those outcomes for these patients? Speak about why a multidisciplinary approach is so important here.

Goutham Vemana, MD: Oh, because bladder cancer is a multidisciplinary disease, especially these patients with muscle-invasive bladder cancer, but now even the non-muscle-invasive space. But oftentimes these muscle-invasive bladder cancer patients, this is a advanced disease, it's complex. These patients need to be evaluated by urologists. They have to be evaluated by a medical oncologist. many of these patients have multiple medical comorbidities that make them challenging surgical candidates or systemic therapy candidates. It's important to have a good team that involves urology, medical oncology, radiology, radiation, oncology, pathology.

We kind of need a full complement of people here helping to make decisions. We have a multidisciplinary tumor board that meets twice a month that we discuss complex cases. We get consensus treatment plans for these complex patients to make sure they get the best care possible. We're always discussing the most up-to-date studies, and it really does push patient's care forward as much as possible. We also have nursing navigation that helps patients through, making sure they get timely appointments, they get in to see the urologist as soon as possible, as well as touching base with the medical oncologist. I mean, it is incredibly important that these patients have this team moving forward with them throughout their entire treatment.

Alex Helfand, MD: And I would just add to that, that the radiation oncology in particular is a critical asset that we have in the management of this cancer. And that in speaking about muscle-invasive disease and options for treatment, that for those patients who either are not interested in or refuse or are not eligible for surgery, certainly a bladder-sparing approach with the combination of local resection with TURBT as well as chemotherapy and radiation to the bladder is also another tool in our arsenal that we use all the time to try to treat patients in the best way.

Goutham Vemana, MD: Yeah. And we have good collaborations with radiation oncology. And so, we all kind of work together. The urologists still follow along when they get these therapies, but we have all these avenues available to patients in our network

Alex Helfand, MD: The other thing I'd like to just mention, and I don't know if, Melanie, you were going to get to this, but I want to just emphasize that in particular, in the advanced setting for bladder cancer, that it has become ever more important, that we do molecular profiling and appropriate pathologic testing for these patients because we now have multiple targeted agents that can be used for these patients.

So, that includes both HER-2 testing, for which we offer a drug called N-HER2 for the treatment, which is highly effective. And in fact, there's actually new data presented a couple weeks ago showing a combination of HER-2-directed antibody drug conjugate called disitamab, along with immunotherapy, provided around 31 months of overall survival, which was about double that of chemotherapy, which is a remarkable achievement in patients who have HER2-positive disease. Patients who have FGFR mutations are also a candidate for treatment with a drug called erdafitinib, which we also offer here that is quite effective in that subpopulation and for which we also have a pending clinical trial opening up for use in the first line setting for patients with metastatic disease. So again, there are other targeted therapies as well. And I would just reinforce that doing early molecular profiling and genetic testing is critically important in order to identify these avenues of treatment. And when you see somebody in our group, we make sure that these tests are done and that we address all avenues to get the best possible, least toxic treatment.

Melanie Cole, MS: I'm glad you brought up the molecular issue, because that was going to be a question and so important in your field right now because it is advancing quite quickly. And Dr. Vemana, one thing we really haven't touched on is the surgical options. So, tell us a little bit about what's exciting in that realm for bladder cancer, robotic-assisted surgery. Is that evolving? Tell us what's going on there.

Goutham Vemana, MD: Yeah. So, I do a lot of robotic surgery for bladder cancer and specifically for muscle-invasive bladder cancer. When these patients complete their systemic or their neoadjuvant treatments, we're often taking them for radical cystectomy. So, these are procedures that historically have been done with an open incision. It's a lower midline incision and it can be somewhat of a morbid procedure with a lot of complication risks associated with it and a lengthy stay in the hospital. Robotics has definitely moved the needle here. Patients can have these very complex surgery done with small incisions with the robotic platform by Intuitive. And I'm often getting patients out of the hospital in three to five days now, where they would be there for sometimes over a week. So, we've definitely shaved off days of their hospital stay, less blood loss, less pain, early return to normal activity, and patients just do better with these procedures. So, I've been doing robotic cystectomies now for over 10 years and doing not only the bladder removal, but the urinary diversion. Because once you take out the bladder, you have to find a way to get the urine to be diverted out of the body.

