Introduction

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice, and welcome to What I Tell my Patients: New Treatments and Clinical Trial Options, as today we finish up our 10-part series focusing on urothelial bladder cancer. We have a great faculty today, and in a minute we’ll have them introduce themselves. As I mentioned, this is the tenth and final meeting of our 15-hour experience, so I want to particularly say hi to — there are a bunch of people out there that have been to all these, and that’s the way to do it because we have 40 people that we’re making rounds with here today, and it’s been a great and exciting week.

Just a reminder, your iPads have all the slides we’re going to show today, and a lot more. The faculty put together a bunch of slides. We’ll got through some of them, but there are others for you to check out. There’s also a survey for you to take. If you take that you’ll get a lot more out of this meeting. And also you can use the iPad to ask questions or present cases to the faculty, as well as do the evaluation. And for our online crowd, hey, how are you? Good to see you again. I’ve been hanging out with you all for the last couple years, and all those functions are available in the chat room as well.

We are video and audio recording this. We’ll be posting this, and for those of you who missed some of the programs and for your colleagues who aren’t here, they can check it out online.

This is where we’ve been over the last few days. There are a bunch of themes that we’ve had as we go through this, and we’ll talk about that. In addition, we’re doing — there were a couple other webinars we couldn’t really squeeze in, or a couple other programs, so we’re going to do them as webinars over the next couple of weeks.

So just as we’ve been doing for the last couple days we’ll introduce the faculty. And just a reminder, we’ve been talking about the fact that we know that about a third of this audience here has been in oncology less than 10 years. And first of all we want to say to you — well first of all welcome, but also just things were not the same 10 years ago. There’s a big, big difference in oncology. So much more research, so many more options coming out. It’s really difficult for us to keep up, and that’s one of the main reasons we’re here today.

So with that we’re going to introduce the faculty. And in keeping with the idea that we know some people are kind of new to oncology and the question of isn’t oncology depressing, which we know, we did a poll earlier this — the last couple days, and I think on average people get asked that more than once a month. And so one of the keys we found over the years listening to our faculty, to kind of take care of yourself in the midst of what can be a lot of stress, to get away from it. So to introduce everybody I’ll ask them kind of what they do to get away from oncology, beginning with Monty Pal.

DR PAL: Oh. Thanks, Neil. Well it’s an honor to be here, and thanks for having this program right in my backyard. I actually live about 15 minutes away from here, so this was really convenient.

DR LOVE: Did you go to Coachella? Because we’ve been saying this isn’t Coachella, this is Woodstock here today. But I think Dr Garon from lung cancer at UCLA, he was over there at Coachella. Anyhow…

DR PAL: Oh, you’re kidding. I didn’t go to Coachella, no, but I will say that dovetails nicely into my hobby, which is music. I spend a lot of time in my garage playing guitar, 80s, 90s rock in fact, and I’ve actually cultured my son into the same genre of music, and now he’s on the drums. He’s 9 years old. He’s terrific.

DR LOVE: Great, yeah. That was the music. So Shilpa?

DR GUPTA: Thank you, Dr Love. I’m really excited to be here with all of you. And in my free time I’m not as talented as Monty, but I like to play with my puppy and my kids and just hang out.

DR LOVE: Puppies are good. Brenda?

MS MARTONE: Thank you, Dr Love. I actually live in Chicago right next to the lake, so I love just walking by the lake, and I always challenge myself to go as far as possible. So actually this last summer I walked half a marathon.

DR LOVE: Wow. Awesome.

MS MARTONE: It was wonderful.

DR LOVE: So Monica, actually we just met. We’ve been working online the last couple years, now we get to work — so many people like that. Monica, what do you do to get away from things?

MS AVERIA: When I’m not working at my full-time job I’m at my other full-time job. I’m a mom of 2 boys.

DR LOVE: That’ll do it. How old are they?

MS AVERIA: 16 and 14.

DR LOVE: Interesting. Yeah. I’ve got a 16-year-old son as well. Pretty interesting challenge.

So before we jump into the content for bladder cancer, one of the themes we’ve had is like where are we with cancer research, and again to sensitize people new to the field that what’s been going on in the last few years, where like you wake up in the morning, you check your phone to figure out what’s been approved, it has not always been that way. And there’s a real reason. I mean look, we just got saved by technology in terms of COVID, right? So technology is ramping up. We’re seeing so much more research.

But we asked you, what do you think is going to be going on in 10 years. Is this all hype? Do you think we’re going to be back where we were 10 years from now? Well, let’s see what you all think, and then maybe we’ll ask the faculty.

So actually nobody’s in my camp. I’m down there at the bottom. I think this is going to be all over in the next 10 years, but maybe that’s a little overoptimistic. But I’d say this looks moderately optimistic.

Monty, when we asked you, and later on we’ll ask you to comment on where you see things going in bladder cancer, but just globally can you paint a picture for the audience and kind of put in perspective what’s been going on the last few years and how that contrasts to kind of what was going on 5 or 10 years ago?

DR PAL: Oh, yeah. I just don’t know if there’s a better example in oncology than bladder cancer. I think back to when I started in practice 16 years ago, and things just seem to be inching along. It was just cisplatin and gemcitabine, cisplatin/gemcitabine for over a decade. And then over the course of the past 5 years, man, there’s just been an onslaught of new therapies, and I think it’s really transformed things. So I share your view. I’m hoping that we’ll be able to eliminate this thing a decade from now. We’ll see.

DR LOVE: So Shilpa, any thoughts about that? Again, one of the things that’s a real challenge nowadays, oncologists are struggling to keep up to date, particularly clinics where you see all kinds of cancer, the general medical oncology setting. I always use bladder cancer when I talk to the hematologic oncologists and say they have 5 lines of therapy in metastatic disease approved in bladder cancer. I mean what are you doing? Shilpa, any thoughts about where you think we’re heading in the future and what it’s like now for a patient to go into a trial, where they might get an agent that really is going to help them as opposed to the past where a lot of times we were comparing A versus B and neither of them were too exciting? Any thoughts about that?

DR GUPTA: I agree with Dr Pal. In the last five years we’ve seen a tremendous growth in the therapies and more and more therapies are moving to earlier, noninvasive muscle bladder cancer setting, and I think the goal is elimination, and over the next decade we probably will be able to meet it.

Management of Localized Urothelial Bladder Cancer (UBC): Adjuvant Treatment, TAR-200

DR LOVE: So let’s jump into the content here in terms of urothelial bladder cancer. We’re going to start out talking about localized disease, then we’ll talk about metastatic disease, first in general and then a specific subset FGFR mutant. And that’s also been a main theme this week and a main theme in oncology is biomarker-driven decision making, and we’ll talk a little bit more about that. And we’ll finish out with a little bit of projection for the future both in terms of research and in terms of clinical patient care.

But first of all, let’s talk a little bit about management of local urothelial bladder cancer. And Monty, many patients will actually start out with noninvasive bladder cancer. They often are treated, and they’ve been treated for many years, with BCG, an immune form of therapy. Monty, can you talk a little bit about your vision for what noninvasive bladder cancer is and how BCG gets utilized?

DR PAL: So this is actually probably the perfect example of how things have morphed over the years. We were talking a little bit about this transformation in bladder cancer, no better state is non-muscle-invasive disease. When I used to talk to the fellows when I was starting out, I used to tell them look, you’re never going to see cases of non-muscle-invasive bladder cancer. That’s really the urologist’s domain. And it was true. For the longest time we gave essentially the oldest immunotherapy we have in our arsenal, which is BCG.

But that’s really changed. Patients would get on BCG. If they didn’t respond they’d see our urologist still for cystectomy. Now we have options to push immunotherapy with checkpoint inhibitors into that space. So as medical oncologists, as I think many of you are in the room focused on in practice, you may start seeing more and more of these patients who fail BCG and are candidates thereafter for checkpoint inhibitors like pembrolizumab.

DR LOVE: So Shilpa, you put together this slide providing an overview of non-muscle-invasive bladder cancer. We’ll put it up there in a second. There you go. Can you talk a little bit about how these patients present, how they’re diagnosed, and how they’re managed?

