But the focus on TURBT, I think, is really important. The quality of TURBT is important for risk stratification, obviously, and also important in terms of determining residual disease, upstaging, etc.

I think 1 of the key components of T1 disease we really emphasize from the get-go is for T1 to do a repeat TURBT. It is important, obviously, in terms of restaging, but also in terms of therapeutic benefit as well.

[00:02:44]

AUA Risk Stratification for NMIBC

When we look at risk stratification, these are the AUA guidelines, putting patients into buckets. We have a low-risk bucket, intermediate-risk bucket, and a high-risk bucket. What I tell folks is really, you will know what the low risks are. You will know what the high risks are. The big bucket is the intermediate-risk, which entails quite a few different patient populations.

[00:03:06]

BCG Shortage: Treatment Prioritization in NMIBC

As we determine those, we are attempting to treat patients with a variety of intravascular treatments. The most common for high-risk diseases is BCG. Unfortunately, we have had issues with BCG supply. The inconsistent supply of BCG. As a result, we have certain recommendations. For low-risk disease, it is really something we should discourage use of. For intermediate-risk disease, really, the use of intravesical chemotherapy is what is recommended now by the AUA and other organizations as well. For high-risk disease, we really prioritize it for induction courses, for patients with T1, as well as CIS. Less so perhaps than with papillary disease.

For very high-risk features such as variant histology, those with prostatic urethral involvement, extensive T1 disease, we really talk to them about actually doing a timely cystectomy or an upfront cystectomy.

[00:04:03]

Update in LG-IR-NMIBC: Intravesical Mitomycin (UGN-102)

Start talking about new initiatives, new findings, new treatments. One is an update, then, for low-grade intermediate risk disease. This is a question that would be ripe for any type of in-service or certifying examination.

Because now we actually have a treatment that is FDA-approved for patients with intermediate, low-grade disease that is recurrent. That medication is actually UGN-102. The trade name is Zusduri. That is actually given as a treatment once a week for 6 weeks. It is a chemo ablative treatment.

Instead of doing a TUR and giving a perioperative adjuvant treatment, or giving something actually once a week after surgery, a tumor that is identified when the patient has recurrent disease, that has been low-grade, the medication is, in fact, given. In 80% of the time, the tumors are gone at that 3-month mark.

If you look at 12 months, 80% plus continued to actually be disease-free after receiving this medication. You can definitely see where this medication comes into play. For those patients who have more comorbidities, patients who may be on anticoagulants, patients who have had recurrent disease, or current disease, definitely something to consider. This is now FDA-approved.

[00:05:29]

PIVOT-006: Cretostimogene Grenadenorepvec in IR-NMIBC After TURBT

Another agent that is being studied in this space is something called cretostimogene. Cretostimogene is a medication that you will also hear about. I will talk about high-risk disease. But this medication is actually looking and being studied in this intermediate-risk population. This is a treatment actually given after a TURBT. But we will see how those studies actually play out in this intermediate-risk population.

[00:05:58]

Patient Case 1: 68 Yr Old White Woman With Gross Hematuria 2 Mo Prior to Presentation

We will start off with a patient case, a typical case in terms of gross hematuria presentation. Some delay, perhaps in diagnosis, with antibiotics being given. A TURBT was performed that showed actually 3 papillary tumors, high-grade T1 disease, CIS as well. Muscle was present but not involved. This is a polling question that we will ask you to fill out.

[00:06:29]

Poll 4

Based upon the current guidelines, I do not think this will change as we are updating them now, what would be the optimal next step for a patient with T1 disease?

Initial resection, muscle was present but not involved. Multiple tumors were there. We will see what the polling is, and we will have answers here. Just a few seconds. The vast majority chose C. That is correct. Re-staging TURBT. We will talk about that as well.

[00:07:02]

High Risk Non–Muscle-Invasive Bladder Cancer

Shifting to high-risk disease. Intermediate-risk disease, we have a new FDA-approved agent. We have several trials going on.

[00:07:09]

High-Risk NMBIC: Current Treatment Recommendations

For high-risk disease, if you look at the NCCN and the AUA guidelines, the treatment is BCG. It is the initial treatment choice. You can consider radical cystectomy as well. We know the outcomes are quite good in terms of cancer efficacy for bladder removal, but the comorbidities, the complication rate, etc, are quite high.

