Introduction

DR PAL: It seems like it’s a packed house tonight to hear about bladder cancer. This is hopefully going to be a wonderful event. I really want to say thank you to Research To Practice for hosting us today, and we have a really terrific panel. Shilpa Gupta from the Cleveland Clinic is with us, Guru Sonpavde, who’s at Harvard is here as well, Dan Petrylak from Yale, and myself will be leading you on a journey through various aspects of bladder cancer management.

I want to thank our sponsors for this program. I also want to thank the planning committee of Research To Practice. You can find our disclosure information associated with the program.

Just a couple of quick housekeeping notes here. There are iPads, as you can see, right in front of you there. If you’re in the room virtually there’s going to be options we’ll review in just as second as well. You can review all the program slides, and so if we’re not able to get to a slide or 2, just as a safety net you’ll have those at your avail. In addition to that, we’ll pepper this with some survey questions. You’ll complete a premeeting survey, hopefully before this, and we’ll actually present survey results as we go through the meeting. And do feel free, and I’d love to make this super interactive if we have time, to ask questions through those iPads, as well, if that’s a possibility. And at the end of this if you can complete your evaluation, at the very bottom an option will pop up for you on your iPads.

If you’re joining remotely via Zoom, just bear in mind that you have an opportunity to review program slides as well, back and forth on your monitor at home. We’ll also raise some survey questions along the way, and certainly there are opportunities for you to ask questions as well.

Now keep in mind this is an enduring program, so everything that you’re seeing today is going to be video recorded, audio recorded, and all of these, including PowerPoints, are going to be available to you at the Research To Practice website. So do feel free to use that as a little bit of a safety net as well.

Integrating Novel Agents into the Treatment Paradigm for Nonmetastatic Urothelial Bladder Cancer (UBC) — Sumanta Kumar Pal, MD

DR PAL: So we’re going to get right into it. We have a packed agenda. I think our onus is to finish right by 8 am on the nose, so I’m going to dive right into the program here. 8 am. Did I say 8 am? 8 am on the nose, that’s right. 8 am. So we’re going to jump into first integrating novel agents in nonmetastatic urothelial cancer, then Shilpa’s going to walk you through front-line management, then Dan’s going to take over with relapsed and refractory disease, and then we’ll have a discussion around toxicities and practical considerations with Guru in the fourth module.

As we go through this we’re going to have a lot of discussion that really centers on a survey that’s been distributed to some bladder cancer experts. You can see them listed here on this slide. Their responses are going to be reflected in some of the survey data that I go over, so you’ll see how they’ve responded. I’ll ask Dan, Shilpa, and Guru for some comments on how they’ve responded individually, and hopefully we’ll be able to talk through some very relevant clinical scenarios.

So with that we’re going to go ahead and start the timer here. We’re going to play a little game tonight. We’re going to try to see who amongst the 4 of us can come closest to the 10 minutes that’s been allotted for our talks, and there will be a fantastic prize for 1 of you at the end. So let’s jump right in.

So again, the task today is to discuss the integration of therapies into nonmetastatic urothelial bladder cancer. And I used to tell my fellows that, frankly speaking, there wasn’t a big role for us as medical oncologists in the nonmuscle-invasive disease space, that was really the urologists’ domain. And of course that’s really flipping on its head. The paradigm’s really changing.

This is from The Lancet Oncology. Arjun Balar published the KEYNOTE-057 trial. This was a study that looked at the nonmuscle-invasive population unresponsive to BCG therapy. I have some of the notes here on the publication below. You can see that this study enrolled 334 patients in total, 101 eligible patients were ultimately analyzed. What you can see here is that the complete response rate, the primary endpoint of this trial, was 41%. So this agent is approved as being used in the clinic.

I think what everybody has been looking for is some component of randomized data in this setting, and to that end I wanted to quickly highlight some of the ongoing randomized experiences. Now just bear in mind, this is in a different context, this is in the context of BCG-naïve disease. But this particular trial, known as the ALBAN trial, is taking patients and randomizing them to receive BCG therapy with induction followed by maintenance either alone or with atezolizumab.

There’s the study called the POTOMAC trial. Really creative names here. Again, this takes patients with high-risk disease, and this also evaluates patients in the BGG-naïve setting. This actually cased patients to receive durva in combination with BCG in both induction and maintenance phases. As you can see in the first option there. In the second arm of the randomization it’s durva plus BCG with induction only. And finally BCG with induction and maintenance.

And this is the KEYNOTE-676 study. Again, slightly different context here. This is for persistent or recurrent nonmuscle-invasive bladder cancer that’s high grade after adequate BCG induction. Ashish Kamat presented this trials in progress and has a nice publication associated with it in KEYNOTE-676. This trial actually looked at patients and randomized them to either BCG monotherapy or BCG plus pembrolizumab.

So a lot of movement in this space. Some randomized data that we hope will emerge in the coming years.

But let’s shift to a domain that has historically been in the wheelhouse of medical oncologists, and that’s muscle-invasive disease. So this is the so-called CheckMate 274 trial, and this takes patients who had either T3 disease and up from the get-go or had neoadjuvant chemotherapy and had T2 disease and up. So you see that reflected in the eligibility, and that’s going to be fairly consistent across some of the other studies that we look at, so just bear that in mind. These individuals, following the time of surgery, would get randomized to nivolumab for a year or placebo for a year.

And I really wanted to highlight some of the elements of this trial. So in the bottom right you can focus your attention on that PD-L1-positive population. So as you see in the table, highlighted at the very bottom, this reflects about 40% of the patients included in this study. And my suggestion is that that’s really where we’re seeing the benefit. The hazard ratio for disease-free survival in that subset was 0.55. Put them together in the intention-to-treat population and the hazard ratio increases to 0.7.

I’ll also point out here there’s some interesting subsets that we should probably focus on. So if you look to the study population, again on the table on the left, I’ve highlighted the fact that about 20% of patients in total either had renal pelvic disease or ureteral disease. And that upper tract population, I think, is quite unique. If you focus your attention on this forest plot here, again, I’m drawing your attention specifically to the subset of patients with upper tract disease, you can see that they don’t seem to fair quite as well with nivolumab in this context.

So a couple of ideas on this. Upper tract disease is something that’s heavily enriched for FGFR3 mutations. So when you look at FGFR3 mutations it’s now a targetable entity in advanced bladder cancer. We have erdafitinib, which we’ll discuss in the context of Dan’s talk and Shilpa’s talk. But infigratinib is another agent in this space. We published this paper in Cancer Discovery a couple years ago; 25% response rate.

And what’s quite striking is that if you focus on the population of patients with upper tract disease you see particularly good outcomes there. So again, I think this lends itself to the biology of upper tract disease. 100% disease control rate here. You see response rate of 50%.

And this really led me, and Siamak Daneshmand, and Shilpa, and Guru, and a handful of others to design this trial, which is the PROOF 302 clinical trial. So this is an adjuvant trial. The focus here is on patients who are FGFR3 altered, so inherently that implies that we really are thinking of capturing an upper tract population. They’re randomized to infigratinib or placebo. This is a trial that really definitely needs help with accrual, so if you’re able to consider this trial for your patients, certainly do so.

I wanted to highlight another reason that we might have pause in terms of CheckMate 274. A) We haven’t seen the overall survival data as yet. B) There’s some competing data sets out there that actually have a very different result.

So this is the IMvigor010 study. This is a randomized trial. Very similar eligibility to CheckMate 274. This study randomizes patients to atezolizumab or observation. And what we saw was completely different in this context. So in IMvigor010 we didn’t see that disease-free survival benefit as we did in CheckMate 274. And we have the OS data here, and you can see that these curves are virtually overlapping with one another.

So why is that? Again, there might be nuances in the study design. This trial included an observation control arm. CheckMate 274 had a placebo control arm. A very significant difference.

I really want to give kudos to Tom Powles and investigators at Genentech, who did a tremendous job of dissecting the biology of this trial. And what they’ve really honed in on is that if you have ctDNA positivity — so this is using an ultrasensitive assay. If you have ctDNA positivity following the time of surgery that’s really the subset of patients that seems to benefit from adjuvant therapy with atezolizumab.

And this really serves as the foundation of a study that’s ongoing now called the IMvigor011 clinical trial. And in this study patients who are ctDNA positive, and you see this in the top part of the algorithm, are going to be randomized to receive atezolizumab or placebo. If you’re ctDNA negative you receive standard of care outside of the context of the study. And I personally think this is a brilliant design. I think one of the issues we have in adjuvant therapy across the board is making sure we’re not overtreating patients. So this may really hone down on a population of folks who really warrants adjuvant therapy.

Very quickly here, in the interest of time, I’m going to highlight what I think is a very, very excited space and has such immense potential. So this is data that Andrea Necchi has really championed for several years now. It’s the PURE-01 study, a study that he’s conducted almost wholly at his institution and several others in Italy. So this actually takes patients with muscle-invasive disease and treats them in the neoadjuvant setting with single-agent pembrolizumab.

There have been multiple, multiple publications emanating from PURE-01, lots of great biological yield from this. What I put up here for the sake of simplicity are just some of the highlights. What you see is that about 37% of patients here have a complete response to therapy. A larger proportion have pathologic T1 disease or less. This is, again, just with single-agent pembrolizumab in this context, so that’s quite encouraging.

And for those of you with interest in variant histologies you can see some of that data in the columns on the right-hand side. Perhaps a subtle drop in terms of response rate there. It certainly needs a little bit more work, but compelling data, nonetheless.

And he and investigators in Italy aren’t the only people to do this. This is the ABACUS trial, which is published in Nature Medicine. This is a really interesting effort led by Tom Powles and Daniel Castellano and multiple other colleagues throughout Europe. This particular trial looked at neoadjuvant atezolizumab. And what you see in the context of this trial are again pretty impressive complete response rates in the context of single-agent checkpoint inhibitor. In the PD-L1-positive population striking result there, 37%. Even the PD-L1 negatives were getting some responses there.

So of course the obvious question after that, and I picked 1 example amongst many here, is to see what the role of perhaps combined chemotherapy with immunotherapy is. Chemotherapy’s long been the standard in the neoadjuvant setting.

