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Ascending to Higher Heights in the Treatment of Locally Advanced/Metastatic Bladder Cancer – Expert Insights on Navigating the Latest Guidelines and Therapeutic Advances

 

So, you know, we're going to talk a little bit about how rapidly changing all of this landscape is. I think that we've all been a little bit—you know, you all have been engaged in this research for a while and you've seen this. But let's start with what do you consider to be the most exciting recent advance in bladder cancer, maybe in the last couple of years?

 

Dr Gupta: Yeah, I think in the last couple of years, we've seen a lot. You know, I think the ADC immunotherapy combinations and the wealth of the new drugs that's coming after EV/pembro revolutionized the treatment of metastatic bladder cancer, is really a big advancement that we've now seen it move to already muscle-invasive setting in cisplatin-ineligible patients. And now we’ll see the data for cisplatin-eligible patients here at this meeting.

 

In addition, we've seen really a robust biomarker like ctDNA. So I think the field has a lot of promise.

 

Dr Grivas: I agree with Shilpa. I think, you know, the excitement with ADC antibody drug conjugate plus checkpoint inhibition, specifically enfortumab vedotin plus pembrolizumab that has revolutionized significantly, they’re tired of carrying both metastatic disease and now in localized disease. And we're going to see data here at ASCO GU in San Francisco with pembrolizumab plus enfortumab in perioperative treatment of muscle-invasive bladder cancer in cisplatin-eligible patients. And we have a slide for that.

 

I think that's the most, you know, recent exciting I would say transformative data set. And as Shilpa mentioned, there are many other new agents coming up and there are multiple questions at the same time, which brings to the second question, the challenges, right?

 

And there are many challenges, of course, who are not done in any way. We have way to go. But in my mind there are are many, but 1 of them is how to personalize the treatment approach. You know, how can you escalate or de-escalate treatments, especially if you talk about perioperative management before and after radical cystectomy, how do you manage the adjuvant therapy component? Do you give it to everybody as per trial design? How do you decide in the individual patient level? Do you use pathologic staging, circulating tumor DNA? To Shilpa's point, how do you make this individual decision vs just following the trial design that how - how it's done so far?

 

Dr Gupta: Yeah. I think that is our bigger challenge now over treatment of patients.

 

Dr Ghali: Yeah. Yeah, yeah. I think those are perfect summaries. I don't have much to add to that. I mean treatment sequencing is a real - is a real question here. You know, many of the trials - many of the trials will evaluate a therapy in 1 disease state, you know, adjuvant setting. And by the time the trial is out or being implemented, both the pre and the post has evolved so much that it's hard to know how to contextualize that finding.

 

And so I think it's a real question. And then these biomarkers, like you say, ctDNA and others incorporating them into trials maybe that don't have them as part of their results is going to be a tricky thing. So we'll talk about some of those things today.

 

[00:10:13]

 

Abstracts of Interest at ASCO GU 2026

 

Okay. These are some of the abstracts of particular interest at ASCO GU here in San Francisco. And - and so we're excited to - to see these and be able to discuss them at the conference. I'm going to just leave them up for a second.

 

We talked a little bit about the sandwich or neoadjuvant and adjuvant enfortumab vedotin and pembrolizumab in cisplatin-eligible patients. And so that's the top 1 there.

 

Dr Grivas: And you know, I see the second, I remember Shilpa's great presentation. I think, it was ASCO, Shilpa, when you discussed the depth of response and duration of response, right?

 

Dr Gupta: Yeah.

 

Dr Grivas: From EV-302 to trial.

 

Dr Gupta: And in this poster, actually it got selected for poster walk, so you'll see it tomorrow. But in this we are describing how the patients who may not be complete responders evolve eventually.

 

Dr Grivas: Very interesting. So characterize the patient's response, you look at both CR and PR.

 

Dr Gupta: Right. And how PR can become CR.

 

Dr Grivas: Interesting. Like depending of response over time in some patients. Interesting, EV-302.

 

Dr Ghali: And then some new antibody drug conjugates as well. So being incorporated. So a lot of exciting abstracts.

 

[00:11:20]

 

10 Yr of Progress in Bladder Cancer

 

So I really like this slide. This is a summary slide of the progress that has been made in bladder cancer in just the last, you know, 10 years or so. So, you know, folks who have been treating bladder cancer patients for some time now will remember, cisplatin really has been the backbone for decades. And we did not have a lot of therapies that were clearly advantageous over cisplatin, either in the perioperative setting or in the first-line setting.

 

And then very quickly, with the advent of checkpoint inhibitors, early in 2016 and then onward, we can see that both targeting therapies and checkpoint inhibitors have really made a huge change in bladder cancer. You know, Dr Grivas here mentioned that I had trained with them in Seattle as a fellow. And even since I was just a few years ago when I was in training with you, the landscape has already changed. And it's already - there's new things that we, you know, didn't have just a few years ago.

 

And so this is just a summary slide to hopefully explain, I think, the value of a discussion like the one we're having today and also just generate excitement. I mean, it's a great era to be treating bladder cancer patients because we're seeing a ton of progress.

 

Dr Grivas: For sure.

 

[00:12:27]

 

Muscle-Invasive Bladder Cancer

 

I'm going to start with just a brief discussion about muscle-invasive bladder cancer in the perioperative space. And so we're going to discuss some trials exploring systemic therapy in the perioperative arena as well as some surgical data as well.

 

[00:12:42]

 

          Poll 4

 

So here's a polling question to start. Approximately what percentage of patients with muscle-invasive bladder cancer do you consider for perioperative therapy, either neoadjuvant or adjuvant in your clinical practice?

 

Dr Grivas: Or both?

 

Dr Ghali: Or both. Yeah. Or both as we'll see here.

 

Dr Grivas: Going back to this, you know, Shilpa’s point, right. Overtreatment, Undertreatment. That's an interesting hot topic of discussion. But…

 

Dr Ghali: Yeah, especially as we consider folks earlier and earlier in the natural history of bladder cancer, you know, as we move therapies up, I think the risk benefit of systemic therapy changes a bit. You know, if you're a second-line metastatic patient, that's a different type of patient than a muscle-invasive patient. And sometimes I think that that can, you know, be underemphasized in our - in our work. So.

 

Dr Grivas: Different populations. Yeah. Different therapy intent, sometimes depending on the therapy setting.

 

Dr Gupta: I think it would be interesting, you know, who's answering this question. You know, if a urologist is answering it, what are their referral patterns to med/onc. If a med/onc is answering, of course, they're already seeing patients who've been referred. So I think that's an important point.

 

[00:13:51]

 

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

 

Dr Ghali: Well, I think a discussion around perioperative therapy in muscle-invasive bladder cancer. This is a very nice starting point. This is a review of a study called the NIAGARA study. The NIAGARA trial evaluated the addition of durvalumab, both in the neoadjuvant setting and the adjuvant setting. So before and after surgery, in addition to what would be considered standard at the time, which is gemcitabine and cisplatin, neoadjuvant chemotherapy followed by observation after radical cystectomy.

 

And so you can see the schema down below of the trial. You could see in the grey is the control arm. So GemCis neoadjuvant, then surgery, and then no treatment at all vs the treatment arm - excuse me. That was the control arm. And then in the treatment arm, you can see durvalumab plus the chemotherapy, followed by surgery and then durvalumab by itself.

 

And these were localized bladder cancer patients. So you could see here the inclusion criteria on the left side of the slide. And then a baseline characteristics table here, which describes I think a fairly young population compared to the average bladder cancer cohort, but generally otherwise fairly similar to what we see for a cystectomy group.

 

And those were the coprimary endpoints as event-free survival and pathologic complete response.

 

[00:15:04]

 

NIAGARA: EFS and OS

 

And here are the Kaplan-Meier that we all get very excited to see. And what - what you can see here is that there's an improvement. The red line, which is the treatment arm that includes durvalumab, has an improvement compared to baseline just chemotherapy and an observation following surgery. And both event-free survival and overall survival are improved and pathologic complete response is also improved.

 

And you can see the hazard ratios down below and the p value demonstrating statistical significance here.

 

[00:15:33]

 

KEYNOTE-905/EV-303: Perioperative Pembrolizumab ± Enfortumab Vedotin

 

So the NIAGARA study was really, I think, the first to be published demonstrating this sandwich therapy model, this neoadjuvant therapy plus adjuvant therapy afterwards. More recently we've seen the publication of EV-303. Actually, I think it was just in the last couple of weeks we saw the paper published, which evaluated a similar paradigm, this time in cisplatin-ineligible bladder cancer patients.

 

So by definition, a little bit of a different group. I think classically, a more high-risk group with fewer options than maybe the folks in the NIAGARA study.

 

And what you can see here is the investigators evaluated both enfortumab vedotin and pembrolizumab before and after surgery, compared to a group who just got surgery, who went straight to surgery. And again, this is reflective of the cis-ineligible status and not having a lot of reliable good options for neoadjuvant therapy.

 

And hopefully, Dr Gupta will get you to comment on this in a little bit.

 

[00:16:32]

 

KEYNOTE-905/EV-303: EFS

 

But, you know, I think that the Kaplan Meier demonstrated a really strong signal here. I mean, we really see a clear separation of the curves, very - very early, and - and they stay quite separate throughout. And we see a really favorable hazard ratio of 0.4. We don't see a lot of 0.4 hazard ratios in bladder cancer.

 

Dr Gupta: Especially such a high-risk, frail patient population.

 

Dr Ghali: That's right. I mean - and you know, I hope we have a slide here. Oh, you can see at the bottom. This is an exceptionally high-risk cohort.

 

Dr Grivas: Yeah.

 

Dr Ghali: I mean, 78% that were T3 or T4 - T4 pathology. You know, so that's a really  significantly high-risk group.

 

Dr Grivas: And to your point, Fed, you know, as, you know, Shilpa mentioned, this is a high-risk population. Almost 80% clinically T3, T4. And if I remember it was a very small proportion of patients with N1 disease. Very, very few patients. Right?

 

Dr Gupta: Yeah.