We tell our patients in Nashville that they have a 40% complication rate, or we do, within the first 3 months after that surgery, 40%. The mortality rate, if you are over 70, is 2% within the first 90 days. This is a significant operation. Everything you hear, I think, recently from medical oncologists, as well as from other urologists, is let us do everything we can to avoid bladder removal.

[00:08:01]

Induction and Maintenance BCG for High-Risk NMIBC

BCG has really been the backbone of treatment. These are slides from the SWOG trial, looking at induction BCG vs maintenance BCG, and the outcomes. Clearly, the impact and benefit are from a combination of induction BCG with continued maintenance. There are some studies regarding shortening that maintenance. There seems to be some equivalence. But clearly, the additional BCG is beneficial. That is not only in terms of recurrence, but probably for progression as well.

[00:08:35]

CREST: Sasanlimab Plus BCG in BCG-Naïve, High-Risk NMIBC

Why is this important? I am going to start going over some trials that may change practice dramatically. It may not. I do not know. But we know that now studies have been shown. This is the CREST trial. This is a trial that was presented at the AUA this spring. This was a combination of a subcutaneous medication, this sasanlimab. All these drugs have these all these long names. But this is a subcu PD-1 inhibitor that is actually given, as opposed to IV. This was studied in combination with BCG vs BCG alone.

I think, to many of our surprise, actually, there was a significant benefit to the combination therapy. A 32% reduction in events. An event could be a repeat TUR, progression, disease, etc. But a 32% reduction when a subcu IO, immunotherapy, was given with BCG vs BCG and maintenance.

We had thought, for non–muscle-invasive disease, that BCG alone will be good. You will not need the IO. But, in fact, there was a significant benefit. What is the trade-off? The slide actually does not have this, but it is the side effects. You have a 17% side effect ratio. A significant adverse event associated with the immunotherapy arm, given subcu, that was not present with BCG by itself. Is the trade-off going to be enough to give this combination therapy?

[00:10:21]

POTOMAC: Durvalumab Plus BCG vs BCG in High-Risk BCG-Naïve NMBIC

If only 1 trial shows a benefit, you are not always so sure. But a second trial was just presented, literally less than a month ago at ESMO, looking at another immunotherapy. This is actually durvalumab, which is a PD-L1. This was given intravenously. But again, the combination of systemic immunotherapy plus BCG was better than BCG. This is BCG with maintenance.

[00:10:50]

POTOMAC: DFS (End Point)

Importantly, if you look at their primary endpoint, which is a little bit different, it was actually disease-free survival, what was the difference? 32%. Very, very similar to the CREST trial. You have 2 different immunotherapies given with BCG, but both showing very similar decreases in either disease or event-free survival. There is clearly a signal. The question is, again, cost, side, effects, etc, is this really going to become standard of care for patients with high-risk non–muscle-invasive bladder cancer? It is unclear at this point if that is really going to become the case, but there clearly is a disease benefit with this combination therapy.

[00:11:43]

Intravesical BCG vs Intravesical DOX/GEM Treatment BCG-Naïve High Grade NMBIC (BRIGDE)

We are always looking for alternatives to BCG. A lot of trials are being done, actually looking at, let us give something else instead of BCG for these high-risk patients. I think this is a very important trial. This is a BRIDGE trial, looking at combination chemotherapy, gemcitabine and docetaxel. Actually, comparing it and randomizing it to BCG.

We do not have the results yet. But this will be important because again, a similar event-free survival is the endpoint up to 2 years to see if, actually, this combination chemotherapy is better. We have retrospective studies. We have institutional studies that show perhaps it is equivalent. Perhaps it might even be better. We do not know. This trial, I think, would be really important.

[00:12:31]

Patient Case 1: Update

If you look at the patient who received the TUR and has T1 disease, got BCG, got maintenance BCG, ends up actually developing more tumors. This is within less than a year.

[00:12:47]

Poll 5

How would you classify this patient? These are the choices.

1. Intolerant
2. Unresponsive
3. Inadequate
4. I do not know

Another polling question. Intolerance would imply, obviously, I cannot tolerate it very well. Inadequate BCG. This patient got induction plus 2 rounds of maintenance therapy. I do not know, is an answer I usually choose as well. But we will see how the polling goes. The majority of people chose the right answer, I am going to say. It is BCG-unresponsive.