So this particular trial, which is reported by Tracy Rose, now published in the JCO, looked at the combination of chemotherapy with pembrolizumab. And you can see here a pathologic response rate of 56%. Now this is T2 and below. So what I would propose here is that it’s really hard to juxtapose this against the other data sets that I just reviewed. This really begs for randomized data. Guru gave a terrific talk today during the ASCO GU Meeting that summarized the landscape of neoadjuvant therapy.

But rather than focusing on that right now I’m going to focus on what I think is really the holy grail, which is getting patients away from cystectomy. So this is a study that Matt Galsky led. We accrued many patients to this trial at City of Hope.

This took patients and gave them cisplatin, gemcitabine, and nivolumab in the neoadjuvant setting. And this is, I think, pretty phenomenal. If you have a complete response to this regimen you actually have the possibility of not receiving cystectomy and maintenance therapy with nivolumab. So you can see the denominator of patients enrolled in this particular trial. 30 patients actually ultimately received no cystectomy, and that’s a huge, huge paradigm shift for the field. So it remains to be seen how those folks are going to do with long-term follow up. Many of those are in my practice and still doing well, which I think is really encouraging.

And then I wanted to wrap up in the last couple of seconds here and pay homage to this outstanding presentation from Dan Petrylak. We talked about pembrolizumab in the neoadjuvant setting. He presented just really outstanding, compelling data with the combination of enfortumab with pembrolizumab; pCR rates of 36.4%, pathologic downstaging rates of 50%. So we’ll have some discussion around this, and I think I took maybe 10 seconds over my allotted 10 minutes. So I’m not setting the bar very high here.

Okay. Well thank you for that, and we’re going to jump immediately into what I think is going to be the more interesting component of all this, and that’s several surveys that we’ve administered to experts in the domain of bladder cancer, including the folks that you’re seeing here on this stage.

So this question posed a scenario where we have a patient who’s BCG unresponsive with nonmuscle-invasive bladder cancer. Let’s make the assumption that this patient is 65 years old, otherwise healthy, and prefers not to undergo cystectomy. Shilpa, what are you thinking for this patient? Would you offer them pembrolizumab in that context?

DR GUPTA: Absolutely, Monty, with the data that you presented it’s a very valid option.

DR PAL: And Dan, what do you think? This is a young patient. Would you really try to put a little more pressure on them to go for cystectomy? Do you think pembrolizumab is reasonable in this context?

DR PETRYLAK: Well, I think it’s the patient’s right to have what he has done to his body because there are complications, both sexual as well as having either a neobladder or a pouch, and that has an important impact on quality of life.

DR PAL: Yeah. Totally fair. Totally fair. And Guru, I’m going to turn this next scenario over to you. So let’s imagine this is not a 65-year-old patient gentleman, but a 70-year-old gentleman. I was actually kind of curious about this result, and it may play into the patient preferences that are expressed here or perhaps lack thereof. But let’s say this is a 70-year-old with minor comorbidities. Are you going to offer that patient pembrolizumab in this context?

DR SONPAVDE: Yeah, so in general I don’t use age as a major criterion for offering or not offering pembrolizumab. So if the patient is fit, reasonable performance status, and we have a long discussion of the pros and cons of the efficacy and the toxicities, and then the patient makes the decision. So it’s really a balancing act, and it’s just my experience that when I go through all of the efficacy and toxicities, with a 20% CR durability at 1 year and a 20% significant immune events, my experience is most patients don’t want it, but it could be different with somebody else.

DR PAL: Dan, has that been your experience too?

DR PETRYLAK: Exactly my experience.

DR PAL: Yeah. So Shilpa, I’m going to turn it back to you here. So we’re going to make this patient now 80 years old, and let’s say they have significant comorbidities, they’re not a candidate for cystectomy. I mean you can see there’s probably a little bit more homogeneity in our response here. What are you thinking? Pembro yes/no?

DR GUPTA: Absolutely, Monty. That was the patient population, and the patient fits the bill with being significant comorbidities and not a surgical candidate. So pembrolizumab is the best option.

DR PAL: I think that’s totally fair. So pretty much the general consensus from the stage here around these scenarios. And as you can see from this response a lot of consensus around this scenario too. So we might breeze past this discussion, but this will offer some context to the remaining cases.

So let’s imagine this is a 65-year-old gentleman. He receives neoadjuvant dose-dense MVAC, something we’re using more and more often in the clinic nowadays, for PD-L1-positive muscle-invasive bladder cancer. He undergoes cystectomy, which reveals significant residual disease and positive pelvic lymph nodes.

So if you didn’t have any issues with reimbursement, any regulatory issues, I don’t even envision that would be much of a problem in this case, but what adjuvant systemic therapy would you recommend here? Guru, maybe I’ll start with you this time.

DR SONPAVDE: Easiest question to answer. So nivolumab is what I would do. I think the data are strong. I know there is a camp out there that says that we only have improvement in disease-free survival and not survival, so should we adopt this. The point is that it was an endpoint that was approved by the FDA for approval. So it’s approved in a patient like this, so I would give it, especially in a PD-L1-positive patient, where the hazard ratio was better than the PD-L1-negative patient.

DR PAL: Yeah, and just a question on that, Guru. Are you checking PD-L1 in these patients? Is there a good role for that, in your opinion?

DR SONPAVDE: No, I’m not because the trial was positive in all comers with a hazard ratio of 0.7. The median DFS improved from 11 months to 21 months. 10 months, that’s a big improvement, so I’m not checking it.

DR PAL: Dan, what about you? Are you checking PD-L1?

DR PETRYLAK: The only situation I’ll do that is in a platinum-ineligible patient who I’m considering for up-front immune therapy, but otherwise I never check it.

DR PAL: Okay. That sounds pretty reasonable. So we’re going to go into this scenario, which actually triggered maybe a little bit more debate amongst the folks that were polled here. So this is the same — the general scenario. Again, a 65-year-old gentleman, neoadjuvant dose-dense MVAC, PD-L1 positive, undergoes cystectomy, but this time there’s small amounts of residual disease and negative pelvic nodes. Shilpa, what are you thinking for this patient?

DR GUPTA: I think based on the data from CheckMate 274 patients who get neoadjuvant chemotherapy and have T2 or higher disease, they are eligible. Now if by a small amount of residual disease it’s T1, then we could go with the other option of no therapy. But if it is T2, then we would give nivolumab. So I’ll assume that this was nonmuscle-invasive disease at cystectomy, and none is a good, reasonable option.

DR PAL: Got it. Got it. Okay. That makes sense. That makes sense. What are you thinking, Dan, for this patient?

DR PETRYLAK: Yeah. If this were muscle invasive, yes. If this were carcinoma in situ, Ta disease, no.

DR PAL: No. Okay. That’s totally fair. Guru, anything to add to that?

DR SONPAVDE: No. I agree with that.

DR PAL: Okay, okay. Fair enough. So we’re going to change the scenario here. And again, we probably don’t need to have a ton of discussion. A lot of harmony in terms of this response here. PD-L1 negative patient, again, that may be the 1 decision point we can reflect on, and in this case the patient has significant residual disease and positive pelvic lymph nodes. Guru kind of gave us his answer already on this one, so maybe Shilpa, I’ll start with you and see if you have any differing thoughts.

DR GUPTA: No, that’s absolutely the right answer. Fits the bill for the patient population in that trial that demonstrated improvement in disease-free survival. So I would offer nivolumab.

DR PAL: Dan, what do you think?

DR PETRYLAK: Completely agree.

DR PAL: Completely agree. Okay. Outstanding. So we’re really breezing through this guys. I think we’re going to — we’re going to get you home way before 8 am.

DR PETRYLAK: We’re going to make up the 10 seconds.

DR PAL: Perfect. Perfect. Okay. So again, flipping these scenarios a little bit here. Now this is a patient who has pathologic T3N1 disease. You’re getting those pathologic criteria up front. This is PD-L1 positive. What adjuvant systemic therapy are you going to recommend in this particular scenario? Let’s go to you, Dan.

DR PETRYLAK: So 65, and he did not have neoadjuvant chemotherapy.

DR PAL: Did not have neoadjuvant chemotherapy.

DR PETRYLAK: Yeah. This is a tough choice. I probably would go with adjuvant nivolumab since I’ve got survival data. Now the trouble with that is that when you look at the subgroup analyses, the patients who did not receive neoadjuvant therapy, the hazard ratio was closer to 1. But we don’t have a randomized trial showing survival benefit for cisplatin-based chemotherapy. So I have to go with the data and go with nivolumab in that situation.

DR PAL: What are you thinking, Shilpa?

DR GUPTA: I think it depends on if the patient is cisplatin eligible. But most of the times, if they are, they do undergo neoadjuvant. So going with what Dan is saying, I would say if the patient can get cisplatin-based chemotherapy I would prefer that. If not, offer nivolumab.

DR PAL: Got it. Got it. And then Guru, any differing thoughts on that scenario before we jump to the next one?

DR SONPAVDE: Yeah. Actually, I agree with Shilpa that I would go with cisplatin-based adjuvant therapy in patients who are cisplatin eligible. If they’re not eligible is when I consider nivolumab. The trial with nivolumab of course allowed patients who refused cisplatin.

DR PAL: Right.

DR SONPAVDE: So I think — so that would be a discussion to have with the patient.

DR PAL: So if they did refuse cisplatin you’d give them that option then. Yeah. Very good.

And actually, this is our last scenario for this section, I believe, and then we have a little bit of time for Q&A, so do submit any questions that you have here in the WebEx.

So this is 65-year-old gentleman in this particular context, T3N1 disease, PD-L1 negative, okay? So a little bit of a ringer in there with the PD-L1-negative status. Dan, does that change your opinion at all?

DR PETRYLAK: I may be more inclined to give platinum-based chemotherapy in this situation. Again, we don’t really have a lot of data one way or the other, but I’d probably be more inclined to do so.

DR PAL: Okay. Okay. What about you, Shilpa?

DR GUPTA: I would in this case, cisplatin-based chemotherapy.

DR PAL: So stick to your guns in that setting, go with cisplatin since they’re eligible. Is the PD-L1 status an influencer for you or is the cisplatin eligibility a bigger driver?

DR GUPTA: I don’t check for PD-L1, so this would be the option.

DR PAL: And Guru, what about you in this scenario?