 

Dr Grivas: The - the interesting thing to me was again going back to the over vs under treatment. If you look, I think at the presentation, about two thirds of the patients received the adjuvant therapy component and one third did not. And the question is what happened with those patients? I think, you know, maybe the manuscript has more details about those patients.

 

Dr Gupta: Yes.

 

Dr Ghali: Yeah, yeah. And I think another thing to note about this, especially as we think about something like enfortumab vedotin and pembrolizumab perioperatively is the - the surgery arm, just the pure surgery arm. Very few of those – actually, I think it was 1 patient saw enfortumab vedotin and pembrolizumab on subsequent therapy upon progression.

 

Dr Grivas: Right.

 

Dr Ghali: And I think this is a really key question because, you know, we now have several studies showing EVP has clear activity. It's clearly an effective therapy in bladder cancer. But it does leave open the question of what—where is the best time in bladder cancer to give this therapy? And - and do you give it to everybody, or do you give it guided by some - some other marker? And so those are still wide-open questions. And we're looking forward to teasing that out.

 

Dr Gupta: I think in the control arm, eventually 16% saw EV.

 

Dr Ghali: EVP.

 

Dr Gupta: But, you know, it also depends. It's a global trial access. It's a big challenge.

 

Dr Ghali: Yeah, it's a real challenge. Sure.

 

[00:18:42]

 

KEYNOTE-905/EV-303: OS and pCR

 

Dr Grivas: And it's interesting. You know, it brings to mind, you know, I talk about the EV-302 trial in a second. And we actually published a recent paper looking at informative censoring and how the control arm would be performing in ideal scenarios. And we saw that the EV/pembro would still have won, even if the control group of EV would have done better.

 

So, you know, in my mind—and tell me, what do you think Shilpa and Fed? I think, you know, it's good to use your best therapy upfront. And EV/pembro seems to be the best therapy we have so far, so it makes sense to use it in that setting in patients who can tolerate it with the vast majority of patients.

 

Dr Gupta: Yeah. Just want to clarify. So the 16% was eventual immunotherapy because, you know, in the control arm, immunotherapy was not allowed in the protocol. And nivolumab got approved somewhere 2 years into the study. So that's also another question. You know, it had become a standard.

 

Dr Ghali: Yeah.

 

Dr Gupta: So very few people got EV. But we don't have the long term.

 

Dr Grivas: Got you. Got you. Because to Shilpa's point, in the control arm of this trial, there was no immunotherapy.

 

Dr Ghali: That's right.

 

Dr Grivas: During the conduct of the trial, as Shilpa alluded to, nivolumab got approved adjuvantly.

 

Dr Ghali: That's right.

 

Dr Grivas: It was, I think, August 2021 or so in US and April 2022 in Europe. So again, it's the control arm, you know, has evolved over time. But still the difference is so robust.

 

Dr Ghali: We're going to see this as a challenge in a couple of the other studies as well as by the time the study is enrolling and ongoing, suddenly another trial reads out and we now have a new standard. And this impacts how we do it. And so you all, with your experience, hopefully you'll get to comment on that a little bit too.

 

So, and this is, you know, of course, what we all love to see is an overall survival separation of the curve. And again, clearly, EVP is an active regimen, improves overall survival compared to surgery alone here.

 

Dr Gupta: And I think here, you know, the key is, you know, that, okay, the control arm was QRBT[?] only, right? And then - but you see we've never seen with any regimen to-date in decades 57% pathCR rates. I think that's the key here regardless of what the control arm.

 

Dr Ghali: That's right.

 

Dr Gupta: You know, 15%. So I think never with dose-dense MVAC or the GemCis/durvalumab. So that I think is really unprecedented pathCRs.

 

Dr Grivas: In a phase III trial.

 

Dr Gupta: Yeah.

 

Dr Grivas: Large phase III. And to Shilpa's point, this 57% pathCR rate includes patients who never got into surgery because they selected or opted. So those were included in the denominator, but not in the denominator. So the actual pathCR rate in those who underwent radical cystectomy was a little bit higher than 60%. So really depending on how you see the - how you define the population.

 

[00:21:20]

 

KEYNOTE-B15/EV-304: Perioperative Pembrolizumab + Enfortumab Vedotin vs Chemotherapy in Cisplatin-Eligible MIBCb

 

Dr Ghali: Yeah. Great. So this is EV-304. So this is perioperative, enfortumab vedotin and pembrolizumab vs chemotherapy in cisplatin-eligible patients. And so this is the complement to the study that we just reviewed here looking at preoperative and postoperative EVP compared to this time, cisplatin neoadjuvant therapy as this is cisplatin-eligible cohort.

 

And this abstract will be presented here at GU ASCO. And so we're all eager to see the presentation. I think it's tomorrow.

 

Dr Grivas: Tomorrow morning.

 

Dr Gupta: Tomorrow morning. Yeah.

 

[00:21:53]

 

CheckMate 274: Adjuvant Nivolumab vs Placebo in MIBC Post Radical Surgery

 

So now we're going to review several trials that just looked at adjuvant therapy. So these are patients who have had their cystectomy. Many of them have also had neoadjuvant therapy prior to enrolment in the trial. And this study basically randomized patients to adjuvant nivolumab, which is an immune checkpoint inhibitor or placebo for high-risk pathology.

 

So this is a more select group. This is not all-comers with clinical muscle-invasive bladder cancer. These are patients who underwent radical cystectomy oftentimes after neoadjuvant therapy and then had high-risk features on pathology as we'll review here. And so were then randomized to nivolumab or placebo.

 

So already a smaller group that's higher risk. And what we can see here is some baseline characteristics. Again, a similar cohort to some of the studies that we have just reviewed in terms of age and sex distribution and so on.

 

[00:22:49]

 

CheckMate 274 5-Yr Follow-up: DFS in ITT Population and Patients With PD-L1 Expression ≥1%

 

And here are the outcomes for CheckMate 274. So the initial publication demonstrated even within the intent-to-treat population an improvement in disease-free survival. It’s clear that nivolumab adjuvant therapy improves disease-free survival. And the PD-L1 positive population saw an even clearer benefit. And longer-term follow-up did show an overall survival benefit to nivolumab as well in the adjuvant setting.

 

[00:23:18]

 

AMBASSADOR: Adjuvant Pembrolizumab vs Observation in MIBC

 

Here's another study evaluating adjuvant checkpoint inhibitor. This is adjuvant pembrolizumab vs observation. It’s a multicenter, open-label study, phase III. And really quite similar I think to CheckMate 274 as high-risk pathology looking at disease-free survival and overall survival. Again, we see baseline characteristics like those that we would expect for this cohort.

 

[00:23:42]

 

AMBASSADOR: DFS and OS (Coprimary Endpoints)

 

And what we can see here is that a disease-free survival benefit was seen with pembrolizumab. You could see here in the left panel there was a separation of the curves and an improvement, quite a bit of an improvement actually to almost 30 months in terms of median disease-free survival, but compared to 14 months of observation in terms of median.

 

The overall survival data were quite immature and don't - don't show a survival benefit. I think a key thing to note about this study is that the AMBASSADOR trial during the conduct of the AMBASSADOR trial, we got CheckMate 274 results which really were quite positive.

 

And so many of the patients that were not receiving pembro, that were in the observation arm, likely crossed over to the nivolumab arm. And this can really undermine the OS reading. And so this is kind of speaking to the point that we were just making about an evolving landscape here.

 

Dr Gupta: But even so, if you see in the CheckMate 274, even though OS was not significantly better, there was some separation. In this, we see there is no separation, and that could be the reason of the blinded or—but this is not going to become positive at any point.

 

Dr Ghali: No, no. Unlikely. Yeah.

 

[00:24:49]

 

IMvigor011: Atezolizumab vs Placebo in Patients With HR-MIBC Who Are ctDNA+ Post Cystectomy

 

Dr Grivas: And also what the treatments you get if someone has metastases, what access to treatments you have? The AMBASSADOR is fully US.

 

Dr Gupta: Yes. That's a great point, because they have access to all the therapies later on vs...

 

Dr Ghali: Yeah, this subsequent treatment issue in clinical trials is such a challenge. You know, we see this as - in multiple studies. And so, yeah, I think it's clearly a real challenge.

 

IMvigor011 is a study similar but quite different from the others. And so it's probably worth just reviewing. This is a clinical trial that really spun out from another trial, IMvigor010, which was an evaluation of atezolizumab vs placebo in the adjuvant setting, kind of like the trials we just reviewed, which was overall a null study.

 

It showed no detectable benefit to adjuvant atezolizumab. But a subset analysis within that study looking at ctDNA as a biomarker for receipt of adjuvant therapy was significantly positive. And it led to this randomized trial, the IMvigor011, which looked at atezolizumab vs placebo in ctDNA-positive patients.

 

And so you can see here a similar cohort of high-risk muscle-invasive patients after systemic therapy. But if ctDNA was then used within the surveillance period after surgery and if it was positive, patients that had no radiographic evidence but positive ctDNA were randomized to atezolizumab vs placebo.

 

If they were negative, they received no treatment. And I think this cohort is probably worth just looking at for 1 second.

 

[00:26:24]

 

IMvigor011: DFS and OS in Patients Testing ctDNA+

 

These are outcomes of the ctDNA positive cohort. So you could see here an improvement in disease-free survival with a hazard ratio of 0.64 and an improvement in overall survival with a hazard ratio of 0.59 for receipt of atezolizumab adjuvantly driven by ctDNA positivity, suggesting really that ctDNA may be a really quite effective tool for detecting molecular residual disease in the adjuvant setting, even with negative CT scans.

 

[00:26:58]

 

IMvigor011: DFS and OS in Patients Who Persistently Tested ctDNA-

 

This is a slide summarizing the ctDNA negative cohort. And what we can see here is that ctDNA negativity is not perfect. It does not portend a perfect prognostic marker for the absence of metastatic disease, as you can see in the left panel. But it is quite good. At 24 months, 88.4% were alive and disease-free. I mean, that's - that's a pretty good marker, I think. But not perfect. And I think it's a reminder for all of us that even in our ctDNA-negative patients, we still have to be attentive to their imaging and surveillance. And they're not - you know, we can't let them off.

