Introduction

DR YU: Good evening. Welcome so much to “Consensus or Controversy,” where clinical investigators provide their perspectives on the current and future management of patients with bladder cancer. I’m Evan Yu. I’m a GU medical oncologist from the University of Washington Fred Hutchinson Cancer Center in Seattle. I’ll be moderating this evening. As you can see, we have a very illustrious faculty this evening. I’m going to go ahead and introduce them briefly: Dr Matthew Milowsky, who’s at the University of North Carolina, Dr Peter O’Donnell at the University of Chicago, Dr Jonathan Rosenberg at Memorial Sloan Kettering and Dr Arlene Siefker-Radtke at MD Anderson. All good friends and colleagues. We’re going to have some great discussion tonight. It’s going to be a lot of fun.

Here are the relevant disclosures and Research To Practice conflicts of interest. I’m going to go ahead and flip through these so you can take a look.

So this program’s going to contain discussion of some nonapproved uses of agents and regimens, so please refer to official prescribing information for each project for the approved indications.

Okay, let’s go ahead and get started with the program. This is the agenda for tonight. As you can see, Dr Milowsky’s going to kick us off and talk about the role of anti-PD-1/PD-L1 antibodies and therapy for nonmetastatic urothelial bladder cancer, then Dr O’Donnell will talk about other novel strategies under investigation for nonmetastatic urothelial bladder cancer, and then Dr Rosenberg will talk about front-line treatment for metastatic urothelial bladder cancer. I’ll jump in and talk about the emerging role of HER2-targeted therapy for metastatic urothelial bladder cancer, and Dr Siefker-Radtke will bring us home talking about the selection and sequencing of therapy for relapsed/refractory metastatic urothelial bladder cancer.

So in order to make this meeting more relevant to the participants there’s been interesting survey questions that have been sent out to all the faculty and conducted, and we’ll be reviewing those survey questions during the program. Additionally, Dr Love interviewed some other experts in the field, Dr Terry Friedlander and Dr Betsy Plimack, as well, interviewed them on multiple key clinical issues, and we’ll be playing their videos, and they’ll be asking this illustrious panel many questions throughout. So we’ll get to hear people’s opinions on certain clinical situations, and we’ll have that throughout.

As a special feature Dr Love also decided to interview Dr Priyanka Sharma, who’s a breast cancer expert, because of the increasing role of HER2 potentially in urothelial bladder cancer. And she’s an expert that’s been using HER2-targeted therapies for many years in breast cancer, so it’ll be interesting to hear her perspective and also hear her questions for the panelists.

Role of Anti-PD-1/PD-L1 Antibodies in Therapy for Nonmetastatic Urothelial Bladder Cancer (UBC) — Dr Milowsky

DR YU: So without further ado we’ll get started with the first module. This is the role of anti-PD-1/anti-PD-L1 antibodies and therapies for nonmetastatic urothelial bladder cancer. Again, we’ll have a video and have some questions and see what the panelists think. And then Dr Milowsky will talk about this topic more.

So Dr Plimack and Dr Love sat down and talked about adjuvant nivolumab after neoadjuvant chemoradiation and surgery for muscle-invasive bladder cancer and discussing this in relation to patients.

DR LOVE: Good evening, everyone. I’m Neil Love from Research To Practice. Over the last few weeks I worked with Dr Betsy Plimack and Terrence Friedlander to plan this meeting, and I sat down with each of these investigators to record a series of questions for the faculty on the stage to address. Dr Plimack began by commenting on some of the issues involved in the use of immunotherapy following neoadjuvant chemoradiation treatment and surgery.

DR PLIMACK: In terms of adjuvant, approved is nivolumab for adjuvant urothelial that’s high-risk. High-risk is defined based on pathologic staging.

One of the hot topics there is that we have yet to see an overall survival benefit, although we’ve seen a disease-free survival benefit.

The second issue that we come up with in clinic is that the upper tract group in that study that was included, for some reason, on the forest plot really just did not achieve the same benefit as the overall group which was mostly bladder cancer patients.

At GU ASCO we’re going to see the adjuvant AMBASSADOR trial. That’s with pembrolizumab.

DR LOVE: How do you approach discussions with patients nowadays in terms of adjuvant immunotherapy?

DR PLIMACK: I really try to be as even as possible. And I start the conversation by saying normally, if you ask me for a recommendation, I can give you what I think you should do. In this case, it really has to be both of us coming together and meeting for the first time. Your values, your perspective, your gut feeling are going to weigh heavily into this because there’s no right answer, right? You may be sitting here in front of me already cured with all your cancer gone from surgery, in which case this is all overkill. You may be sitting here with cancer still in your body and this treatment may or may not work to eradicate it.

My job is to explain that very complicated set of concepts to someone and then let them, their family kind of bring their values to bear to decide.

DR YU: Okay. Well, it looks like there’s some nice questions that Dr Plimack had for the panel. So the first one is how do you discuss the benefits and risks of using adjuvant nivolumab with patients receiving neoadjuvant chemoradiation therapy. So Dr Milowsky, how do you do this?

DR MILOWSKY: Yeah. So this is neoadjuvant chemoradiation therapy. I mean the indication is for patients who undergo radical cystectomy followed by adjuvant nivolumab, and so in the setting of chemoradiation therapy I would say there’s not really a clear role for the use of adjuvant nivolumab in that particular setting. I think the idea of this balanced discussion with the patient is extraordinarily important.

I do think, that being said, it’s the story kind of with perioperative chemotherapy across the board, even if you look at chemotherapy that which is associated with a survival benefit, it’s very similar. I mean you don’t know whether the patient in front of you is ultimately going to, on an individual patient level, derive a survival benefit that’s associated with the adjuvant therapy that you’re going to use. And so I think any situation like that that requires perioperative therapy with potential toxicity requires that shared decision making.

DR YU: Okay, great. Dr O’Donnell, do you use adjuvant nivolumab for patients with upper tract disease?

DR O'DONNELL: I do, but I use it with some skepticism about whether I’m doing the right thing. I know that there’s certainly a theory that patients with upper tract may not benefit as well, perhaps because those patients have higher FGFR alteration rates, which may describe cold tumors, and so those patients may not be as likely to respond. Yet I think that what we have to caution ourselves in looking at these subgroups analyses that weren’t always planned and drawing too many conclusions from them. The trial allowed patients with upper tract, and the trial was positive overall for disease-free survival, so I’d come back to that at the end of the day.

DR YU: Okay. Great. Dr Rosenberg, so this is relevant to what we just saw a little bit earlier today, the Phase III AMBASSADOR trial of adjuvant pembrolizumab. I think everyone wants to know how do you choose now that in the future you might have a couple options?

DR ROSENBERG: I think it’s a very relevant question. The data, I think, in many ways are very similar between nivolumab and pembrolizumab. They both show significant DFS advantage. Neither of them have shown an overall survival advantage at this point. The AMBASSADOR trial released the OS results, and the nivolumab study, CheckMate 274, did not, and presumably not positive at this point.

And so we have a treatment that reduces the risk of relapse or death. And living with metastatic urothelial cancer is not the best existence for people for the most part, and so I think there’s real value in the idea of preventing and delaying relapse for many of these patients. And many of them are older, and so there are competing causes of mortality in many of these patients, and so some of it is around convenience and schedule.

Nivolumab in the original study was on a 2-week schedule. Most people are giving it on a 4-week schedule. Pembrolizumab can be given on a 3-week schedule or a 6-week schedule. So I think we’re going to start to see how these drugs are actually used in the wild in this situation.

DR YU: All right. Great. Let’s move on to the discussion between Dr Love and Dr Friedlander on the ongoing evaluation in the role of cell-free DNA assays to enhance adjuvant treatment strategies.

DR LOVE: Dr Plimack raised a number of issues about the adjuvant setting, and I’m also personally very curious about whether we’re going to see subcutaneous checkpoint inhibitors in the clinic and how that’s going to affect the patient experience and flow in the oncology clinic. Dr Friedlander provided some additional perspective on the adjuvant setting.

DR FRIEDLANDER: It’s now an approved option to give nivolumab. I actually use it fairly often in my patients.

There’s some controversy in the field. And the questions that arise, first of all, is like efficacy-wise, right? Is a 10% or so improvement in DFS, is that worth it?

About half of patients have no side effects, but about 10% can have serious autoimmune side effects, and that can be really problematic.

The MODERN study is being launched as we speak from the Alliance, and this is using cell-free DNA as a tool to test different adjuvant strategies.

And so I think we might be seeing a movement in the adjuvant space to try and tailor therapy to patients who are only cell-free DNA-positive.

In terms of neoadjuvant therapy there’s a study of enfortumab vedotin plus pembrolizumab, a Phase III trial. I think there’s a lot of hope that this is going to have a strong benefit in the neoadjuvant setting because it seems to perform better than standard platinum-based chemotherapy in the metastatic setting.

DR YU: Okay. It looks like Dr Friedlander had some interesting questions here. This is about subcutaneous immune checkpoint inhibitors and what do we think about their potential availability and the impact that might have on the patient experience and flow in the oncology clinic. Dr Siefker-Radtke.

DR SIEFKER-RADTKE: Well, that’s certainly an interesting question. When you think about flow it certainly takes time to sit in the chemo unit, and what we’re seeing in urothelial cancer is an extension of life, patients getting weekly treatment regimens, and we’re seeing this across tumor types, which impacts the ability to treat patients when you have to wait. And if you can give a simple injection with the same efficacy, and the patient can get in and out quickly, I think that would certainly be very desirable.

The challenges are, are they going to pay for it. We’ve seen what happens to other injectables. How will this be considered? How will payment impact the business model in the community oncology setting? Because certainly we see all across the healthcare spectrum cost reduction becoming very important to maintaining healthcare for all, yet we don’t have quite all the resources we would like to have for using this. But I think it could improve flow. Patients would, I believe, find it desirable, getting out quickly. How will they manage the cost? How will it be reimbursed?

DR YU: Okay, great. I’m going to go back to Dr Milowsky. I think this question actually fits with the theme of the first question I asked you, which had a little bit to do with your discussion with the patient about risk/benefit ratio, giving adjuvant nivolumab. What do you think about introducing ctDNA in this setting in the design of ongoing trials?

DR MILOWSKY: Yeah. So I think this is really exciting. I mean we talk a lot about biomarkers, and this is in fact a biomarker that’s looking very, very good. I mean in the IMvigor010 in a retrospective analysis there was both what looked to be predictive and prognostic value. And there are 2 studies, the IMvigor011 study, which is looking really in the ctDNA-positive population of patients to determine whether or not they benefit from adjuvant immunotherapy, and then there is what I think is a particularly exciting study that was designed by Dr Galsky, which is the MODERN study, which has just opened, which is looking at an escalation strategy in those patients with positive ctDNA and a potential for de-escalation in those patients who are negative for ctDNA.

So I’m really excited about the potential role for ctDNA. I’m not sure we could use it at this moment until we have more prospective data.

DR YU: Okay. Looking forward to seeing it. Oh, go ahead.

DR SIEFKER-RADTKE: So I really think the circulating tumor DNA is going to be essential. I personally don’t really like the adjuvant nivo because we are delaying recurrences; we’re not curing patients. And if you look at the control arm, about 30-40% of patients are cured. 30-40% of patients are now undergoing financial toxicity, time toxicity, and those potential side effects, and some patients will still die of their immunotherapy. But circulating tumor DNA, which has a high predictive value for recurrence, I think removes some of the concern that we’re overtreating patients because we’re treating them in their minimal residual disease state.

DR YU: Okay, great. Good thoughts and opinions.

All right. So the faculty were presented some cases, and I wanted to put up what the faculty thought. So let’s run through this case. This is a 65-year-old patient, receives neoadjuvant therapy for muscle-invasive bladder cancer, undergoes cystectomy. How do the presence of absence of residual disease and PD-L1 status affect your decision whether the patient should receive postoperative adjuvant immunotherapy and which immunotherapy to administer? And for how long do you generally administer adjuvant immunotherapy?