That category of patients, the BCG-unresponsive, really is 1 that we have started to tap into. A lot of trials have been done. I am going to show a lot of trials because there are now a lot of options.

[00:13:39]

Pretest 1

If you look at this question, this is a patient with a significant past medical history, had a TURBT, has BCG-unresponsive disease, continues to have the disease despite BCG. What is appropriate? A, more BCG, at this point that would be a wrong answer. Already received enough BCG. B, intravesical nadofaragene. We will talk a little bit about that. C, intravesical mitomycin C. That may still be 1 of the most common treatments that we have, but the data showing a benefit from intravesical mitomycin C shows about a 5% to 8% response rate. An ineffective therapy. Systemic chemotherapy really does not have a role. The right answer is actually B.

[00:14:32]

BCG-Unresponsive/High-Risk NMIBC

In putting these medications together, these trials together, the FDA brought a group of us together regarding a consensus of, what is disease that really should be focused on? We came up with the idea of this BCG-unresponsive group. It basically is, you get BCG, but you need to get enough BCG to give it a chance to work. If patients have a disease that comes back, then they become BCG-unresponsive. If they do not clear the disease or the disease comes back within a shorter period of time, you have BCG-unresponsive disease.

Now, fortunately, we have a lot of trials open still in this space and we have medications. One thing I do want to emphasize is, if you have BCG, do not forget that second attempt, either induction or maintenance. Because that second round, in fact, will get a response rate of 10%,15%, up to 20% of patients will respond to that second round.

We will have patients refer to us that have only had 1 induction, 6-week course of BCG. The first thing we will do is give them more BCG because the response rate is real. But then, again, do not keep on giving BCG if the patient continues to have disease. You have this group of BCG-unresponsive disease. Since there were no really good options, the FDA said, you know what, we will allow single-arm trials, and we will see if there is a difference or a benefit. That is what led to a significant number of approvals.

[00:16:06]

NCCN Guidelines: Management per NMIBC Risk Group

This is a slide now looking at medication options out there. If you were to take a picture of 1 slide, this is probably a slide I would look at because it gives you the options that are FDA-approved, gives you options that would be guidelines also consistent, and goes a little bit over the risk groups. Risk stratification is important and therapeutic options are important.

[00:16:32]

KEYNOTE-057: Single-Arm Trail of Pembrolizumab Monotherapy for BCG-Unresponsive High-Risk NMIBC

Let us go through what options are out there. The very first treatment that really started this road to systemic therapy was the KEYNOTE-057, which looked at actually giving systemic immunotherapy for non–muscle-invasive bladder cancer. I think people were very, very surprised, in fact, that there was a response.

The response at 3 months was about 40% of patients had disease clearance. But unfortunately, over time, you can see the curve going down over time, at the 1-year mark, less than 20% actually continued to have a response. Overall, you worry about the longevity. I can tell you, when this was first approved, now probably 4 years ago, 5 years ago, since then, the use of this has decreased just because of a combination of lack of response, as well as the lack of durability of response. FDA-approved, however, in this cohort of patients.

[00:17:41]

IFRα-2b Vector-Based Gene Therapy With Nadofaragene Firadenovec in BCG-Unresponsive NMIBC

The second medication, now also FDA-approved, is a medication that is based on interferon. The trade name is Adstiladrin. It is nadofaragene. This medication actually stimulates the immune system. This is based upon a nonreplicating virus that is placed into the bladder. The beauty of this is an immunotherapy that is given once every 3 months. The response rates actually were better than we saw with systemic immunotherapy. What we saw was that we had an overall initial response rate of 40%, 50%, and that complete response rate at 1 year was almost 25%.

Again, over time, you see a decrease in the effectiveness, but there seems to be a tail. What I tell folks is, if you respond and you respond for a period of time, then there seems to be this significant longevity associated with that therapy. FDA-approved.

[00:18:50]

IL-15 Superagonist NAI

Third FDA-approved medication is actually an IL-15 superagonist called NAI or nogapendekin. This medication also depends upon the immune system. It actually ramps up the immune system by presenting this IL-15, another form of immunotherapy, bringing in natural killer cells, dendritic cells. By doing this, again, hopefully stimulating the immune system to have a long response.