 

Dr Gupta: And has to be serial monitoring, you know, just not 1 ctDNA and letting it be.

 

Dr Ghali: That’s right. Yeah, there's a conversion rate from negativity to positivity. So that's a great point. But overall their overall survival here is on the right side - in the right panel. And you can see a really favorable overall survival.

 

[00:27:52]

 

Ongoing Challenges in Adjuvant Therapy Decision-making

 

And so, this is a slide just summarizing what many of us, as clinicians, know about the challenges of adjuvant therapy. You know, most of these patients have no evidence of systemic disease and they've just underwent a major surgery. And they're now in a position where we see some feature that is high-risk and have to balance the discussion of how do you make a decision about getting more therapy in the wake of this really quite large surgery vs undergoing observation?

 

And so, you know, these are the 3 options that we're faced with is, is do you really kind of do a wait-and-see approach, let patients recover, and then treat in the metastatic setting? Do you give patients adjuvant therapy before there's any visible disease where we risk overtreating a potentially significant cohort that's cured from surgery alone? You know, maybe 40% to 50% depending on their presurgical treatment. But then treat metastatic disease earlier, and while it's micro metastatic and not visible.

 

Or option 3, which is hopefully be able to incorporate some of these biomarkers that help us delineate these populations a little bit more effectively—the actually cured and those with residual disease that's just not visible yet.

 

And so I think this is some of the challenge. And there's not a lot of answers here yet about how many of these trials that will bear out with ctDNA. So.

 

[00:29:17]

 

Multidisciplinary Team Collaboration Is Critical for Managing Bladder Cancer Care

 

Just a note about multidisciplinary team collaborations. And so I just want to highlight a study. This is a study out of the University of Washington looking at their bladder cancer multidisciplinary clinic, which is, I think, a really nice example of bringing together folks from medical oncology, radiation oncology, surgery, and then pathology and radiology expertise, as well as stoma nurses and so on. A lot of the folks who really get patients through this care.

 

And this is a review of their experience here. So they went back and looked at over 200 patients who had gone through their multidisciplinary clinic.

 

[00:29:53]

 

Multidisciplinary Team Collaboration: Real-world Outcomes

 

And this just highlights, I think, the value of getting lots of smart people in a room to think about complicated patients. You know, muscle-invasive bladder cancer is at this point a fully multidisciplinary disease. And we see that here, you know, review - patients reviewed at - at their multidisciplinary clinic had significant numbers of changes in their staging as well as changes in their treatment plans just by having folks sit around and discuss patients all together.

 

And so it results in changes in care and is probably a good goal for all of us to incorporate multidisciplinary collaboration for MIBC.

 

Dr Grivas: And you see, definitely changes in the treatment planning. You know, you see more use of neoadjuvant treatment with bladder cancer multi clinic. You see in selected patients bladder preservation with chemo radiation. You see changes of course in the clinical stage. So to your point, Fed, this was—to us, it was, you know, eye opening that you need this multidisciplinary expertise. You need pathology radiology to review real-time images and slides. You need this, you know, expertise in the room and it makes a difference.

 

And we try to communicate back and forth with community colleagues. If the patients get treated there, for example, neoadjuvant treatment, you know, in collaboration with our urologists, they coordinate care. And of course, you will have clinical trials. Or if the patient wants to be treated at our center, we may treat them there. But it's that dialogue with the community helps a lot.

 

Dr Ghali: Yeah. Well said. Yeah.

 

[00:31:24]

 

SWOG S-1011: Standard or Extended Lymphadenectomy for Localized MIBC

 

One note for a surgical trial just to include here in the muscle-invasive section. This is a SWOG trial, SWOG S-1011, which evaluated the extent of lymph node dissection in muscle-invasive bladder cancer. So on the surgical side, many of us were trained with very extensive lymph node dissections. We all sort of in surgery believe that more surgery fundamentally will hopefully help the patient. So we like to do these really extensive lymph node dissections.

 

And this is a fantastic effort led by the SWOG group and Dr Seth Lerner and colleagues who pulled off, really a randomized surgical trial with a picture verification of all of these cases, comparing extended lymph node dissection, including the common iliacs and presacral and pre-sciatic nodes compared to a more standard pelvic lymph node dissection in muscle-invasive disease.

 

And the results, I think, surprised many of us in the surgical part of all of this care, which is that there was no significant improvement with doing more surgery and more lymph node dissection. And in fact, there was a significantly higher rate of adverse events. Grade 3 through 5 adverse events as well as even a 90-day mortality was 7% compared to 2%.

 

And so again, I think that even with surgery, we're learning a bit about how to not overtreat, how being more aggressive is not necessarily better for patients. And I think it's a lesson all of us are learning over and over again in bladder cancer.

 

Dr Gupta: Yeah. This is really - I think the first surgical, you know, phase III trial that sets this question to rest, right? It's really impressive.

 

Dr Grivas: I think, to Shilpa's point, there was a trial in Germany, showed similar results. Right?

 

Dr Ghali: That's right. And, you know, we at conferences love to go back and forth about these trials and discuss, for example, you know, I think if there is a benefit in more extensive lymph node dissection, it's a benefit in very high-risk patients with that isolated nodal metastasis.

 

And so there's, you know, some discussion as always about the event rate in the trial, whether or not the event rate of nodal metastasis is high enough to detect a difference here. But this is maybe, like you say, the best effort we've had at answering this question really in a scientific way. And as far as we can tell, there's not clear evidence that there's a big benefit. But we love debating trials, I think, conferences. I certainly do so. Yeah.

 

[00:33:51]

 

          Case Discussion

 

So here's a case discussion I'm excited to hear your thoughts on. So this is a 64-year-old healthy male, muscle-invasive bladder cancer. The only real comorbidity is hypertension with no previous therapy and does have some baseline hearing loss, which has rendered him generally cisplatin-ineligible.

 

He receives the neoadjuvant 3 cycles of enfortumab vedotin and pembrolizumab prior to surgery and undergoes a successful radical cystectomy. And you can see final pathology here, had a really fantastic outcome. One of those 57% that we saw in EV-303 which is pathologic T0. And then actually here we've added a little wrinkle which is they're circulating tumor DNA is also - is also negative.

 

And so you know, we just reviewed this trial. It's a sandwich therapy trial. So in the - in the protocol, everyone got therapy afterwards, at least per the intention-to-treat. So that's the protocol. How do you approach a patient like this in the real world? Dr Gupta, maybe we can start with you.

 

Dr Gupta: Yeah. So that's a great question, right? So patient had a complete response. Now if you just look in the totality of the data for all the adjuvant studies, such a patient would not be offered anything adjuvantly, right? Adjuvant nivolumab or pembrolizumab.

 

Now in this study, yes, they used sandwich approach. But we have to also try to incorporate what the ctDNA is showing, what the—did patient have any toxicities from this? You know, 3 cycles of EV/pembro and then cystectomy. Does the patient have neuropathy or anything?

 

But I would have a frank discussion with the patient that this is what the study showed, but this is what ctDNA is showing. And not just go by 1 ctDNA. Maybe do a couple of serial testing and then make an informed decision.

 

Dr Grivas: I agree with Shilpa. You know, it's a big challenge because we do not know the right answer in this setting. You know, if you go by trial design, as Shilpa mentioned, in theory the intent-to-treat is to continue, resume systemic therapy in the adjuvant setting. Having said that, in the EV-303, KEYNOTE-905 trial, only two thirds of the patients actually received the adjuvant therapy component. So it's a discussion with the patient informed shared decision-making.

 

Dr Gupta: And, you know, offering 7 cycles postoperatively when somebody has no evidence of disease is, you know, something we need to really have that discussion with the patient.

 

Dr Grivas: And depends on toxicity as well. That's a big other factor. Did they cruise through no toxicity vs neuropathy, other things. All this play into account.

 

Dr Ghali: Yeah, I’m tempted to push you both on a firmer answer here because I'm curious what you do. You know, doc, what would you do if it was yourself? You know, we get patients who ask us that, you know.

 

Dr Grivas: I’ll ask Shilpa, first.

 

Dr Gupta: Yeah, I think I would get a serial ctDNA tested and then make choice.

 

Dr Ghali: Yeah. And hold off on adjuvant. Yeah, yeah. Is that what you what you would do, Petros?

 

Dr Grivas: Yeah. I'm struggling. In the NIAGARA trial, I would have given you a very clear answer that I would continue adjuvant durvalumab regardless of ctDNA or pathCR. Again, it’s ad hoc exploratory analysis, but gives me the flavor that you may need this probably 1 year of immunotherapy. So in this case, again I would do all this discussion informed decision-making.

 

I would probably on the side to consider adjuvant therapy and depending on the toxicity, maybe pembro alone as a kind of middle ground because the 3 options are no adjuvant treatment or pembro alone or EV/pembro. There are 3 options here.

 

Dr Ghali: Yeah, yeah.

 

Dr Grivas: No right answer.

 

Dr Ghali: Yeah. Yeah. Well, we think about this a lot. And this comes up at our tumor boards. And I'm sure you all are in this situation. You know, 1 thing I think about a lot is the IMvigor011 data showing ctDNA is a helpful marker in adjudicating who would benefit from adjuvant therapy.

 

You know, I think - I think it's not obvious to me why ctDNA would be a good marker for atezolizumab and not something else. I think it's clearly a marker about the disease and the biology of what's happening in the patient, and not about the regimen. But, you know, we hate to treat patients in a data-free zone, of course. And so it is tricky. And I wrestle with this too. But I will tell you when I get asked this, I say, you know, I would wait, but we're in a data-free zone.

 

Dr Gupta: But you know, to that point, Fed, also, yeah, I think it's very unrealistic to think of ctDNA-based IMvigor011 like trial for every regimen.

 

Dr Ghali: That's right.

 

Dr Gupta: Right?

 

Dr Ghali: That's right. Yeah. We're going to have to make the leap, I think, in caring for these folks.