So as you can see, the faculty were fairly consistent in their thoughts, but one thing that stood out here, I mean you can see that the key thing is residual T2 disease or greater after neoadjuvant chemotherapy showing some sense of chemo insensitivity, was generally what the faculty picked to offer adjuvant immunotherapy. But one key question is about PD-L1 status. I think you all have seen that PD-L1 staining in patients, you look at the forest plot, they seem — those that were PD-L1 high seemed to garner more benefit. And so one question is do you check? Do you routinely check? Dr O’Donnell, what do you do there?

DR O'DONNELL: Not routinely, but I think it says on the slide, if I’m on the fence, right — I mean in reality I know it’s great to have shared decision making, but the patient is looking to us to give the recommendation. And so there are patients that I’m on the fence about how much more do I want to push this patient through therapy, they had a hard time maybe through neoadjuvant or they’ve had a tough recovery after their cystectomy, how hard do I want to push them for a year. And so I tell those patients I want to get a little bit more information that might tell me a little bit about what our payoff might be. And if they’re PD-L1 high then I’m much more likely to push that patient toward therapy.

DR YU: Makes sense, perfect sense. All right. Then we asked the faculty to describe their last patient in practice diagnosed with muscle-invasive bladder cancer who received adjuvant nivolumab after neoadjuvant therapy. Everyone described their cases. Dr Plimack had a very young patient at 43 years old. PD-L1 status was there, and they asked the question about how long the nivolumab, and many patients still have ongoing treatment, et cetera.

What about the tolerability issues, okay? And Dr Friedlander had a patient with an infusion reaction. I had a patient that had a mild rash, which might be the most common IO toxicity, but didn’t have any significant IO-related reactions there. So with that being said and done I think we all know about the autoimmune toxicities of IO. We use it for many, many different diseases. Rash tends to be the thing that we see the most, and it’s kind of a mild toxicity. This group has been real fortunate without a lot of toxicities.

So I think we should just move on to the next situation, which is Dr Milowsky. He’s going to give us a talk on the role of anti-PD-1/PD-L1 antibodies in nonmetastatic urothelial bladder.

DR MILOWSKY: Great. Thanks, Dr Yu. So I’ll just move forward quickly here, and I’ll start with some of the data related to monotherapy with pembrolizumab. And so this is the KEYNOTE-057 trial in patients with high-risk non-muscle-invasive bladder cancer using single-agent pembrolizumab. There’s 2 cohorts here. There’s Cohort A, which is patients with carcinoma in situ with or without papillary disease, and then there’s a Cohort B with papillary disease that’s high-grade Ta or T1 disease in the absence of CIS.

And so in the study patients are treated with pembrolizumab for up to 2 years. They’re assessed at 12 weeks. If they have a complete response then they continue on therapy. They’re followed by the disease assessments that are listed in the slide. And here there are different primary endpoints for the cohorts. The first is CR. That is the absence of high-risk NMIBC in Cohort A with CIS, and then disease-free survival in Cohort B.

And so this is the topline results from this study. In Cohort A you can see the median follow up of about 3 years of 96 patients with BCG-unresponsive disease. 41% had a CR at 3 months. Median duration is 16.2 months. And of 39 responders 46% remained in CR greater than or equal to 12 months. And so I would say that the issue here is really the durability in those responses. So on the order of somewhere around 20% or less of patients will have durability of those responses if one looks out at a year plus.

In Cohort B, when you look at the disease-free survival in those patients with high-grade Ta or T1 disease, here it’s 43.5% at a year. This is not much different if you look at some of the other novel agents that are being studied with regard to disease-free survival in this population. I will say it’s a little bit confounded by the fact that this is a heterogeneous-type population of patients with progressive, persistent, and recurrent disease. And the majority, about 60% of the patients, were patients with recurrent disease who may fare somewhat better than those with, for example, progressive or persistent disease.

Bottom line is pembro was FDA approved in January of 2020 for the treatment of patients with BCG-unresponsive high-risk NMIBC with CIS with or without papillary tumors.

There’s a number of ongoing Phase III trials of anti-PD-1/PD-L1 therapies plus BCG in BCG-naïve NMIBC. These have been completed. There’s the POTOMAC study with durvalumab, ALBAN with atezolizumab/sasanlimab, which is subcutaneous as Dr Love had mentioned, and then there’s the KEYNOTE-676 study with pembrolizumab. And these generally have both induction and maintenance schedules of BCG, and you can see the primary endpoints are really DFS/EFS outcomes.

This is just the schema from the POTOMAC trial. Here it includes an induction and maintenance BCG schedule and induction only, and then you can see the BCG is with induction and maintenance. And then this is the ALBAN study, which is designed a little bit differently but a similar population of patients looking at BCG induction and maintenance as compared to induction/maintenance with atezolizumab.

And so we look forward to these studies reporting out to understand if there’s a role for the use of immune checkpoint blockade in the context of BCG therapy in naïve disease.

The KEYNOTE-676 study also has a component in patients with persistent or recurrent disease, again here randomized to pembrolizumab in BCG versus BCG monotherapy, here with a primary endpoint of CR rate in the patients with carcinoma in situ.

What about the use of neoadjuvant immune checkpoint inhibitors in patients with muscle-invasive disease again staying with the theme of nonmetastatic disease? So this is a series of studies that have looked at immune checkpoint blockade, 1 in combination, NABUCCO, using as few as 2 cycles of atezolizumab in the ABACUS study. And these are the pCR rates and the < pT2 rates, ranging from 31 to 46%, pT0 and <pT2 upwards of 58%.

If you look at these data along with data from the use of conventional cisplatin or dose-dense cisplatin or chemotherapy with GC in combination with immunotherapy with regard to pathologic complete response I think we’d all probably agree in this room that it’s really difficult to parse out whether 1 of these approaches is better than another when simply looking at pathologic complete response.

So what we really need are time to event endpoints, and this is a little bit of a dirty analysis kind of comparing some studies with time to event endpoints. The VESPER looked at dose-dense MVAC and GC. The SAKK study looked at GC and durvalumab. And here’s ABACUS again with 2 cycles of atezolizumab.

And if you look at the 2-year PFS/EFS outcomes and the 2-year overall survival you can see that even the 2 cycles of atezolizumab looks good with regard to 2-year overall survival, perhaps not as good as dose-dense MVAC or GC/durvalumab, but really dangerous to compare across trials. And here and 85% disease-free survival in patients who achieved a complete response.

So I think we need more data, and that data is coming from randomized trials. These are several of the trials that are looking at neoadjuvant immune checkpoint blockade in combination with chemotherapy. And you’ll notice that many of them have immune checkpoint in the adjuvant setting, as well, which may confound things with regard to really understanding whether or not that’s truly needed in the context of combining chemo and immunotherapy.

There’s also trials that are looking at ICI plus enfortumab vedotin. We’re all aware of the excitement with enfortumab vedotin. So here’s some trials in the cisplatin eligible, EV-304, as well as EV-303 in the ineligible patient population, and VOLGA study. And so we look forward to these reporting out to understand whether or not this benefit we’re seeing in the metastatic setting when we include enfortumab vedotin comes to fruition in the perioperative setting as well.

Adjuvant trials we touched on. The IMvigor010 study was negative with atezolizumab. CheckMate 274, again, a positive study, FDA approved in August of 2021, and AMBASSADOR, a late-breaking abstract here at this meeting.

This is the most recent, I believe, update of CheckMate 274, here with a median follow up of 36 months. I think you’ve already seen the randomization to nivolumab versus placebo with a primary endpoint of DFS in the ITT, as well as in the PD-L1 positive by tumor score. A majority of patients with bladder, about 20% upper tract, PD-L1 40%, and prior neoadjuvant chemotherapy 40%. This is just showing the ITT in the muscle-invasive population.

Here’s the DFS data. Here hazard ratio of 0.71. You can see the medians. This is the muscle-invasive bladder cancer cohort, hazard ratio 0.63. If one looks in the PD-L1 greater than or equal to 1% population it’s a hazard ratio of 0.52. If you look at the medians it’s pretty striking at 52.6 months versus 8.4 months. And again, there has not been survival data that’s been shown. The safety data can be seen here, and this is something that is manageable, but I think as others have said it’s something that we need to be very attuned to in our discussions with patients with regard to the potential for significant immune-related adverse events.

This was the AMBASSADOR study that was presented today, pembrolizumab here versus observation, with dual primary endpoints of disease-free and overall survival. And here’s the bottom line, hazard ratio 0.69. The median for pembro was 29 months versus 14 months, so a 15-month improvement in disease-free survival. This is the overall survival curve, and so this is early, and we will need to continue to monitor to see if ultimately there is a survival benefit.

This is the toxicity data. A little bit difficult to compare it to what I showed you with CheckMate 274. This is looking at all AEs regardless of attribution.

And then just turning to the chemoradiation therapy scene, this is a Phase III trial. And there are not so many trials as I’ve shown you in the neoadjuvant setting looking at concurrent chemoradiation therapy with or without atezolizumab for localized MIBC. This is SWOG 1806, and here a randomization to concurrent chemoradiation therapy versus the same with atezolizumab, with a primary endpoint of bladder intact event-free survival.

And so my conclusions are pembro monotherapy is a treatment option for patients with high-risk NMIBC that’s BCG unresponsive, but additional studies are needed prior to incorporating ICIs into the neoadjuvant treatment of patients with MIBC. Adjuvant ICI I think does represent a standard of care in patients with high-risk muscle-invasive bladder cancer. We have more data today with the AMBASSADOR trial and ongoing Phase III clinical trials with immune checkpoint inhibitors in combination with chemotherapy, immunotherapy and chemoradiation may change the treatment landscape for patients with nonmetastatic disease. Thank you.

Other Novel Strategies Under Investigation for Nonmetastatic UBC — Dr O’Donnell

DR YU: All right. Thank you so much, Dr Milowsky. Great talk. Let’s move on to Module #2, and this is where Dr O’Donnell’s going to talk later about other novel strategies that we’re looking at for nonmetastatic urothelial bladder cancer. So let’s start off with a video that Dr Love had in conversation with Dr Plimack on perspectives on bladder preservation and the evolution of systemic therapies for patients with muscle-invasive bladder cancer.

DR LOVE: The integration of neoadjuvant chemotherapy into the management of invasive urothelial bladder cancer not only allows a high-risk patient with residual disease to receive treatment that would reduce the risk of recurrence but also the potential for bladder preservation, as commented on by Dr Plimack.

DR PLIMACK: In terms of localized disease, let’s talk about muscle-invasive bladder cancer, the standard of care is neoadjuvant chemotherapy followed by surgery.

Some of the hot topics in the field include subbing out alternative treatments for neoadjuvant cisplatin-based chemotherapy, such as checkpoint inhibitors, enfortumab vedotin or the combination.

As our systemic therapies get better or our ability to deploy them and understand pathologic response without removing the bladder become better. Can we leave some healthy bladders in place and just use systemic therapy to clear them of cancer, allowing patients to live without going through surgery and without, for instance, an ostomy?

We’ve had a lot of bladder-sparing clinical trials at Fox Chase.

We do always have people who get treatment. We look in their bladder, we don’t see anything. We do imaging, we don’t see anything. And they say no thank you, I’m going to take my chances. Let’s do a scan in a few months. And some patients have done really well with that and not recurred. And some have recurred but are happy that they had their bladder for the amount of time that they did. And then when we’re treating them for metastatic disease, it’s not also with an ostomy, right? They didn’t go through both things.

DR YU: Okay. Her questions for the panelists here. Dr O’Donnell, I think you’re up next, and so we’re going to ask you what you think is most promising for neoadjuvant therapy approaches.

DR O'DONNELL: I think what’s on everybody’s minds is whether the EV paradigm, EV plus pembro, is going to move earlier in this disease course and result in more patients being cured, right? I mean we all would want to prevent patients from getting to the metastatic setting, if possible, because we all know this is an aggressive disease when it’s metastatic.

DR YU: Okay. Dr Rosenberg, as we continue to improve upon neoadjuvant systemic therapy could we find more patients that can avoid cystectomy? Do we need to continue with radiation there? And so what are your experiences with bladder sparing, and what do you look for in the future?