DR GUPTA: Yeah. So like Monty said, non-muscle-invasive bladder cancer has been the urologists’ domain forever, and it wasn’t until a few years ago that we actually learned the definition of BCG unresponsive disease when we were running the trials for pembrolizumab. And typically they present with hematuria, which is often attributed to UTIs, but the key point here is they should be promptly referred to a urologist, where the gross hematuria or microscopic hematuria could be a sign of bladder cancer and more serious than what we sometimes presume to be UTI. They can sometimes have abdominal pain, painful urination, and typically a urine cytology and imaging is done to diagnose. And cystoscopy is a must, and if urologists see anything abnormal on that they do a transurethral resection of the bladder tumor, and by pathology diagnosis it’s certain whether it’s non-muscle-invasive or not.

DR LOVE: So let’s go through some of the data behind this and also some new things. Very interesting developments that have occurred in this scenario over the last couple years. And first we can kind of maybe talk a little bit about the anatomy of what we’re talking about here. Monty, can you kind of go through the way — the staging of these primary lesions, and again how you think through whether or not to treat the patient?

DR PAL: Yeah. It’s funny. As we’re going through this question I’m looking at Kary, who’s one of our outstanding nurses from City of Hope Orange County here, and she’ll probably recognize this from some of the dialogues I have with patients. We get out a big whiteboard and we draw out this very picture over here to explain. And this is complicated, I think, many times in conversations with patients, how the stage of cancer really affects therapy.

So that critical distinction is what you see in that red box over there. When you look at bladder cancer, if the tumor has not penetrated into that muscular layer you fall into this category of non-muscle-invasive disease. It implies that you’re T1 or less than that, and that really puts you initially in the urologist’s camp. As I mentioned, there’s overlap between the 2. If you have T2 disease or above, if that disease is penetrating into the muscular layers, that’s a major, major distinction. It means that there’s a much higher chance for systemic spread of disease, and that’s where you want to start thinking about cystectomy or radiotherapy and chemotherapy, and the medical oncologist really becomes involved in that particular domain.

DR LOVE: So Brenda, one of the big advances in this field occurred a couple years ago when patients with this situation who were progressing after getting BCG, other intravesicular therapy, intravesicular chemotherapy, gemcitabine for example, were treated with immunotherapy, checkpoint inhibitors. We know — at one point there were 5 checkpoint inhibitors approved in bladder cancer, so certainly they’ve been a big part of the story, and that’s been mainly muscle — initially in metastatic disease, then adjuvant therapy, as we’re going to talk about, but also non-muscle-invasive disease. And you are seeing people coming in now who are not responding to BCG, and rather than go to cystectomy, perhaps they’re older or comorbidities or they just don’t want to go through it, they take a shot at pembrolizumab.

We’ll take a look at the data in a second, but I’m just kind of curious, Brenda, how this plays out clinically. It’s a very kind of a challenging situation, when you know you can take their bladder out and maybe cure them, to treat them with a therapy that is only going to benefit a minority of patients. How have you seen this played out in your practice?

MS MARTONE: Well, I think the first thing that we kind of see is we have to work with the patient and meet them where they’re at and respect their decisions. They understand their options, and if they’ve chosen to kind of keep their bladder, which is a big deal, actually, to lose your bladder, having an opportunity to provide them with a checkpoint inhibitor, possibly, even though the chances are small, give them some long-term control of their bladder cancer. And the challenge has also become based on what they’ve had previously kind of educating that patient about what not to expect is how I kind of approach it, given all the particular side effects that go with immune checkpoint inhibitors.

DR LOVE: So Monica, one of the challenges of this situation is occasionally you’ll see a younger patient, perfectly fit for surgery, who just does not want to have a cystectomy and would rather try, for example, immunotherapy. Very challenging for the oncologist when you know — of the urologist, when you have a curative form of therapy that the patient is going to not use.

Here’s the most recent data using pembrolizumab, and you can see there are patients who have good responses that last a long time, but there are a lot who don’t, so it’s not a 100% thing.

I don’t know if you’ve seen any younger patients who could have a cystectomy that preferred to take this route. And have you seen any issues with autoimmune toxicity in this situation?

MS AVERIA: So we do see them a lot. We see patients in the preoperative setting and postoperative setting. As what Brenda just mentioned, the key is really educating the patient about what their options are, both from the surgical perspective and the medical oncology perspective. In terms of offering immunotherapy, we take them through the potential side effects that can happen. I tend to tell the patient about the side effects that can happen, but I also do emphasize to them the most common side effects that we see. Most often patients come back and tell me that the side effect profile that I reviewed with them is actually not as much as I’ve discussed. And for me it’s important to let them know what they can expect, so we can take them through the side effect profile each and every time we see them in clinic.

DR LOVE: So Monty, we’re going to be going to the American Urological Association Meeting and doing a couple meetings, one on prostate cancer and one on bladder cancer, and when we were doing some videos with urologists getting ready for — getting some cases and stuff, and they started telling me about this TAR-200 delivery system to deliver gemcitabine into the bladder, very interesting because it’s a different pharmacology. When you give IV gemcitabine you get a peak and drop. With this pretzel that gets put into the bladder and kind of almost sounds like an IUD in a way, and a slow release of gemcitabine over 3 weeks.

And they’re seeing responses in muscle invasive. That’s where it was initially studied. It’s having systemic effects, almost like giving systemic gem through the bladder in a way, but it’s totally new. None of us — I guess we really haven’t started to see patients, it’s pure trial. But just again, thinking about the future, any thoughts, Monty?

DR PAL: I think it’s incredible technology. And when you think about it, for years we’ve been giving chemotherapy intravenously with the hope of getting a smidgeon of that towards the bladder to treat muscle-invasive disease, so this is a brilliant approach. And I would argue that this approach that TAR-200 takes, which is this gemcitabine-eluding pretzel, it could also be applied to other drugs as well, so now there are efforts to cultivate the same, so you might have FGFR inhibitors that are actually slow releasing from pretzels. You might have checkpoint inhibitors, and this is earlier in pipeline, that might get released from these pretzels. So it’s incredible technology, and again it really just increases the intersect between urologists and medical oncologists.

DR LOVE: And Shilpa, another theme that we’ve gotten into this week started with lung cancer with chemo plus IO, immunotherapy, checkpoint inhibitor, standard of care first line, everybody’s going to get some form of immunotherapy. Many other cancers right now are combining chemo and IO. Head and neck cancer for example. We talked earlier this morning about cervical cancer, first-line therapy in metastatic disease, chemo plus IO. But here you’re looking at — this is a new IO, cetrelimab, but combined with chemo, but chemo getting delivered through this pretzel. Any thoughts — and we of course heard about enfortumab plus chemotherapy, very exciting. We’ll talk about that later. Any thoughts about this kind of research, Shilpa?

DR GUPTA: Yeah. I think this is really an exciting study design where they are looking at the combination of this pretzel, which has gemcitabine in it, given in the bladder, and cetrelimab, which is a checkpoint inhibitor, and comparing it to just a pretzel or cetrelimab alone. And we really need such trials because we know pembrolizumab is approved for BCG-unresponsive non-muscle-invasive bladder cancer, but we really don’t know what single-agent TAR-200 would do, for example. So I think this approach is very — really very novel, and we know there’s some synergy between gemcitabine and checkpoint inhibitors from other cancers, including bladder cancer, as well, so this is a great study design, in my opinion.

DR LOVE: And Monica, you were saying that you’re seeing patients who are having this procedure done by urology. How do the patients seem to be tolerating it?

MS AVERIA: So currently we have 2 patients. I’ve not been physically present for the placement of the TAR-200. I know it’s placed every 3 weeks and removed every 3 weeks for a total of 6 months. And then — 3 months. And then the patient gets a rest period. And then after 3 months it gets placed again for a total of 2 years.

We see the patients in the medical oncology setting for the infusion. What I’ve seen on these 2 patients, 1 patient developed skin toxicities which required steroids. Unfortunately, with the steroids he actually had to be admitted, ICU, because he developed AFib and A flutter, so he went off the IV part. The other patient that we have, he’s 86 years old. He does not have any side effects from the infusion. As far as the TAR-200 he does not have specific side effects or toxicities. He did come onboard to us with a lot of comorbidities, mostly related to age. So he’s had 2 admissions, but one of the study principal investigators did not attribute the admission to the TAR placement.