 

Dr Grivas: And we hope that, you know, they will do a ctDNA analysis in the context of those 2 trials. And I hear they will do that. That would be very helpful if they do that analysis and show us the whole data set.

 

Dr Ghali: That's right.

 

Dr Grivas: The entire data set and ctDNA analysis in EV-303 and EV-304.

 

Dr Ghali: Yeah, we always want the data. That's right. All right. I'm probably eating into a lot of your - your time here. So we'll move on.

 

[00:38:53]

 

Let's Revisit a Question

 

Let's revisit some of the questions we discussed here.

 

[00:38:55]

 

          Posttest 1

 

So post-test. I'm confident in implementing shared decision-making and caregiver engagement to support personalized use of adjuvant therapy in patients with muscle-invasive bladder cancer.

 

Dr Grivas: So we want more agreement.

 

Dr Ghali: We want more agreement. Yeah. We don't want…

 

Dr Gupta: Strongly agree.

 

Dr Ghali: We don't want to lead the witness here. But hopefully this has been instructive.

 

Dr Grivas: We need an improvement in the...

 

Dr Ghali: That's right.

 

Dr Grivas: Although we have not seen the baseline data. But I agree with you. You know, these decisions take time in clinic, right? And you're in a busy clinic running around, these decisions take time.

 

Dr Ghali: Yeah. All right. I think we did see a shift towards more agreement. So that's - that's encouraging to see.

 

[00:39:42]

 

          Poll 5

 

All right. Poll 5. Which of the following questions would you most like the experts to discuss? Okay, so this is hopefully something that we can all talk about that's helpful for - for the audience here.

 

1. Selecting adjuvant therapy candidates;
2. Adjuvant immunotherapy sequencing in muscle-invasive bladder cancer;
3. Impact of adjuvant therapy on options post progression. This is a question I think about quite a bit;
4. Multidisciplinary discussions.

 

So no easy questions here. So.

 

Dr Grivas: Yeah, it's, you know, I think multidisciplinary care, I think, as you both mentioned, is critical. You know, we need to think about multidisciplinary approach and have, you know, all the players in the room, ideally in expert centers. And the question is how do you provide access to multidisciplinary care in a rural community, right, with less access to multiple disciplines? I think these are real, practical, real-world scenarios we need to address and work together with colleagues in community.

 

Dr Ghali: That's right. All right. So some questions about multidisciplinary discussions at stage of treatment and then impacts on adjuvant therapy on options post progression. So this might be worth discussing maybe as we discuss first-line and second-line therapies, maybe we can go back and say how does this all fit together.

 

All right, Dr Grivas, here you go.

 

[00:40:58]

 

Big Changes in the 1L Management of mUC

 

Dr Grivas: Thank you. Thank you. I have my…

 

Dr Ghali: Your own. Okay.

 

Dr Grivas: But you know, that's why we're a team. We complement each other. Great discussion, Fed. Really, really well done. You know, you did a great job in a very rapidly evolving landscape. And talking about rapidly evolving landscape, we similarly have significant rapid changes in metastatic disease.

 

[00:41:16]

 

          Poll 6

 

So we'll start with these polling questions. Approximately what percentage of your patients with newly diagnosed metastatic urothelial carcinoma undergo tumor NGS, next-generation sequencing and HER2 testing? And you see the options, right? So please vote. And thanks for being awake by the way this early morning.

 

Dr Ghali: Yeah.

 

Dr Grivas: We're all excited about ASCO GU.

 

Dr Ghali: This is - this is interesting because I think there are data that patients who are referred to medical oncology are more likely to get genomic testing. I think we in the surgical side don't do…

 

Dr Grivas: Yes.

 

Dr Ghali: Could have room for improvement in terms of early testing for some of these patients that we meet. So.

 

Dr Grivas: Exactly. Yeah. I think it's it's interesting, right, to expand the use. And I think in metastatic disease we need that. We need both genomic and HER2 testing. I don't know if we have the answers ready. Otherwise we can move to the next question. Oh here we go. Okay. So there is a, I would say, variability in practice. Okay.

 

[00:42:19]

 

EAU Guidelines Have Been Updated Regarding the Tx of mUC

 

So a lot of discussion about the rapidly evolving landscape in metastatic disease. And these are the EAU, the European guidelines. And you see that EV/pembro. We just talked about that in the context of localized muscle-invasive bladder cancer. Of course, we have seen data in metastatic disease frontline with EV-302 trial. I'll show you the slides in a second.

 

And EV/pembro has become the standard of care. And as I mentioned, Shilpa, you will have the poster tomorrow looking at the characterization of the responders in that trial. And of course, you know, subsequent therapies depend on multiple factors. You know, you got first-line, do you have access to EV/pembro? There are countries, right, that they do not have access to EV/pembro because of reimbursement issues.

 

So EV/pembro is the right answer, I think for the vast majority of patients, assuming there is access to it. And of course, how do you sequence subsequent line of therapies? You have a question coming up. You know, FGFR3 activating alterations. Do you do erdafitinib? You have HER2 IHC 3+ in the US. You have the option of trastuzumab deruxtecan. And of course, you know, platinum-based chemotherapy is - you know, has been around for - for a long time.

 

So I think subsequent therapies depends on multiple factors, medical comorbidities performance status, organ function, patient preference, familiarity of the providers with the regimen, and so on and so forth.

 

[00:43:38]

 

ESMO 2024 Guideline Updates for the Treatment of mUC

 

And this kind of a similar discussion here. These are the ESMO, the medical oncology guidelines in Europe. The previous was the urology guidelines. And again in metastatic disease frontline EV/pembro is the standard of care preferred regimen, if available. And platinum-based chemotherapy or erdafitinib in selected patients based on biomarker presence, FGFR3 alterations can be considered as second-line.

 

And as I mentioned, trastuzumab deruxtecan is an option in the US for HER2 3+ based on the gastric scoring system. And of course, if you do not have access to pembro/EV, options are GemCis plus nivolumab in cisplatin-eligible patients or the JAVELIN Bladder 100 regimen, Gemcis or GemCarbo followed by maintenance avelumab, again, in countries with no access to EV/pembro. And again, subsequent therapies depend on all those factors we discussed.

 

[00:44:28]

 

JAVELIN Bladder 100: Study Design

 

So we go now back in time. This was back in the COVID-19 pandemic, ASCO 2020. It was a virtual ASCO and we had a plenary session presenting the JAVELIN Bladder 100, trial randomized phase III trial with a kind of a selection factor, right? We took patients with response or stable disease, no progression to GemCis or GemCarbo carboplatin-based chemotherapy. They got 4, 5, or 6 cycles.

 

And these patients were randomized, again, assuming no progression on chemotherapy to avelumab anti-PD-L1 plus best supportive care or best supportive care alone with primary endpoint being overall survival.

 

[00:45:13]

 

JAVELIN Bladder 100: OS and PFS

 

Secondary endpoint was PFS, toxicity and safety. 700 patients, large randomized phase III trial that was actually positive and showed a significant overall survival and progression-free survival benefit with switch maintenance avelumab as immunotherapy that you switch to after you achieve disease control with chemotherapy. And you see the data in this slide, OS on the left, PFS on the right with, I would say, a significant p value and also hazard ratio 0.76 for overall survival. And you see 0.54 for PFS. And this changed the landscape back in 2020 with an FDA approval of available maintenance on June 30th, 2020.

 

[00:45:46]

 

JAVELIN Bladder 100: Additional OS in Patients Receiving 1 or 2 Yr of Avelumab

 

And these are some conditional survival data that I presented at AUA about a year ago. This was, I think, an effort to look at prognostication. We may have a few patients in clinic who actually received avelumab back in the day before the EV/pembro data came out. And the question is, how do these patients do if they're still on avelumab? And of course, there's huge selection bias and guarantee time bias, right?

 

So if you do well and you're surviving and you're not progressing on avelumab already, you know, in your 1 year or 2 years in, you're destined to do well.

 

Dr Ghali: It's a different group really, than the whole cohort.

 

Dr Gupta: Yeah.

 

Dr Grivas: Exactly. It's a very selected group of patients, of course, selection bias there. So you see the numbers again. These are mainly for prognostication for these selected individuals who made it to 1 year in or 2 years on avelumab maintenance therapy.

 

[00:46:39]

 

JAVELIN Bladder 100: Time to Deterioration in FBISI-18 DRS-P Score in Overall Population

 

And this is, I think, relevant to think about quality of life. And we have seen data with quality of life PROs even with EV-302 trial. So this is a specific score looking at quality of life metric and deterioration-free survival. And you see that there was no significant difference. You can argue, you know, the hazard ratio confidence intervals overlap with 1 with a unit. So the point is that avelumab maintenance significantly prolonged overall survival and PFS without detriment to quality of life.

 

[00:47:16]

 

EV-302/KEYNOTE-A39 1L Enfortumab Vedotin + Pembrolizumab vs CT for LA/mUC

 

And that brings us to the KEYNOTE-A39 or EV-302 trial. This was back in 2023, Shilpa I think it was Madrid when we saw the data and we saw this standing ovation because it was the first time that a regimen beat platinum-based chemotherapy in metastatic disease at the time. These are patients with locally advanced, unresectable or metastatic urothelial carcinoma treatment-naive metastatic disease. So this is frontline, EV/pembro. The dose of EV 1.25 mg per kg starting dose, Days 1 and 8 on a 3-week cycle, and pembro given 200 mg IV once every 3 weeks, the classical EV/pembro.

 

The same regimen we showed previously with fairly localized disease, and the control group here is GemCis or GemCarbo. As you see in the control group, there is no maintenance avelumab built in. This trial was, you know, developed before again JAVELIN Bladder 100 reported out and about 30% of patients ended up getting maintenance avelumab and 60% of patients in the control chemotherapy alone group got immunotherapy at some point. And again, this reflects probably real-world data.

 

[00:48:23]

 

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

 

So this trial, it showed impressive results. Overall survival on the left and progression-free survival on the right. And you see a really huge difference. Hazard ratio for overall survival 0.47 favoring EV/pembro. You see a dramatic separation of the curves that remains separate over time. And you see on the right also very impressive PFS benefit. Hazard ratio was 0.45 for PFS. Again, these hazard ratios, you know, below 0.5 and the initial data cut, very impressive.