DR ROSENBERG: Yeah. I think there’s a lot of promising approaches. I think biomarker selection is still an open question, although not quite ready for primetime, to identify patients with exquisite sensitivity to either conventional or novel therapies. We’ve known for a very long time that you can actually spare the bladder after chemotherapy in a small proportion of patients with only a very modest decrement in long-term cure rates, and so you just have to appropriately select the patients. And in fact the patient selection criteria for those approaches aren’t clinically all that different than selection for optimal chemoradiation, small tumors, no hydronephrosis, T2 tumors completely resected or completely resolved after neoadjuvant therapy. And so I think we’re going to see more and more of that, but for young patients, obviously people want to keep their bladder, but they’re going to have to live with the consequences of having a bladder that might have problems for a very long time also. And so it’s a double-edged sword, but we have to push that forward because organ preservation is very important to our patients.

DR YU: I’m going to push you a little harder. Dr O’Donnell talked about using EV in this situation. We see really good complete response rates for advanced disease, metastatic disease, what’s it going to take for you to have a pT0 and decide to spare someone’s bladder?

DR O'DONNELL: I think we have to get to that point, right? So the EV monotherapy data for muscle-invasive disease is about a 35% pathologic complete response at the time of cystectomy. The converse is 65% of patients still had invasive disease present. And so I think the problem that we have is that clinical staging is not nearly as good as we’d like to think it is, and so as advanced imaging improves, and more use of MRI to evaluate postop, we might find that our clinical evaluation post-treatment may improve so that we can — it may not matter how you get to at T0, right? We’ve seen that in other trials.

DR YU: Okay. Dr Milowsky.

DR MILOWSKY: Yeah. I would just say I agree. I mean I think the biomarker question is really the most important question here because the truth is we already do have a bladder-sparing approach, right? I mean we have chemoradiation therapy, which is often well tolerated and has a track record. It may be underutilized, but it’s something that already exists. And so of course we’d like to do better and provide even less therapy to patients, but just making the point that we do have a bladder-sparing strategy in patients with muscle-invasive disease for appropriately selected patients.

DR YU: Okay. Great. Let’s move on to the discussion Dr Love had with Dr Friedlander about pembrolizumab as treatment for BCG-unresponsive high-risk non-muscle-invasive bladder cancer. Let’s go ahead and see the video.

DR LOVE: As discussed in both the first and second module, intravesicular therapy and immunotherapy are key current components in the management of non-muscle invasive disease, and Dr Friedlander commented on the challenge of avoiding cystectomy particularly in elderly patients with comorbidities.

DR FRIEDLANDER: Cystectomy is a huge insult to the body, and we’re talking about patients who tend to be elderly, in their 60s, 70s, maybe 80s. A lot of them are smokers. They may have vascular disease. And doing a surgery in someone that age, it can take months to recover. And so a lot of people don’t want cystectomy for the immediate risks, for the perioperative risks, and then the long-term outcomes.

A lot of people are excited about pembrolizumab because it offers the opportunity to keep their bladder and have durable responses.

And actually just yesterday I saw a patient of mine who started 4 years ago, got pembrolizumab for refractory non-muscle-invasive disease, is still without any recurrence, and the hardest thing with him is I’m trying to convince him to stop the pembro.

DR LOVE: Anything else in local therapy you want to comment on?

DR FRIEDLANDER: I think the most exciting intravesical therapy is TAR-200, and it literally is a pretzel. So this is a piece of plastic, more or less, that is deployed as a linear thing in the bladder through a catheter, and then it’s tied into a pretzel shape inside the bladder, and it can stay there for up to 3 months. And they can load basically any drug they want into the pretzel, and it slowly elutes the drug into the bladder. So it’s kind of a conceptually straightforward idea, and the pretzel shape keeps it from leaving the bladder.

They actually presented at ESMO 2 Phase II trials. One was a gemcitabine impregnated pretzel. Most patients seemed to respond, and the tolerability was pretty good. You might think having chemotherapy constantly in your bladder would be irritating and causing a lot of cystitis, but patients seem to tolerate it pretty well. Maybe it’s a lower dose of chemo.

The second pretzel that was used was pretty interesting, and that was a pretzel that elutes an FGFR antagonist, erdafitinib basically. So we know that anywhere between like 20 and 50% of non-muscle-invasive bladder cancer has FGFR mutations.

DR YU: Okay. So let’s talk a little bit about this. I think we left off with Dr Siefker-Radtke. So what are the unique challenges associated with cystectomy in elderly patients with comorbidities?

DR SIEFKER-RADTKE: Well, cystectomy is a major surgery. It’s a deep pelvic operation. It’s recovery time. Patients are elderly and frail. If they spend a few days in bed they may not walk well again. And for some patients they’re really not good candidates for surgery. They cannot tolerate it. They will not recover.

So it’s really an unmet need finding better treatments allowing patients to maintain their bladder, avoid that cystectomy, and have that satisfaction that disease is controlled and not spreading or mutating further and about to take their life.

DR YU: Thank you. Dr Milowsky, TAR-200, TAR-210, what do you think? Do you think they’re going to make a major difference?

DR MILOWSKY: Yeah. I mean I do. I mean I think they’re very exciting. I mean there’s even data looking in patients with muscle-invasive disease in a small group of patients that demonstrated some very interesting results with regard to response rates, complete response rates.

And so I think that both of those agents are very exciting. I think there’s also some other exciting agents in NMIBC as well. There’s nadofaragene. There is N-803, which is an IL-15 superagonist. And so I think that there’s a lot rapidly coming down the pike that are hopefully going to help these patients with high-risk disease to avoid cystectomy, but I’m definitely excited about these 2 agents.

DR YU: And I’m just going to stick with you for the next question. You’re excited about them, but what do you think about their tolerability?

DR MILOWSKY: Yeah. So I’m not a card-carrying urologist, but it sounds like they are well tolerated by patients. There’s some irritated bladder symptoms, but I think that the fact that they can be left in the bladder and don’t have to be instilled as frequently as other agents makes it particularly promising from the standpoint of patients and the experience that they have.

DR YU: Okay. So next the faculty were asked to describe the last patient in their practice with a localized urothelial bladder cancer who was enrolled on a clinical trial. And I’m just going to pick on Dr O’Donnell there. You want to just tell me about your patient a little bit there and the trial they went on?

DR O'DONNELL: It was the trial I was alluding to, the comparison of EV plus pembro neoadjuvant treatment versus cystectomy alone. The trial is one that I think, as we’ve talked about, has a chance to change the paradigm in this field.

DR YU: Okay. Great. Let’s move on. This is asking about the global perspective on the efficacy and tolerability of the TAR-200 delivery system. So I’m just going to take a look here and say most of us, like myself, haven’t really used it there since we’re medical oncologists. Dr Rosenberg, what about your experiences with this?

DR ROSENBERG: Yeah. So I personally haven’t had experience until I see them in my clinic for metastatic disease after they’ve relapsed after one of these devices. I think with muscle invasive disease my concern is that local therapy alone may not be sufficient. We know that many of the patients have occult micrometastatic disease, and you put an eluting device in the bladder, and it doesn’t necessarily treat the whole disease. So for non-muscle-invasive disease, on the other hand, I think it’s going to be potentially a killer app, so to speak, for non-muscle-invasive bladder cancer.

DR YU: Great. All right. Well, let’s move on to Dr O’Donnell’s talk about novel strategies for nonmetastatic urothelial bladder cancer.

DR O'DONNELL: So I’m going to summarize a lot of what we’ve just been talking about. So what is TAR-200? It is this idea that the way things are done now by urologists after a transurethral resection is to instill come gemcitabine into the bladder. It has as short dwell time, the patient voids it the same day. And so from a standpoint of treating tumors or any residual disease that might be after the transurethral resection it doesn’t make a lot of sense because the chemotherapy’s not there for very long. TAR-200 tries to address that.

As it was said, everybody describes it as a pretzel because that’s what it looks like. It’s instilled into the bladder, stays there for a week, and then it’s removed. After 21 days, so 2 weeks off, the patient will come back and have the pretzel deployed again for another week. And so you notice some of the features of this are that plasma gemcitabine levels are undetectable, and patients seem to tolerate this pretty well. You can see most of the adverse events are urinary irritative type of symptoms that are of low grade.

So how does it actually work after it’s deployed in the bladder? You can see there’s water flowing into the pretzel, which releases the drug over the span — slowly over the span of the 7 days that it’s dwelling. And if you look at the bottom curve, which is showing intravesical gemcitabine levels, you can see that those levels are quite high over the duration of the 7 days. If we look at the blue bar at the bottom that’s perceived to be the level at which gemcitabine needs to stay above in order to have optimal treatment effect. And you can see that that is achieved over the full 7-day period.

So the device now has been investigated in SunRISe-1, which is looking in non-muscle-invasive bladder cancer. These are patients that are BCG unresponsive and have carcinoma in situ. You can see this was a 3-cohort trial. The top group was TAR-200 plus cetrelimab. Cohort 2 here the TAR-200 alone, and Cohort 3 was cetrelimab alone, with the primary endpoint being complete response rate in these CIS patients.

Before we look at the data it’s important to think about well what are we trying to beat in this setting, so the historical benchmarks for 12-month CR rates. So for pembrolizumab, which is approved in this setting you get about 19% CR rates at a year. For atezolizumab it’s about 15%, and for nadofaragene firadenovec, which has FDA approval as well, it’s at 23%.

So here’s TAR-200’s results. You can see the types of patients listed on the left, and I think what stands out is that overall CR on the right of 76%, which was centrally assessed in this trial, really high numbers, is there durability? So this is a slide that shows the 54 patients that have some degree of follow up at this point. You can see that there’s not been a median duration of response reached yet in this cohort, and that’s with a median follow up of 48 weeks. And so if you think about Kaplan-Meier estimates for what the durability response rate might be it looks like it might come in somewhere around 84% at 12 months, so to put that in comparison to some of the drugs that are already on the market for this scenario.

TAR-200 is being looked at in combination with PD-1 inhibitors in other settings. So this is SunRISe-3. These are also patients with non-muscle-invasive bladder cancer that right now had not been treated with BCG, so going straight for that standard of care, the gold standard being BCG. The bottom group of this trial is BCG alone, and then the top 2 groups are TAR-200 or TAR-200 with the anti-PD-1. And the primary endpoint here will be event-free survival, so a very interesting trial that also could upend the current standard of care.

This is what Dr Rosenberg was just alluding to. I’m personally a little more skeptical about whether muscle-invasive bladder cancer patients are the right type of patients to be treated with this type of intravesical therapy, but this trial will evaluate that, TAR-200 plus cetrelimab versus cetrelimab alone as a neoadjuvant therapy in patients with muscle-invasive bladder cancer. The path CR rate will be the primary endpoint for this study.

And we’ve alluded to the idea of chemoRT as a bladder-sparing alternative in these patients, and so this trial will look at the TAR-200 system plus cetrelimab compared against chemoRT in patients with muscle-invasive bladder cancer.

So we’re seeing now a series of investigations for TAR-200, which looks very promising, immunotherapy which has shown very promising results in the neoadjuvant setting, and whether these treatments can now really displace current standard of care.

Lastly, I think it as alluded to that there’s a next formulation of this, which is TAR-210, which instead of gemcitabine being in the pretzel it’s erdafitinib. And one of the advantages I think of this system is that we have seen data that erdafitinib oral tolerability for patients with non-muscle-invasive bladder cancer was not very great, the toxicity rates were deemed unacceptable for those patients, really, with non-muscle-invasive bladder cancer, and so this type of delivery system avoids those large systemic levels of erdafitinib and instead delivers the erdafitinib right where we would want it to go. And so these series of cohorts in this trial are looking at that erdafitinib delivery system. And interestingly in this the device can be placed once every 3 months, and erdafitinib lasts in the bladder with detectable levels for that 3-month period.

Here’s some really early results with TAR-210 in a non-muscle-invasive bladder cancer setting. You can see there’s 11 patients that have had a response assessment so far. Nine of those 11 patients were recurrence free at some timepoint. This is really early data from this trial yet.

And then here’s what I was alluding to about the idea of achieving sustained urinary erdafitinib release over 90 days. You can see on the left-hand side is the urine concentrations of erdafitinib, and the plasma concentrations are 50 times lower than one would expect using an oral erdafitinib dose of 9 mg daily, and no patients had hyperphosphatemia.

Lastly, I’ll mention intravesical EV, which is also a very interesting idea. Instead of using systemic EV to give it intravesically. And so this study, EV-104, is looking at exactly that in patients who were BCG unresponsive.