DR LOVE: And I guess presumably the dermatitis is from the IO, from the immunotherapy that he’s getting.

MS AVERIA: Yes.

DR LOVE: Of course, we’ve been talking a lot about tolerability issues with IOs and dermatologic problems, although they’re usually not that troubling are still extremely common.

So Monty, let’s talk about another major advance in terms of localized bladder cancer. And we saw several new trials coming out. We mentioned we’re going to do this program after ONS on upper GI cancers, and now adjuvant IO standard of care after chemoradiation there, renal cell cancer adjuvant, and now we’re seeing, last year, this trial looking at nivolumab as adjuvant therapy in non-muscle-invasive disease.

Shilpa, can you talk a little bit about what was seen there and what your take was and whether or not this is enough to get you to bring it into your practice? We’ve been talking all week long about the hazard rate that you look for, and here it’s 0.70 for recurrence. So that means at any given time there’s a 30%, 70 minus 100, 30% reduction in the chance of relapse. We don’t know right now about survival. Monty — I’m sorry, Shilpa, can you talk a little bit about what you think about this trial and was it enough to get you to start treating patients?

DR GUPTA: So this trial was a big step forward for showing efficacy of nivolumab in high-risk muscle-invasive bladder cancer after surgery. And like you mentioned, Dr Love, the overall survival data is not — has not been demonstrated. 12 months of treatment did delay progression by around 12 months, but we do need to understand if everybody really benefits from this approach and what is the survival benefit.

Another trial of a similar patient population with atezolizumab was a negative trial. So I think while this is an exciting approach this is not a universal approach for all patients. We do need more follow up data. And especially in this study patients who had upper tract disease did not seem to benefit, so I think it’s a little premature to say that this approach should be used for everybody.

DR LOVE: So you’re not doing it or you’re doing it selectively?

DR GUPTA: I am doing it selectively.

DR LOVE: What would be a situation where you would do it?

DR GUPTA: For a patient, for example, who got neoadjuvant gem/cis and still had residual disease I am offering it to them. For a patient with upper tract disease, if they are candidates for cisplatin-containing chemotherapy after surgery, many times they have solitary kidney and we do not — we’re not able to give them cisplatin, we do offer this. Although we have a trial that is led by Monty which is selecting patients based on FGFR expression, and we try to offer that personalized approach to those patients.

DR LOVE: So Brenda, of course one of the challenges of adjuvant therapy, we were talking about this last night in breast cancer, where adjuvant therapy really — that was the first really tumor where it was used extensively, is because you can’t figure out who’s going to relapse. You end up treating people who were cured, so you’re exposing them to toxicity, but you can’t figure out who’s cured and who’s not. That’s why we use prognostic tools. We talked about Oncotype DX, for example, in breast cancer.

And so any kind of toxicity that you’re going to induce, particularly if it’s going to be serious or permanent, in a cured patient is very problematic. I’m sure that’s a big part of why Shilpa feels a little conservative about utilizing it.

What are some of the toxicities that concern you most in terms of in the adjuvant situation? This comes up in melanoma, where adjuvant IO — these are often young patients. You can induce diabetes, type 1 diabetes with a checkpoint inhibitor, and they have that for life. The patient maybe is already cured. What are some of the toxicities that come up that concern you the most in the adjuvant setting, Brenda?

MS MARTONE: So those would include some of the more serious adverse events, such as if the patient ends up with colitis. That’s a significant adverse event that could predispose them to having other issues in the future. Hepatitis for sure. And I think anything that involves the pituitary and adrenal axis is the most bothersome side effect, if it does occur, because these patients are going to have to alter their lifestyle and be supplemented with medication throughout the rest of their life. So that could be a significant impact.

DR LOVE: Yeah. Last night — checkpoint inhibitors are just coming into breast cancer now in the neoadjuvant and adjuvant setting. We had a case last night of a patient who had hypophysitis from the checkpoint inhibitor, inflammation of the pituitary gland, panhypopit, endocrine wise.

Monty, this is a slide that shows that the patients who had high PD-1 levels, and this really gets into, again, a huge issue all across oncology, how do you interpret PD-1 levels. You often see, like you see here, when you have just patients who have positive PD-1s, now you look at the hazard rate, and it’s 0.55. Now you’re talking about a 45% reduction, and the curves are a little bit farther apart. It kind of gets, Monty, into the idea of are you a lumper or a splitter, because overall the trial was positive, and you can certainly justify it. But then you have certain selectivity issues, and maybe if the patient has a high PD-1 would you be more likely to offer adjuvant therapy? And what in general is your approach? Are you kind of seeing it the way Shilpa does?

DR PAL: I have to tell you I really think Shilpa nailed it. I use a lot of the same selection criteria in my practice for picking who should get adjuvant therapy. I think a lot of us are really holding our breath until we get that overall survival data. And really tying together what Shilpa said and what Brenda said so eloquently around toxicities, I think when we’re offering adjuvant therapy we’ve got to be fairly confident that there’s at least a whiff of an overall survival advantage before we start using it indiscriminately. So things like this PD-L1 status, which I would probably hazard a guess are very challenging for us to interpret in a harmonized fashion, I don’t think are really going to influence my decision-making.

DR LOVE: And again, we’ve talked about this a number of times this week in terms of trials like this, where early on all you see is reduced relapse rate. It takes a while to start seeing survival. And theoretically you could say well, we can wait until relapse and then treat the patient then. I’m curious, Brenda, though, for the patients who kind of are getting into — I mean you could have a patient who’s a nurse or doctor who understands this, how do you think patients view the benefit of just preventing relapse? Maybe in the long run the outcomes going to be the same, but they’re going to live longer without relapse. Do you see that as a valuable benefit, Brenda?

MS MARTONE: It’s a careful conversation, actually, and it’s full disclosure of what we know and what we don’t know. And basically that’s informed decision making with our patients if we provide them with the information, and then together we can come to a decision that is a safe one for that person, and that person can decide if they want to do treatment or not. I never assume anything about people, so sometimes that person sitting in front of you, anything that will delay progression, doesn’t even need to be a curative intent, anything that’s going to delay their progression because they have certain life events they want to be around for, can influence decisions. And then I have other patients that say well, look at the risks, look at the possible benefit, I’d rather wait and be followed, or I would rather just wait until something is proven with the overall survival because that’s what’s important to me.

DR LOVE: So we asked Monica to put together some thoughts on some of the issues that come up in these patients, and one thing that’s important, in oncology of course we think a lot about systemic therapy, but the reality is these people are also getting, often, local therapy, and they may have significant morbidity. You’re going to have to deal with that at the same time you’re dealing with systemic disease. And in bladder cancer you’re dealing with a major, major procedure in terms of cystectomy.

So Monica, I’m just kind of curious what your experience is with patients going for cystectomy, urinary diversion. What are some of the challenges that occur as you’re starting to sift through the issue what kind of systemic therapy, or for example whether to give adjuvant treatment?

MS AVERIA: Sure. So radical cystectomy and urinary diversion patients require tremendous support. In the preoperative setting the patients are inundated with information regarding their cancer diagnosis. On top of that, they need to go through the treatment options that I offered to them with the oncologist and the surgeon. And then there are the self-care challenges, when the patient and the care provider need to learn the skills that are necessary so they can safely transition home to the home setting after the extensive surgery. So they now need to rapidly deal with learning the skills to handle the ostomy, the catheterization supplies, mucus production, skin irritation, leakages, and all the potential of normal issues that can arise for someone who just had cystectomy and urinary diversion.

Postoperatively it’s also very overwhelming for the patient because following extensive surgery some patients now need to begin adjuvant therapy, and this certainly complicates the scenario in terms of their recovery process.

DR LOVE: You also mentioned here some of the psychosocial issues that come up in this situation, for example, with a radical cystectomy and urinary diversion. Can you comment on that?

MS AVERIA: Sure. Because radical cystectomy and urinary diversion is an extensive surgery and is often associated with permanent alteration in the patient’s body image and body function, I listed a bunch of — a list of potential issues that can arise with these patients. One, there is the body function changes, odors, leakages, digestive issues is common and a sensitive issue.