 

And as I mentioned tomorrow, there's a poster that Shilpa is leading that is looking at the characterization of the patients with response. The response rate in that trial, I want to say it was 68% with EV/pembro and about 44% with chemotherapy. And the - the complete response rate was about 30%. So about a third of the patients had complete response.

 

[00:49:18]

 

EV-302/KEYNOTE-A39: TRAEs

 

A very important slide is about toxicity. And I always discuss with community oncologists who do not treat a lot of patients with this disease. So they are not very familiar with enfortumab, at least in the beginning, a few years ago. Now they're becoming more familiar. And of course, it pays, you know, attention to this slide, you know, to get familiar with these side effects, peripheral sensory neuropathy, more than half of the patients. And it's usually sensory numbness, tingling, you know, sometimes weakness. It's important to do a good history and physical exam in those patients to try to evaluate and grade the neuropathy.

 

Is it impacting daily living, you know, buttoning your shirt or tying shoelaces or in the bathroom, you have to like grab to avoid falling gait changes? All those are very important questions for the patients. Skin pruritus, skin rashes, alopecia, fatigue, loose stool, anorexia and nausea are other side effects to think about with pembro/EV.

 

Hyperglycemia happens about 10% of patients with EV, and half of them can be life-threatening. So extra attention to the glucose in both diabetic and non-diabetic patients. Cytopenias are less common with EV/pembro, I would say, are more common with chemotherapy, but something of course we keep track with CBCs.

 

[00:50:33]

 

EV-302/KEYNOTE-A39: TRAEs of Special Interest With Enfortumab Vedotin

 

And here again some adverse events of special interest. Peripheral neuropathy is usually sensory, but about 10% or so can be motor neuropathy. So extra attention again to - to assess the strength, the hand grip and other measures there.

 

Ocular changes, usually dry eyes that usually gets better with eye lubricants and artificial tears. In many cases, hyperglycemia, we talked about that. Infusion-related reactions are - are rare. Infusion reaction is about 2% and usually low grade.

 

[00:51:04]

 

CheckMate 901: 1L Nivo + Gem/Cis vs Gem/Cis for Unresectable/Metastatic Urothelial Carcinoma

 

So this brings us to the CheckMate 901 trial. This trial was presented at the same session with the EV-302. So it was a positive phase III trial. Otherwise it would have been a huge plus. But you know, in a way it was overshadowed by the EV-302 trial data in the same session at the Madrid 2023 ESMO. So this is GemCis plus nivolumab vs GemCis. Again, the control arm is GemCis alone.

 

No carbo and no maintenance avelumab. About 20% of patients got maintenance avelumab there and about 40% got immunotherapy in the control group at any point in the treatment course in metastatic disease. So this is platinum-eligible patients only.

 

And you see nivo was concurrent with GemCis and then continuation for up to 2 years, assuming no progression and no unacceptable toxicity.

 

[00:51:55]

 

CheckMate 901: OS and PFS (Coprimary Endpoints)

 

Overall survival and PFS were key endpoints and both were met. You see OS on the left, PFS on the right. And what you see there is a significant hazard ratio for OS, 0.78. You see there is a little bit tail of the curve that is higher with GemCis/nivo properly reflecting some immunotherapy responders who may have benefit long term.

 

You see on the right the PFS. The median PFS is about the same, but the curves separate later. And that creates this hazard ratio of 0.72 favoring GemCis/nivo over GemCis. So overall positive trial, but the degree of benefit was less impressive.

 

Dr Gupta: And a lot goes to the maintenance avelumab similarity here. Like how much did the combination add vs the maintenance part?

 

Dr Grivas: Good point by Shilpa. Exactly. And it's hard to tease apart the concurrent vs sequential or both contribution.

 

[00:52:48]

 

CheckMate 901: Response

 

So this is the response rate data, 58% response rate with GemCis/nivo, 43% with GemCis alone. And you see, you know, the complete response rate also was shown in this slide. You see the complete response rate 22% vs 12% higher with the addition of nivolumab. And it makes sense. You had 2 different mechanisms of action, cytotoxic chemotherapy plus checkpoint inhibition. You capture more heterogeneity of the tumor. So higher response rate.

 

And you see on the right, objective responses and complete responses. And you see the median time to response and the median duration of response. What is interesting is that you look at the right lower corner, the median duration of complete response. If you get a CR, the median duration is about 3 years with GemCis/nivo. Of course, you know, many of those patients had lymph node-only disease.

 

And people with lymph node-only disease do better with every regimen, right? EV/pembro this regimen or JAVELIN, those with lymph node-only disease do better compared to those with visceral metastases if you characterize those patients. But interesting data for sure.

 

Dr Ghali: Or get surgery.

 

[00:53:52]

 

CheckMate 901: Safety Summary

 

Dr Grivas: That's a big question. And Dr Ghali actually is leading an important trial at Yale, looking at potential consolidation surgery in patients who had great response to EV/pembro. Is that right?

 

Dr Ghali: That's right. So systemic therapy with EV/pembro and then consolidating with radical surgery of the bladder and any residual metastases, if there is metastasis.

 

Dr Grivas: We're designing a similar trial at our center, looking at radiation as potential consolidation because the role of consolidation is not clear in metastatic disease.

 

Dr Ghali: It's an open question, I think, in this era of responses.

 

Dr Grivas: So the side effect profile here, no surprise, is what you expect with chemotherapy, what you expect with checkpoint inhibition, immune-related adverse events. So no surprises there.

 

[00:54:37]

 

CheckMate 901: Response in Cisplatin-Ineligible Patients

 

And these are some interesting data. Again, if we look at the patients who were cisplatin-ineligible, there was a different cohort in CheckMate 901 trial. Separate - almost a separate trial but it was under the CheckMate 901 umbrella. This is cisplatin-ineligible patients got ipi/nivo vs carbo/gem. And there was a numerical benefit with ipi/nivo. But this did not reach statistical significance.

 

So technically this was a negative trial. So the role of CTLA-4 inhibition is still investigational experimental in urothelial carcinoma based on the data we have so far.

 

[00:55:12]

 

RC48-C016: Disitamab Vedotin + Toripalimab in HER2+ Advanced UC

 

Of course, very interesting data from China. Professor Jun Guo and colleagues look at disitamab vedotin. This is an interesting HER2-targeting antibody drug conjugates plus toripalimab, a checkpoint inhibitor. So a different ADC, antibody drug conjugate plus inhibition combination. DV is targeting HER2, toripalimab checkpoint inhibitor compared to chemotherapy GemCis or GemCarbo. This again is in a front-line setting.

 

PFS and OS were the primary endpoints. And this data set again by design it looks a lot like EV-302 trial, just different drugs and, you know, different target here for the antibody–drug conjugate.

 

[00:55:54]

 

RC48-C016: PFS

 

PFS, significant difference. Disitamab vedotin, anti-HER2 ADC plus checkpoint inhibition toripalimab, significant improvement in PFS. 0.36, the hazard ratio for PFS. The red line is a DV/toripalimab.

 

[00:56:07]

 

RC48-C016: Tumor Response and DoR

 

And also the overall survival data showed significant benefit with DV/tori compared to GemCis or GemCarbo. Usually, the response rate favoring again DV/toripalimab.

 

I think the data to me look very similar to EV-302 trial that the trial was done in China, and this regimen is available there. And there is another trial with DV plus pembro, phase III trial vs chemotherapy that just finished accrual in the rest of the world.

 

Dr Gupta: Yes.

 

[00:56:36]

 

          Case Discussion

 

Dr Grivas: So stay tuned for the DV/pembro vs chemotherapy phase III trial as well. So this case discussion, 68-year-old gentleman, metastatic bladder cancer, frontline, hypertension and controlled type 2 diabetes mellitus. And this population of patients may have comorbidities. And we work with primary care providers endocrinologists to optimize their diabetes control. So ECOG PS 1, creatinine clearance is robust, 90 ml per minute. HER2 is low by IHC gastric scoring and the patient has an activating FGFR3 mutation.

 

[00:57:09]

 

          Posttest 2

 

So we can, you know, think about what do we do in that setting. And - and I think - I think this is, again, a real case scenarios. And I think most of those patients in our clinic would get EV/pembro, I think it's fair to say. But I think the question is, you know, what do you do in practice? You have type 2 diabetes here. Technically, in the EV-302 trial, patients with uncontrolled diabetes mellitus were not included in the EV-302. Of course, in the real-world practice, you know, you have to use your judgement what to do.

 

Dr Gupta: It's the same thing though, you know, even if you're using platinum, they get so much steroids with it. So I think either way things like diabetes need to be controlled.

 

Dr Grivas: I agree. I agree with Shilpa. I think, you know, try to, you know, give the best regimen and then control the - the diabetes.

 

So kind of another question which goes back to your pre-test question. So 68-year-old gentleman, metastatic urothelial carcinoma. No contraindication to platinum-based chemotherapy. This patient has an FGFR3-activating mutation. HER2 is low by IHC. And what do you do based on everything we discussed today? The guidelines, the data sets.

 

1. Do you go with the JAVELIN Bladder 100 regimen from back 2020 data;
2. Do you go with EV/pembro based on the EV-302;
3. Do you go with checkpoint inhibitor alone; or
4. You use erdafitinib.

 

Again, this is front-line setting metastatic disease. Please vote. There's no more coffee left. I think we're out here.

 

Dr Ghali: We got too excited with all these trials.

 

Dr Grivas: All these trials. Exactly.

 

Dr Ghali: And we might be needing to make up a little bit of time here, I think.

 

Dr Grivas: Yes, exactly. So let's try to move here in the next slide and you see – okay, the EV/pembro seems to be the winner. There are few people still thinking about the JAVELIN Bladder 100 regimen. But yeah, I agree. I think if EV/pembro is the way to go. Based on what we discussed, it’s the preferred standard of care regimen based on the NCCN guidelines, the other guidelines, based on the totality of the data, is the best regimen we have so far, EV/pembro. And again optimized comorbidities of course.