There are many other trials that are looking at agents in this space. Those are summarized on this slide. We’ve mentioned a number of them. Dr Milowsky actually just nicely summarized a number of those, and so lots of activity in the non-muscle-invasive bladder cancer space. So I’ll conclude by saying novel delivery systems, I think they have a huge potential upside for giving traditionally what we think of systemic drugs as intravesical drugs. TAR-200 has actually been granted FDA breakthrough therapy designation just last month in the BCG-unresponsive, high-risk non-muscle-invasive space. Lots of combinations being explored, and really the hope is that maybe some of these therapies will change the game enough that patients will either delay or not need cystectomy.

DR YU: Okay. Thank you very much. We actually have a few minutes for some questions, and I’ve been receiving some questions online, so I’m going to go ahead and throw them to the faculty panelist, one of which is what’s the role of radiotherapy for high-grad non-muscle-invasive bladder cancer? Dr Siefker-Radtke, thoughts on that?

DR SIEFKER-RADTKE: So for non-muscle-invasive bladder cancer there has been a role for using it more in multiple tumors, for that superficial disease space. Carcinoma in situ there’s been some debate whether it’s beneficial to give radiation in that setting due to the high rates of recurrence. So it is something that is currently being used and explored, but I personally think with some of these, especially a product — this drug-eluting pretzel that can result in sustained concentrations of active drug for a long period of time, and the control that they’re providing, I’m very hopeful this will help slow or delay progression, keep more patients from that muscle-invasive disease. So time will tell how many patients need radiation, will they need radiation if they fail a pretzel product, or will we see sequential pretzel products coming down the pipeline that can address potential mechanisms of resistance.

DR YU: Okay, great. So here’s another one. We’ve been thrown a couple cases, so the audience is great. They’re throwing us some tough cases. So Dr Milowsky, I’ll throw this one to you. This is an 80-year-old patient, has CAD, CKD, Stage 3 disease, recurrent high-grade non-muscle-invasive bladder cancer, has had multiple cystos. What do you think about in this case? How are you going to approach that?

DR MILOWSKY: So this is high-grade presumably NMIBC BCG unresponsive?

DR YU: So this is all that they’ve given us, so why don’t you run through the considerations? Let’s say they’re BCG — they’ve received BCG and they’re unresponsive because they’ve gone through multiple —

DR MILOWSKY: Yeah. I mean let’s say they’re treated standardly with intravesical therapy, and they develop a recurrence of disease, and the question is what to do next. And there are obviously different potential options for these patients. It depends on availability. Docetaxel/gemcitabine intravesical therapy is certainly an option that’s widely used in the community, and I think many urologists represent a de facto standard type of approach. Pembrolizumab is an option for a patient like this. Obviously cystectomy is the standard. If they’re not a candidate for a cystectomy then I think using one of those approaches. Nadofaragene is approved. It is not widely available. It will be available more widely soon. That’s nicer in some ways, I think urologists feel, because it’s administered at 3-monthly intervals, and so it might be a little bit more patient friendly in that way.

I know I’m giving a lot of options. Part of it is I’m not a urologist, but I think that there is a lot of potential opportunities for patients like this now with all of these therapies that are coming quickly.

DR YU: Right. So let’s follow along that vein. Now that there’s so many options, I mean what is the role of the medical oncologist here? That’s one of the questions here. I mean many of these are cystoscopic. I mean I know that we’ve been seeing them for pembrolizumab, but how involved should we be? Peter, what do you think?

DR O'DONNELL: I’m finding I’m getting more consultations for patients in this space over the past year or 2, where patients are coming in, they want to know the medical oncologist’s opinion about all these possible options, trials that they’re getting offered by the urologist. And I think part of it is because we’re seeing these drugs that we’re used to using, or in the same class of drugs that we’re used to using, we know the toxicity profile, and so patients want to know well what’s the real story when you’re going to offer me this treatment.

DR YU: Great. And one more case here. I’m going to throw this to Dr Rosenberg. This is a 70-year-old gentleman with painless hematuria, cysto finds a tumor blocking a UO, but it’s grossly fully resected. Wants to know what treatment, if any, you’d recommend prior to surgery.

DR ROSENBERG: And this is muscle invasive presumably?

DR YU: I’m going to assume it’s muscle invasive. I mean it’s blocking the UO.

DR ROSENBERG: Yeah. So these are patients where cisplatin-based combination chemotherapy if they have good renal function is appropriate still in 2024. Preferred I would say dose-dense MVAC in the fit, healthy patient and gemcitabine/cisplatin in folks that you’re more worried about clinically for usually 3-4 cycles, depending on tolerability of either of them, I think are acceptable. And so that’s traditionally what we’d offer.

Patients who have an obstructed UO are not great candidates for a bladder preservation approach because there’s likely very deep tumor that can’t be completely resected by TUR, and so cystectomy is ultimately likely the goal if the patient’s willing to go along with it.

Front-Line Treatment for Metastatic UBC (mUBC) — Dr Rosenberg

DR YU: Excellent. All right. Let’s move on to the next module. This is for front-line treatment for metastatic urothelial bladder cancer. Dr Rosenberg will give us a nice talk later, but let’s go to see what the consulting faculty want to talk about here. So EV with pembro as first-line treatment for metastatic urothelial bladder cancer, management of rash and neuropathy associated with enfortumab vedotin.

DR LOVE: First-line treatment of metastatic urothelial bladder cancer was dramatically impacted by a series of trials evaluating the combination of the anti-nectin ADC enfortumab vedotin and pembrolizumab, which seems to have a significant benefit compared to cisplatinum chemotherapy.

DR PLIMACK: I would be very comfortable offering someone who is cisplatin eligible EV/pembro as first-line for metastatic disease. I think the trial included cisplatin eligible patients. They still saw a benefit there compared to gemcitabine-based chemotherapy.

And I would definitely recommend EV and pembro across platinum eligibility categories.

DR FRIEDLANDER: With cisplatin I think we all know managing kidney, electrolytes, nausea, fatigue, neuropathy, taste, hearing are big problems. With EV it’s rash, and rashes can happen really early. They can happen in the first cycle of therapy. We had a patient on trial, it’s been reported, gave him the first dose, and within 3 days they’re calling to say hey, I have a rash.

In my experience most of the rashes are very treatable. I’ve moved to just giving patients, or prescribing patients topical steroids and having them use it liberally early because the target for EV, which is nectin-4, is expressed in the skin.

It’s a cell adhesion molecule, so you’re on target getting deposition of chemotherapy all throughout the skin when you give EV. It’s being directed to the tumor cells, but to wherever nectin-4 is being expressed. So it’s about 50% of patients get some form of rash, and that happens early.

The neuropathy is cumulative, and the median onset to neuropathy is about 2 and a half months.

And if you look in the trials a lot of patients are getting dose reductions when they go on EV. And so I have a very low threshold, both to give patients symptomatic care, but also to either take a break if the rash is severe, and I try to lower the dose early.

DR YU: Okay. Great practical questions I can see. And I think we left off; I’m going to go with Dr Siefker-Radtke. Are you using enfortumab/pembro already as first-line therapy for metastatic urothelial bladder cancer? And I like the way the question’s worded, “regardless of platinum eligibility.” So let’s talk about does cisplatin eligibility matter or not anymore with this as first-line therapy. And the way the question’s worded is platinum eligibility, so what are your thoughts on this?

DR SIEFKER-RADTKE: Well, the data is very compelling. We’re seeing great responses. We’re seeing patients having a median life expectancy that currently is really premature because the median follow up is 17 months. They’re reporting a median survival of 31 months. And as far as platinum eligibility, keep in mind that’s because we have a large cohort of patients with urothelial cancer who really weren’t candidates for standard cisplatin. So the whole reason for the platinum eligibility is to give cisplatin versus carboplatin, and especially for clinical trials what is accepted as the standard.

But when you look at the data for EV/pembro, regardless of cisplatin eligibility criteria, we are seeing similar benefits. We’re seeing the cisplatin-ineligible benefit, the cisplatin-eligible benefit. So I would argue in a front-line setting where you’re considering EV/pembro platinum eligibility goes away. It doesn’t make a difference.

DR YU: Okay. Dr Milowsky, what’s your experience been with the tolerability of this combination?

DR MILOWSKY: Yeah. I mean we were fortunate because we were involved in the EV-103 study, so we had a lot of opportunity to learn how to use these agents, and I think we have learned, like Dr Friedlander says, when — to understand when a toxicity is most likely to occur, in the skin early and the neuropathy later, so things that we monitor very closely.

I would say that our experience has been that if you are monitoring closely, and you recognize and teach the patients about what to look for, then the toxicity is quite manageable with dose modification, dose holds for sure. But if you look at the patient-reported outcome data which was presented for EV-103, I mean the quality-of-life data looks good, the improvement in pain is pretty dramatic, and so I think in general it’s something that’s very manageable.

DR YU: Right. Well, Dr O’Donnell, do you have any other tricks on the common side effects? Rash? Peripheral neuropathy? I mean I think we’re doing dose holds/dose reductions. Other tricks that you like to use?

DR O'DONNELL: Well, I think I want to emphasize that you’ve got to make an alliance with the patient before you even start treatment. That’s what I do. I tell the patient at some point I’m likely to have to stop enfortumab in you, and it’s going to be okay, and you’ve got to be a partner with me telling me how your nerves are doing because I can use that information to start toggling back on the dose of that EV, which will allow you to stay on it longer and then get you the durability you want. And when patients realize that you’re trying to get durability they’re not hiding the neuropathy symptoms, where patients get into trouble. So that’s been one of my tricks is telling them up front that at some point we’re going to de-escalate this or likely stop it.

DR YU: I like it. Great. Just warn them in advance so they know. Otherwise they’re worried about holds and decreases, is this going to hurt me in terms of my tumor recurrence. But if you let them know in advance it’s okay, this is expected, I think that’s really helpful.

All right. Let’s go on to the discussion between Dr Love and Friedlander about autoimmune contraindications in immunotherapy.

DR LOVE: Clearly immunotherapy has become an integral part of the management of urothelial bladder cancer, and as in other areas of oncology where checkpoint inhibitors are used, a central issue is the use of these agents in patients with prior autoimmune disease or solid organ transplant as commented on by Dr Friedlander.

DR FRIEDLANDER: I run into this a lot, unfortunately. For example, a patient has rheumatoid arthritis, which is a debilitating disease for some people, but is rarely life threatening. And you contrast that with cancer, which is life threatening. And so thinking through like how do you weigh those side effects is really challenging.

So deciding when to use these drugs, I tend to reserve them for very late line if somebody has autoimmune disease, like active autoimmune disease, which to me means that they’re on therapy for it or they have obvious clinical manifestations.

There’s a question of how do you define which patients who have autoimmune disease are eligible. The same is true for transplant. I’ve had patients who had, for example, a transplanted kidney who developed urothelial cancer, and the big question was is it safe to give them a checkpoint inhibitor if they’re willing to go back on dialysis.

DR YU: Okay. Well, it is a good question there. So Dr Rosenberg, what do you think are absolute contraindications to treatment with an immune checkpoint inhibitor here?

DR ROSENBERG: It’s a great question. So my general feeling is with the exception of things like active colitis and SLE (lupus) I’m often willing to take a risk with patients and talk to them about the potential benefits. Sometimes the benefits, it’s clear that it’s not worth it, but for other patients they’re very much of the mindset of treat my cancer. When you talk to the rheumatologists they’re usually like go do what you need to do, and we’ll deal with the consequences. Maybe I’ve got very good rheumatologists at my disposal, but rheumatoid arthritis, I have many, many patients who have RA who are getting immunotherapy, and some of them have flares, and they may need biologics — or other biologics to control it.

So I think it’s a matter of what the manifestations have been, what the treatments that their on for it are, and what the consequences might be if they flare. And so that’s a complicated decision that often is best made with a rheumatologist in discussion.

DR YU: Great. Great answer there. Okay, Dr Siefker-Radtke, let’s draw out the specific scenario that Dr Friedlander started talking about. What about solid tumor — I mean solid organ transplant?