DR SONPAVDE: I agree. I think I already said cisplatin for PD-L1-positive patients if they’re cisplatin eligible, so I stick with that, cisplatin if cisplatin eligible.

DR PAL: Very good. Very good. So before we jump into the next session, which is going to be led by Shilpa here, we have a couple minutes here to probe Dan a little bit. We alluded to the results from Cohort H that you presented today. Really, really exciting data with that combo of enfortumab and pembrolizumab. Tell us, what’s that future for that?

DR PETRYLAK: So actually it was just enfortumab. Yeah. It was just a single-agent trial.

So the future is there are trials — there’s a second cohort in the 103 trial that is actually giving 3 cycles of enfortumab by itself, cystectomy, and then another 3 cycles of adjuvant afterwards. And that will be the last cohort from EV-103.

But there are randomized trials looking at enfortumab combined with pembro as therapy for — neoadjuvant therapy comparing this to standard cisplatin-based chemo. So I think that those are exciting trials. I think that they’re important and certainly can change the standard of care as to what we give neoadjuvantly.

DR PAL: And folks actually brought up an interesting question around, for instance, the ototoxicity. I think Guru mentioned that in his discussion there. What do you make of that? Cisplatin ineligibility in this context was defined by the typical Galsky criteria. It saw 40% of patients in the study defined as cisplatin ineligible on that basis. Is that curious or is that typical in our bladder cancer population? Maybe, Dan, I’ll throw that to you.

DR PETRYLAK: I think we have to look for it.

DR PAL: Yeah.

DR PETRYLAK: I think — and you had — this was a Grade 2 or greater toxicity based upon an audiogram. And so predominantly we’ve seen in the past it’s been renal dysfunction. Now the real question is would that affect the results. And I’m not sure that it would, but who knows? I mean I certainly think we need more patients, more data to really understand the biology of platinum-ineligible disease.

DR PAL: Makes sense. Makes sense. Perfect. So we’re right on time.

Current and Future Front-Line Management of Metastatic UBC (mUBC) — Shilpa Gupta, MD

DR PAL: I’m going to turn it right over to you, Shilpa, for your section.

DR GUPTA: Thank you, Monty, for an excellent module. Now I’ll switch gears to management of metastatic urothelial bladder cancer, the current and future front-line prospects.

We all know, and we have learned in the last couple of years that despite a lot of advancements platinums remain the backbone of front-line therapy in metastatic disease. The gemcitabine and cisplatin median overall survival is around 14 months, response rates around 50%. With dose-dense MVAC it’s around 15 months, responses of over 70%. And recent contemporary trials with gem/carboplatin are also showing increased overall survival compared to historic trials, with survival of 13 months and responses of 43%.

Only a minority of patients receive second-line therapy for metastatic disease, and there’s an unmet need to improve survival with front-line therapy.

We saw that unlike lung cancer, in metastatic urothelial cancer, combination of chemotherapy, that is platinum-based chemo, with immunotherapy did not improve overall survival compared to chemotherapy alone. And there are 2 large, randomized trials to prove this. The KEYNOTE-361 trial used pembrolizumab and chemo versus pembrolizumab versus chemo alone, in this case platinums, and there was no PFS or OS improvement regardless of PD-L1 status.

In the IMvigor130 study, similar patient population, but cisplatin or carboplatin was decided based on investigator discretion, it showed a slight PFS improvement, which was not clinically meaningful. So far we have not seen significant overall survival benefit, but we are hoping to learn more in the future.

DANUBE was a front-line durvalumab plus/minus tremelimumab, so an immunotherapy doublet, versus standard of care chemotherapy in locally-advanced or metastatic urothelial setting, and these are the 3 arms. Primary endpoint was overall survival versus durvalumab versus standard of care in PD-L1 high, and the durva/treme versus standard of care in all comers. And this was a negative trial. It did not improve overall survival compared to chemo. And last year the durvalumab indication was voluntarily withdrawn based on the negative results from this trial.

How has front-line therapy evolved in cisplatin-ineligible metastatic disease? And I know a lot of you in the audience have seen how this has evolved over the last many years. Prior to 2017 gem/carbo is all we had for these patients. The outcomes were quite dismal, with median overall survival of only 9 months. And then in 2017 we saw really very encouraging data with single-agent atezolizumab and pembrolizumab in 2 studies, which were Phase II trials, and they showed around 25% responses and really remarkable duration of response of around 15 months. And these were approved, and we all had changed our standard of care from carbo to single-agent immunotherapy.

And then based on the Phase III trials’ assessment, it was found that patients who received immunotherapy actually did worse, they had worse outcomes, compared to carboplatin. And FDA restricted the label for this to use only in cisplatin-ineligible patients with high PD-L1 expressing tumors or those who were not eligible to receive even carboplatin, that is very frail patients.

And now, as you’re all aware, gem/carbo followed by avelumab maintenance is the preferred standard of care based on Level 1 evidence from the JAVELIN Bladder 100 trial. And more recently the FDA restricted pembrolizumab label only to platinum-ineligible patients regardless of PD-L1 status. So we’ve kind of gone a full circle back to gem/carbo.

The KEYNOTE-361 trial also looked at pembrolizumab alone or combined with chemotherapy versus chemo. And in this, when you look at pembro alone versus gem/carbo, we see that the response rates and disease control rates were lower with pembro compared to gem/carbo. And I’ve highlighted in the boxes in all comers responses were 27% with pembro and 42% with gem/carbo. And like CPS high has always in the past predicted better responses, but in this trial, even in the CPS high — patients with CPS-high tumors response rates were lower with pembro, 30% versus 46% with chemo.

Importantly, there were early deaths on the pembrolizumab arm, and overall survival for pembro did not cross significantly enough for a positive trial. So even though eventually it caught up we were losing patients early on, those who were enrolled on the pembro arm.

Similarly, in the IMvigor130, we are waiting for the overall survival data, but this trial showed something different compared to the KEYNOTE trial. In this the PD-L1 seemed to predict some responses to atezolizumab. Now this data is all an exploratory analysis, so we can’t make much out of it, but as you can see, in high PD-L1-positive tumors patients had higher response rates and survival.

Now switching gears to maintenance immunotherapy approaches. This was a study in which patients who received front-line gem/cis or gem/carbo and did not progress after treatment received avelumab versus best supportive care within 4 to 8 weeks and were randomized in these 2 arms. Primary endpoint was overall survival in all patients and PD-L1-positive patients. And this was really a practice-changing study a couple of years ago. Maintenance avelumab improved overall survival compared to best supportive care by 7 months, and in the PD-L1-positive patients it was even more pronounced.

And just in this meeting, as you all know, there was 38-month median follow up data shown, and the median overall survival was well maintained up to 23.8 months versus 15 months with best supportive care alone. And this is now the standard of care which we prefer to use. These are the patient demographics and other factors. There was no new safety signals from avelumab.

And in the subgroup analysis, as we can see, across all the categories there was a benefit of avelumab. But in the visceral metastases it was less pronounced, so there’s a need to intensify this backbone to further improve outcomes.

We saw in this meeting there was a lot of PARP inhibitors talk today in the urothelial cancer. A couple of years ago some of the trials had reported no benefit with PARP inhibitors, and this meeting provided kind of reinvigoration of that. There was PARP inhibition following chemotherapy, same setting as the JAVELIN trial, maintenance trial, the ATLANTIS rucaparib arm, and in the biomarker-selected patients there was improvement in PFS. Granted, these are early data and needs to be studied further.

In another study niraparib was studied in the same setting, and we did not see much activity. But in the biomarker-positive patients there was some activity there, so we need to see this further.

And the question now comes like how do we select patients for first-line treatment in metastatic disease, as we have seen from these randomized trials PD-L1 is not a reliable biomarker, based on KEYNOTE-361 and the restriction of the label by the FDA. We recently worked together on defining these patients who are not platinum ineligible — eligible, that is they can’t even get carboplatin, and really, as you can see in this, like patients who have poor performance status, creatinine clearance lower than 30, bad peripheral neuropathy, heart failure, and poor performance status, and creatinine clearance of less than 30. And we are providing an update coming soon.

But this is just a rough guide. We all use our discretion as to whether a patient can get chemo or not. And in 2022 I think the treatment paradigm is based on purely clinical factors. If a patient is cisplatin eligible we offer cisplatin-based chemo. If the patient is not cisplatin eligible we offer gem/carbo. If they progress we offer anti-PD-L1, most preferably pembrolizumab or erdafitinib if they have FGFR alterations. If they do not progress we offer avelumab maintenance. And then upon progression there are options like erdafitinib in biomarker-selected patients, enfortumab vedotin, sacituzumab govitecan. And only around 10% of patients belong to that platinum-ineligible category where you can use single-agent pembro or atezo.

PD-L1 is not a reliable biomarker. And enfortumab vedotin and pembrolizumab in front-line cisplatin-ineligible metastatic urothelial cancer was studied in EV-103. It showed these remarkable responses, as you can see, 93% of patients responded, and median follow up of 25 months showed a progression-free survival of 12 months. And erdafitinib and cetrelimab, another antibody of PD-L1, showed activity in this small trial, in 19 patients, in the NORSE study; needs to be further studied for sure.

The PARP inhibitor data was presented today by Dr Jonathan Rosenberg, in the BAYOU study, in platinum-ineligible front-line durvalumab plus olaparib versus durvalumab and placebo, and in the HRR-positive patients there’s activity. We need to study this further.

These are the ongoing trials which may help us understand how therapy will evolve in the future. And this is a trial that we are building on avelumab maintenance with cabozantinib in the future.

Right on time.

DR PAL: Wow. That was right to the second. Very impressive. Okay. So you’re in the lead, Shilpa. Awesome. Very good.

So we’re going to kind of jump through a couple of questions here. Some of these are actually a little bit more contentious, I think, amongst the respondents, so I think we’ll have some good discussion around this.

So this is a question that I think immediately derives from your excellent talk. So what would your preferred first-line regimen be for a 65-year-old gentleman with de novo metastatic urothelial bladder cancer? Would it be cis/gem followed by maintenance avelumab? Would it be just cis/gem by itself? What do you think?

DR GUPTA: I think cis/gem followed by maintenance avelumab based on the JAVELIN Bladder 100 data.

DR PAL: Yeah. I think you presented a very clear explanation for that. Dan, any thoughts?