The downside to this medication is it must be given with BCG. If you have trouble getting BCG, you cannot give this medication. There have been trials now with a new recombinant version of DNA. The FDA has said this is fine to give in combination with this medication. The difference I see with this medication is that there seems to be even a higher complete response rate, and again, this durability over time.

In fact, the majority of patients have a response, if they do have a response, that lasts for years. The median duration of response now is almost 4 years. Again, a majority of patients may not get a long-term benefit, but those that do show an initial sign seem to have this tail and have a long-term response. FDA-approved.

[00:20:15]

SunRISe 1: TAR 200 ± Cetrelimab vs Cetrelimab Monotherapy in BCG-Unresponsive HR-  MIBC

Fourth treatment FDA-approved, is actually another intravesical treatment. But for the first time, it is not an immunotherapy. It is chemotherapy. It is a chemotherapy that is actually impregnated into a device that everybody fondly calls the pretzel. This medication is actually placed by a cystoscope. It is placed by a special catheter. You can confirm its placement with cystoscopy. But this medication is changed every 3 weeks. This is gemcitabine placed into this pretzel that is released over time. About 60% or more of the gemcitabine is gone after a week. Then, over time, it continues to dissipate, and then you place another pretzel device.

If you look at the outcomes, again shows a signal that shows this is an active drug. You had a complete response rate of more than 80%. Looking into the bladder, doing biopsies, doing cytology, bladders have been cleared. There seems to be a long-term benefit as well, with a complete response rate at a year, at almost 50%. Not an immunotherapy. A chemotherapy. Requires the placement of a small device. But again, FDA-approved literally in early September.

[00:21:44]

Pretest 1

Going back to this question, this is now a posttest question, I will have you fill things out in the pretest. We had the same questions for this patient with BCG-unresponsive disease. We have now a variety of options that are FDA-approved. There is a single answer here that has FDA approval. There is a difference between chemotherapy and immunotherapy.

[00:23:05]

Posttest 1

I will now show you this. The right answer being nadofaragene on this slide. This is approved specifically for patients with CIS, that have recurred or are still present, despite adequate BCG. We have a systemic immunotherapy, pembrolizumab. We have systemic intravesical immunotherapies. That is Adstiladrin, that is Anktiva. These are trade names. Adstiladrin, which is nadofaragene. Anktiva, which is nogapendekin or NAI. Then we have the TAR 200, which is the gemcitabine-impregnated pretzel. Those are all treatments. The last 1 is a chemotherapy agent.

[00:23:11]

Investigational Studies: Emerging Novel Treatment Options for BCG-Unresponsive/Recurrent NMBIC

With this, now comes even more medicines you are going to need to know about, because these are likely going to get FDA approval.

[00:23:14]

BOND-003 Cohort 3: Intravesical Cretostimogene Grenadenorepvec for High-Risk BCG-Unresponsive NMIBC

The 1 that is probably closest to that is the medication called cretostimogene. This is another intravesical agent. Another agent that is put into the bladder. This is actually a conditionally replicating adenovirus, though. This actually goes into the bladder. It grows. It is a combination of GM-CSF as well as the E2 pathway. You have a combination of immunotherapy as well as some cell death with this medication.

This medication is given once a week for 6 weeks and then maintenance afterwards. The data was presented at AUA. Again, shows a very high response rate, 75%, almost 76%. A significant percentage had no disease at 1 year. Almost half, again, had a complete response at 1 year. This medication is again placed in the bladder. It is up for FDA's evaluation and review. The data is very similar to the data that has already been used to approve those other agents, and 1 that will likely lead to FDA approval.

[00:24:24]

CISTO: Radial Cystectomy vs Bladder-Sparing Therapy for Recurrent High-Grade NMBIC

We are doing all these things to avoid taking out the bladder. We are doing all these treatments. But something else that was presented at the AUA that you will need to know about is this CISTO trial, C-I-S-T-O. This is a trial looking at not who should get what, but what happens when a patient chooses cystectomy or when a patient chooses more systemic or intravesical therapy.

The primary endpoint of this was physical functional well-being, how patients really did and felt after either bladder removal or after treatments in the bladder. In fact, the primary endpoint favored bladder removal. All these steps that we are taking to try to avoid bladder removal based on patient-reported outcomes, physical functional well-being, in fact, was better for bladder removal for this cohort of patients.