DR SIEFKER-RADTKE: Yeah. That is definitely a challenge, especially if a patient is on chronic immunosuppressive therapy. We do advise them that yes, if we give this, first of all we have to take you off the immunosuppression. If it’s a patient with a transplanted kidney they are likely to have further failure of that kidney ultimately needing dialysis.

Where it becomes even more problematic is what if it’s a transplanted liver or transplanted heart. Those are extraordinarily challenging cases because we don’t have a great liver or heart bypass mechanism. So I think those are patients that are probably true contraindications since we don’t have that great alternative for the solid organ transplants.

And you also have to tell them you’re going to be off your immunosuppression. It doesn’t make sense to drive a car and put one foot on the accelerator and keep a foot on the brake, right? You need to take them off their immunosuppression in order for the checkpoint inhibitor to work.

DR YU: All right. Great discussion. All right. Now we’re going to go through some faculty slide surveys, and this is about the last patient in our practice who received EV/pembro as first-line treatment for metastatic urothelial bladder cancer, and you can see the difference in ages. And most of us didn’t know about the PD-L1 status because it probably didn’t affect our decision making, and it seems like either it was a little too early or most of the patients had some benefit there.

I’m going to draw our attention to the side effects there. Dr Milowsky, you mentioned Grade 1 neuropathy. This is an important point to bring out to the audience, the CTCAE grading system is kind of unique depending upon the toxicity. So we always worry about Grade 3/4 toxicities, but Grade 2 neuropathy is pretty significant because it actually affects function. So what do you do in this instance, Dr Milowsky?

DR MILOWSKY: Yeah. It’s an excellent question. I recently gave a talk on this and brought up the issue of Grade 2 neuropathy, which is actually not called out very well in the studies because they usually combine them as Grade 1/2. And you’re right. So it’s something that could affect someone’s ability to function, and it’s very bothersome to patients. And so I take Grade 2 neuropathy actually very seriously, and in the event that someone is developing Grade 2 neuropathy then that could be a place where enfortumab vedotin is held for sure, and I think I do that routinely in practice.

And I think it speaks to the real potential utility of using things like patient-reported outcomes, CTCAE, to better understand that. That was brought up in a talk today. I mean we don’t use it in practice, but these are the things that really can make a difference for patients.

DR YU: Okay. This next case that was thrown to the panel is a first-line treatment regimen for an 80-year-old with metastatic urothelial bladder cancer, no prior systemic therapy, is not a candidate for cisplatin, and does PD-L1 level affect your decision making. And look at this. This is the most unanimous slide you’re going to see. Everyone said the same thing, so I’m not going to belabor this point. Everyone said EV/pembro. And the reason everyone said PD-L1 doesn’t affect their decision making is that we’re not afraid to give them EV/pembro, and we don’t need a reason to give them the EV/pembro I think.

So with that let’s just move on to the next one, which takes an 80-year-old patient with metastatic urothelial bladder cancer, has not received prior systemic therapy and is not a candidate either for cisplatin or for carboplatin. Does PD-L1 level affect your decision making here? And now we have a little bit of mixed audience — or mixed answers in terms of who would use EV/pembro, who would just use pembrolizumab, and whether PD-L1 matters or not. Dr O’Donnell there, you said just pembrolizumab. What are your thoughts on this?

DR O'DONNELL: This is tricky, right, because the question really is asking do we think that there are patients that are carbo ineligible that can get EV. Clearly some of the experts here think that those patients exist. I’m not so sure. Carboplatin is a pretty well-tolerated therapy. I don’t use it anymore, but if we’re talking about a tolerability comparison in an inexperienced treating physician I think enfortumab is probably as difficult, if not more risky, to a patient than carboplatin. In an experienced treating physician who understands the learning curve for EV/pembro I think you could certainly safely do this.

I also think one of the factors we’re not given in this case is what kind of disease does this patient have. Is it lymph node only disease? If so this patient might do really well with pembrolizumab for a while.

DR YU: Okay. Well, Dr Siefker-Radtke and I felt differently, so let’s start the debate. Arlene, why did you say EV/pembro here and that you don’t care about PD-L1 staining?

DR SIEFKER-RADTKE: Well, compared to those who think carbo is not toxic, it really is toxic. You see myelosuppression, thrombocytopenia, increased rates of infection. So there’s many different reasons why a patient may not be a candidate for carboplatin. And they may be able to tolerate enfortumab. It doesn’t have that myelosuppression as commonly as we see with carboplatin. So I personally do think enfortumab vedotin is more tolerable compared to a gem/carboplatin regimen. And as a result when you give me a case like this I would say well, you haven’t said not chemo eligible because enfortumab vedotin is a type of chemotherapy, I would say if I think I can give it, give it because the response rates are compelling, and the survival is compelling compared to what’s achieved with single-agent immunotherapy.

DR YU: I’m with you. All right. Let’s move on to Dr Rosenberg. First line and maintenance therapy for metastatic urothelial cancer.

DR ROSENBERG: All right. So we’ve seen dramatic changes over the last several years of the treatment of metastatic disease, and enfortumab vedotin has really transformed our treatment paradigm. Platinum-based chemotherapy I would say is really no longer the default option for patients, and therefore the role of avelumab maintenance is becoming reduced in this new paradigm. There are some patients who are not necessarily candidates for cytotoxic agents for which pembro monotherapy might be an option, and I’ll leave that at that.

So looking at the avelumab maintenance strategy. So we do know that in patients who’ve received chemotherapy and had good responses that they — or stable disease they’re candidates to receive maintenance immunotherapy, and randomized Phase III data, the JAVELIN Bladder100 study, demonstrates this. And longer follow up of the study shows benefit continues out to 3 years in terms of improved overall survival and a tripling of patients who are progression free at that timepoint.

And we also see that in contrast to some of the early discussion and thought that it really doesn’t matter what your chemotherapy response is, your benefit if you had a CR or PR or stable disease, you do better if you get maintenance therapy. And probably because many of these patients when they relapse after platinum-based chemotherapy it’s like they’ve just fallen off a cliff, and you may not be able to rescue them with a checkpoint inhibitor at relapse, and so by giving it early you actually help people do much better.

Enfortumab vedotin we’ve heard about, talked about, a nectin-4 targeted ADC with MMAE or monomethyl auristatin E, is released within the cells, targets the microtubules, leads to cell death, presumably with some immune effect stimulating androgen presentation, which probably then synergizes with pembrolizumab and leads to improved outcomes compared to just giving enfortumab vedotin by itself.

And this is data from EV-103 Cohort K, which looked at either EV/pembro or EV monotherapy to demonstrate contribution of components, and we see that the response rate for the combination is 64.5% compared to 45% with monotherapy. That’s actually pretty good for patients who might not be checkpoint inhibitor candidates. But anyway, so validating the fact that there is improved activity with the doublet and that it’s not just enfortumab.

And then of course we saw the results of EV-302, where patients who are platinum candidates were randomized to EV/pembro or platinum-based chemotherapy, and interestingly about a third of patients ended up receiving maintenance avelumab on this study, which is not all that different than what’s actually happening in the general population based on a lot of data from public data sets, with the primary endpoints of PFS and OS dual primary endpoints.

And so this is the progression-free survival data. As you can see, dramatic improvement in progression-free survival in patients receiving EV/pembro doubling almost PFS with a hazard ratio of 0.45. And then OS similarly practically doubled, 31.5 months for the combination compared to 16.1 months. We really haven’t broken 24 months in an unselected patient population previously, so this really is a game changer. And you see that there is quite dramatic improvement, 53% reduction in the risk of death if you have advanced bladder cancer and receive EV/pembro.

And the tail on the curve suffers from a lot of censoring, so I think we’re going to see the overall survival data evolve as time goes on. And all of us hope that we may see a plateau on the curve, but we will see about that.

The confirmed response rate was much higher, 67%, with 29% CRs compared to 44% with EV/pembro.

Toxicities, as we talked about, are a bit different than chemotherapy, with neuropathy, rash and itching, and some GI toxicity. Not a lot of cytopenias with EV/pembro compared to chemotherapy.

So this has really become the standard of care with a doubling of overall survival, and there really isn’t a group of patients who don’t seem to benefit, and I think this is going to — this has changed the paradigm, as we’ve all talked about.

There were data presented at the last ESMO of CheckMate 901, which is 2 Phase III trials. The first one did not show any data other than the fact there was a press release saying that the ipi/nivo portion of the study didn’t meet its primary endpoint. But we heard the data from the chemotherapy comparison, adding nivolumab to gemcitabine and cisplatin.

And this is the randomized design, gem/cis/nivo versus gem/cis. This is the only chemo combination trial that didn’t mix platinum analogs, and so really was focusing on a cisplatin-eligible patient population, gem/cis/nivo and then nivo maintenance for patients who were doing well, and showed that there is a modest but real improvement in overall survival, hazard ratio of 0.78, a roughly 3-month improvement in overall survival, and this would have been the biggest news except for EV-302 that had been presented about a minute beforehand at ESMO.

So again, progression-free survival clearly better. Tail on the curve doesn’t start to separate really much until about 6 months. Hazard ratio of 0.72. And so it really is an option in jurisdictions where they’re not going to have EV/pembro available for a while but might have nivolumab available, a higher response rate, a higher CR rate. I think what’s interesting is that in patients receiving nivo and gem/cis if they got a CR that CR lasted 3 years, and so maybe identifying those patients will be a way for this regimen to be used.

And the toxicity profile didn’t really reveal anything new and unexpected, some immune-related adverse events, but really nothing that was prohibitive when added to chemotherapy.

And so it improved PFS and OS, although not to the degree that EV/pembro does, and this is really the first study in bladder cancer where checkpoint plus chemotherapy has improved outcomes with cisplatin only. To extrapolate this and say well we can give gem/carbo, nope, cannot do that.

I happen to think that avelumab — this strategy treats all comers starting with a checkpoint inhibitor, and so I suspect that this is probably going to be, in jurisdictions where they don’t have access to EV, this may be the preferred approach.

And then just a tiny bit of data with first-line cisplatin-ineligible patients, data that Arlene has actually — knows a lot better than I do, a randomized Phase II study of erdafitinib monotherapy in untreated patients or erdafitinib plus a PD-1 inhibitor looking at — in patients with FGFR3 alterations and showed that there is a modest increase in the objective response rate with increased CRs if they’re in the combination arm, about 54% versus 44%, and some interesting and provocative data perhaps with prolonged progression-free survival and overall survival in the Phase II setting. Where this is going to go in the future we don’t really know given the presence of EV/pembro, although perhaps maybe one could think about adding an FGFR inhibitor to EV/pembro.

There’s other data that’s consistent with this, atezolizumab and regorafenib, another FGFR inhibitor looked very similar in a single-arm study.

So we’ve now finally changed the landscape in therapy for metastatic disease. It’s very exciting times. We’re seeing survival approaching 2 1/2 years, longer than 2 1/2 years, and so hopefully we’ll continue to be able to build upon this. And one of the big questions is what to do if someone has a recurrence after adjuvant checkpoint, do you actually continue the checkpoint when you start EV if they relapse. I don’t have an answer for that one. Thank you.

Emerging Role of HER2-Targeted Therapy for mUBC — Dr Yu

DR YU: All right, great. So I think we should move on to the next module here. This is the one that I’ll be taking. This is on the emerging role of HER2-targeted therapy for metastatic urothelial bladder cancer, and we have some consulting faculty questions from Dr Sharma here in a discussion with Dr Love on the perspectives from the breast cancer experience. Obviously they have a lot more HER2 experience than we do. HER2 testing, durability of responses with trastuzumab deruxtecan.

DR LOVE: The emerging concept in urothelial bladder cancer of the use of HER2 ADCs includes the development of trastuzumab deruxtecan and disitamab vedotin.

As data evolves in tumors outside of breast cancer we see specialty oncologists dealing with T-DXd for the first time. While general medical oncologists in practice have used it many, many times over the last few years, particularly in breast cancer.

We thought I might be useful to hear from a breast cancer oncologist about how T-DXd has settled in to the breast cancer situation, and maybe get your thoughts a little bit about how this process might evolve over the next couple years in urologic oncology.

I asked Dr Priyanka Sharma to share her experiences with T-DXd in breast cancer.

DR SHARMA: HER2 testing is the key issue for these drugs that are targeted, right? So you have to make sure you have an optimal and reliable method of measuring that target.