DR PETRYLAK: No disagreement.

DR PAL: Yeah. Guru, how about you? I mean maybe if you agree, as well, maybe you can account for why there might be some skepticism. You do see 4 of the respondents just using cis/gem alone there.

DR SONPAVDE: So the JAVELIN Bladder 100 trial really changed the paradigm of first-line treatment. So this was a trial in which all comers who had responding or stable disease after 4 to 6 cycles of platinum, it could be cis/gem or carbo/gem, and that’s the vast majority of patients because 70%, 75% have stable or responding disease on platinum-based chemo. So when these patients got randomized to avelumab or best supportive care there was an improvement in overall survival. The hazard ratio was like under 0.7.

And so that really changed the paradigm for us. So it’s all comers. There was a trend for more benefit in PD-L1-high patients, but the PD-L1 — that was a coprimary endpoint. PD-L1 high, as well as all comers, everybody benefitted. So that’s really the standard for everyone.

The only question is in someone with CR do you still do it. At the moment we think we should do it because the CR patients actually also had poor outcomes. The median PFS was kind of short, 3.7 months, even in the avelumab arm, and in the CR patients it was also kind of low at around 7.5 months. So I would also lean towards giving it in everyone, including the CR patients.

DR PAL: Yeah. I think probably we have consensus around that on the panel, right? I mean I think that benefit in CR from chemotherapy is probably pretty fleeting.

So this is interesting. We had what I thought would be a pretty straightforward question here. So this is a 65-year-old gentleman who experiences disease recurrence in the liver 9 months after cystectomy and adjuvant cisplatin/gemcitabine therapy. This patient has FGFR wild-type disease, just FYI. So we see some respondents favoring pembrolizumab, some favoring enfortumab. Again, this is a liver recurrence, relatively short span after cystectomy. Shilpa, what would you err on the side of here?

DR GUPTA: I would use pembrolizumab based on the KEYNOTE-045 data. While enfortumab vedotin is a great option, the ideal label is prior chemo- and prior IO-treated patients. So we should offer pembrolizumab. That’s what I would do, and scan quickly after 2 cycles and switch to enfortumab if the patient doesn’t have response.

DR PAL: That makes sense to me. Dan, anything to add to that?

DR PETRYLAK: I would disagree with that. And I’m doing this to be provocative —

DR PAL: Great.

DR PETRYLAK: — because my feeling is that pembrolizumab does not do well with visceral disease. And if I’m going to give pembro, I’m going to give it with enfortumab, and I’ve done that. So either enfortumab alone or enfortumab plus pembro is what my choice would be in this situation.

DR PAL: Interesting. Okay, got it. Very good. And how do you make that distinction between using enfortumab alone or the combo?

DR PETRYLAK: Well, it’s all depending upon insurance.

DR PAL: Yeah, yeah. Yeah. Sure. Sure. Absolutely. Guru, what about you? What’s your answer here?

DR SONPAVDE: I agree. I mean we are bound by regulatory considerations, but if that were not an issue I agree with Dan. I would love to use enfortumab in somebody with liver metastases because this drug does work, even in patients with liver metastases, while the checkpoint inhibitors don’t work so well with liver metastases.

DR PAL: Got it. Got it.

DR SONPAVDE: But the standard answer is an immune checkpoint inhibitor.

DR PETRYLAK: Yup.

DR PAL: Right, right. Absolutely. Okay. Good. So some really good discussion. Thank you for being provocative, Dan. We appreciate that.

DR PETRYLAK: Any time.

DR PAL: So this actually lends itself, perhaps, to some great, provocative discussion. So this is a 65-year-old patient who experiences disease recurrence in the liver 9 months after cystectomy and adjuvant nivolumab. So this is really veering on a scenario we may see in the coming months or years, right? And so this patient has FGFR wild-type disease. Guru, maybe I’ll start with you this time. Would you give this patient enfortumab? Would you give them cis/gem? Cis/gem followed by, and this is tricky, maintenance avelumab since they’ve already been exposed to nivo? What do you think?

DR SONPAVDE: So this patient, I’m not clear if the patient received neoadjuvant cisplatin-based chemotherapy, so I’ll just talk about both.

DR PAL: Let’s envision they haven’t.

DR SONPAVDE: Okay. So if they haven’t received cisplatin neoadjuvantly, perhaps they’re cisplatin ineligible, so they received adjuvant nivolumab, and they’re cisplatin ineligible, so I would actually give enfortumab vedotin in a patient like this because cisplatin ineligible in the second-line setting that is an approved drug. It’s a very active drug. I think it’s the single most active drug. I don’t think you would be wrong in giving platinum-based chemotherapy, but personally enfortumab, to me, is a more exciting drug than giving carboplatin/gemcitabine in a cisplatin-ineligible patient.

DR PAL: Well let me ask you, Guru, what if that patient was cisplatin eligible in this scenario, then what would you do?

DR SONPAVDE: Without neoadjuvant cisplatin?

DR PAL: Without neoadjuvant cisplatin, yeah. I’ll make some of this stuff up. Yeah.

DR SONPAVDE: That’s — so in that situation I think you have the option of giving cisplatin/gemcitabine, but I think you might still have the option of giving enfortumab if the patient is now cisplatin ineligible. So it depends.

DR PAL: Okay, okay. So Dan, what would you do? What do you think? Would you do cis/gem, or would you do enfortumab? What are you picking between the 2?

DR PETRYLAK: I would pick enfortumab, and the reason why I would pick it is if you go back and look at the multivariate data from MVAC, as well as gem/cis, the patients who did the best with those 2 combinations had nodal disease and no liver metastasis. And even though it is front-line standard of care the response rate with enfortumab in liver is 40%. It’s 40% in all Phase I — all trials, Phase I, Phase II, and Phase III. And for that reason, and the experience we’ve had, we have patients alive still from the Phase I trial, 6 years out, who had hepatic metastases. So I’m very confident that this drug offers the patient the best chance.

DR PAL: That’s very convincing. So since you offered to be provocative I’ll ask you a provocative question here. So let’s say this particular patient was seen outside, right, and you didn’t have the ability to choose amongst these regimens, they get challenged with cisplatin and gemcitabine after adjuvant nivolumab therapy, okay? So in that setting you’ve got 2 potential options. Would you give them maintenance avelumab or would you just give them chemotherapy alone? What do you think?

DR PETRYLAK: Well, the question is, is avelumab any different than the adjuvant nivolumab.

DR PAL: Yeah.

DR PETRYLAK: I probably would not give the adjuvant nivolumab because I don’t think that that’s going to — this patient has progressed on checkpoint, and in my experience switching checkpoints has not made a difference. So I don’t think it’s going to.

Now, the other argument you can make is you’ve given chemotherapy, perhaps changed the microenvironment, and it would make it susceptible to going on a maintenance trial. But I still probably would go with something different.

DR PAL: Shilpa, can I ask you the same question? So again, you didn’t have a choice in this case. The patient got cisplatin/gemcitabine outside of your practice, would you put them on maintenance afterwards given the prior nivo?

DR GUPTA: No, I wouldn’t. I totally agree with Dr Petrylak here that we don’t want to switch immunotherapy agents if they progressed after nivolumab. And my choice in this case would also be enfortumab vedotin, especially we also have data in patients who get IO only followed by enfortumab vedotin; it’s very effective, so…

DR PAL: Dan, maybe I’ll keep picking on you since you offered to be provocative here. So let’s say this patient actually didn’t have a 9-month interval there, but let’s extend that out to 2 or 3 years, okay? And then that patient gets treated with cisplatin/gemcitabine, winds up in your clinic. We might be seeing this in a couple of years, right?

DR PETRYLAK: Yeah.

DR PAL: So what do you think? In that case would you offer them maintenance avelumab after?

DR PETRYLAK: Yes. I probably would.

DR PAL: Okay.

DR PETRYLAK: And just taking the analogy of other tumors, like renal cancer, where people have stopped treatment because they’ve had a complete response or minimal disease, I think that the later reinduction could potentially be beneficial.

DR PAL: Excellent. Excellent. All right. So I’ll move on to the next scenario here. These are fantastic questions. So what would you recommend for a 65-year-old patient who experiences disease recurrence in the liver 9 months after cystectomy and adjuvant nivo and has now an FGFR3 mutation? You can see there’s a huge diversity of opinions here, and the 1 element that gets introduced, right, is the erdafitinib there. So Guru, I’m going to turn this over to you. What do you think? Erda now, given the FGFR3 mutation?

DR SONPAVDE: Yes, I would give erdafitinib now. I assume the patient has not received neoadjuvant cisplatin that could potentially be a problem since erdafitinib is approved in the post-platinum setting, but if that drug were available I would go for erdafitinib as the next drug. In somebody with this mutation I try to get the biologic agent in first. That makes sense based on the biology and the data.

DR PAL: Got it. This has been a big point of contention, I think. And again, this is not a huge population of patients, typically it’s about 20% to 30% of our patients where we’re going to see these FGFR3 mutations, in the lower tract, higher and upper tract disease. But Dan, what is your thought here? Are you going with enfortumab or erda? Or something else?

DR PETRYLAK: Well, I think that both choices are reasonable. I think the choice would also be can I get targeted therapy in if the patient progressed after enfortumab because in my experience erdafitinib is a little bit of a more difficult drug to administer because of fatigue, you have to monitor the phosphorus levels, nailbed changes, but the fatigue can be pretty significant in these patients. So I think you really have to see what the patient’s performance status is, and also their other comorbidities. But I would favor enfortumab in this situation.

DR PAL: And Shilpa, what about you?

DR GUPTA: Yeah, I think both enfortumab and erdafitinib are very reasonable choices, but I would favor enfortumab also because it’s not as — the toxicity with erdafitinib can be quite nagging, but it’s still an option afterwards. It’s not like we can’t use these drugs in either sequence.

DR PAL: Yeah.

DR GUPTA: So in this patient’s journey you’d probably see both these drugs in some sequence.

DR PAL: Got it. I think sometimes the biggest consideration in enfortumab — erdafitinib, rather is just getting that genomic testing done. So what are you telling your colleagues in the community, Shilpa, about when to go ahead and get genomic profiling in bladder cancer? It seems to be a moving target, right?