I do not think that bladder removal or cystectomy is totally out of the picture for non–muscle-invasive bladder cancer. But I definitely think it is going to need to be discussed with patients that, look, if you are having a lot of symptoms, a lot of issues, the bladder removal may actually, in fact, be the best choice.

A lot is going on. We got intermediate-risk, newly approved medication, BCG-unresponsive, 3 medications approved recently in the past couple of years, another 1 likely be approved in next year. We are just scratching the surface because invasive disease has been a sea change as well.

[00:26:09]

Pretest 2

If we start off with this patient here with the pretest, a 42-year-old woman has difficulty voiding. She ends up having stage III muscle-invasive disease. She is platinum-eligible at this point. What would be the treatment of choice?

I can tell you, the treatment of choice in the past 18 months has changed 3 different times. We will go over some of those changes as you fill in the pretest.

[00:26:40]

Initial Therapy in Muscle-Invasive Bladder Cancer

If you look at initial therapy for muscle-invasive disease, this is a list on the left and on the right of patients who have disease that may or may not be more aggressive depending upon the stage. It is a busy slide. I am going to go through some of these trials that just a year or 2 ago, changed practice. But honestly, are going to become obsolete because things have changed just recently as well.

The first is a combination, actually, of perioperative chemotherapy plus immunotherapy, followed by cystectomy, followed by more adjuvant immunotherapy. As of probably a year ago, this became standard practice, maybe even less than a year ago, where instead of neoadjuvant chemotherapy followed by cystectomy, it is actually a combination of neoadjuvant chemotherapy plus durvalumab, followed by cystectomy and more durvalumab.

[00:27:38]

NIAGARA: Durva + Neoadjuvant CT in Patients With Operable Bladder Cancer

What was found was, if you look at the overall outcomes of event-free survival as well as pathologic complete response, you saw a significant benefit when you combine chemotherapy with immunotherapy. As a result, if you look on the non–muscle-invasive side, we already are seeing some of these combination therapies. That definitely was not the case, actually, with invasive disease. That became standard, like I said, less than a year ago.

[00:28:08]

Keynote 905/EV 303: Perioperative Pembrolizumab ± Enfortumab Vedotin

But what is going to change everything, what everybody has been talking about, though, is this combination of perioperative pembrolizumab with a medication called enfortumab. This was actually done in a CISplatin-ineligible population. This was presented, again, less than a month ago or about a month ago at ESMO. What this was is that instead of chemotherapy, you give this combination of enfortumab and pembrolizumab.

You may not want to know the details, but pembrolizumab immunotherapy and enfortumab is actually an antibody-drug conjugate that actually, its target is something called nectin-4. What you need to know is the medication is incredible in terms of its efficacy.

If you look at these curves, these are curves, again, looking at event-free survival. You can see the advantage of the combination therapy compared to the control. The control was actually chemotherapy, that 2 years ago was the standard practice, the gold standard. You can see the difference in terms of the event-free survival.

You had a pathological complete response rate of almost 50%, clear of tumor. The basis for all this was the fact, if you look at the secondary endpoints, actually a difference in overall survival. The genesis of all this has been based upon this combination used in metastatic disease and worse disease. This has replaced any chemotherapy as first-line, enfortumab plus pembrolizumab.

This trial comes out. Instead of doing chemotherapy or this or that prior to cystectomy, it is this combination that is going to start and has started in many places already. The key side effects of enfortumab are ones that are dose-limiting, that we may not be so used to. Clearly, the main thing is neuropathy that tends to drive these patients in terms of downsides. There are others as well, but neuropathy seems to be 1 that is most dose-limiting. There is a pretty significant rash that can develop as well, but the combination of pathologic pCRs [? 00:30:34] is significant.

[00:30:37]

Phase III Checkmate 274: Adjuvant Nivo vs Pbo in MIBC

Combination therapies, other therapies, they are all being studied. The data is all coming out. Unfortunately, what we do not know is what is going to be the benefit of these next few trials. These next few trials looked at, we have taken the bladder out. What can we do to help prevent cancer from coming back? The first trial was nivolumab. 4 years ago, 3 and a half, four years ago, this came out. Yes. 2021, by Dr Bajorin. When you saw that data, it was, if they have bad disease after I removed the bladder, I need to give them nivolumab because I can actually improve their metastasic-free survival as well as progression. That became standard. Now, though, we do not know where nivolumab will fit in because almost everybody is going to get enfortumab. We do not know where it is going to fit in.