There’s major financial impact. Cancer is not cheap. It’s quite expensive. There’s a lot of unexpected costs, from the medications, supplies, the copays, it also tends to affect our patient’s ability to work and ultimately their livelihood. It has an effect on the patient’s independence. Cancer poses a loss of control for our patients. Once a previously independent patient may now need to rely on their care provider to assist them with their ostomy management, to assist them with all their treatment schedules, their side effects. There’s lifestyle changes impact. There’s loss of spontaneity in the daily activities. Hygiene, bathing, choosing your clothes actually takes planning now. Having access to toilet facilities is essential for these patients. And the lifestyle changes also involve changing your activities, which can actually affect the patient’s social network.

There’s also a major effect on the patient’s sexuality and their intimacy. Because the surgery is quite extensive there’s a permanent alteration in the patient’s body function and body image. So there’s a sense of anxiety and self-consciousness with the changes that have occurred. And we all are aware of the feelings of anxiety and depression that’s ongoing over patients worrying about cancer recurrence.

And last but not the least, pain management after bladder surgery. Bladder pain is not uncommon. So this is something that’s not going to help the patient.

DR LOVE: How do you deal with bladder pain, just pain meds? Or is there anything local?

MS AVERIA: As a nurse practitioner I’m very big with enforcing the pain medication to them. Every patient has different needs. Every patient has different tolerance. Breaking through the cultural barriers and expectations of “I’m not allowed to be on pain medication” or going through why they’re not taking the pain medication so they can understand you’re getting constipated from the pain medication. We need to be on top of the medications to prevent constipation.

DR LOVE: It’s interesting. As you were talking, I was noticing the faculty was kind of nodding their head in agreement as you were saying things. Brenda, anything you want to add to what Monica was just talking about, particularly in terms of the personal effects, the psychosocial impact of cystectomy?

MS MARTONE: It’s interesting because it’s not just in terms of sexuality and intimacy. It’s not just the visible changes. There’s actually physical changes, and especially for a woman that may include actually taking out part of her vagina. And so I’ve had ladies say that even though they still do want to have sex that there’s limitations there, and that can be quite challenging. And then again the cost. I work in downtown Chicago, and there are multiple visits, and parking is expensive. And so the financial toxicity can also be a barrier because patients may not be able to come to their appointments or will delay follow up, or if they’re on a treatment maybe extend or not take their medication as prescribed just to make things last longer.

DR LOVE: And of course sometimes we have to see patients, but another thing we’ve been talking about this week is the complete revolution that has occurred in medicine over the last 2 years. I mean people 50 years from now are going to look back on 2020 and say that was the point at which telemedicine really got forced into practice, and it’s not going away. So we’ll see whether we can avoid some of these situations where people are coming in, and really you could — for a well-baby visit kind of thing, you could do that virtually as well.

Management of Metastatic UBC: Antibody-Drug Conjugates, Checkpoint Inhibitors

DR LOVE: Well let’s spend the rest of our time talking about metastatic disease, because as I mentioned, 5 lines of therapy, a lot to talk about. So one critical issue, of course, chemotherapy is usually the first modality that’s used in metastatic bladder cancer, and Monty, one of the key issues is whether or not they’re going to be able to receive platinum agents because that’s critical to the chemotherapy that’s utilized. Can you talk about what the optimal type of chemotherapy is and then how you evaluate the patient in whether or not they’re eligible to receive it? Or for example maybe they can’t get cisplatin, but they can get carbo?

DR PAL: Yeah, absolutely. And it’s a simple and such an essential paradigm, but it’s one that actually turns out to be fairly subjective in some respects. And Shilpa’s actually doing a lot of really great work to help revise and clarify what is and isn’t platinum ineligible. Essentially amongst these choices here I think you see a lot of the practical considerations. You look at a patient’s kidney function. Typically what we’re looking for is a GFR that’s above 60 to define cisplatin eligibility. Some might soften that to around 50. Very few, I think, go beyond that.

Poor performance status. So if a patient is ECOG 2 or greater you probably wouldn’t consider administering cisplatin. Peripheral neuropathy. If that’s Grade 2 or above, if it’s really clinically significant neuropathy, you’re probably going to steer away from cisplatin. And then we also look at cardiac function in addition to this, and we also look at a patient’s sensorineural hearing loss. So those round out some of the criteria that we use to define cisplatin eligibility.

Oh good, perfect. I think I got most of those right there. Perfect.

But like I said, there’s lots of soft calls in the clinic. I see our stellar urology nursing team in the fifth row there, and when you think about these criteria we do hedge a little bit in terms of what we offer in terms of cisplatin to really that healthy and robust patient.

DR LOVE: Shilpa, what about the patient who you feel really should not get even carboplatin? How do you approach them in terms of metastatic disease?

DR GUPTA: That’s a great question. We are trying to define this patient population because recent data has shown that patients should be offered carboplatin if they can’t be offered cisplatin. And the truly platinum-ineligible patients are a minority of around 10%. So I think those patients whom we feel based on these criteria, and we are going to present at ASCO Annual Meeting the results from our work, I would say those are the only patients we should offer front-line immunotherapy with pembrolizumab or atezolizumab at this point.

DR LOVE: And does it matter what the PD-1 level is in terms of whether you’re going to do that?

DR GUPTA: Not really. The PD-L1 has really not panned out as a good biomarker, and the Phase III trials have shown that despite the expression of PD-L1 carboplatin did better than immunotherapy in the front-line setting.

DR LOVE: I’m curious, Brenda, what you’ve seen in terms of immunotherapy in older patients. Now we’re talking about people who have comorbidities. There’s reasons they can’t get platinum. How does that go in giving immunotherapy? What fraction of patients have cruised through without any problems? What fraction do you see significant problems, Brenda?

MS MARTONE: I would say the majority of them do well, to be honest. These are well-tolerated agents. There is always the risk, again, for immune-mediated — immune-related adverse event. So I think most of my work is in telling patients, again, like I said earlier, what not to expect. So they shouldn’t have nausea, vomiting, shortness of breath, cough, diarrhea, just in case these patients associate what they’re getting, thinking it’s chemotherapy. And then having — reaching out to them and asking them prophylactically do you have these things. Because we all know patients who will come in and say I feel great, and then you’ll go through the review anyway, and they’ll be like oh yeah, I do have a cough. Or oh yeah, I do have diarrhea. And they didn’t share that earlier. So it’s better if we get these events identified sooner, when they’re not so severe, so we can intervene and perhaps at least eliminate or reduce the risk of having a more serious adverse event.

DR LOVE: So we’ve talked about a number of what we call practice-changing clinical trials. You see the data, and you go uh-oh, it’s time to change what I’m doing like right away. And this is one of them, I think, that was presented a couple years ago at ASCO, we just saw an update a couple months ago, of using immunotherapy as maintenance treatment after chemotherapy as opposed to combining it with treatment. You give the chemo first and then give it as maintenance. This is avelumab, a different checkpoint inhibitor commonly utilized with a number of other agents, but avelumab was the one that was studied in this trial.

Monty, can you kind of go through what was — how this trial was done and when people looked at that why they ended up — a lot of people ended up utilizing this strategy?

DR PAL: Yeah. So to dovetail on what Shilpa had just said, when we approach the front-line patient with advanced bladder cancer we’re usually looking at them to see whether or not they’d qualify for cisplatin-based chemotherapy, perhaps carboplatin-based chemotherapy. I agree with Shilpa, it’s really a small minority who can’t get either one of those. And what we used to do in yesteryears, we used to just twiddle our thumbs after they completed chemotherapy and wait for them to progress. And inevitably most of our patients did progress. Like I can count on my hands over the past 16 years the number of folks that have responded to chemotherapy alone for metastatic bladder cancer.

This is a really important trial because what it suggests is that rather than just waiting after chemotherapy to institute immunotherapy we should probably be diving right in. This trial randomized patients to either get chemotherapy followed immediately by immunotherapy with avelumab or best supportive care alone, and it really showed what I thought was a fairly substantial survival advantage in this setting. Shilpa’s got a great trial that’s actually dovetailing on this particular data set. But nowadays in the clinic if you have a patient who’s achieved stability or has had a response to chemotherapy you don’t just wait around anymore. You don’t just do scans on those patients. Typically, you’re going to segue them right onto immunotherapy with avelumab.