DR GUPTA: Yeah. I think at the time of metastatic disease, whenever — because like you said, the turnaround can be pretty long, and we don’t want to wait for prior auth and all these things for the drug. So whenever they get a chance to they should sequence and keep that for later.

DR PAL: What do you think about that, Dan, because I’m thinking through this scenario, right? The patient has muscle-invasive disease, progresses on adjuvant nivo, you’d love to know about that option of erda right off the bat.

DR PETRYLAK: Absolutely.

DR PAL: And if you wait until they’re metastatic is that too late? Would you sequence them when they’re muscle invasive?

DR PETRYLAK: No. I’d sequence them — I mean if they’re high risk I would sequence them. I don’t think it’s absolutely necessary to do that if they’re muscle invasive, but if they’ve got node-positive disease and you think they’re going to relapse, yeah, I think that’s reasonable to do in that situation. But we like to get the profiling as early as possible.

DR PAL: Okay. And Guru, what’s been your practice at the Farber? You guys sequence everybody, right?

DR SONPAVDE: I would sequence them, Monty, so I would put them on your trial comparing adjuvant infigratinib versus placebo.

DR PAL: That is the correct answer. Very good. That’s what I was looking for. Perfect. Perfect.

DR PETRYLAK: There you go.

DR PAL: Very good. Very good. So we have 1 more scenario to work through here, and it looks like we’re going to breeze through this one. It seems like there’s a lot of consensus. “Based on current clinical trial data and your personal experience do you believe pembrolizumab in combination with enfortumab will result in superior outcomes compared to currently up-front available regimens?” So this is really predicated on the up-front trial that you presented, Shilpa, right? Do you want to maybe expand on that a little bit?

DR GUPTA: Yeah. I think the data is pretty compelling, and right now we don’t have approval of this combination, but once it’s approved this would be a great option for cisplatin ineligible if that is what it’s approved in. But there’s an EV-302 trial which is comparing this combination with standard of care chemo and maintenance immunotherapy’s allowed, and we are hopeful that this could probably beat chemo. So I think it’s certainly the unanimous choice here.

DR PAL: Fantastic. Fantastic. Well, we are right on time, guys.

Selection and Sequencing of Therapy for Relapsed/Refractory mUBC — Daniel P Petrylak, MD

DR PAL: I’m going to pivot over to Dr Petrylak to run through his section there.

DR PETRYLAK: Terrific. So we’re going to talk selection in sequencing of therapy for relapsed or refractory urothelial carcinoma.

So as we know, enfortumab vedotin is an antibody-drug conjugate. It delivers 3.6 molecules of MMAE, which is monomethylauristatin, to the urothelial cancer cell, and that interferes with tubulin and causes cell death and also an ADCC-like reaction to the cells.

There have been several studies that have led to the approval of enfortumab vedotin in metastatic urothelial carcinoma. The EV-201 trial had 2 cohorts. The first, of course, was — are those patients who had received a prior checkpoint and chemotherapy, and that reported out and showed a response rate of approximately 40%. Cohort 2 was reported last year at ASCO, and that looked at those patients who had prior PD-1 or PD-L1 therapy, they were platinum naïve, cisplatin ineligible, and that has actually shown a very, very interesting response rate.

So we see here that the confirmed objective response rate was 52%, with 20% of patients demonstrating a complete response, 31% demonstrating a partial response.

And if we look at the waterfall plot involving responses, 88% of patients had some form of tumor shrinkage in Cohort 2.

If we look at the sites, the hazard ratios are the same. Of course, if we have — depending upon — or didn’t really matter whether it was an upper or lower tract tumor, whether these patients had visceral metastases, again, also if they did not respond to prior PD-1 or PD-L1 therapy.

The overall survival was 1.7 months, which in comparison to the other agents does seem to be better. The progression-free survival was 5.8 months.

Of course we needed a confirmatory trial for enfortumab in the third-line setting, and this is the EV-301 study, which was published in The New England Journal of Medicine early last year. And it was a randomized trial that compared enfortumab vedotin to standard of care chemotherapy, and that could have been a taxane-based treatment with docetaxel or paclitaxel, and in Europe it was vinflunine. This is the same group of patients that was in Cohort #1 of the 201 trial, prior platinum therapy and prior checkpoint therapy.

As we see here on an intent-to-treat basis there was an improvement in the median survival. It was 12.88 months for enfortumab, 8.7 months for standard of care chemotherapy. And that also, of course, was consistent for progression-free survival on an intent-to-treat basis and actually overall response rate. And here again you see that 40% number for enfortumab, and objective response rate for standard chemotherapy was 17%.

Now we’ve mentioned the FGFR3 inhibitors, and erdafitinib has had Phase II data. This has been published, and this is in patients who either were platinum ineligible or had received prior therapy, and they had to be FGFR3 positive. Patients received erdafitinib at 8 mg daily, and it was uptitrated if the patients’ phosphorus levels remained the same.

The primary endpoint was objective response rate, as we see here. Again that 40% number is popping up, a 40% objective response rate. But a lower CR rate, only 3%, and 37% had partial responses.

This is the survival. The progression-free survival was 5.5 months, and the median overall survival was 13.8 months. And that’s at a follow up of 11.11 months, and then 21% of patients were still on treatment at that time.

Now this is a chart that shows the relative response rates of the different FGFR agents. As we see here, regorafenib is about 24%, infigratinib is about 24%, but erdafitinib is the one that really seems to have the highest response rate. And of course the question is which is the better of these agents. We really don’t know because they’ve not been compared in randomized trials. And this is based on Phase I and Phase II data.

Now another ADC is sacituzumab govitecan. It’s a different target, and it’s also a different payload, which is SN38, or topoisomerase 1. And a very, very similar trial to the EV studies has been designed looking at sacituzumab given on days 1 and days 8 at 10 mg/kg on a 21-day cycle. And this was in patients, same thing, 2 cohorts, 1 of about a hundred patients, in those patients who had prior platinum therapy and a PD-L1, and Cohort 2 were the platinum-ineligible patients.

So this is the response assessment for the Cohort 1. As we see, the response rate’s 27.4% with a 6% CR rate. And the objective response rate in liver was 31.8%, and 23.5% of those patients in those patients who did not have liver metastases. The median progression-free survival was 6.4 months and 10.0 months for the overall survival.

Now are these drugs cross resistant? The answer is no. So this is a case that we treated at Yale, and this was actually presented by Scott Tagawa at the ESMO meetings a couple years ago, a 61-year-old gentleman who had had cisplatin-based chemotherapy prior to cystectomy. He progressed in lymph nodes. He had been on actually adjuvant cisplatin/gemcitabine. He had been on atezolizumab, and then he was on enfortumab vedotin for 8 months and did have a response. We at that time did not have an open trial, so we put him on pemetrexed. And when the sacituzumab trial opened we put him on sacituzumab, and he had a response as well. And as you can see, some pretty bulky adenopathy regressed, so these drugs are not cross resistant. It makes complete sense, a different epitope and a different payload.

And Cohort 2, again, very similar data — very similar data to what we had seen in Cohort 1, 40 patients overall, and these are patients who were ineligible for platinum-based therapy and who progressed after prior checkpoint therapy. As we see here, the objective response rate is 29%, very, very parallel to what we see with the platinum patients who had progressed after platinum therapy and checkpoint therapy. And 62% of patients had some form of tumor reduction, and in some patients the response duration went to as long as 13 months. Survivals, again, comparable to what we had seen previously. The median survival was about 11 months in those patients who were treated with sacituzumab govitecan.

Now there is a trial that has combined — Petros Grivas presented at this meeting. TROPHY-01 has a number of different arms, and Petros presented the data that was with sacituzumab combined with pembrolizumab. And as we see from this study, 63% of patients had some form of tumor shrinkage. The objective responses include 1% CR, and the remaining responses were partial responses.

HER2/neu has been a target that has really elusive in this disease. There have been a number of attempts to look at trastuzumab in urothelial carcinoma. We actually tried to design a trial in SWOG a number of years ago. But there are ADCs, as well, that can actually target HER2/neu. This is disitamab vedotin. Again, this is delivering MMAE. And this was evaluated in 43 patients who had HER2 positivity, either 3+ or 2+. A progression-free survival of 6.9 months and a median survival of 13.9 months, and a 50% objective response rate. And treatment-related adverse events, including hypoesthesia, alopecia, and leukopenia.

And then there was a Phase IB trial of trastuzumab deruxtecan combined with nivolumab in those patients who expressed HER2/neu. And again, we’re seeing some nice responses, a 38% response rate. 11 patients overall responded in this particular trial. And again, this was seen predominantly in those patients who had high levels of HER2 expression.

Cabozantinib, another drug, and Shilpa’s looking at this in combination with checkpoint inhibitors as switch maintenance therapy. That also, in refractory urothelial carcinoma patients, has an objective response rate of 19%.

So in conclusion, enfortumab vedotin is FDA approved as third-line therapy in patients who have progressed on chemotherapy and checkpoint inhibition therapy, has accelerated approval in those patients who are cisplatin — actually full approval in patients who’ve progressed on 1 treatment. Sacituzumab govitecan is FDA approved, and that received accelerated approval; has promising activity in patients who fail 2 or more therapies. There are studies looking at the combination of checkpoint inhibition therapy, targeted therapies, and all metastatic urothelial cancer patients should be checked for FGFR3 mutations. Erdafitinib has a 40% response rate in this patient population. And I’ve got 10 seconds left.

DR PAL: Wow. How about a round of applause for Dan.

DR PETRYLAK: I made up your 10 seconds.

DR PAL: That was more than 30 slides in 10 minutes. And you went over them.

DR PETRYLAK: Do you remember the Federal Express guy?

DR PAL: Fantastic. Fantastic.

DR GUPTA: Guru has a high bar now.

DR PAL: Absolutely. Good luck, Guru.

DR SONPAVDE: I give up.

DR PAL: So we’re going to get right into some rich discussion around this. Dan, excellent, excellent talk, and I think you pretty much laid the framework for this question. We’re not going to spend a lot of time on this here, but this is a patient who is FGFR wild type, 65 years old, metastatic disease to the liver, progresses on cis/gem followed by avelumab maintenance. I mean any other options, Dan, in your mind besides enfortumab in this context?