[00:31:39]

Checkmate 274: DFS in ITT and PD-IL-Positive Patient 5-Yr Follow-Up

Same thing with CheckMate.

[00:31:41]

AMBASSADOR: DFS and OS (Coprimary Endpoints)

I am going to go to AMBASSADOR. It was also actually an adjuvant. Give nivolumab. That was positive. How about giving pembrolizumab? That also actually showed a benefit. If you look at the curves with disease-free survival as well as overall survival, overall survival, they did not see a signal yet, but clearly a difference with disease-free survival.

As a result, adjuvant therapy seemed to make sense. But again, what happens when we treat patients now upfront with enfortumab and pembrolizumab? We already know more pembrolizumab will be helpful. The question is, how much more and what do we give them afterwards?

[00:32:26]

IMVIGOR 011: Atezolizumab vs Placebo in Patients With ctDNA + HR-MIBC Post Cystectomy

The reason why this IMVIGOR trial, also recently presented, was, long story short, when the IMVIGOR trial first was presented, looking at atezolizumab as an adjuvant treatment or something to give afterwards, there was no benefit. It came out as a negative trial. Everybody said, this does not work. It is not helpful.

What they did was they went back and looked at the data. They had all this urine and serum and other biomarkers banked, and they saw a signal that, if you separate and look at only those patients with circulating tumor DNA that was still present, the atezolizumab seemed to have a benefit. This trial, IMVIGOR 011, actually studied that prospectively. In other words, if you had circulating tumor DNA still present, then you were given atezolizumab vs standard of care or placebo.

[00:33:28]

IMVOGOR 011: DFS and OS in Patients With ctDNA+

What happened? Just as what was found with the retrospective evaluation, there was a difference in advantage based on that circulating tumor DNA being present. This is really an important trial in terms of showing the impact of, we have got biomarkers that may help tell us what patients may need, how they may benefit, as opposed to giving everybody everything.

[00:33:54]

IMVOGOR 011: DFS and OS in Patients Persistently Testing ctDNA-

If you look at the curves here, overall, those patients that had no evidence of ctDNA did not really need any additional therapy, we think. Not so sure. But if you go back and you see the difference with those that were ctDNA-positive, clearly an advantage of giving more therapy. In this case, that therapy was atezolizumab.

[00:34:21]

Adjuvant Immunotherapy Shared Decision-Making

This adjuvant therapy curve what you do, what is the benefits. You have to weigh that against the risks. You have costs. You have side effects. We are trying to do the best we can to determine who is most likely to benefit. But clearly, there seems to be advantage, especially if you still have evidence of disease. That evidence we think may be circulating tumor DNA.

[00:34:47]

Adjuvant Treatment of MIBC Following Cystectomy (Stage II or Stage IIIA)

Strategies now. The first bullet is, if patients had not had any chemotherapy, maybe we give them more chemotherapy. It might be helpful if they have a high-risk disease. I think the vast majority of people are going to get, actually, not chemotherapy anymore, but enfortumab and pembrolizumab.

What about adjuvant nivolumab? It makes sense, again, if they got chemotherapy. But if they did not get chemotherapy upfront, which I think most people will not, again, we do not know where nivolumab will fit in.

Pembrolizumab. Similar data to nivolumab, not yet FDA-approved. Then this whole ctDNA is helping guide what we do. I think ultimately it would make a difference.

[00:35:34]

Posttest 2

As I show this posttest slide of what is the treatment of choice, probably right now if you do not have enfortumab and are not familiar with it, or do not use it, then the standard of therapy, I think, becomes pretty clear, combining of chemotherapy and immunotherapy. I will tell you which answer that is.

We have not really talked about chemo radiation or neoadjuvant immunotherapy by itself. That is been evaluated, but has not shown much promise. We will see what the answers are here. I am going to go to the answer slide.

The right answer, if the patient got chemotherapy, would be to give a perioperative immunotherapy with CISplatin-based chemotherapy as the neoadjuvant treatment, followed by bladder removal, and then additional adjuvant immunotherapy. That is the NIAGARA trial. That is a durvalumab.

[00:36:48]

Metastatic Bladder Cancer and the Urologist

I have got a couple of slides on metastatic bladder cancer. I told you guys the answers regarding what has really taken over for a patient with metastatic disease. You can have renal compromise and still get enfortumab. Your performance status does not have to be great. You can still get enfortumab.