 

[00:59:19]

 

          Poll 7

 

Which of the following question would you most like experts to discuss? So for the audience, you would like us to discuss:

 

1. How we assess eligibility for EV/pembro in clinical practice;
2. How do we do patient selection or therapy selection after prior adjuvant immunotherapy, which is very interesting question about the adjuvant immunotherapy or perioperative immunotherapy; What about rechallenge, if the patient of immunotherapy, if a patient gets metastatic disease later on. Hopefully we cure more patients localized disease and we see less metastatic. But if the patient has a recurrence, what do you do;
3. How about biomarker testing for treatment planning; and
4. How do you balance guideline recommendations with real-world patient factors, medical comorbidities, performance status.

 

And here you see that the spectrum of answers spread across the different options.

 

Dr Ghali: They're all good questions.

 

Dr Grivas: All good questions.

 

Dr Ghali: Audience notes.

 

Dr Grivas: Exactly. And I think that brings us to Dr Gupta, I think. Yes.

 

[01:00:15]

 

Sequencing in the Second Line and Beyond

 

Dr Gupta: Thank you, Petros. Do you want to see if there's anything the…

 

Dr Grivas: Yeah. Let's see in the tablet here. Nothing. I don't see any questions. I think everything seems to be clear.

 

Dr Gupta: Yeah. We really evolved well from the MIBC to the front-line metastatic setting. And let's talk about the sequencing in second-line and beyond, and I'll try to make up some of the time.

 

[01:00:37]

 

Guidelines Have Been Updated Regarding the Treatment of mUC—Current NCCN Guidelines (Version 3.2025)

 

So these are the current NCCN guidelines. As we know, regardless of cisplatin eligibility in the front-line, the preferred standard of care is EV/pembro, like Petros you just showed. And alternative regimens are GemCis/nivolumab for cisplatin-eligible patients. But they're not the preferred frontline or platinums followed by avelumab.

 

And in second-line, there's, you know, all these chemotherapy options or FGFR-directed inhibitor. And also we have the HER2-directed ADC, like you mentioned.

 

[01:01:10]

 

THOR Cohort 1: Erdafitinib vs Investigator’s Choice Chemotherapy in FGFR3-Altered mUC

 

So just talking about the only targeted therapy that we have approved in urothelial cancer, that's the FGFR inhibitor, erdafitinib. This was the pivotal trial, THOR trial in which in the salvage setting post-immunotherapy, 1-2 lines of prior therapy is allowed. So they could have had chemotherapy as well. Patients were randomized to erdafitinib or investigator's choice of chemotherapy which is docetaxel in the US, vinflunine in Europe.

 

[01:01:43]

 

THOR Cohort 1: OS

 

And primary endpoint was overall survival which was statistically significantly better with erdafitinib. Now, just as a point, you know, Petros we participated in trials. In the real-world, the prevalence is much lower than what we may think, you know. So a lot of patients need to be tested, so you have to go look for FGFR alterations if you really want to have this option for your patients.

 

[01:02:06]

 

THOR Cohort 2: Erdafitinib vs Pembrolizumab in FGFR3-Altered mUC

 

And then there was the THOR cohort 2, where a very important question was answered where whether patients who have advanced disease and have had 1 prior treatment, but they are immunotherapy-naive. Should you give pembrolizumab first or erdafitinib first? Because we know post-platinum pembrolizumab was the level one evidence for standard of care.

 

And a lot of people always—you know, we know Arlene[?] talks about the luminal subtype. And maybe they are resistant to immunotherapy. But this question is actually answered with this. So this is more of a sequencing question.

 

[01:02:45]

 

THOR Cohort 2: OS and PFS

 

And this showed, as you can see that, giving pembrolizumab was not better than giving erdafitinib. So it was a negative trial in that setting. So actually pembrolizumab - sorry, giving erdafitinib was not better than giving pembrolizumab first. And so that tells us that after chemotherapy, even if patients are - they have this alteration, you should give them immunotherapy, then erdafitinib. Although there were some numerically different responses with erdafitinib.

 

[01:03:14]

 

EV-301: Enfortumab Vedotin vs Chemotherapy in Previously Treated Advanced UC

 

And again EV-301 was—this is again not applicable in today's setting unless patient is getting chemotherapy first and then immunotherapy. This was the pivotal EV-301 study, which said EV monotherapy as the standard of care for patients who progressed on chemo and immunotherapy. So this was again compared to standard of care salvage chemo, could be docetaxel, paclitaxel or vinflunine.

 

[01:03:43]

 

EV-301: OS and PFS

 

And as we can see we saw some really impressive overall survival difference. Almost 4-month improvement and PFS improvement.

 

[01:03:52]

 

EV-301: Safety

 

And safety already went over, Petros. The key things to look for are rash, neuropathy, hyperglycemia. And really, we're getting better with this as time goes.

 

[01:04:05]

 

TROPiCS-04: Study Design

 

And TROPiCS-04. Petros, and you've been involved in this study. This was the phase III study, which, based on the initial TROPHY cohorts, which set the single-agent sacituzumab govitecan, which is an antibody drug conjugate against TROP2, and it has SN-38 as the active payload. It got accelerated approval by the FDA based on activity seen in single-arm study. But unfortunately in the phase III study, TROPiCS-04 compared to salvage chemotherapy, it was a negative study.

 

[01:04:41]

 

TROPiCS-04: OS

 

And not only that, there were more toxic deaths from toxicities like neutropenic fever and diarrhea.

 

[01:04:47]

 

TROPiCS-04: Conclusions

 

So even though we know this drug is active in urothelial cancer, this phase III study being negative. This was withdrawn from the US markets, but it is still an option if somebody wanted to use it. But of course when you have a phase III trial showing a negative data, I think very few people use it.

 

[01:05:07]

 

EA8231: Pembrolizumab + Sacituzumab Govitecan vs SoC in Advanced UC

 

And through ECOG, Petros, you and Jeannie[?] are leading to answer this combination study with pembrolizumab in advanced setting. So good luck with this study.

 

Dr Grivas: Thank you. This is with - to your point Shilpa with Dr Monika Joshi.

 

Dr Gupta: Oh, yeah, Dr Joshi. I’m sorry.

 

Dr Grivas: We're doing the checkpoint inhibitor rechallenge question with saci/pembro vs platinum, gemcitabine or taxane depending on prior therapy. So yeah, thanks for highlighting.

 

Dr Gupta: These are, yeah, important studies.

 

[01:05:36]

 

Efficacy and Safety of T-DXd in HER2-Expressing Tumors (DESTINY-PanTumor02)

 

Now this is a basket study called the DESTINY-PanTumor study, where patients who have HER2 expression based on the gastric cancer scoring, IHC 3+ or 2+ were treated with T-DXd, which we know is a revolutionary drug and has really revolutionized how breast cancer patients are treated.

 

And in this, there were not a whole lot of patients, but many patients with bladder cancer, too, who were treated with this and it showed efficacy. And this is approved as a tumor-agnostic approval for our patients.

 

[01:06:10]

 

DESTINY-PanTumor02: Efficacy of T-DXd

 

This is the data, you can see here. The bladder cancer patients, 41 patients. Response rates were around 39%. Very few complete responses. And that's what we see in the real-world as well. And disease control rate is about 70% at 3 months now. Long-term durability is, you know, a challenge with this monotherapy. But this is an added option for our patients, which means unless we check for the HER2 status by the gastric scoring, we won't be able to offer this. So it's important to make that note to start testing our patients in the metastatic setting.

 

[01:06:50]

 

DESTINY-PanTumor02 in HER2-Expressing Solid Tumors: T-DXd Responses Across Tumor Types

 

And this is across tumor types. We don't need to go over this. But the key point is that it's an important option. And some of the side effects we need to manage like interstitial lung disease and be cognizant to that.

 

[01:07:03]

 

          Treatment Sequencing in mUC

 

And this is how we are using treatment sequencing right now but this can change any minute. You know, so try for EV/pembro whenever the patient can get it. And in my practice, actually over 90% patients can get it. Very, very few patients can't get EV/pembro, but they then can't get even GemCarbo. So that's the only patient you give monotherapy with pembrolizumab. I would say only 5% or so. If patients progress - you can use platinum or you can use erdafitinib.

 

And again, it depends on a patient's toxicities from prior therapy. But the bottom line is patients should get the opportunity to be exposed to all the available drugs in their journey, so there's no right or wrong answer. Whether if somebody has FGFR2, 3 alterations, should you use erdafitinib first or platinum first. But a lot of people are using platinum, but you may use erdafitinib as well.

 

And if you've used platinum and immunotherapy instead of EV/pembro first, then EV monotherapy is an option, of course, and truly platinum or EV ineligible patients are the ones who will give monotherapy with pembro.

 

Dr Grivas: It's interesting because in the initial approval, Shilpa, to your point, the accelerated approval by FDA was FGFR2 and FGFR3. In the revised approval, the FDA approval of regular approval is also only FGFR3.

 

Dr Gupta: Only FGFR3, right.

 

Dr Grivas: Because FGFR2 is very rare.

 

Dr Gupta: Very rare. Yeah, yeah. So I should revise that.

 

[01:08:29]

 

          Case Discussion Continued

 

So let's do the case discussion continue at 68-year-old man with newly diagnosed metastatic bladder cancer, well-controlled diabetes, hypertension, treatment naïve. Gets EV/pembro, has response for about 18 months and then progresses with new metastases to lung, liver and bone. Performance status is still pretty good. Creatinine clearance is excellent at 90. HER2 has been tested, but it is low, IHC 1. And there is the FGFR3 mutation here in S249C.

 

[01:09:07]

 

          Posttest 3

 

So let's revisit this question. What would you use for this patient?

 

1. Would you give another checkpoint inhibitor;
2. Would you give a dose-dense MVAC;
3. Erdafitinib;
4. GemCarbo or docetaxel or paclitaxel; or
5. T-DXd.