Oftentimes, we're doing something called an ileal conduit, which is like a stoma that the urine drains to a bag or even neobladders, which are creating reservoirs out of the small intestines that kind of function as a facsimile for the bladder itself. And these are, again, also done robotically in select cases.

Melanie Cole, MS: Wow, this is such an enlightening discussion. I'd love to give you each a chance for a final thought here. And Dr. Helfand, and tell us a little bit about what goes on as far as the physical and the psychosocial challenges of bladder cancer from diagnosis through survivorship. I'd like you to speak to other providers that are referring their patients as far as communication with the referring physician, working with the families because it can be quite a change of life. And so, speak a little bit about that navigation and how you help the patients and their families.

Alex Helfand, MD: Certainly patients with bladder cancer can have significant symptom burden and that can manifest itself in different ways that often presents with urinary symptoms or hematuria. And that is certainly a domain in which we work closely with the urology team to try to optimize symptoms and to try to help patients feel better.

By the nature of the drugs that we give for these diseases that can also lead to symptom burden as well. And so, with the help of our nurse navigators and colleagues in other disciplines, whether it be palliative care or orthopedics, radiation oncology, even ophthalmology in the setting of various drugs, which can cause visual changes and other ophthalmic complications, working with dermatology closely. We try to provide this multidisciplinary care that makes sure that every patient is taking care of regardless of what the symptom may be. And what I often encourage primary care doctors and patients to do is to please just keep us in the loop so that we're dealing with symptoms closer to the time they start as opposed to once they've gotten particularly burdensome.

 Certainly, when patients are on treatment, it's really important that when these patients present to their primary care doctors or other specialists, that if they are presenting with new symptoms, that the oncologist is kept in the loop, just so that we can address, is this really something that we think may be a consequence of the cancer itself or of the treatments? Or does this seem like it's something that is not related?

Melanie Cole, MS: Dr. Vemana, last word to you. What are you most excited about, emerging therapies, technologies that you feel will dramatically change the standard of care for bladder cancer in the next five years or so? Give us a little blueprint. What's on the horizon? How is AHN positioning itself to be at the forefront of bladder cancer?

Goutham Vemana, MD: I'm very excited about in the near future about getting TAR-200 and getting my hands on that for patients. I'm excited that this is a device that is almost a proof of concept as well. So, they're using gemcitabine in this now, and I think that there are other agents that they can put into this device, this drug delivery system.

So, I'm excited about that being the case, but I'm also excited about the future, about us doing a better job of selecting patients for the types of treatments that they should be getting. And there's some molecular testing that we have been doing for prostate cancer that allow us to help identify where patients should go with their treatments.

These are options that I'm excited about getting to AHN, which we've already been using for prostate cancer, for example. We'll call it decipher score. And so, they're planning on doing that for bladder, and we would hopeful to get that in as well. But ultimately, while I do a lot of surgeries for cystectomies, I'm excited to avoid cystectomy as much as possible, because it is a very difficult procedure to get patients through and it's a very big change in their lives. So, I'm optimistic about all of these new therapies to hopefully minimize the use of this tool as much as possible.

Melanie Cole, MS: Thank you both so much. What a great discussion this was. Thank you so much for sharing your expertise with other providers. And to refer your patients to Dr. Vemana or Dr. Helfand and at AHN, please visit findcare.ahn.org and search the doctor's name. And to learn more, you can also call 844-MD-REFER. Thank you so much for listening to this edition of AHN Med Talks with the Allegheny Health Network. I'm Melanie Cole.