The challenge is across different tumor types different criteria are present, right, for who is eligible. It’s the same story as our checkpoint inhibitors, where you have different cutoffs for breast and lung, and that just creates confusion for our pathologists.

In terms of first practical issues, pathology labs might need to set up some sort of a system where if it’s looking at HER2 perhaps the group that does most of it does it no matter what the primary tumor is.

What we’ve seen from breast cancer is, the trials that we have thus far, at least in the truly HER2 amplified, that the durability of response is tremendous. So even if the proportion of patients, let’s say, in bladder cancer that are eligible for this and respond to it is modest, the durability, if it mimics breast cancer, would be quite good, which I think is going to be very meaningful for the patients.

DR YU: Okay. So she had some questions for us. Dr Milowsky, what’s your approach to HER2 testing?

DR MILOWSKY: Yeah. So I’m starting. So I think that after the DESTINY-PanTumor02 I think that there’s a real rationale there with T-DXd to begin to consider this, and certainly the data that’s been presented from the trials looking at disitamab vedotin.

I mean this is not new, this HER2 idea. In fact, Dr O’Donnell has been involved in this for some time. We did a collaborative study at multicenter looking at afatinib that Peter led, and years ago there was studies looking at trastuzumab that Maha Hussain was involved in.

And so it’s really exciting to see that it’s now actually happening, and patients are responding, but clearly the data from that experience is pushing us to now begin testing our patients.

DR YU: Great. Tougher question here, Dr O’Donnell. What’s the appropriate threshold? How are you going to — where’s your cutoff going to be?

DR O'DONNELL: Well, this is still evolving, so my opinion now might change. But right now I’m most interested and the patients that I’m kind of targeting are those that have at least 2+ and then also FISH positive. If they’re 3+ then certainly those patients would be eligible. I’m a little bit more skeptical still about the really low group for HER2. I’m not sure in bladder cancer that that will pan out, but it remains to be seen.

DR YU: Okay. And Dr Rosenberg, let’s assume you can get T-DXd here for bladder cancer and disitamab vedotin. How are you going to integrate these agents? Where are you going to use them in the treatment algorithm?

DR ROSENBERG: I think we have to start thinking about what is the role of high-level expression versus moderate expression and how does that relate to outcomes. And so if I had to make a guess the 3+ patients with some of these drugs are going to do very well compared to the people getting enfortumab. Disitamab vedotin and enfortumab vedotin are very similar in their mechanism of action, in terms of intracellular effects, and so the augmentation with an immune response might be very similar. And in fact the data from China with disitamab vedotin in the 3+ patients receiving a checkpoint inhibitor looks better than EV/pembro, albeit very small numbers.

So for high level of expression perhaps as a first-line option and for other patients with refractory disease certainly it’s something that I’m starting to test on a regular basis, looking to grab onto T-DXd. And perhaps with a pan tumor indication we’ll be able to use it without having to beg and plead for the drug.

DR YU: Okay. It makes a lot sense here. Okay, let’s go on. Dr Love and Dr Sharma had a conversation on identification and management of T-DXd-associated side effects.

DR LOVE: We understand that there are many differences between breast cancer and urothelial bladder cancer, but we also felt it would be useful to hear more from the breast cancer community particularly about prevention and management of T-DXd toxicity.

DR SHARMA: Nausea/vomiting is clearly an issue. Most patients need some sort of a delayed nausea regimen with this drug, and if you don’t they’re quite miserable. If you’re very proactive then they’re fine. You do your long-acting similar to dexamethasone or other things, what you typically do for cisplatin and doxorubicin apply to T-DXd, and you’ll probably be fine if you stuck to that.

ILD I think is an issue because it’s different than ILD that we see with other drugs, and also to be cognizant of a patient with ILD with other drugs in the past.

And to remember that all of the trials of T-DXd require scans every 6 weeks, so the trials are quite hypervigilant in being able to find Grade 1 ILD, where it’s totally asymptomatic because that’s where you need to hold the drug. Once it gets to Grade 2 then the chances of it getting to be an irreversible form or fatal get higher.

At least for the first year I’ve stuck with doing scans every 9 weeks. In the winter months you just have to be careful. If the patient complains of cough, and it persists, don’t chalk it to a viral bug or something if somebody’s on T-DXd. Have a low threshold to get high-res CT for the patient.

The best way to detect this is when it’s asymptomatic, when you see some ground-glass opacities in the CT.

The good thing is it’s an every-3-week infusion, so you’re seeing the patient, or the patient is showing up to the infusion center in clinic every 3 weeks, so it’s a good practice to make sure you get O2 sat every time they show up and just to make sure we educate the patients to let us know if they start having a cough, and it isn’t going away, and we tested for COVID, that’s negative, then have a low threshold to do a high-res CT of the lungs.

DR LOVE: Bladder’s got 2 ADCs and 1 of them just moved up to first line with pembro. You’ve got not only T-DXd but disitamab vedotin coming along.

DR SHARMA: Yes. And I think then the question will be to try to figure out how to optimally sequence them.

DR YU: Okay. Here are their questions for the faculty. What’s your approach to the prevention and management of T-DXd-associated nausea and vomiting? Dr Milowsky?

DR MILOWSKY: Yeah. So again, I mean I really don’t have experience so I’m going to do what Dr Sharma’s telling me to do. I think that it sounds like using agents that we would use for drugs like doxorubicin and cisplatin, so I think that it sounds like it’s fairly straightforward.

DR YU: Okay. How about screening for ILD? Dr O’Donnell, do you have experience?

DR O'DONNELL: No, but I do think this is analogous to how we learned to detect pneumonitis from our immunotherapies. You’ve got to pay attention to those early, subtle symptoms that the patient’s talking about. I often will then walk my patient around the clinic with the pulse ox on their finger to see if I detect something on exertion with desaturation, and those are signals for me to certainly get that CT scan.

DR YU: And Dr Rosenberg, have you had experience with T-DXd and disitamab vedotin and observed clinical meaningful responses?

DR ROSENBERG: More personally with T-DXd. And yes, I think whenever you see the DESTINY data presented there’s 1 patient, who’s the only bladder patient still on study in a CR, is my patient, and he’s still on treatment several years later. And obviously that’s a bias in my mind, in favor of the drug, but watching for ILD is really important with this, and we’ve had plenty of CT scans that haven’t shown anything, but you really have to look out for it.

I think disitamab vedotin is a little different in its toxicity profile even than enfortumab, and so I think as we get it in our hands more we’re going to learn those differences.

DR YU: Okay. So this survey to the faculty asked about describing a patient with HER2-positive metastatic urothelial bladder cancer, received T-DXd, and I’m just looking here. I’m going to stick with you, Dr Rosenberg, because you mentioned mild fatigue. So is there anything you can do about that?

DR ROSENBERG: You can dose reduce. You can actually hold, and the patient did much better after a hold of skip a cycle essentially and dose reduced on study. And he’s back, plays full time in a band and is back to playing gigs.

DR YU: Very nice. Okay. Have you offered or would you offer HER2-targeted therapy to your patients with HER2-positive metastatic urothelial bladder cancer outside of a protocol? Well, I’m going to go with you, Dr Siefker-Radtke. You said you haven’t, most of us have, but you would for the right patient. So who’s the right patient?

DR SIEFKER-RADTKE: Well, I think this question asks about an off-protocol setting, and then the question if they’re not on trial, and you don’t have something on the guidelines panel, how do you get approval. How do you get insurance coverage for that patient?

So I do have a patient currently where I am considering this as one of their options downstream. They have severe peripheral neuropathy. They’re not a candidate for enfortumab vedotin as a result of their severe pre-existing neuropathy. But they are HER2 expressing, and if it’s a situation where money is no object, which you run into that occasional patient, then giving them these options seems very reasonable based on some of the early preliminary data.

DR YU: Okay. Great. Well, it looks like this is unanimous. Would HER2 testing be ordered for patients with metastatic urothelial bladder cancer? There are no approved agents yet in this disease, but everyone on this panel felt yes. So does that mean we’re all confident that there’s probably going to be a therapy there? Dr Rosenberg?

DR ROSENBERG: So yes, but it’s not that hard to get compassionate use for trastuzumab deruxtecan when you have a positive HER2 test with the DESTINY data.

DR YU: Okay.

DR ROSENBERG: We’ve been very successful at getting compassionate access for it.

DR YU: It sounds like you’re quite optimistic about the future.

DR ROSENBERG: I am. I think there will be a pan — probably a pan tumor approval, hopefully, and disitamab is a very promising and interesting drug.

DR YU: Okay. Great. Regulatory and reimbursement issues aside, in which line of therapy would you generally offer targeted treatment to a patient with HER2-positive metastatic urothelial bladder cancer? Where earlier Dr Rosenberg gave us his opinion, Dr Siefker-Radtke, you said third line. Would the HER2 staining matter there? If it were high staining, 3+, would it push you to move it up a little bit? Or would you stick with third line?

DR SIEFKER-RADTKE: Well, I think that’s where we don’t quite know where the cutoffs are for HER2 and which targeting agent one might be using since there is some data with disitamab vedotin showing benefit even in the low HER2 expressors. So at the moment I don’t know which I would choose.

We also don’t know the impact of sequencing. If someone has had enfortumab vedotin do you give them disitamab vedotin? Is the mechanism of resistance loss of nectin-4, where if you can get the drug to the tumor environment targeting HER2 you’ll see activity that is present? Or is it some type of drug efflux so even if you get the drug to the tumor cell it will already be excreting the vedotin, or the monomethyl auristatin E.

So I think there’s still pieces of the puzzle that we need to put together to know firmly how we should place these strategies.

DR YU: Great. All right. So this one’s based on personal clinical experience and/or knowledge of available data, for each of the following agents estimate the chance the patient will experience toxicity during treatment that will require withholding administration. What’s that’s primary toxicity patients experience that leads to withholding the drug? So I’m going to call on Dr O’Donnell there. So why don’t you explain your answers and what you’ve seen?

DR O'DONNELL: Well, I don’t have a lot of personal experience with trastuzumab deruxtecan yet, but I think from the available data that we’ve seen, PanTumor and otherwise, I think my estimate is probably reasonable here. Disitamab’s more interesting because I view it right now as very similar from the vedotin part to our experience with EV and the fact that basically all patients are probably going to develop neuropathy if they’re on that agent long enough, and so that’s why I put such a high number there.

DR YU: Okay. Great. Well, I think I’m up. So I’ll stand up here, it’s good to stretch, and talk to you all about HER2-targeted therapy in metastatic urothelial bladder cancer.

So here are the discussion topics. I’ll talk a little bit about HER2 expression. I’ll talk about the different antibody drug conjugates, and you’ve heard just a lot of discussion about T-DXd and disitamab vedotin. I’ll talk a little bit about both monotherapy and combination therapy of the ADCs with checkpoint inhibitors.

So here’s a graphic that I pulled from a review manuscript in Nature Reviews Clinical Oncology, and this just looks at HER2 as a cancer-specific target. And of course you can see there amplification, overexpression, and mutation. Breast obviously is in the lead there, but gastric cancer is something we all think about and use HER2-targeted therapies as well. But bladder cancer’s not insignificant, 8.5% amplification, 12.4% overexpression, and 9% mutation there. So mutations do happen, and it seems like it’s actually reasonably, I wouldn’t say common, but not uncommon in urothelial bladder cancer.

So the real question is there’s a lot of ways to measure HER2 expression, how should we be doing it. And this is a nice manuscript that was from a slide there from Dr Vadim Koshkin who shared this with me. And we have to recognize that we’re not regularly testing for bladder cancer. There aren’t standardized criteria. But he did a nice systemic review here, or literature review, pulling out probably about 621 patients or so from different studies, or it actually might have been more like 7 or 800 patients there. I can’t even read it myself there on the slide, so I apologize for it being small there.

But in summary what he did is he provided weighted averages, and what he saw was that HER2 2+ or 3+ or greater was about 12.3%, and HER2 low, which was considered 1+, that was about 47.9%. Now that looks pretty high, actually. So what he did is he went back and did his own study there, and this was from surgical samples like transurethral resections of tumors, and then they did it in a standardized fashion. They used a standardized antibody, and they used a standardized-ish DNA probe cocktail, and this is what they found here.