DR LOVE: So Monica, I’m curious what you see clinically when you implement this strategy, but just a real quick question from the audience, can the new targeted therapies, and we’re about to talk about that, and the antibody-drug conjugate enfortumab, as well as erdafitinib, can they be used in people who are not platinum eligible. I’ve never thought about that question, but I guess there’s no reason you can’t, right? Or do you?

DR GUPTA: Yeah. I think we don’t have any trials suggesting that, but it is under review by the FDA for front-line cisplatin ineligible to be used along with pembrolizumab, but not yet approved.

DR LOVE: That’s first line, but what about in the relapsed setting?

DR GUPTA: In the relapsed setting I think if a patient is — if a patient has relapsed we are free to use immunotherapy, and then it is approved for use after that, so I don’t see any issues with that.

DR LOVE: So Monica, what do you see in these patients who are getting maintenance therapy, they’ve just completed chemotherapy? What kind of shape are they in, and then what happens when you put them through the maintenance phase?

MS AVERIA: So when they go through this maintenance phase they have gone through the regimen, so they’re tired, fatigued. They’ve gone through decreased counts. Some of them have neuropathy. Some of them have decreased performance status. So we evaluate each of the residual side effects that they have from the previous chemotherapy before this is offered to them. So that’s how we evaluate them.

DR LOVE: And again, looking at this trial, and we’ve been talking about hazard rate. This is for survival, 0.76, so at any point in time there’s a 24% reduction in the chance of dying. So that’s a tangible benefit. And also progression-free survival, even more, hazard rate of 0.54, so almost a 50% reduction in progression, and similar very significant effect on survival.

So let’s move over now to what might be termed targeted therapy, and again, so amazing and exciting. Typically these patients are going to get checkpoint inhibitors either in the maintenance setting or in the second-line setting, and the question is what comes after, and that’s where we get into the fact that there are actually 3 more lines of therapy that these patients might get.

So Shilpa, you can imagine, we’re talking a lot about antibody-drug conjugates nowadays in oncology. We’ve been talking about the fact that just in December we saw an antibody-drug conjugate, polatuzumab, approved as first-line therapy for diffuse large B-cell lymphoma, the most common lymphoma. Last night we were talking about T-DXd and T-DM1 against HER2 breast cancer. We talked this morning about tisotumab vedotin, another antibody-drug conjugate being utilized now in cervical cancer. What about enfortumab? And we have 2 antibody-drug conjugates, actually, in urothelial bladder cancer, also sacituzumab, which again we talked about last night in breast cancer.

DR GUPTA: I think this is really a novel class of agents that has revolutionized how we treat metastatic bladder cancer patients. Even though immunotherapy was a big step forward, unfortunately only about 20% of patients respond to it, and the majority progress. And the approval of enfortumab vedotin really set the stage forward for its activity, and now we have sacituzumab govitecan, which can be used even after enfortumab vedotin in patients. So this is really an important drug class that has shown consistent efficacy in bladder cancer.

DR LOVE: So I’m curious, Brenda, how do you explain to patients what an antibody-drug conjugate is. I’ve heard all kinds of colorful things, from trojan horse to a bunch of other models. How do you explain it to a patient?

MS MARTONE: I actually keep it a little bit more simple. I tell them that there’s like receptors on their bladder cancer cells that have this nectin-4 if we’re using enfortumab. And basically the antibody-drug conjugate kind of looks for that receptor and attaches, and then basically it puts in the cytotoxic material right into the cell. So I tell them it’s a targeted therapy, but of course there are some bystander cells that will unfortunately get the effect when these cells that are bladder cancer die.

And I also — I’m sure you’re going to ask me what side effects I tell them to expect, can I —

DR LOVE: Sure.

MS MARTONE: Okay. And then — sorry. I read the notes. And then — so basically they’re like hey, that’s really cool, so I also have to tell them that we have nectin-4 receptors on some of our healthy cells, especially our skin, and so this whole drug conjugate has a unique set of side effects that they may not have been familiar with with the chemotherapy or even the immunotherapy.

So it’s important to let them know up front that the most common side effects that we can see are definitely skin rashes, and they can be anywhere from mild, just a maculopapular rash, maybe with or without itching. It can actually be quite diffuse with papules. I’ve actually seen some patients have more significant skin toxicities. So that’s why it’s important I’m letting my patients know ahead of time use lotion, don’t go out in the sun or put skin — sunscreen on.

And then as well as the peripheral neuropathy, so with all of their previous treatments they very well could come in with some baseline peripheral neuropathies. It’s not an exclusion factor for this medicine, but I think it’s important as nurses and providers that we kind of assess where they are at baseline objectively. So mild, moderate, severe doesn’t really tell us a lot — too much about where that it. So maybe asking your patient can they button their buttons, zip their zippers, tie their shoes, and then kind of get a grading system in terms of how much those peripheral neuropathies interfere with their ability to do their instrumental ADLs or even their most basic ADLs.

DR LOVE: You had this 49-year-old woman. Can you talk a little bit about her?

MS MARTONE: So I met this patient when she was 45, when she was first diagnosed, and she has a complex medical history. She had spina bifida. So she had already spent multiple years in medical care and undergoing surgeries, et cetera. So when we first started treating her we gave her dose-dense neoadjuvant, she underwent cystectomy, and she did well for a period of time but unfortunately ended up with recurrence of her disease.

And she really had poor tolerance of the cisplatin during dose dense, and so she begged us no more cisplatin. So then we treated her with a checkpoint inhibitor, and we got some mileage out of that, but unfortunately her disease did come back. And to get her to come into clinic to try to come for treatments was always a big struggle for her.

And so we started enfortumab vedotin. She understood the side effect profile. Actually, she did very well with the medication, very minimal side effects. And actually she had a great response. We actually saw a CR in this patient and actually confirmed it with several additional cycles and scans.

But at that point coming to the clinic to see us was so anxiety provoking that — her mother was one of her caregivers, and so her mother had to drag her in kicking and screaming sometimes, as well as she would be so depressed that she would spend all of her time in bed, even though she was getting this great response.

So we had a really good conversation about the potential risks and benefits of stopping treatment. We both came to the conclusion just because of all the anxiety, the psychosocial, that it would be best if we just took a break. I have never seen anyone so happy in my life. And actually I am really pleased to report that she’s been off treatment now for I’m guessing close to 9 months, and she remains in a CR, which is remarkable. And every time I tell her her scans are negative she just lets out the biggest scream I’ve ever heard. And she is like so happy now, and I’m hopeful that we can continue on this path, and she’ll continue to obtain benefit.

DR LOVE: You mentioned that she had spina bifida. Can you kind of paint a picture of her function level, and when you saw her initially what the manifestations were?

MS MARTONE: She was pretty functional. She only used the wheelchair if she had to come a long distance. She used her assisted devices to walk. During the chemotherapy, unfortunately, she became more incapacitated, and we often saw her in a wheelchair. During the enfortumab vedotin, with control of the cancer, she actually left her wheelchair in the trunk of her car and would walk all the way from the parking garage to see us in the clinic. So she was very high functioning.

DR LOVE: So I mean just to paint a balanced picture here. It’s common for people to present patients who do well; very important to know that something like this can even happen, but certainly not something you would expect or extremely common. Maybe we can talk a little bit about the actual data that we have and kind of come back to Brenda for more thoughts about how this translates clinically.

But let’s just take a look, and Monty maybe you can review the — this is a big trial. Whenever you see this type of look, the New England Journal, you know it’s important. All the big papers get in that journal. So it went into The New England Journal, Monty. What did they look at in this study? What did they find? And how did people translate it into practice?

DR PAL: Yeah, absolutely. So the profile of the patient who went into the study very much akin to what Brenda described, patients who had gotten chemotherapy, immunotherapy, and these individuals were randomized to either get enfortumab or what you might call a dealer’s choice of chemotherapy. And this is really key because prior to this trial we were really predicating use of enfortumab on just some really solid data we’d seen in single-arm studies. This big, randomized trial really was proof in the pudding that it was better than existing standards that we have. And Neil used the analogy before suggesting that when you look at these hazard ratios this translates to a benefit of 30% in terms of survival, but 38% benefit in terms of delaying cancer growth.