[00:37:13]

Pretest 3

This is a pretest question. This is all based upon the data that I had mentioned before, alluded to, giving a combination of this vs actually just chemotherapy.

[00:37:31]

EV-302/KEYNOTE -A39: OS and PFS (Coprimary Endpoints)

If you look at the curves here, this was presented 2 years ago and published a year ago. These curves are dramatically different. If you have ever had a patient with advanced disease, metastatic disease, that has had a response, they clearly are dramatic. Liver lesions, lung lesions, bone lesions resolving. Not everybody, but a real percentage. You can see the benefit not only in progression-free survival, but also in overall survival.

[00:38:07]

Guidelines Have Been Updated Regarding The Treatment of muC-Current NCCN Guidelines (Version 2.2025)

 The guidelines have been updated, looking at this as the treatment of choice, either in CISplatinum-eligible or ineligible. It has really become the treatment for patients with metastatic disease. The guidelines have been updated to show that.

[00:38:24]

ESMO 2024 Guideline Update for the Treatment of moc

It is only if EV and pembro were not available or contraindicated, then you start thinking again about other options, chemotherapy being 1. Then we have other treatments that I have not even talked about that can depend upon certain presentations of molecular changes, HER2-positive, EGFR-positive, etc, that may show a benefit.

[00:38:48]

Posttest 3

If we go to this post-test slide. I have emphasized the overall the difference in terms of the benefit associated with combination EV and pembro. Here is the key polling question.

[00:39:08]

Poll 6

Do you plan to make any changes in how you manage patients with bladder cancer based on what you learned in today's program?

1. Yes
2. No
3. Uncertain

I do not know if people will change dramatically, but at least now you know options are present, and what may be beneficial to patients as you consider counseling them. We have not talked about cost. We have not talked specifically about side effect profiles. Needless to say, the intravesical therapies all have side effects. Most commonly are lower urinary tract symptoms. But they are overall tolerated actually well.

[00:39:44]

Poll 7

Please text 1 change you plan to make to your practice based on this education. Scan this QR code to text your response.

While you guys are scanning that, I have got a couple of other scan slides, but I am happy to take questions. Happy to tell you what I think or what I do not know, which is a lot. But thank you for your attention.

[00:40:10]

Question and Answer Session

I have got other slides here. This, I think, is an important 1 here, that you all need to get access to your CME codes, etc. This other QR code to the right does give you access to slide presentations for any of the residents who want them as well. Information. Overall, it is quite helpful. Thanks for the opportunity. Happy to take questions. Thank you all for your attention. Speaker: Do you have any questions in the audience?

Dr Chang: Yes. Sam. Please call me Sam.

Speaker: We need some help. In Lexington, we are on a BCG shortage again. Do you think, gem dosing, no no-brainer for intermediate-risk people, but high-risk people? I know data is pending, but is that what you would go to?

Dr Chang: Yes. We have had intermittent issues. Is it not frustrating not being able to get BCG? I did not even go there a little bit. I do not know if we have any folks from Merck here. Merck is building this factory. I have got pictures of the factory. It is from some drone. It is great. But it is actually getting up to speed. It should be completed by next year. They are going to triple the supply, so that is long-term.

Secondly, the inconsistency of the supply of BCG is what bothers me the most. You all have an idea of liquor distribution and what happens or what doesn't happen. I do not think it is too dissimilar.

I saw Chad in here, how Atlanta cannot have BCG either. But Cookeville, Tennessee, population of 50,000, has oodles of BCG. It just does not make any sense to me. When we have trouble with BCG, we will go to a half dose. But if we do not have any, then we will do a combination of gemcitabine and docetaxel. If we are strained and it is terrible, it is only papillary disease, sometimes we will go to gemcitabine monotherapy.

Speaker: Walk me through your protocol.

Dr Chang: For gem dosing?

Speaker: Yes.

Dr Chang: Basically, it is run by our NP, Meredith Donahue, who does a tremendous job. She actually gives presentations, actually, across the country. We have an intravesical clinic. On Fridays, they come in.