They found that 44.2% had HER2 expression there, 1+, 2+, or 3+, and when you break it on down it was pretty similar to what they showed in that manuscript where they did the systemic review, 15.7% for HER2 high and 28.5%, a little bit lower there because I think they were in the 40s there for their systemic review, but 28.5% for HER2 low here, and about a little more than half the patients were truly HER2 0.

When you break it down on stage I can’t say that you see dramatic differences between the different stages there on the breakdown of HER2 high versus HER2 low, but I think this is important literature to refer to as we’re thinking about moving into the era of HER2-targeted therapies.

Now let’s review real quickly. Some of the panelists have brought up some of the stuff here. The early experience, if you rewind the clock way back, I still remember Dr Hussain’s manuscript where she combined trastuzumab deruxtecan with chemotherapy, paclitaxel, carboplatin, and gemcitabine. And actually the objective response rate was quite high, it was like 70%, but there were a few patients with significant cardiotoxicity. And I think that gave it a little bit of a bad name, and it kind of got just canned and thrown to the side for many years because of that. So it's a little bit unfortunate.

But there have been other studies as well. This was a reasonably promising, small number of patients, trastuzumab/pertuzumab basket trial. 33% objective response rate. And there are small molecules and even an autologous cellular immunotherapy, which was essentially like sipuleucel-T but targeted towards HER2 that was used I believe in more of an adjuvant fashion there, but didn’t see very, very obvious efficacy results.

And then there were the studies with T-DM1, which we have to look really hard to find the data for, but the fact is that we didn’t see great results with T-DM1, a little bit not surprising. I mean if you look into gastric cancer they didn’t necessarily see great results there either. And in breast cancer there are situations where maybe T-DM1 might be replaced by other agents, as well, but that was obviously the first agent to come out there. So in bladder cancer maybe not the best results.

I’m not going to spend a lot of time on this slide because Dr Rosenberg showed a slide already, but I am going to say that there are many components that are really important to an antibody-drug conjugate, and it’s really important to recognize that they are not all created equal, okay? And that the antibody’s important, where it targets. The antigen’s obviously important. How well does the antibody internalize? How good is the linker?

And what’s the payload? There’s different types of payloads there. There’s topoisomerase inhibitors. There’s microtubule inhibitors. But how good the linker is is also very, very important because how cleavable is it. Does this break apart when it gets into the circulation or does it really hit its target, get intracellular, and the break out?

And then the DAR, the drug antibody ratio, is important. How much of the payload does it carry per construct there? A lot of people see higher numbers, and they think that’s great. Well maybe that might lead to more efficacy, but it also leads to more off-target effects, as well, so we have to be mindful of that. And there are different ways to construct an antibody-drug conjugate that either leads to a more homogenous or maybe heterogeneous DAR, and then you might get more off-target effects there.

All right. With that being said and done the mechanism of action, we know that it’s supposed to hit its target antigen, get internalized, form an endosome, bind to a lysosome where the pH is low, and in an ideal world that’s where the payload gets broken off, and that’s where it does its nefarious deeds against the cancer cell.

All right. So we’ve talked a lot about this. These are just diagrams of what trastuzumab deruxtecan and disitamab vedotin look like. They are different constructs. They do have different payloads with DXd being a topoisomerase I inhibitor. And MMAE, we know from enfortumab, being an antimicrotubule inhibitor there.

So Dr Rosenberg earlier referred to the DESTINY study, as well, and you can see pretty good confirmed objective response rates there, in the 39, 56, 35%, depending upon whether you were looking at all comers or whether you were looking at IHC 3, which you’d expect to have higher objective response rates, which you do see, 56.3% there. And also you can see the maximal change looks good on the waterfall plots, and there are patients with durable responses as well. Maybe PFS and OS we can’t really tease out too much in the small study at this point in time.

So there’s also a focus on patients with HER2 mutations. And it’s a small number of patients, 7 patients there, but early hints that there are patients that can respond with HER2 activating mutations at 28.6%.

What about disitamab vedotin here? You can see greater activity in the 2, 3 versus the 1+. This is not surprising. We see this time and time again. And there’s been combination studies here. So I will point out that they didn’t accrue well to the HER2 low, so it was all HER2-high patients that were studied with trastuzumab deruxtecan, and this was a breast cancer and urothelial cancer study. You can see the objective response rates, 36.7%, but this was combination with nivolumab. A little bit surprising there that it wasn’t higher there with T-DXd with nivolumab.

Now this is disitamab vedotin and toripalimab, which is another IO agent in China, and you can see high objective response rates at 73.2% there, and very nice spider plots.

So here’s the ongoing Phase II design with disitamab vedotin for patients that have been previously treated there. They’re broken down into 2 cohorts, A for HER2 high, Cohort B for HER2 low. And Cohort C is essentially for first-line untreated patients, it doesn’t matter whether high or low, and is randomized to disitamab vedotin plus pembro versus DV monotherapy. Objective response rate being the primary endpoint.

And here’s a randomized Phase III trial that just recently kicked off which is really first line, and it’s essentially DV plus pembro versus standard chemotherapy. You declare up front whether you’re going to use carbo or whether you’ll use cisplatin. And maintenance avelumab is allowed. Dual primary endpoints of PFS and OS.

So the take home: HER2 expression is not that uncommon for urothelial bladder cancer. Antibody-drug conjugates are showing efficacy, and it’s being revisited as a promising target now, an old target that’s being brought back with better drugs. Trastuzumab deruxtecan and disitamab vedotin both have promise as monotherapy and combination therapies.

Selection and Sequencing of Therapy for Relapsed/Refractory mUBC — Dr Siefker-Radtke

DR YU: So with that being said and done we’ll move on to the next module there, which is selection and sequencing of therapy for relapsed/refractory metastatic urothelial bladder cancer. And we’ll look at Dr Love’s conversation with Dr Plimack there on selection and sequencing of therapies for this patient population, potential integration of erdafitinib for patients with metastatic urothelial bladder cancer and FGFR alterations.

DR LOVE: With the increasing number of treatment options available to patients with metastatic urothelial bladder cancer a key issue is the sequencing of available therapies as commented on by Dr Plimack.

DR PLIMACK: I can’t really think of a reason I’d want to give sacituzumab before enfortumab vedotin. I find the toxicity harder to manage, probably because we give it later in the course of things. But just in general, the neutropenia can be really tough. Enfortumab vedotin, I have a lot more experience with. We’ve given it for a lot longer. We’re pretty confident about the efficacy. And so that would definitely be something I would go to first.

DR LOVE: What about in the FGFR patients? Where does erdafitinib fit in?

DR PLIMACK: I would still use EV first. I think the efficacy is a little bit better.

I often phone Arlene Siefker-Radtke when I have questions about erdafitinib because she has such deep experience with it. I have a lot less. I think there’s really clear dose modifications in the package insert that are really helpful. So for hyperphosphatemia, you know exactly what to do when it hits a certain threshold.

There is the risk of central serous retinopathy with erdafitinib. And so it does require visits to the ophthalmologist regularly. Again, if you run into that, it’s typically detected before they have any changes to their visual acuity. So you do have a chance to, again, intervene with a dose modification. And so I think those 2 things are the easiest to manage because it’s very clear that you decrease the dose when you see it.

DR YU: Okay. Here are her questions for us. I’m sure that she threw questions out there for Arlene or Eddy there. So how do you generally sequence enfortumab, erdafitinib, and sacituzumab for patients who are eligible to receive all 3 agents. And I’ll just start with Dr Siefker-Radtke.

DR SIEFKER-RADTKE: Sure. So I think it comes mostly down to toxicity. We have patients with different comorbid conditions. We have different levels of evidence now with Level 3 evidence with enfortumab vedotin and erdafitinib. Sacituzumab has an accelerated approval based on a Phase II trial.

So my preferred sequence is to do either enfortumab vedotin or erdafitinib for that patient; erdafitinib of course for the FGF-altered tumor. And I think when we compare the antibody-drug conjugates the response rates with enfortumab vedotin do seem a little higher compared to sacituzumab govitecan. The toxicity profile is different, with more neutropenia with sacituzumab, so I’m typically reaching for the enfortumab vedotin first and then following that up with sacituzumab govitecan. And that’s of course if they haven’t received enfortumab vedotin with pembro in the front-line setting.

DR YU: Okay. And the next question is about ocular toxicities. Dr Milowsky, how do you screen for this? Do you have an ophthalmologist you work closely with? And what do you do when you see problems?

DR MILOWSKY: Yeah. So I also call Arlene. No. I think we do have an ophthalmologist, fortunately, within the system that we’re able to send these patients to. And there’s more and more clinical trials that are requiring ophthalmologic evaluations of patients, so they’re getting more and more used to looking at these patients. And so they’re seen regularly by the ophthalmologist during the course of the enfortumab — the erdafitinib.

Fortunately I have not seen a lot in the way of central serous retinopathy or certainly retinal pigment epithelial detachment in our patients. I mean I know it can happen. I’ve had 1 or 2 patients where we’ve had to hold therapy for some time, and then we were able to reinitiate treatment. But I think in terms of how we do it as medical oncologists we have to rely on the ophthalmologist.

DR YU: Okay, great. Dr Rosenberg, yes?

DR ROSENBERG: It’s very good to have your patients have an Amsler grid they can stare at once a day, take a look to see if the lines on it are getting wavy. It’s a good reason to have them go see their ophthalmologist sooner rather than later.

DR YU: Absolutely. Okay. Next Dr Love and Dr Friedlander had a conversation on the efficacy and tolerability of erdafitinib.

DR LOVE: Biomarker based targeted treatment has become a standard part of the management of most solid tumors, and in urothelial bladder cancer the FGFR erdafitinib is now a standard option in patients with this mutation.

DR FRIEDLANDER: My take on erda is that it’s great to have another tool in the kit. I’ve treated patients with erda and seen good responses.

I think the challenge is that the adverse event profile of erda is more challenging. We see a number of side effects. There’s skin side effects in terms of rashes. There can be a lot of issues with hands and the nails particularly, and there’s a lot of published reports of fingernails that have turned gray or even fallen off, and they can have cracking and pain associated with that. Stomatitis can be an issue because the FGFR is just in the skin and the mucosa.

So I do think there’s a good utility for it. It now has Phase III data. So I think that that’s a good option for people who have FGFR mutations.

Really it’s the only oral therapy we have in metastatic bladder cancer. I have patients who come to me from the Oregon border, from Nevada, from Fresno, which are hours away, and it’d be great to give them oral therapy and not require them to drive to an infusion center. And so I love that idea.

DR YU: Okay. What are the common toxicities? Rash, nail changes, hand/foot syndrome, stomatitis have been reported with erdafitinib. How do you manage each of these? I’m going to throw this to you again, Dr Siefker-Radtke. You’ve had the most experience.

DR SIEFKER-RADTKE: Sure. I think they’ve listed the most common side effects, and I look at it as prevention helps. When you think of what fibroblasts do they’re involved in mobility, in migration, when you have cuts they help with healing. So I think a lot of what we’re seeing with the hand/foot or the palmar/plantar erythrodysesthesia is really due to the chronic damage that we’re causing to our hands as we go about our daily activities.

And when I give erdafitinib I tell patients usually after about 2 1/2 to 3 months everyone needs a short break. And I try to keep that break or anticipate it early enough that the break is around 2 to 3 weeks, and then they go back on treatment often at the same dose. Sometimes I will do a dose reduction.

And then use preventive measures. Emollient creams for the hands and on the nails. Make sure the nails are clipped short. Don’t use nail polishes because those will cause damage or trauma to the nails.

With the central serous retinopathy, again, having that ophthalmologist keeping an eye on the patient. I encourage patients to do the Amsler grid test. If they call you with blurry vision, the first thing I ask them, blink your eyes, is your vision still blurry. Because they also get dry eyes, and sometimes it’s a little bit of mucus that’s going back and forth across their cornea.

So as far as the mucositis and mouth sores, again, gentle cleansers in the mouth. Don’t use astringents. Use a soft toothbrush, nothing hard. I use salt and soda. I personally avoid steroids because I think this is again a wound healing issue, and would you give steroids if someone has a wound that’s trying to heal? I would say not, so my preference is to avoid oral steroids.