And if you look at it — look long and hard at this curve over there I think you could see a bit of a tail on the curve, maybe not the same as what you’d expect with immunotherapy. But this encompasses patients like the one that Brenda has described, I actually have 1 or 2 of those in my practice, as well, who have really had nice and durable and sustained responses to enfortumab. Now I have 1 patient just like yours, Brenda, in fact, who’s been able to stop treatment with several months off of therapy, still has CR.

MS MARTONE: Wonderful.

DR LOVE: Shilpa, we’re going to talk about what people see clinically, but what did they see in the trial in terms of toxicity, specifically — well, first of all, in terms of response rate? It looks like half the patients responded. Does that correlate with what you’re seeing in practice? And also what about toxicity? What was seen in the trial, and what do you actually see in your patients?

DR GUPTA: Yeah. I think the response rates are pretty remarkable in patients who’ve been treated with prior platinums and immunotherapy, especially those with liver metastases where immunotherapy doesn’t always work well.

And the unique thing about this agent is that if it is working you can tell clinically. Right after cycle 1 patients start turning around. I had a patient who was wheelchair bound when we started the treatment. Right on the day of the second cycle he was walking on his own, and we knew it’s working. And the scan showed complete resolution of liver metastases. I almost thought I’m looking at the wrong patient’s scans and had to review it with the radiologist. So we do have these great stories of responses in patients just like Brenda and Monty described.

And neuropathy is one of the big side effects, and that’s why we have to be very cautious and not keep pushing the drug, and take a break when needed, especially because they’ve had prior platinums also. And now we are hearing more and more about the skin toxicities, especially —even in the subcutaneous toxicities, and fatal cases have been described. So I always make sure we actually look at the torso of the patient and not just take it lightly because that can be very serious.

So I would say neuropathy, skin disorders, as well as hyperglycemia, especially in diabetics and those whose sugars are not controlled. And not to minimize the skin discoloration issue, I’ve had patients being really concerned about it, especially in their knuckles and their — one person had her skin turn black, and that’s a big concern for patients. So I think we have to be cautious and give a break when needed.

DR LOVE: I’m curious about your experience, Monica, with this agent in terms of toxicity. If you look at the trial you can see quite a few patients had their dose reduced or interrupted, but relatively few, actually, had it discontinued. And actually of course you see on the chemo arm a lot of issues as well. What’s your experience? And one of the themes we’ve been getting into this week is how patients react when you say we want to reduce the dose.

MS AVERIA: So my — one of my experiences on this drug is a patient who went through cisplatin-based chemotherapy and went on avelumab maintenance. And then on avelumab the patient developed pain and was noted to have disease progression, so he was offered EV. And unfortunately this patient developed disabling peripheral neuropathy to the point that he cannot button his shirt, cannot zip up his pants, cannot write checks. He went from walking 10 miles a day to having to use crutches, assisted device so he can actually walk without falling. We had to stop EV for this patient. We had to do dose interruption with this patient. Within 3 weeks of giving the patient a break his peripheral neuropathy improved.

In regard to the skin toxicities, it’s very important to really assess the patient because they will not tell you what’s going on with them. But if you actually — you need to take the time to roll up their sleeves, look at the chest, the back, the buttocks, the legs because I’ve had 2 patients who told me they’re doing fine, but they had blisters on their skin that I can only attribute to this treatment. I stopped the drug, gave them a break, it resolved, and we were able to continue with these 2 particular patients.

DR LOVE: What about chemo-like side effects? I mean you are giving chemotherapy, it’s just extremely targeted. We were talking last night in breast cancer, that agent T-DXd, which is really effective, but also they see hair loss, they see nausea/vomiting. Do you see that with enfortumab?

MS AVERIA: I see peripheral neuropathy, skin reactions so far in clinic. A little bit of hair loss for some patients. I haven’t seen anything else beyond that with the group of patients that we have.

DR LOVE: Monty, when you really think about it, we’re giving them chemotherapy, and yet you don’t see a lot of the chemo side effects. And along those lines, again, you see so many trials now, and actual therapies where you’re combining immunotherapy and chemotherapy. And if you think about it, okay, this is targeted chemotherapy, so the idea of combining it with an IO seems very logical. And in fact, I guess everybody’s pretty excited about what’s been seen so far.

This is the waterfall plot. We’ve been talking about this all week. Each one of these lines is a patient. If it’s going down the tumor’s shrinking. If it’s going up it’s getting bigger. You can see what’s going on here. Monty, any thoughts? Is this going to be in our future?

DR PAL: It’s interesting because when this waterfall plot was first shown at ASCO I think there were jaws dropping to the floor. I mean it was just really remarkable to think that you could have something like this happening in advanced bladder cancer.

So I would say at this point probably not quite ready for primetime, but there’s a trial underway right now, our site’s running it, I know many other sites are as well, which is going to be actually comparing this strategy to the more conventional approach of chemotherapy. And when you look at waterfall plots like this it’s hard for me to believe that this isn’t going to ultimately win out. This is very, very impressive.

DR LOVE: So Shilpa, I’ll tell you my fantasy. TAR-200 plus enfortumab plus IO. That’s a future first-line therapy. Just saying. We’ll see if I predict right.

Anyhow, I want to get into the other antibody-drug conjugate. Again, we talked about this last night. It was first approved, actually, in breast cancer, and we heard a lot of good stories coming out of breast cancer, going beyond the trial. We were talking about this last night. In breast cancer you see great effects, triple negative. Now this — in a month we’re going to see actually one of our faculty members. Hope Rugo is about to present data in ER positive, which is much more common. We couldn’t get it out of her last night what the results are. We tried, but she wouldn’t tell us.

But what about sacituzumab in bladder cancer, Shilpa? What do we know about that?

DR GUPTA: So this is another antibody-drug conjugate directed against TROP2, which is expressed across the membrane ubiquitously along a lot of cancers, especially triple negative, as you mentioned, Dr Love, and bladder cancer. And the side effect profile of this different from enfortumab vedotin. Here the payload, SN38, is a derivative of irinotecan, so we see a lot of GI toxicities like diarrhea, and myelosuppression, which at least we can prevent with adequate support and pre-emptive approach.

And in this study patients had had prior platinums and immunotherapy, and I believe around 6% had also received prior enfortumab vedotin. And we did see response rates of 27%, which is quite encouraging in this heavily pretreated patients. So this is another advancement in the field after patients have had enfortumab vedotin.

Management of UBC with an FGFR Mutation

DR LOVE: So we’re going to move on now and talk about targeted therapy — another form of targeted therapy in bladder cancer, again, along the lines of biomarker-driven therapy, specifically the drug erdafitinib. And Monty, maybe you can talk a little bit about what FGFR mutations are. Now these are mutations in the tumor. Again, we’ve been talking about this all week. You can see germline mutations, inherited, every cell in the body, but you also see situations where there are mutations within the tumor. What’s FGFR, Monty, and what do we know about erdafitinib in terms of first of all the mechanism of action?

DR PAL: Yeah. So you’ve talked about a lot of different therapeutic settings. Lung cancer probably does it best, where you can use a gene profile that actually parses out treatment for patients, if their ALK positive, EGFR mutated, et cetera, et cetera. We never really had this for bladder cancer. And you could look to the current guidelines to figure out sequencing for a lot of the therapies we’re talking about today, but the one thing that’s not really reflected there, and my main message, would be try to get that gene profiling done early for your bladder cancer patients. Because we now know that if you fall into about the 20 or so percent of patients who have this FGFR mutation you can actually apply a targeted therapy towards that.

So again, it’s not going to be in every patient, about 15% to 20% of patients manifest with this alteration, higher if you have an upper tract tumor. There it’s about 40%. But if you’ve got it you may be a candidate for erdafitinib.

Erdafitinib, much like the small molecules that we use in lung cancer or in breast cancer and so forth, really targets specific mutations, and in this case it’s mutations in FGFR3 in particular.

DR LOVE: So Shilpa, you put this slide together to provide an overview of FGFR mutations and erdafitinib. Can you walk us through it?

DR GUPTA: Yeah, sure. So we find that the expression of FGFR is a little bit stage dependent, like Monty said. In earlier settings it’s believed to be highly expressed, and that’s why it’s being looked at in non-muscle-invasive setting too. In muscle-invasive setting it’s about up to 20%, and metastatic also is around that. And I’ll say our experience has been around 15% to 20% of all patients we screen genomically.