They all know each other, they start meeting. It is quite an efficient process. The way it is set up is, patients know it is Friday. They know they are going to have to spend a few hours. They come in, they leave a urine sample first. Some will leave a urine sample early on in the week just so that they can get out of there sooner. We make sure the urine is negative. Then the patients are brought in, MAced [? 00:43:38], then prep them, place catheters in.

For gem dosing, we do the gem. We leave it for an hour. We do not push anymore. Our gem dosing, honestly, we started at 2 grams. We are down to 1 gram now. It can be a little tough to hold, but we will do 1 gram. We dropped from 75 to 37.5mg of docetaxel. But once they get the docetaxel, we take the catheter out, and then we have them leave.

Speaker: Sequentially?

Dr Chang: Sequentially, yes. We drain it, then we put the docetaxel in. We leave the catheter in. Honestly, we leave them in the room. We tried taking them out of the room. We keep the gem-dosing patients in that room for that hour, drain, place it, and then the room is turned over after that. Other questions?

Speaker: Thank you.

Dr Chang: Yes, Dr Eifler [?].

Speaker: Quick question. Do you think we are stuck with the BCG-unresponsive definition? Is it always going to be 5 plus 2 for the rest of time?

Dr Chang: Yes. Honestly, I think that is not going to change. I think what is going to change is the single-arm trials are no longer going to be accepted in this group. To be honest, everybody is going to shift away from that group because you have got these approvals. Then everybody is going to know what if this does not work? Can you give this?

What is going to happen is the majority of patients are going to see at least a couple of these medications. What the right order is, honestly, probably will not ever be figured out because not a lot of money will go in there. But they are all shifting it to earlier stages, BCG-naive or higher-risk, intermediate, etc.

I think that definition will change. The question I always get is, which 1 do you use? Which 1 is better? They all have their pros and cons, and their advantages and disadvantages. We talk with patients. We talk about availability.

Currently, we give the Adstiladrin and we give the Anktiva. We have pembrolizumab with our med [inaudible 00:46:00], but we have not used that for non–muscle-invasive disease for, honestly, probably 3 years. We will be working on getting the TAR 200, the pretzel. We have not gotten that through our P&T [? 00:46:14] committee yet.

People say gosh, do you think chemotherapy would work better because they failed in immunotherapy? I think, honestly, all these trials were done on patients who failed in immunotherapy. I think maybe if you try an immunotherapy next, and that does not work, then it makes some sense to do chemotherapy.

There is going to be a lot of questions on, where should you go, what should you do. I do not know the right answer to that. I do not think anybody does. Yes, sir.

Speaker: You briefly skimmed over. But chemo radiation with immunotherapy for bladder preservation in the high-risk patient that just cannot stand an operation, or will not do it, anything new on that?

Dr Chang: I think S1802, which is a combination of chemotherapy, with immunotherapy prior to radiation therapy, we do not have a read on that. That has finished accruing. I think that we are going to remove a lot less bladders. I think the bladders that are going to be removed are going to be, unfortunately, the worst-case scenarios.

Significant symptoms, hematuria, significant size, no response. We have already started seeing that because people are getting such good responses to the therapy, and because the radiation for many tumors is an effective treatment. It is an effective treatment.

I trained with J. Smith, and we never radiated a patient. I will be honest, we never did. I think now, I would say 10 patients come in with muscle-invasive bladder cancer, almost all of them will at least see our radiation oncologist. I would say 2 or 3 choose radiation, 30%. Not with cystectomy. I am talking about chemotherapy plus radiation. I would say 30% will end up choosing that. Some of those patients, absolutely, I think they should do that due to other issues.

There are others who could not only tolerate, but get through a cystectomy well. But make that choice. If they have a lesion that is amenable to it, and not have the issues that they are concerned about; a lot of CIS, hydronephrosis, bladder neck involvement, multiple tumors, all those types of things.

I would say a lot of them have responded well. I have not had 1 that actually had disease recurrence. We have not had to do a salvage cystectomy in quite some time, which is a real change.

I do not know if you all have had experience. You can tell, enfortumab and pembrolizumab, all the medical oncologists out there saying, we will never do another cystectomy again. I do not think that is right. I have not seen in my short time tumors melt away. Not everybody, but a lot.

Unresectable disease, where after 2 treatments it is not there, and we have taken out bladders after a big response. I think that is going to be the big question, too. We take out these bladders, and the surgery is much more difficult because of the reaction of fibrosis and their DT is zero