And then if they’re doing a lot of activities, water activities, have them use rubber gloves on their hands. If they’re doing gardening, leather gloves. Everything that can protects their skin, goggles to prevent or keep corneal abrasions under control.

DR YU: That’s great. I just learned some new tips there that I’m going to take home and use there.

Dr O’Donnell, do you think there’s an advantage to giving oral medications here? Most of our agents are IV.

DR O'DONNELL: This is a blessing and a curse, right? Your patient obviously would love the convenience of taking an oral therapy for the reasons Dr Friedlander talked about. However, we know that there’s adherence issues with all oral therapies; patients taking blood pressure medicines at a rate of about half the time. So do we have those concerns? You’ve got to think about that in the patient that’s sitting in front of you.

Plus with erdafitinib you are supposed to track phosphorus levels 14 days after starting because we don’t know really whether the dose is appropriate for that individual patient, and then you’re supposed to dose adjust based on those phosphorus levels. And so you want to make sure you’re not overdosing or underdosing the patient. It becomes a little tricky and challenging for my nurse because if we do have to change the dose then you have to often change the prescription because now you need a different pill milligram size. And so there’s some clunky issues with the dosing of this drug that can be challenging for the medical system and the patient.

DR YU: Okay. Thank you so much. Go ahead.

DR SIEFKER-RADTKE: Yeah. If I could mention the dosing part. The reason it has the uptitration is when we looked at some of the PKs it seemed about half the patients needed a higher dose, and we wanted to avoid giving too a high a dose in patients, as well, and having even more toxicities. And that’s why in the most recent clinical trial we looked for a target phosphorus level of 7. If it was less than 7 at day 14 or 15 we up-titrate to 9 mg. If the phosphorus is above 7 then we would not up-titrate that patient.

I agree it’s a little challenging. You can’t pick it up at the local CVS. You have to order it, wait for it to be shipped. And over time patients do need dose reductions, so I view it as induction maintenance. When we go to the appropriate dose we may get that deeper response that we can then maintain even when we have to reduce the dose of erdafitinib at a lower level.

DR YU: Okay. So here are the surveys. And this was the last patient in our practice that got erdafitinib and what side effects they experienced and benefit, et cetera. I mean I think the person who stands out here is Dr Siefker-Radtke. Everybody else’s patients did have toxicity. So I have to think whether it’s a dosing strategy or reduction strategy or your prevention strategy. What do you think there? Your patient had no toxicity.

DR SIEFKER-RADTKE: Well, so far they’re about a month into treatment, and again, a lot of prevention; avoiding things that cause trauma, a low-phosphorus diet to start with, which helps keep the phosphorus low. And as you continue the erdafitinib compensatory mechanisms kick in, and you start excreting more phosphorus through the kidneys. So when they’re tired of the low-phosphorus diet they now have better control because they’re excreting more phosphorus.

So I do think there’s a lot of that whole stitch in time that helps delay some of the toxicity. It will develop. I’m not going to say it’s not going to happen. He’s going to get hand/foot syndrome, everyone does, but the longer I can delay it, the longer he’s on the therapeutic dose, and then catch it early so I have a shorter interval break, around 2 to 3 weeks.

DR YU: Okay. This one I’m not going to discuss too much because this is a patient, 65-year-old, had FGFR-mutated metastatic urothelial bladder cancer and had first-line pembro, second-line EV, and it’s unanimous, everybody said let’s give erdafitinib here to this patient there.

What about this one? Is it reasonable to refer a patient to an optometrist rather than an ophthalmologist prior to commencing therapy? And Dr Siefker-Radtke, you said no. Why no?

DR SIEFKER-RADTKE: So a lot of optometrists are trained more for getting the right prescription, getting the eyeglasses, which is a corneal issue. When you look at central serous retinopathy it’s a retinal issue, so you need someone with experience looking at the retina, someone who has the machines that can help, like the optical coherence tomography, which does imaging of the retina looking for thickening or fluid behind the layers.

Now that being said, I have heard now there are some optometrists in the community who are capable and have some of this equipment, and we know not every community has an ophthalmologist. So I would encourage those in the community setting to chat with your ophthalmologists if you have them and chat with our optometrist because they might be able to provide some of what is needed to help patients. But in general I’m looking for an ophthalmologist first.

DR YU: Got it. Okay. This is a sequencing question. Erdafitinib, enfortumab, sacituzumab, metastatic urothelial bladder cancer, eligible to receive all 3. Most of us answered the same way except for Dr O’Donnell answered a little differently, EV, sacituzumab, then erdafitinib instead of the other way around with erda and sacituzumab. Why did you answer it that way?

DR O'DONNELL: I’m not answering it based on evidence. Clearly erdafitinib has the higher level of evidence here. It’s for the reasons I just alluded to, the difficulties of actually administering that oral agent erdafitinib, which we think would be easier, may actually be more challenging in certain patients.

DR YU: Okay. And the last one I’m not going to spend a lot of time on because we want to give Dr Siefker-Radtke plenty of time for her presentation. This is just do you pre-emptively prescribe a steroid mouthwash, and most of panelists said no except for Dr Friedlander, but he’s not here to make his case. So I’m going to turn it over to Arlene. Go ahead and take us home.

DR SIEFKER-RADTKE: Okay. I’ll take you home, but I won’t feed you otherwise you’ll stay, right?

But anyways, we all know what’s really made a difference in urothelial cancer are these new novel targeted strategies. And we now have several good targets that are stable, reproducible, and good drugs that are targeting or hitting these targets.

When we think of second-line treatment, we can’t forget front line as you heard from Dr Rosenberg, we have multiple options that patients are receiving. I think it’s transitioning to more enfortumab vedotin with pembrolizumab, but we still have a lot of patients getting chemotherapy, maintenance immunotherapy, and then even neoadjuvant chemotherapy.

So as we think of previously treated metastatic unresectable urothelial cancer a few basic concepts. This does include patients who progress within 12 months of their neoadjuvant or adjuvant chemotherapy. A general concept is if you’ve given it before don’t give it again. At the moment we don’t know that there is any benefit from giving the same drug sequentially.

That being said, I know many of us are giving EV/pembro if a patient has had prior immunotherapy as part of their neoadjuvant or adjuvant strategy just because we don’t know.

We also look for mutations. As you heard about for erdafitinib you want to look for those FGF alterations. Given the time needed check early. There’s limited information on sequencing except with erdafitinib that you’ll hear about. So most of the decisions are really based on toxicity, what toxicities are we trying to avoid.

We’ve all seen enfortumab vedotin, the same slide of this wonderful antibody-drug conjugate that’s working extraordinarily well in front-line setting now but was first approved with Level 1 evidence in the post-platinum setting. And it was on the basis of the EV-301 trial where patients who received prior chemotherapy and immunotherapy were randomized to enfortumab vedotin versus a taxane, and we saw improvement in response rate, overall survival, progression-free survival, so really something that had an impact even in previously treated patients.

But nothing is without side effects. We have side effects for everything, and what we see with enfortumab vedotin is that rash, those cutaneous reactions, the peripheral neuropathy, which is cumulative over time, and accumulates more — at a rapid rate in patients who have pre-existing conditions for neuropathy. We also see that hyperglycemia can occur in these patients as well.

And then we have the black box warning for enfortumab vedotin, which is currently called Stevens-Johnson syndrome, although I think this is really likely due to deposition. There’s nectin expression in the skin, and we might be getting the enfortumab vedotin into those dermal layers which cause the peeling or bullous lesions that unfortunately have been associated with deaths.

Now why do people die from this? Well, let’s talk a little bit about metabolism. There’s a bit recovered in the feces, 17% over a week, that’s the metabolites of monomethyl auristatin E. Very little recovered in the urine.

There’s no need for dose reductions for renal impairment, but if you look at the label, I mean who reads the label, I guess I did, but if you look at the label it says even for mild hepatic impairment there’s a 48% area under the curve increase with products that have monomethyl auristatin E. And I’ve personally found even if they have a Child-Pugh score A/borderline B, they’re not quite B, or you’re not sure of some of that low albumin is a B, they cannot tolerate even front-line — or even dose-reducing the enfortumab vedotin up front. So definitely you want to avoid this in patients with hepatic impairment.

When treating patients I look for hyperglycemia, hold the dose if the glucose is above 250, as that could be an early sign of toxicity, perhaps delayed clearance, which is my personal hypotheses as to cause. And those side effects that are associated with peeling of the skin, diarrhea, ketoacidosis that’s insulin resistant, flaccid paralysis, my hypothesis is that it’s just so much monomethyl auristatin E that’s causing a diffuse tubule breakdown where the tubules don’t work, patients cannot use their glucose, 80% is consumed by muscle, and that might be why we see this constellation of side effects if we’re not clearing it adequately. And I see these most commonly in those cirrhotic livers.

Sacituzumab govitecan is a second antibody-drug conjugate approved for urothelial cancer. We’ve all seen the pictures. This targets TROP2, which is expressed in over 80% of bladder specimens, so no need to test, and it brings irinotecan more directly into the tumor microenvironment.

We saw some updated data at this year’s GU ASCO looking at objective response rates where the objective response rate was 32% in the TROPHY-01 trial, and as you can see from this plot we do see some patients who continue in their response, with a promising progression-free survival of 5 months and overall survival of 10 months looking at the TROPHY-01 cohort.

But again, side effects. Sacituzumab govitecan does have neutropenia. It has myelosuppression. And in my personal opinion in our pretreated urothelial cancer cohort they have comorbid conditions, they’re older than the typical breast patient. I am personally giving prophylactic growth factor support following the day 8 dose due to the frequency of neutropenic fevers that I’m seeing in these patients.

And then we also get to erdafitinib, the first biomarker-targeted therapy where you need to have FGF alterations. This Phase III trial, or the THOR clinical trial, took patients who had prior chemotherapy and immunotherapy and randomized them to erdafitinib versus single-agent taxane or vinflunine, which is approved in Europe. And what we saw was a significantly improved overall survival with a median survival of 12 months compared to 7.8 months with that single-agent chemotherapy. We also saw improvement in response rate and progression-free survival with the objective response rate coming in around 40%.

But as we talked about, it does have side effects, those nail disorders, paronychias, hand/foot syndrome, and the central serous retinopathy. And I would argue monitoring for that, learning to recognize it, and holding the dose a little earlier keeps patients on treatment longer. So it is a side effect, but I personally do find it manageable.

Now what about sequencing? What evidence do we have for actually sequencing something? I would argue we have some with erdafitinib. There was a second cohort of the THOR trial randomizing erdafitinib versus immunotherapy in patients who had not received a prior checkpoint inhibitor, the idea being FGF alterations were enriched for immunologically cold tumors. And even though this treatment, erdafitinib, had an improved objective response rate, 40% versus 21% with pembrolizumab, and an improvement in progression-free survival, when we looked at overall survival it was initial benefit from erdafitinib but the durability of benefit from pembrolizumab contributing to that tail of the curve which impacted the survival benefit, so we did not see a significant improvement in overall survival.

So if we think about options I would say checkpoint inhibitors second line. We have immunotherapy options that are listed here, the antibody-drug conjugates, and then there’s mutation-driven recommendations with erdafitinib, which should be given after immunotherapy, although I would argue there might be patients with the need for cytoreduction, such as those with visceral crises, where response is needed, and where you might consider giving that first even before an immune checkpoint inhibitor.

But one thing that’s missing, what do we do with platinum now? What if patients are starting front line with enfortumab vedotin/pembrolizumab? How do we fit platinum in the mix? Or do we even need to fit platinum into the mix? I would argue we don’t yet know. If we look at some of the EV/pembro randomized trials in the front-line space a lot of those patients are getting second-line platinums. It’s in countries like Europe and overseas where they might not have access to sacituzumab govitecan or other agents.

So if that survival advantage, which on the trial 31 months is better than Jonathan did at Sloan Kettering. He’s pretty bright. Why is that, right? We saw 2 other cohorts, 22 months, 26 months. If that trial truly reads out in the 30-month setting is it just variability or is it because they’re still giving 2 active regimens by giving platinums in the post-EV/pembro setting? So I think we’re going to need more data to tell us what do to in the future.

DR YU: All right. With that we conclude the program. Thank you so much. You’ve been a wonderful audience.

Thank you and have a wonderful rest of the meeting.