 

Reminder, it was 1+, not 3+. So please answer this question.

 

Dr Grivas: It's an interesting real-world question, right?

 

Dr Gupta: Yeah. I don't know if a lot of people are still using dose-dense MVAC in the - you know.

 

Dr Grivas: Especially, second-line metastatic disease. Yeah. And also the other question is with enfortumab 18 months, what about neuropathy?

 

Dr Gupta: Yeah. It said patient didn't have it but. So let's see what the—so it's a good mix of responses, you know, between erdafitinib and GemCarbo. I think it's a pretty equal mix just like we were discussing, Petros. Like what do you do first? It doesn't matter as long as you offer the patient the treatment. But again, you know, T-DXd, you do need 3+, although there was not much difference between 2+ and 3+, but for 1+, there was not much activity.

 

Dr Grivas: And to your point, Shilpa, you know, there's a huge debate. You know, erdafitinib is still the right answer for - for many patients.

 

Dr Gupta: Yes.

 

Dr Grivas: And there is no right answer. There's no defined prospectively standard second-line therapy in this setting.

 

Dr Gupta: Yeah.

 

Dr Grivas: You know, many people may use platinum gemcitabine. You know, GemCis could be an option if the patient is still fit for cisplatin. If neuropathy doesn't get in the way, or you know, if the patient can get cisplatin and do you do GemCis or GemCarbo of erdafitinib? The jury is still out there.

 

Dr Gupta: Right. And there is now trials actually addressing this unmet need like the bispecific antibody trials vs platinums, which is the IZABRIGHT trial.

 

Dr Grivas: Exactly. Interesting trial. Yeah. But again, it goes back to your point. This informed consent discussion with the patient toxicity profile, you know, oral vs IV. Multiple, you know, factors play a role into deciding the second-line therapy in this case.

 

Dr Gupta: And now, you know, the most important thing we may have all these therapies available. We really need to be able to manage adverse events, especially in the community where, you know, the community doctors are such brilliant folks. They're treating like multiple cancer types, which I cannot do. But there's also a lot of common drugs. But drugs like enfortumab, you're only using for bladder or for erdafitinib. So it's really challenging to remember everything about everything.

 

[01:11:45]

 

Managing AEs of Special Interest With New Standards of Care

 

Enfortumab Vedotin + Pembrolizumab: AEs of Special Interest

 

So I think this is more of a panel discussion and how do we see this? We discussed EV/pembro. The most common toxicities are neuropathy and rash. So, you know, we have to be very vigilant. And in my practice, I do guide my trainees as well as the nurse practitioners every time we have to do a skin check. And like you said, Petros, doing a grip test is very easy. I make the patient walk to see if there's any motor neuropathy, ask the caregivers because patients underreport their symptoms a lot.

 

So I think keeping in mind that unless you ask, you won't know. And the other thing, like we showed at ASCO last year, that it's okay to stop the drug, to discontinue, to dose reduce because patients still derive benefit. So no need to keep pushing through toxicities.

 

Anything to add, Fed?

 

Dr Ghali: Yeah. Just 1 small note. I think we're all still learning how to manage these patients with - with the movement up of enfortumab vedotin and pembrolizumab earlier. The - the trial did not show a lot of patients who were not candidates for surgery as a result of EVP exposure. So that's reassuring for us that we would still be able to get these patients to cystectomy if they receive EVP neoadjuvantly. But I do worry sometimes about the condition of the patient, their candidacy for different urinary diversions. If they develop neuropathy, for example, can they still get neobladders, that sort of thing.

 

And so the concern for overtreatment, I think we're still learning how to parse all that stuff out, but it is reassuring that most of them, almost all of them still make it to surgery.

 

Dr Gupta: Yeah, actually, all of that was the good thing because I think with 3 cycles, one can still, you know, patient is not there. But I think what happens in these patients and that was some of our patients experience that, you know, they have those 3 cycles, they do well, have this big surgery. They do well. And then within 30 days you know, they had to start this adjuvant therapy. And that's when some of the patients just are not in a state to get it.

 

And to your point, Petros, maybe those one third of patients were—it was just too much for them post-op. So I think that's really important that because, you know, you know that cystectomy is a life-altering surgery after a regimen which can have these toxicities.

 

Dr Grivas: Right?

 

Dr Gupta: Anything to add?

 

Dr Grivas: Agree. I think great point, Shilpa. I agree with you that it's interesting to see more data sets, you know, within the context of EV-303 and EV-304 trials. As you said, Fed, you know, the proportion of patients who underwent radical surgery was similar. So that was reassuring that EV/pembro did not compromise the ability of patients to get surgery. But then, you know, what happens adjuvantly recovery time. Why about a third of patients did not get to adjuvant therapy. How can we help refine this adjuvant therapy contribution? And who gets adjuvant therapy?

 

Dr Gupta: And also, you know, like most adjuvant trials have that generous window of 12 weeks. In this, it was 4 weeks. So I don't know if that also contributed. Right? Four weeks. Do you think most patients are up and running around at 4 weeks?

 

Dr Ghali: It’s quite tight.

 

Dr Gupta: Tight, right. Yeah.

 

Dr Grivas: It seems very tight. I agree with you, Shilpa. Yeah, that - if that was the case, that could explain the significant drop off because you get out of the window very quickly. That's right.

 

[01:15:13]

 

Monitoring and Managing EVP-Emergent Skin Toxicities

 

Dr Gupta: Yeah, yeah. So I think, you know this we discussed. But at any appearance of a rash, if it's just a grade 1 minor rash, topical corticosteroids, monitoring it on EV/pembro, of course. If grade 2, we really need to make sure we are not treating and this could be from EV or pembro, but typically we attribute it to EV first and holding EV if it doesn't get better. We also want to attribute to pembro and then starting systemic steroids.

 

And Petros, I know you have a multi-D clinic at your place and so do we. And we have access to all the specialty sites. So referral to dermatologists. I'm sure that's how it's at your place too, Fed.

 

Dr Grivas: Very important point, Shilpa. To your point, I think multidisciplinary care dermatology early on. And there are some tips that may help you tease apart, if you have like under the armpits or, you know, in the flexor surface of the elbows or behind the knees. And it happens early on in the first week or so. It's usually in enfortu[?] to your point, but sometimes it's hard to tell. Sometimes rarely we do biopsies and now maybe even more commonly do biopsies to learn if EV vs pembro. But I think getting, you know, dermatology on board can help sometimes.

 

Dr Gupta: And I think to your point, Petros, about the underarm and the flexor area, those are the hyperpigmentation which we don't worry about in terms of severity that it would not lead to the—but it is actually cosmetically a lot of patients are very bothered by it, although that one is medically not so scary. But when you see the rash, especially if they get the Stevens-Johnson or toxic epidermal necrolysis, that really can be fatal. In the early studies there were some toxic deaths.

 

Dr Grivas: For sure.

 

[01:16:54]

 

Monitoring and Managing EVP-Emergent Hyperglycemia

 

Dr Gupta: So hyperglycemia. You know, it's an easy fix. The easiest way to test this is every time patients are getting a metabolic panel. So if the glucose is above 250, you can't give EV, but it's a fix. You can easily give treatment with insulin and then treat eventually. So unless you want to add anything.

 

And in my experience, it's not the - the well-controlled diabetic that gets into trouble. It's actually, you know, patients who are not diabetic at baseline can get catastrophic diabetes or DKA. So we need to be really vigilant.

 

Dr Grivas: Exactly. There's very few patients who get into this metabolic derangement, and we don't know why. And this end up in the ICU. And, you know, based on the - on the published data. But these are very few patients that we have seen reported in trials with enfortumab vedotin. But many patients, as you said, can be controlled with.

 

Dr Gupta: And even, you know, immunotherapy like pembrolizumab can cause this. And I know our colleagues are always managing diabetes referring to endocrinology and continuing immunotherapy, if that's.

 

[01:18:00]

 

Monitoring and Managing EVP-Emergent Peripheral Neuropathy

 

So peripheral neuropathy really, you know, we want to highlight here that there's no reason why it should get to grade 3. You know, grade 2 is, you know, any time a patient has trouble buttoning their shirt or holding on to a cup or not feeling the ground, that's the time we have to hold EV. So we cannot really continue it, wait for it to be grade 3. That's debilitating almost significantly.

 

So I think grade 2 is where we intervene. Hold EV till it gets better to grade 1 or lower. And in my experience, Petros, we've been able to keep patients off EV, and still they continue their response. And that's what the data showed last year at ESMO, which is also in the Annals of Oncology.

 

[01:18:45]

 

Management of FGFR Inhibitor AEs

 

Dr Grivas: You know, it's very interesting. Every patient gets their own kind of fine tune, you know, dosing that depends on toxicity and adjustment of dose as needed kind of thing.

 

Dr Gupta: Do you want to tackle the FGFR inhibitor?

 

Dr Grivas: Sure, sure, sure, we can. Thanks, Shilpa. You're doing a great job. So I'll try to go quickly here. FGFR inhibition. You know, very important target in metastatic urothelial carcinoma. We show the data with erdafitinib. As Shilpa mentioned, toxicity can be an issue. It's very important for those patients to see an ophthalmologist or optometrist upfront before starting treatment to look at the eye, cornea, retina, dilated eye exam, optical CT to have a good baseline and then being seen monthly thereafter for the first 4 months, and then every 3 months thereafter, assuming there is no ocular changes.

 

Dr Gupta: And, you know, I mean, this is a regimen which I worry about when my patients are on this drug, because this is not a regimen where you can just prescribe it and then do phone like they have serious toxicities.

 

Dr Grivas: Exactly.

 

Dr Gupta: Very close monitoring.

 

Dr Grivas: Very close monitoring. They have to come in in clinic for physical exam. Some people may not report timely or accurately. You have to examine them. Hand-foot syndrome, nail changes, eye changes, phosphorus level. You have to do the phosphorus check because hypophosphatemia can happen and then may also have some dosing implications. You do labs 2-3 weeks after starting the treatment. You may potentially dose adjust from 8 mg once a day to 9 mg once a day if there is no significant toxicity, no grade 2 or higher toxicity, no eye toxicity and depending on the phosphorous level.