DR PETRYLAK: I mean enfortumab’s FDA approved. He’s wild type. The question, of course, is you’d have to also look at some comorbidities in this patient. Does this patient have significant neuropathy, greater than Grade 2? Does this patient have difficulty controlling his diabetes? We do not treat a patient with enfortumab if their serum glucose on the day of treatment is more than 250. So that would be a situation where you may want to consider sacituzumab. But again, you’ve got to look at your patient and see how they’re doing.

DR PAL: Well said. Well said. So we’re going to jump into something that again we’ve sort of addressed in the previous scenario, but I think will be somewhat contentious. Before we get into this scenario which introduces, again, this concept of FGFR3 positivity, I’m seeing some of the questions here, and they pertain to the mode of testing. So Guru, you’ve done a lot of work in the space of ctDNA. Is ctDNA an appropriate way to detect FGFR3 mutation fusion to use some of the agents that Dan underscored?

DR SONPAVDE: Yes. CtDNA seems good to detect these patients. One of the problems with ctDNA is if the ctDNA is negative you can’t fully rely on it. So you might still need to look at the tumor if the ctDNA is negative because if it’s positive it’s positive. If it’s negative you may have missed it. So yes, I think that you should — you could look at ctDNA as a noninvasive assay in a patient where a biopsy is difficult.

DR PAL: So is that your pathway then? So you check ctDNA, and if it’s negative you’ll still get tissue.

DR SONPAVDE: Yes. If the ctDNA is negative, and I don’t have any tissue genomic profiling yet, yes, I would get tissue.

DR PAL: Dan, what do you think about that?

DR PETRYLAK: I would agree completely. I would get tissue if I couldn’t get ctDNA.

DR PAL: Got it. Got it. But would ctDNA be your first choice there, Shilpa?

DR GUPTA: If there’s a tissue option, safe and feasible, I would go with that.

DR PAL: Got it. Got it. Okay, so why don’t we dive into this scenario. Again, we’ve seen tidbits of this in the previous post-adjuvant session, but maybe I’ll go right back to you, Guru, in the context of this patient who’s gotten cis/gem followed by avelumab maintenance therapy. You have options here of erda or enfortumab. What are you thinking?

DR SONPAVDE: So you actually have 3 options, right? So you have erdafitinib. You have enfortumab. You also have sacituzumab, actually. But personally I would go with erdafitinib first just based on the biology, that we have a trial looking at this drug in this specific population. And with a highly-specific drug targeted drug I think you want to get it in early, not too late, just because it hits a very specific target. So if you have many resistance mechanisms when you give it late it might just not be as effective, but that could be just biology-based thinking, so we don’t — I don’t think we have the right answer on what would be the right sequence.

DR PAL: Got it. And there’s some pretty astute questions around here. And this is a tough one, so if you don’t know the answers that’s fine. But during the course of therapy with erdafitinib what happens to FGFR3? Can you use it as a biomarker to assess response? Does it change over time? I’ll throw that to you, Guru.

DR SONPAVDE: Me? Yes. It does change over time. It’s been looked at actually in the study that Tom posted with durvalumab plus/minus targeted agent, where they had an FGFR inhibitor, and the variant allele fraction of FGFR3 mutations actually does decrease in patients who are responding.

DR PAL: Yeah. We saw something very similar in the context of infigratinib in our Cancer Discovery paper too. Very interesting. Okay. So this is a unique scenario with something, again, that I think we see quite commonly in the clinic. We’re going to scale the patient up to 80 years old now, FGFR3 mutation positive, okay? And this patient progresses on front-line pembrolizumab therapy. So Shilpa, you’ve got a couple of options there, enfortumab, erdafitinib, chemotherapy. You can see there’s major heterogeneity amongst the responses here. What are you thinking in this particular scenario?

DR GUPTA: I think really I have to see what comorbidities the patient has. FGFR3 mutation is positive, so erdafitinib is a very reasonable option, although the label is for post platinum, but in the real world the patient only got pembrolizumab, so if we have to use it we can. Enfortumab vedotin, based on what was just discussed, is a very reasonable option too. So I would probably start with one or the other and switch gears if it’s not working.

DR PAL: Well let’s say this 80-year-old patient actually came on his bike to see you from 40 miles away at the Cleveland Clinic, then what do you think? Really robust, fit patient?

DR GUPTA: I think erdafitinib would be a good option, try it, and it is convenient. If the patient doesn’t have toxicity, try to continue for as long, and keep enfortumab vedotin for later.

DR PAL: Got it. Dan, I’m just intrigued by the choice of chemo here. I mean can you offer any justification for that? Are you thinking differently through this scenario?

DR PETRYLAK: No. I’m thinking similarly. Enfortumab because of the liver metastases.

DR PAL: Yeah.

DR PETRYLAK: And perhaps Shilpa’s patient has come through. Yeah. I mean, enfortumab is something I would go for.

DR PAL: Well, let me do this, Dan. Let me take away the liver metastases for a second. Let’s say this is extensive nodal mets or something of that sort. What are you thinking in that scenario? Still erda? Would you give this patient a shot at chemo?

DR PETRYLAK: I’d give chemo a try then.

DR PAL: Yeah.

DR PETRYLAK: I’d give chemo a try first, and then I perhaps would — again, it depends on where the patient progresses. But I would give chemo a try first. Again, nodal disease, that’s something who’s got a good chance of responding to primary chemo.

DR PAL: Right, right. Absolutely. Absolutely. Guru, I’m going to throw this one to you. So this is an 80-year-old patient who’s FGFR wild type, okay, and this patient’s disease has progressed on front-line pembrolizumab. Perhaps as suggested earlier, this patient got second-line enfortumab. I was surprised, actually, to see the heterogeneity of responses here. Again, this is third-line therapy in an 80-year-old patient, and there’s a fair number of respondents for chemotherapy there. Can you help us think through this, Guru?

DR SONPAVDE: Yes. I think that there are a number of options here. So you also have sacituzumab as an option. You have chemotherapy. Sacituzumab is approved post platinum-based chemotherapy and immune checkpoint inhibitor, so I’m not sure if you will have a problem getting it through the insurance. But I think both — I guess this patient is cisplatin ineligible, so carboplatin/gem is an option and so is sacituzumab.

DR PAL: Got it. Got it. Dan, maybe you can hone that in a little further.

DR PETRYLAK: I think, again, it’s going to depend upon the sites of disease.

DR PAL: Okay.

DR PETRYLAK: As we saw from the presentation before, sacituzumab has a fairly high response rate in liver metastases. And so again if I’ve got predominantly nodal disease I probably would go with chemotherapy and then sacituzumab if the progressed. If they have hepatic mets I would go with sacituzumab over chemo.

DR PAL: What do you think it is about these drugs, Dan, that drives that activity within the liver? Any thoughts on that?

DR PETRYLAK: It may be a drug delivery issue. We’ve known — actually if you go back to some of the old literature in SWOG, we did an irinotecan study, and we just missed having that go to the second level based upon 1 response. And that was in second line. Same thing with the taxanes. We’ve known that taxanes and tubulin agents always had activity. And so perhaps you’re able to deliver more of an active drug locally, and that may be the reason why we’re seeing these responses.

DR PAL: Got it. Got it. This is a general preference question here. There’s some heterogeneity in responses here, but I guess this is assuming that this patient is FGFR3 mutated. I guess I could play around with the scenario a little bit here, but let’s say this patient actually has nodal metastatic disease. I’m going to stick with you, Dan, here for a second. Assuming you’ve got all 3 of these agents at your disposal what are you picking?

DR PETRYLAK: Nodal metastatic disease, and only 1 of these 3.

DR PAL: Correct.

DR PETRYLAK: Again, I’d probably go with enfortumab.

DR PAL: Enfortumab. Enfortumab. Why? You just mentioned the activity within the liver specifically.

DR PETRYLAK: Right. And I think that — again, I think that for me it’s just an easier drug for me to administer from a side effect standpoint.

DR PAL: Okay.

DR PETRYLAK: Again, I would look at the patient because erdafitinib’s a great drug, and I don’t deny it — deny that, but again, I’ve had a lot of fatigue on it and a lot of nailbed issues and stomatitis, and also you have to monitor the phosphorus very carefully.

DR PAL: Yeah.

DR PETRYLAK: And the other thing, too, is that they do have to see an ophthalmologist on a regular basis because you can get this central serous retinopathy, which I’ve had happen in a patient who was responding. It was an unfortunate situation, but we had to hold his treatment for a while.

DR PAL: So how are you orchestrating that, practically speaking? Are you getting them into the ophthalmologist right away, or..?

DR PETRYLAK: Well, I try to get a baseline exam, and then I believe it’s at 3 months that this needs to be re-examined. So there is more involved with that drug. You don’t have to have a regular ophthalmologic exam with enfortumab.

DR PAL: Yeah. It’s challenging in some scenarios. We’re a freestanding cancer center so we don’t actually have ophthalmology inhouse —

DR PETRYLAK: Right.

DR PAL: — so orchestrating all of that is a bit of a burden. Shilpa, what about you? Assuming you had all 3 of these agents at your disposal, what are you thinking?

DR GUPTA: I would use enfortumab vedotin also, especially because we have data from the TROPHY study that patients who had prior enfortumab vedotin, they still respond to sacituzumab govitecan, so that would be my first choice. And if the patient can get erdafitinib, always have that for later, based on what Dan said.

DR PAL: Got it. Got it. So a lot of our discussion has really focused on existing therapies in our arsenal, but Dan, you presented some really compelling data for HER2-directed therapies. I thought for the longest time HER2-directed therapies were not going to make a big comeback in bladder cancer, but they’ve really resurfaced.

DR PETRYLAK: They certainly have.

DR PAL: Yeah.

DR PETRYLAK: And there was some single-agent data with trastuzumab a number of years ago. Actually a great study that was published in JCO where she did carbo/gem and paclitaxel along with trastuzumab. And the fascinating thing was that this seemed to have the same response rate in a poor prognostic group of patients. So again, maybe there’s something there in terms of the aggressiveness of the disease and HER2/neu expression.

But I mean I think it’s an acceptable choice. The question is where do you use it. And I’d probably use it in third line in this particular situation since we do have some very, very active drugs. Unfortunately, we don’t have randomized trials to compare them to see what’s better in this situation. But I think it’s something that we keep in the bullpen to be used after patients fail standard therapy.