And erdafitinib is an oral targeted therapy that inhibits FGFR pathway to block cancer growth. It does result in tumor shrinkage in about 40% of patients, and the median overall survival in the single-arm trial was around 11 months. Confirmatory trial is ongoing, which will tell us if this is maintained or it performs better than the standard of care chemo.

And the toxicity of this drug is not minimal. We really need to monitor patients closely. And many times we feel that oral drugs are easier than chemotherapy or other therapies, but with this particular agent the skin and nail toxicity is quite significant, so much so that patients’ nails start peeling off, and there’s painful side effects. Hyperphosphatemia is another toxicity. We need to carefully monitor their phosphorus levels weekly. And not to forget the eye toxicity, the central serous retinopathy and nonretinal disorders. So it’s recommended that patients get baseline ophthalmology exam and follow up when needed. So this, in my opinion, compared to other intravenous agents, these drugs require much more monitoring and dealing with the toxicities.

DR LOVE: Can you remind us what central serous retinopathy is?

DR GUPTA: So that is a toxicity which affects the retina, and it can affect peoples’ vision. Fortunately it is not irreversible, so when we stop the drug it can get better. But the key is to have a multidisciplinary team of — getting patients plugged in with the ophthalmologist right at the beginning so we are not scrambling when it actually happens. Especially in patients who are diabetics and already have retinopathy we have to be very cautious.

DR LOVE: So Monty, before Monica goes through some of the clinical issues, let’s take a look at some of the data. Again, this is a follow up from this Phase II study that was just published in the Lancet Oncology. Can you kind of review again, we see a waterfall plot and the swimmers’ plot there, in terms of how long people are on therapy? Can you talk a little bit about what’s been seen, and also your personal experience? Have you had patients who had responses that really made a difference to them?

DR PAL: Yeah, absolutely. I got interested in this whole premise of FGFR inhibitors pretty early on. I’ve done a lot of work with a different compound called infigratinib, which is currently making its way through Phase III clinical trials right now.

What’s impressive about this waterfall plot here, probably not quite as deep as the waterfall plot that we looked at for the combination of enfortumab and pembrolizumab, is that the response rate is holding up. When it was initially published in the New England Journal response rate was 40%. Now with this follow up still right at 40%. You’re seeing some patients who are on extended courses of therapy, but on average the responses here are going to last for 9 or 10 months or so, in broad terms.

One of the practical considerations that Shilpa alluded to I think is so challenging for us to implement in clinical practice, and that’s those regular ophthalmology checks. Just bay way of example, I’m at City of Hope, we’re a tertiary cancer center, we actually don’t have an ophthalmologist on staff. So we really struggled to identify someone to continuously follow these patients. A little different if you’re at USC or UCLA here in town, where you have those folks there on site. So those are just some of the practical challenges that we’ve faced.

DR LOVE: What about this issue of the ophthalmic effects? This is a plot of what happens to people as time goes on. It looks like after the initial bump it stabilizes. Have you have patients develop central serous retinopathy, Monty?

DR PAL: I have. And exactly as Shilpa said, if you identify it soon enough through these regular eye ophthalmologic examinations — I’ve been fortunate to do this primarily in the context of clinical trials. You pick up on it early, the ophtho visits were mandated there, you stop the drug, and boom, it goes away in many patients.

DR LOVE: So a lot of tyrosine kinase inhibitors are utilized in oncology, and many of them do have side effects. We were talking last night about EGFR — or the night before, EGFR mutations and the anti-EGFR agents, which are TKIs. Shilpa, what are some of the other issues that come up with this agent, and how do you prevent them? What about dysgeusia, problems with taste? Have you seen that?

DR GUPTA: Yeah. We have seen that to some extent. And patients by this time they are a little bit used to that because chemotherapy can also do that and so can antibody-drug conjugates. But it can be very — all these toxicities I find that they are really nagging toxicities patients have to deal with day in and day out, and they can be quite distressing. Like it can also cause alopecia even though it’s not a chemotherapy, dry skin, dry eye, and anything related to the eye really affects their day-to-day functioning. So I think toxicity is — over the spectrum it can be quite disabling if we are not very proactive with dose interruptions.

DR LOVE: Have you seen patients who had significant responses, Shilpa, change in quality of life, relieved symptoms, et cetera?

DR GUPTA: Yeah, we have. And granted not everybody can go on it, so I think in my practice hardly 3 or 4 patients are actually on this treatment because the genomic tests precludes a majority of patients to go on it. But I have seen that. It has shown responses in some patients.

DR LOVE: So Monica, can you talk a little bit about what you’re thinking about when you go into see a patient who’s about to begin erdafitinib? What are some of the things you go through with them?

MS AVERIA: So when I take patients through erdafitinib I tell them that it’s an oral drug, and they’re usually happy with that because they don’t have to come to USC as often, or at least they think, until we take them through the side effects. I tell them that it’s specifically designed for them based on their tumor profiling, which showed FGFR mutation. I also explain to them that on clinical trials it has been shown to decrease tumors, or lesions, in patients who have progressed with other lines of treatment.

I take them through the side effects. There’s fatigue. There’s nausea, vomiting, diarrhea, dry mouth, dry eyes, changes to the nails, hand-foot skin syndrome. We set them up for a baseline eye exam, and as Dr Pal had mentioned we do set them up for an ophthalmology appointment and make sure they have a follow up. For our patients with no insurance problems, then the situation is ideal, but for our patients with insurance problems it can be problematic.

DR LOVE: Can you talk a little bit about this 65-year-old man? What happened with him?

MS AVERIA: Sure. So we have a 65-year-old male from Guatemala who had presented with muscle-invasive disease in 2019. He was referred to USC for management of his disease. He’s from Bakersfield. He received 4 cycles of dose-dense MVAC chemotherapy followed by radical cystectomy and extended pelvic lymph node dissection and ileal conduit. Final pathology showed residual 3 cm nonviable tumor with 0 out of 68 positive lymph nodes.

He went on surveillance —

DR LOVE: Can I just interrupt for a second and say so did you actually treat him from the beginning? How did he do with the neoadjuvant chemotherapy and cystectomy? And what was his life situation?

MS AVERIA: So he is a truck driver who drove from Bakersfield to Los Angeles, but he didn’t mind the drive because he’s used to it. But now, taking him to the present time, because of gas prices it’s impacting him a lot. So sometimes we see him by telemedicine.

DR LOVE: And what’s his social situation? Does he have a family?

MS AVERIA: He has a family. He lives with his son. He has a daughter who lives here in Los Angeles. And whenever we see him by telemedicine we see him with his son, and the daughter, we add her to the telemedicine because while he’s a very smart guy the family is very involved. So while he’s the decision maker we always make sure the family’s involved because when there’s a problem I go to the kids to get him back to the hospital.

DR LOVE: So Brenda, we haven’t talked much about dose-dense MVAC. That’s what this man got neoadjuvantly. We’ll hear in a second how he did with that. But can you talk a little bit about your experience with that regimen and what you say to patients who are about to begin it?

MS MARTONE: I tell them that it’s going to be tough, but we’re going to get them through it, and the side effect profile in terms of there’s nausea, vomiting, have to keep an eye on the counts, the peripheral neuropathies. We actually follow closely with them. There is a difference.

So dose dense is actually given over 2 days, where they get the methotrexate one day and then go ahead and get the cisplatin, doxorubicin, and vinblastine the second day. There’s also an accelerated dose-dense MVAC where you can give everything on the same day, and it’s basically provider choice in terms of what gets offered to what patient.

But they don’t feel very good. In terms of tolerability they’re going to be tired. And then when you tell them that it’s every 2 weeks, and they start getting into the cycles, and they find out they’re tired and they’re already ready to start another one, you really have to provide a lot of emotional support and a lot of kind of being that cheerleader to say well you’re halfway through or you’re almost done. And a lot of just motivation to help them to cope.

DR LOVE: So Shilpa, we’ve talked a lot about neoadjuvant systemic therapy, particularly neoadjuvant chemotherapy. In general, how do you decide whether or not to send someone straight to surgery or to give them chemotherapy first?