 

Dr Gupta: I have never seen a patient like that, but I'm sure there are some. And I want to add that the central serous retinopathy is a serious toxicity, unlike EV, which is superficial, corneal and patients had retinal detachment also. So have to be very cautious.

 

Dr Grivas: For sure and totally agree. Close collaboration with ophthalmology and nutritionists also for the diet.

 

Dr Gupta: And you know, I wonder, Petros, that brings the question of how many resources are there in the community setting. Do they have access to ophthalmologists? I mean, it's hard to get a skin - I mean, for myself, I could not get a dermatologist appointment for like months. So I think.

 

Dr Grivas: For screening. Yeah, it's a real question, Shilpa. I agree with you. You know, you need that access. And it's important to have that dialogue with the patient. It plays a role in the decision-making as well.

 

[01:21:08]

 

Erdafitinib: Cutaneous Toxicities

 

So these are just examples, you know, nail toxicities, onycholysis. It’s a Greek word, Fed. You know, it—onycholysis means kind of destructions of the nail bed.

 

Dr Gupta: I didn't know that.

 

Dr Grivas: Or paronychia as you see it on some pictures there. And they're all Greek syndrome. They're all Greek words.

 

Dr Gupta: All the words are Greek words. Yes. But this is like a very disabling. It's not just cosmetically, but it's a painful side effect for patients. And it's very important to be on top of things.

 

Dr Grivas: Totally agree. You know, nurses on the phone with the patient, physical exam history very important to maintain, you know, the optimal control and try to prevent and manage as possible.

 

[01:21:48]

 

Central Serous Retinopathy

 

Shilpa mentioned the central serous retinopathy, CSR. It can be scary because it creates some visual changes. We always give the patient this Amsler grid. So every morning they can look at the Amsler grid, is agreed with the vertical lines and horizontal lines with a black dot. And they look for blurry vision. It's a self-vision screening that they can do at home.

 

So median time to retinopathy is usually a month and a half. We talk about the Amsler grid. And usually if you stop the drug, it goes away. But it requires, again, very close attention. And an ophthalmologist or optometrist follow-up. And good close monitoring. And you see the details about the severity presentation and management in the slide.

 

[01:22:32]

 

DESTINY-PanTumor02: Safety Summary

 

And some other discussions here. This is the DESTINY-PanTumor02 trial. This is trastuzumab deruxtecan. I would say cytopenias, Shilpa, are common with this drug. Growth factor support, I tend to use it because these patients have multiple prior therapies. Sometimes nausea can be an issue. You see that these are the most common side effects. So anti-nausea medications, fatigue. Diarrhea in a quarter of the patients or so, and anorexia, taste changes. Alopecia is a lower proportion of patients.

 

ILD pneumonitis again is - is not common but it can happen. So extra attention to pneumonitis, extra attention to any lung symptoms. And the CT of the chest is very important. And there have been actually - including breast cancer literature, a lot of discussion about pneumonitis with trastuzumab deruxtecan and other similar antibody drug conjugates.

 

[01:23:25]

 

Managing ILD/Pneumonitis With T-DXd

 

And this is a slide talking about the potential, you know, risks there. If you suspect this is a lung disease, ILD, interrupt the drug. Again, look at the CT. Talk to pulmonology. It's very important again to evaluate people very closely. High-resolution CT. Make sure there's no infection, of course. In some cases, you may get bronchoscopy BAL, pulse ox ambulatory PFTs, blood gas. If all those things, if needed.

 

[01:23:55]

 

          Posttest 4

 

So going back to Shilpa to this question and Fed in patients who get EV/pembro, we talk about a series of side effects. I would probably rephrase the question. I would say which of them should be highlighted even further? And I will let the audience here vote.

 

1. Nail toxicities and alopecia;
2. Skin reactions, neuropathy;
3. ILD, hypophosphatemia;
4. Dry eyes, and hyperglycemia.

 

What do you think is the most common, I would say the most concerning? I don't know if people can vote quickly here since we're approaching the end. Got some music.

 

Dr Gupta: I think we did good with time.

 

Dr Grivas: I think we did very well. We have a couple of quick questions here that we can try to cover if we have like a minute at the end. Let's see. There you go. Okay.

 

[01:24:51]

 

          Posttest 4: Rationale

 

So, you know, I think as Shilpa mentioned before, skin reactions and peripheral neuropathy are probably the highlights of - of - of this. Of course other things can happen, right. You know, alopecia can happen. Dry eyes can happen. Hyperglycemia, high glucose can happen. Or if your significant anorexia and taste changes, you may not eat well and you develop hypoglycemia. But this is less common I would say.

 

[01:25:12]

 

          Poll 8

 

And again which topics of discussion would you like to see in the future - future meetings?

 

1. What are the key treatment-related adverse events that define safety profiles of new regimens;
2. How common are those adverse events and treatment discontinuations and dose adjustments;
3. What multidisciplinary strategies are recommended for AE management best supportive care in order to have adherence with treatment management; and
4. How do you leverage safety efficacy profiles in your treatment decisions.

 

So all of them are great questions.

 

Dr Ghali: Yeah.

 

Dr Grivas: Yeah. And I think, Fed, you have 2 questions for us. I can see that.

 

[01:25:45]

 

Q&A

 

Dr Ghali: Yeah. Maybe while people are reviewing this and answering we can try to answer 1 of these. So 1 question was if a patient is HER2 IHC 3+. So this patient is expressing significant amounts of HER2 in their tumor and has an FGFR3 alteration after enfortumab vedotin in platinum, how do you decide between the 2? So - so it's really - it's subsequent.

 

Dr Gupta: Yeah. And I think again a big - you know, it's good to have multiple options so that patient can have those options, I think. My personal preference would be to use the T-DXd first and then reserve the erdafitinib for later. But you - you could do either way. Yeah.

 

Dr Ghali: Really thinking of it as having multiple options rather than what the correct next one is.

 

Dr Gupta: Right. Yeah.

 

Dr Ghali: And favoring giving the, the option with better data earlier.

 

Dr Gupta: Correct.

 

Dr Grivas: And that's, Shilpa said, you know, that's again a data gap because we do not know the optimal sequencing. And I think it's fair to discuss with the patient or options toxicity profile. Again, you have access to ophthalmology or optometry or nutritionist. And do you prefer oral vs IV. Patients like the oral option. Medical comorbidities come to play. You know, familiarity with the regimen. I don't think there's a right answer.

 

Dr Ghali: The art of medicine a little bit.

 

Dr Grivas: Exactly. And someone can argue, you know, T-DXd has higher response rate, but it was a small number of phase II.

 

Dr Gupta: Yeah. It's not a phase III study, but you know, we do have newer FGFR3 inhibitors on the horizon which don't have these classic toxicities. So I think that'll be a welcome break for our patients.

 

Dr Grivas: Down the road. Yeah. Phase III vs phase II data. All these factors play a role.

 

Dr Ghali: Yeah, yeah.

 

Dr Grivas: And I want to say, Shilpa tell me if you agree. It's not very common to have both EGFR mutation and HER2 IHC 3+. It happens. But you know, it's not...

 

Dr Gupta: That would be an ideal patient. I wish we get to see more of those.

 

Dr Grivas: To have options.

 

Dr Gupta: And in my experience, Petros, I mean, if somebody is HER2 2+, right, it's at the end of the day it's a pathologist looking at the things and patient has no other options. We did see activity. So I think it's reasonable to even consider. Would love to hear your thoughts.

 

Dr Grivas: I think, yeah, Shilpa, you make a good point. I think it's reasonable to try, especially in the absence of other options.

 

Dr Gupta: Right.

 

Dr Grivas: You know, in that case, I may probably do erdafitinib first and then if I have it HER2 2+. But then the question is, you know, what do you do in the 2+? And I think it's reasonable in the - if you exhaust other options, if you can get reimbursement from insurance companies, of course.

 

A very quick comment here is, there was a question about which patients would you not treat with EVP? It will be a very small proportion of patients, Shilpa, right? I think very, very small proportion like that very, very frail patient who is not frail because of cancer but just has all these comorbidities chronically. But that is the patient also would meet our platinum-ineligible criteria like grade 3 neuropathy, super frail. That's the patient you will give a single-agent pembro.

 

And as you know, Petros, we let that study for such frail patients who could not get platinum. And then, you know, with the TIGIT and the immunotherapy and it - it got - the study stopped because of the program not stopping, but we are working on getting the data out. So yeah, there’s…

 

Dr Ghali: What - what about for patients with other autoimmune comorbidities, maybe, or patients with severe Crohn's or ulcerative colitis? Are those patients you consider maybe avoiding that starting with platinum and maybe avoiding the checkpoint inhibitor?

 

Dr Gupta: I think if for those patients. Yeah, that's a good point, you know. But nowadays, I think we are getting more and more bold with patients with autoimmune diseases like our rheumatologist really says, just go ahead and treat and then.

 

Dr Ghali: We'll deal With it.

 

Dr Gupta: We'll deal with it, you know. So I think we are treating patients with those classic contraindications we would be very scared to 10 years ago.

 

Dr Grivas: And it depends to your point. It depends on what autoimmune condition you talk about. You know, it's in - you know, rheumatoid arthritis, well controlled or, you know, eczema well controlled or psoriasis well controlled vs, you know, myasthenia gravis or multiple sclerosis are different - different spectrums. So it depends on what is the autoimmune condition, the severity, etc., management, etc..

 

Dr Gupta: And for multiple sclerosis, actually, you know, I had a couple of patients were already on treatment and we wanted to offer immunotherapy, and the neurologist was completely okay with it because the drugs they are using are targeting B cells, so they don't see any issues with immunotherapy. So that was interesting to learn for me.

 

Dr Grivas: Oh, interesting. Wow. We need definitely more data in this population of patients. And I think it was a trial - I tried to remember it was with Dr Cora Sternberg, the SAUL trial that looks atezolizumab in special populations. We need more of those trials in specific populations to answer those questions.