DR PAL: Really interesting. I actually trained in Dennis Slamon’s lab at UCLA, in the trastuzumab lab, so that’s where I got my start in breast cancer, believe it or not. And it’s interesting to see it come full circle to the diseases I’m treating in clinic.

So we are right on time. Guru, if you’re up to it, you can try to beat Dan’s record here.

DR SONPAVDE: I’m not trying to beat anybody. I’m going to go over 2 minutes.

DR PETRYLAK: This is beat the clock, and we have Monty Pal instead of Monty Hall.

DR PAL: It’s all yours, Guru.

Tolerability/Toxicity of Novel Treatment Strategies and Practical Considerations in the Management of UBC — Guru Sonpavde, MD

DR SONPAVDE: Thank you. So I guess my job is to talk about toxicities of these novel treatment strategies and practical considerations. That stuff took me 1 minute.

DR PETRYLAK: Reset the clock, please.

DR SONPAVDE: So the therapeutic landscape in metastatic disease has of course changed dramatically. We have immune checkpoint inhibitors. We have 2 antibody-drug conjugates, enfortumab and sacituzumab. We have the targeted agent erdafitinib for FGFR2- or 3-altered patients. And we also still have taxanes in the US, and we have vinflunine in other countries and in Europe as a late-line salvage that is still around, so I would not quite give up on those because actually I still see some responses with these late-line agents.

So in the perioperative disease setting of course we’ve had cisplatin-based combination chemotherapy in the neoadjuvant and also adjuvant if not given neoadjuvantly. And now we have nivolumab, of course, approved in the adjuvant setting for high-risk muscle-invasive disease.

So talking about these immune checkpoint inhibitors first because my job is to talk about toxicities after that background. So the immune-related adverse events can affect any organ, so there is a huge learning curve. I would say that all of us are still actually learning and still on the learning curve on this because they’re just to tricky sometimes. You need a ton of patient education, vigilance, ask patients not to self-medicate for diarrhea and other things. You have to collaborate with specialties.

There are common toxicities like fatigue that can be quite important to pay attention to. There can be rare unpredictable symptoms like visual symptoms, uveitis, can cause photophobia. You also have to worry about preventing pregnancy in women of childbearing age group. So really a lot of things to worry about when you give immune checkpoint inhibition.

So several immune events have been seen that you see on the right-hand side in the figure. Almost any organ, any part of the body can be affected. The incidence of severe events is around 10% to 15% with PD-1/L1 inhibitors and is higher, 30% to 60% with the PD-1/L1 plus CTLA4 inhibition. So they might be life threatening if not promptly treated.

So you often hear that these immune checkpoint inhibitors are so easy, much easier than chemotherapy, but the problem is you can get potentially life-threatening toxicities in a small proportion of patients. And also these toxicities are not nicely predictable, and you know when they come with chemotherapy, but with these agents you kind of don’t know when they come. They can occur late. They can occur even a year or more after you stop the drug. And so really you have to be very careful with these drugs.

And one of the things I did want to highlight is that with avelumab there’s a little bit of a different toxicity of infusion reactions that you see with around 20% of patients. So this is the only PD-1/L1 inhibitor — it’s a PD-L1 inhibitor which needs premedication with diphenhydramine/acetaminophen for the 4 infusions at least. So if the patient does well the first 4 infusions you may not need it after that.

So how do you monitor the labs on these patients? So there are some guidelines that have been proposed. CBC and comprehensive metabolic panel. TSH and free T4 can be monitored a little less frequently, maybe not every cycle. Urinalysis and EKG and troponins are recommended, so they’re the ones in yellow. The lipase and amylase is something that we have done on trials and occasionally done in off trials, but it’s not recommended to be done routinely because they’re usually not symptomatic.

So if some of these immune checkpoint inhibitors can cause fatal events, but the fatalities are luckily not that common. As you see here, 0.6% in 1 large study, 0.36% in another study. And so when you look at the causes of these fatalities, with CTLA4 inhibitors you tend to see more colitis, with PD-1/L1 inhibitors you tend to see more — a little bit more pneumonitis, although there’s a little bit more of a spread of toxicities across all these organs with PD-1/L1 inhibitors.

You also have to worry about myocarditis, especially with the combination. You see that figure on the right there, one of the interesting things is the toxicities that are more common are less fatal. The toxicities that are less common, like myocarditis and neurologic, they’re more fatal. So you really have to worry about even the rare events because they can actually be more life threatening.

So what are the principles of management of these toxicities? These are some guidelines put out, and they’re kind of similar. ASCO, ESMO, there’s also SITC guidelines. So a Grade 1 events, you can monitor these events and continue the agent except for some Grade 1 neurologic or hematologic or cardiac toxicity, which you would want to pay more attention to and stop the drug even if it’s Grade 1.

For a Grade 2 event you may suspend the agent, usually I do suspend the agent for a Grade 2 event and consider resuming it when the symptoms revert back to Grade 1. You can use steroids. For Grade 2 you can use your judgment with steroids. Maybe you can get away with a lower dose of steroids, like 0.5 to 1.0 mg/kilo. I would mention that arthritis might respond to somewhat even lower doses, like 0.25 mg. And antibiotic prophylaxis is necessary if you’re using more than 20 mg a day for more than 4 weeks.

For Grade 3 and 4 events you have to suspend the immune checkpoint inhibitor and start corticosteroids and that should be tapered over 4 to 6 weeks. You might have to use high-dose corticosteroids, 1 to 2 mg/kilo per day. You have to re-evaluate the patient after 72 hours of treatment because if the patient is not responding promptly you have to consider second-line agents, and some of these agents are listed here.

These are more potent immunosuppressive agents. For example, you see colitis, a common toxicity. We commonly use infliximab or vedolizumab is an integrin inhibitor that has been used in refractory colitis. In hepatitis we don’t use infliximab because of the hepatotoxicity of infliximab itself, so there we go with mycophenolate or tocilizumab. Pneumonitis similarly infliximab. So there are — these are — these can be quite complicated in terms of decision-making, and you might want to use the help of an immunologist, somebody who’s more experienced with some of these toxicities, and maybe even a rheumatologist and a nephrologist.

So can you do these agents in patients with autoimmune diseases? Yes, you can, but there is a higher incidence of exacerbation of the pre-existing autoimmune diseases, about 75%, 71% as you can see here across 2 studies. But most of these events were managed with corticosteroids.

One of the things to remember is that patients on baseline corticosteroids of 10 mg per day or more might be — might have compromised — you might compromise the efficacy of the immune checkpoint inhibitor in those patients. So really you need to try to get the prednisone down a bit, if you can, in patients who are on steroids for some other reason.

So switching gears to enfortumab. This is an agent that you already heard quite a bit, so I’m going to zip through it. Peripheral neuropathy, rash, neutropenia is seen but not as common. Most of the neuropathy is Grade 1 and not usually Grade 2. About half the patients have some element of neuropathy.

Now in terms of skin toxicities, you see here, this can be quite common, about half the patients. Around 13% can have more serious skin reactions. The median time to skin reactions is quite quick, 0.6 months, so this is something to pay attention to. You can have severe, fatal events, like Stevens-Johnson syndrome or TEN, so that’s something to really pay attention to and get a dermatologist involved.

The neuropathy, as I mentioned, about half of all patients. Usually it’s pretty mild. It can be Grade 3 or 4, but the event — the Grade 2 or higher events with neuropathy occurs around 4 to 5 months, so that’s about the time that you start thinking about should you take a break or dose modify to alleviate the neuropathy. The management of neuropathy is complicated, and we don’t have big drugs. There are nonpharmacologic and pharmacologic, as well as topical therapies I mentioned over there.

Hyperglycemia is a toxicity with enfortumab, but it is usually manageable. We do want to check a hemoglobin A1c at baseline, and patients with an A1c of 8 or over were excluded from clinical trials. And if the glucose was 250 or more these patients should not get enfortumab before controlling the hyperglycemia.

So what about eye toxicities with enfortumab? This is more of a superficial corneal-type toxicity. This is not a deeper posterior toxicity like you see with erdafitinib. This is quite manageable. I commonly do prophylactic artificial tears for preventing these toxicities, and these are usually manageable. In very severe cases you might need topical steroids.

One of the interesting things with enfortumab in the quality-of-life study was that there was an improvement in pain score with enfortumab compared to chemotherapy. This was a third-line Phase III study. But there was actually appetite loss and weight loss with enfortumab. So the tricky thing is patients on enfortumab might be losing weight, and you might think they’re actually progressing with their cancer, but it might actually be one of the unfortunate quality-of-life events you see with enfortumab.

Sacituzumab has a slightly different toxicity profile than enfortumab. As you see, neutropenic fevers and diarrhea are common. GCSF usage was in around one third of patients. You do need antiemesis prophylaxis with this drug as opposed to enfortumab. You do need premedication for hypersensitivity reactions with H1 and H2 blockers, and you might need steroids in people with very severe infusion reactions even with the H1 and H2 blockers. So there is a slow infusion in the first incidence — at the first dosing.

So erdafitinib has a list of metabolic and GI and skin, nail and eye toxicity that I think you already heard. You must know that these patients were on a low phosphate diet at baseline to prevent hyperphosphatemia. You do need to monitor the eye for eye toxicity. You get the central vision defect. And I think you heard that ophthalmologists can be difficult to come by promptly at baseline as is advocated by the manufacturers, but there is something called the Amsler’s grid I show you in the right upper corner. This is something I hand out. I print it out and hand it out to the patient, and the patient can actually self-monitor their vision at home. And thankfully this toxicity is reversible in most patients.

That’s it.

DR PAL: Wow. Guru. Okay.

DR SONPAVDE: I failed. I failed.

DR PAL: Well, you lost, but you still did pretty well.

DR SONPAVDE: I knew I would lose.

DR PAL: That was good.

DR GUPTA: Always very competitive.

DR PAL: That was good, yeah. So Dan, you win. I owe you a beer the next time I see you at a bar, okay? Feel free to cash in on that. Okay.

DR PETRYLAK: I’ll be upstairs later.

DR PAL: Excellent. You got it. You got it. So we’re going to run through some clinical scenarios in the last 10 minutes here. And Dan, you already gave us some good perspective on this. Maybe I’ll turn it over to you, Shilpa. You suggested some of the thresholds around blood sugar and whether or not to give enfortumab. What about hemoglobin A1c levels, Shilpa? Is that something you’re using in clinical practice?

DR GUPTA: I’m not using — if a patient has diabetes I ask them what was their last hemoglobin A1c. But like Guru said, if it’s above 8 that is a poorly-controlled diabetic, and you have to be very cautious and have them intensify their blood glucose management. But routinely I’m not checking it.

DR PAL: And how about you, Guru, just to round things out on that topic? What’s been your practice there?

DR SONPAVDE: Yeah. I do pay attention to the diabetes and hyperglycemia. Patients without a history of diabetes I don’t actually routinely get hemoglobin A1c, but I’m checking their comprehensive metabolic panel.

DR PAL: You are. You are. Okay. And this really dovetails on that scenario. Let’s say you have a 65-year-old patient with a history of poorly-controlled diabetes, FGFR wild type. He progresses on cis/gem followed by avelumab maintenance. So Dan, you’ve done such a good job of reinforcing considering comorbidities and so forth, for this patient, sacituzumab, enfortumab, other chemo? What are you thinking?

DR PETRYLAK: I think sacituzumab would be something I would consider in this patient. Again, as we saw before, HbA1c of less than 8, glucose of 250 on day of treatment. I mean this is probably somebody who would not meet those criteria.

DR PAL: Yeah. Yeah. I’m going to pivot just a little bit here. Guru, you gave us such a nice talk on checkpoint inhibitors. I think you outlined for us something that we’ve come to know pretty well from both bladder cancer and other diseases, when you use combination CTLA4 and PD-1 blockade you really see augmented toxicity. Today we saw some efficacy data, right, for nivo in a sequential approach with ipilimumab. What are your thoughts there on dual checkpoint blockade in bladder cancer?

DR SONPAVDE: I think the dual checkpoint blockade might have a role in bladder cancer. I think the question will be answered by the CheckMate 901 trial, the Phase III trial that’s actually comparing ipilimumab/nivolumab versus gemcitabine/platinum in a Phase III trial. So it should be out hopefully sometime soon this year.

DR PAL: Very good. Great.

DR PETRYLAK: Yeah. And also in the DANUBE trial, treme, that was close. I mean, in the PD-L1-positives. So unfortunately it was not powered for that particular — for the PD-L1s only, but certainly there’s something that’s there.

DR PAL: Absolutely. Absolutely. So many great interpretations with DANUBE and endpoints in the context of that study.

So we’re going to get back to our conversation around toxicity now. So this question here is centered on what proportion of your metastatic bladder cancer patients receiving erdafitinib developed some of these clinically significant ocular toxicities. I mean, Shilpa, Guru gave us some ballpark statistics. Where were you on this continuum in terms of the frequency?

DR GUPTA: I was 10% to 15%.

DR PAL: 10% to 15%. Dan, how about you? Much different there?

DR PETRYLAK: I was the same.

DR PAL: And Guru, is that true to your practice as well?

DR SONPAVDE: I think it’s around 15%, 20% is what I see, but it tends to be mild and reversible.

DR PAL: Got it. Got it. And then Shilpa, what’s been your practice in terms of getting ophthalmology involved when you’re using erdafitinib?

DR GUPTA: As Dan mentioned, I try to get that at baseline and at 3 months, especially in diabetics who already have risk of retinopathy we have to be just more cautious and get it more frequently.

DR PAL: Yeah, yeah. It’s an interesting paradox, right, Dan, because this has the ease of being an oral therapy, right, but then the challenge of necessitating these ophthalmologic exams. So if you have a patient who’s coming from a large distance how does it influence your choice between erda and enfortumab? If they don’t have an ophthalmologist available to them are you not going to prescribe erda?

DR PETRYLAK: Well, I mean I think after what Guru showed us with that grid I think that that’s a terrific way of trying to avoid that issue. I mean certainly enfortumab, you’ve got to be there 3 out of 4 weeks the way the treatment goes, so if you can find some way of replacing the ophthalmologist I think that that’s really a positive.

DR PAL: Right, right. Absolutely. So this actually now shifts over to sacituzumab and some of the related toxicities there. Clearly we saw some neutropenia associated with the drug. Shilpa, are you using growth factors at all in the context of sacituzumab?

DR GUPTA: Yes, I am because neutropenic fever is a big toxicity, and this is something totally under our control, unlike some toxicities with enfortumab. So I do use pre-emptive growth factors, especially in older patients.

DR PAL: Got it. Are you getting UGT1A1 status and all that ahead of time as well in those patients?

DR GUPTA: If need be, right, yeah.

DR PAL: Okay. Okay. Fair enough. Guru, what about you? I’m curious. Are you using growth factor support with saci?

DR SONPAVDE: I am, but more selectively by ASCO Guidelines. I mean the incidence of neutropenic fever was around 10%, but most patients do fulfill ASCO Guidelines, over 65 years, comorbidities. So I do end up giving it in the majority of patients.

DR PAL: Very good. Very good. And we’re going to shift gears here now. So the patient’s having a great response to therapy with sacituzumab for metastatic bladder cancer, found to have an ANC of 900 without fever. What are you thinking in this case? Dan, how would you manage this one?

DR PETRYLAK: I’d hold and wait a week.

DR PAL: And I imagine we’re probably going to find some consensus here. Would you start, though, at the same dose or a reduced dose in that setting?

DR PETRYLAK: No. It depends upon what day — what cycle this is. I mean I generally give growth factor on day 8, 14 days of pegfilgrastim. I got really badly burned with the first patient we put on TROPHY, who was neutropenic after the first cycle.

DR PAL: Okay.

DR PETRYLAK: So I use it pretty routinely. I guess what you can do with this particular patient is give him GCSF daily, if it’s on day 1 for a week, and then hopefully his counts will come up the next week at that point. But I try to integrate the growth factors in with this.

DR PAL: Makes sense. Shilpa, any difference of opinion there?

DR GUPTA: No. I totally agree.

DR PAL: Yeah. Yeah. Well believe it or not we actually have some time now to go to audience questions because you guys did such a phenomenal job with timing today. And this has come up time and time again across the questions, variant histology, metastatic squamous cell histology. Guru, I think I’ve seen some of your papers on this topic. What are your thoughts there? If you have a metastatic squamous patient how are you managing them?

DR SONPAVDE: Well, we don’t know how to manage these patients, so generally I’ve given the same chemotherapy that I would give in routine urothelial carcinoma. These patients tend to be PD-L1 high and might be responsive to immune checkpoint inhibition, but they have not been well studied. Other squamous cell carcinomas do respond. They tend to be PD-L1 high. So that’s something to pay attention to.

DR PAL: And it moves fast, right? So are you giving them the PD-1 inhibitor up front with chemo? Are you sequencing it? What’s been your approach there?

DR SONPAVDE: Generally sequencing after the chemo, similar to — I would apply the JAVELIN paradigm just because I don’t know what else to do with these patients because there’s not enough data. But immune checkpoint inhibition clearly is something to keep on the radar for squamous cell carcinomas.

DR PAL: Got it. Got it. I mean we always get questions like this, right, as second opinions, consults. One thing that has come up in the questions here, and one thing that always comes up in my practice, is how do you manage adenocarcinoma of the bladder. Shilpa, any thoughts on that? That’s a tough one.

DR GUPTA: I typically use the regimen that’s used for colorectal cancer, like FOLFOX-based regimen. I mean it’s such a rare disease, we get 1 or 2 cases every now and then, but that’s my experience, that they respond quite well to that.

DR PAL: Got it. Got it. Yeah. FOLFOX tends to be my mainstay there too. And just to round things out when it comes to variant histologies, Dan, what about small cell carcinoma of the bladder?

DR PETRYLAK: Small cell, etoposide and platinum.

DR PAL: Etoposide and platinum.

DR PETRYLAK: Yeah.

DR PAL: Checkpoint inhibitors in that context? Yes/no?

DR PETRYLAK: I have not done it along the lines of lung cancer. We’ve used that as second-line therapy, but we haven’t combined that up front.

DR PAL: Got it. Got it. Another question that’s coming up from the audience, and again, this really just reflects real-world practice, is let’s say you have a patient who comes in, metastatic disease, let’s say liver mets just to use the same example as Dan had provided. In this context they’re on carbo/gem, having a great response to therapy, but you can’t get them past 2 cycles in that scenario. You get their scans, their doing well there. Would you shift over to maintenance avelumab in that context? Would you — again, they’re responding to therapy, but you don’t think you can give them more chemo. Dan, maybe I’ll start with you.

DR PETRYLAK: Well, the JAVELIN trial gave 4 to 6 cycles of chemotherapy, so I would make every effort to try to get that disease under control first before we went on the checkpoint, if you have to switch to another chemotherapeutic agent, perhaps enfortumab at that point, since they’ve got liver mets. But I would do everything I could to get that fourth cycle in.

DR PAL: And let’s say you can’t. Let’s say they have extenuating circumstances, toxicities that you just don’t feel are —

DR PETRYLAK: I would just go onto maintenance at that point.

DR PAL: Maintenance avelumab. Shilpa, what are you thinking in that context?

DR GUPTA: I would agree, try to do our best to get them to 4 cycles. If it requires delays, that’s okay, but try to do 4.

DR PAL: Got it.

DR GUPTA: They are looking at 3 versus 4 in a trial that’s ongoing, but for the most part we should try 4.

DR PAL: Try for 4. And now we’re going to wrap up with this very last question here, dose-dense MVAC. A lot of the trials that we’re looking at now in the neoadjuvant setting use a base of cis/gem. So Guru, what are your thoughts? Dose-dense MVAC? Cis/gem? What should we be thinking about in the neoadjuvant context?

DR SONPAVDE: So my de facto standard is gemcitabine/cisplatin except in some situations where, for example, in node-positive disease, N1 disease, where I really want to get the tumor burden down to make this patient a surgical candidate. I might want to use dose-dense MVAC, which has a higher response rate, higher downstaging rate. So other than that I’ve tended to use just gemcitabine/cisplatin because it’s just easier.

DR PAL: Fantastic. Well, we’re done, guys, with a minute to spare. Thank you so much for your attention. Hope you have a great rest of the meeting.