DR GUPTA: If patients are eligible for cisplatin-based chemotherapy we always offer them neoadjuvant chemotherapy. For patients who are not fit for cisplatin, historically they’re taken for up-front surgery because carboplatin is not as good. But fortunately we have a lot of clinical trials now where we are offering immunotherapy and other novel agents, including antibody-drug conjugates. So for our practice we try to offer them something, even if they can’t get chemotherapy.

DR LOVE: Is it — what’s the reason to give it before surgery as opposed to after surgery? One of the things, again, we were talking about in lung cancer, they’re starting to use neoadjuvant chemo/IO, and then patients have less surgery. Instead of having a pneumonectomy they have a lobectomy. Does giving neoadjuvant therapy make it easier for the surgeon in bladder cancer?

DR GUPTA: Yes. That is the premise, as with lung cancer, to try to downstage the tumor as much because patients who achieve complete responses, or even downstaging, they live longer than those who don’t have any responses. So the idea is to do neoadjuvant therapy as it’s believed that muscle-invasive disease is indeed a systemic disease.

So I think looking at the future it would probably be immunotherapy plus chemotherapy followed by immunotherapy maintenance in those folks too.

DR LOVE: So Monica, we’ve been talking a lot about the patient with newly diagnosed cancer. Here’s a man who’s a truck driver who now is dealing with chemotherapy and surgery. Can you talk about his initial reaction and what your sense was in terms of how he was coping with it?

MS AVERIA: When he first presented to us he was not a very happy man. It involved a lot of education. But the unhappiness was not directed to us, the practitioners, it’s just like life in general. And that’s the reason why the son and the daughter are very much involved with their care. I have their number — both of their numbers in addition to the patient’s.

Surprisingly, with the dose-dense MVAC chemotherapy we have this regimen where their most common statement to me when we see them every 2 weeks is “Monica, just when I’m starting to feel better I’m in front of you again.” So here I am starting them on more chemotherapy.

He actually came through 4 cycles of dose-dense MVAC without significant toxicities. He didn’t have to be admitted for any neutropenic episodes, none of that. Because of his insurance issues we set him up to pick up the pegfilgrastim; no issues with that too.

Radical cystectomy came through pretty okay for the patient. Not perfect, but when I saw him for follow up he told me he felt like our chemotherapy was easier than the radical cystectomy and ileal conduit.

Fast forward to now. He’s managing the ileal conduit fairly well, but I guess I should say that because he’s also dealt with a lot of things.

DR LOVE: Yeah. We’re going to get to that in a second. So was he able to continue work, either during the chemo or after surgery?

MS AVERIA: He reached 65, so he retired.

DR LOVE: Great. All right. Well, let’s continue. What happened next?

MS AVERIA: So following radical cystectomy with ileal conduit the patient underwent surveillance scans and had had no evidence of disease. More than a year out, I believe it was almost close to 15 months, the patient presented with lesions in the lungs and the lymph node, which was biopsy proven for metastatic urothelial cancer.

Because the patient was more than 12 months out from his cisplatin regimen, cisplatin/gemcitabine chemotherapy was offered to the patient with the family involved. The patient was in agreement to it. We gave him 2 cycles, and on restaging he actually had evidence of tumor shrinkage.

Unfortunately, midway through cycle number 4 I received a call from the daughter. She asked me to cancel all of his appointments. She notified me he was in Bakersfield, was taken to the ER and about to go to ICU because he was intubated. So I did put them lost to follow up because for me if I don’t see you in 2 or 3 weeks you’re lost to follow up as a nurse practitioner. He did show up a few months later, I think 2 1/2 to 3 months, at the end of 2021, presented back for follow up.

Restaging scans showed disease progression in the liver, lung, and lymph nodes. Tumor profiling showed that he has FGFR mutation.

DR LOVE: Before you continue, just to go to the next — to talk a little bit about this next chapter. I’m curious what your interaction was when you saw him after he had COVID, being intubated and all. What was his condition like? What was his mental state like?

MS AVERIA: Amazingly back to baseline.

DR LOVE: Wow.

MS AVERIA: He was a tough guy to begin with. Never developed neuropathy from our chemotherapy. After 4 cycles of dose-dense MVAC still had more hair than my attending.

DR LOVE: That’s true.

MS AVERIA: Just a very upbeat guy. One thing that would irritate him, if you take him through a treatment and not explain things to him. So what I do for this particular patient is I take him through the treatment and then I call the daughter or the son just so everyone’s on the same page if we’re seeing him face-to-face.

DR LOVE: So what’s the current situation?

MS AVERIA: So he progressed after he developed COVID on restaging scan with liver, lung, and mets to the lymph node. Tumor profiling showed FGFR mutation. Options were discussed with the patient. He elected to receive erdafitinib. Restaging after cycle 1 showed tumor shrinkage. He is now on cycle 2 with restaging scan pending.

DR LOVE: Any tolerability issues?

MS AVERIA: Yes. He has fatigue. He has dry skin. He has hand-foot skin reaction. He actually has diarrhea. This is a patient that we referred to USC Ophthalmology, but because of insurance issues we couldn’t get that to happen. So I reached out to the daughter, who got the baseline ophthalmology appointment in Bakersfield. And I’m always calling the daughter to just make sure we’re up-to-date on that, especially if there are any changes in the patient’s vision. So far none to date.

DR LOVE: I want to go back to the decision to give him erdafitinib because theoretically I guess he could have gotten enfortumab, as well, and Shilpa, that’s an interesting and much debated point. But before you comment on that, just coming back to you, Monica, I’m curious how you explained it to him. Was he interested in how erdafitinib works? Did you try to explain it to him? Or he was just like what do I do?

MS AVERIA: So I always say you have to individualize the patient and never really judge them. His occupation, he’s a truck driver, but he wants to know every little bit of information regarding his care.

DR LOVE: Really?

MS AVERIA: Never assume that just because they are not from a white-collar job they’re not interested. I think as a nurse practitioner if you make assumptions you start being a problem from — it’s a problem from day 1. So he is very much interested in knowing, to the point that I have to call the daughter or the son each and every time.

DR LOVE: I’m curious what it was like when you found out that he was intubated with COVID over those couple months.

MS AVERIA: So it was very upsetting for us at USC knowing that he’s done well. What’s also upsetting is the daughter asked me to cancel all his appointments. So I did make 3 calls when I looked in their Cerner system when I was doing these notes because I did call 3 times. But the patient did reach out eventually, and he knew where to come back. He comes from Bakersfield. It’s pretty far.

DR LOVE: So Shilpa, again, can you talk a little bit? We have so many options now in bladder cancer, maybe more than almost many of the solid tumors right now, how you decide how to sequence things. And in particular if you have the patient who has an EGFR mutation do you give that first or do you give erdafitinib first? There are people who think both ways. I’m curious what you see in making that decision.

DR GUPTA: Yeah. Sequencing is really a very important topic, and like Monica said, we have to individualize treatment. There’s no right or wrong answer, but in a patient who doesn’t have significant neuropathy I usually use enfortumab first and reserve erdafitinib for later. If somebody has insurance issues and can’t get erdafitinib that also helps us. But I foresee that every patient should be able to get to the next therapy and no matter which sequence we use it is. As long as we give the maximum benefit to each treatment it’s fine. But I think this patient could have received enfortumab first and then erdafitinib later or erdafitinib first, and I’m sure at some point may need enfortumab if it’s stops working.

DR LOVE: Brenda, any comments on this case of this man, this truck driver? Anything you want to add to what Monica said?

MS MARTONE: I actually had a patient who was also getting treatment, not with erdafitinib but with enfortumab, and unfortunately this older gentleman did develop COVID, and I was devastated. It just breaks my heart when I heard that. The family was really good about keeping us in the loop, so I knew in real time that he was actually pretty tough, and he recovered. Unfortunately, he has some lingering side effects from the COVID that we have to kind of make sure that we’re keeping an eye on. He has a lot of interstitial lung disease, and he’s been — he has O2 requirements now. So it doesn’t — his performance status is good, believe it or not, but it's what we’re going to be looking for, I think, as COVID and the long-term side effects that might impact treatment decision-making in the future.

Oncology/UBC 2032 and a Crystal Ball

DR LOVE: So we’re going to close with some thoughts about where we might be heading in the future. First I’m going to ask Monty to talk a little bit about his view of where we were heading in terms of urothelial bladder cancer, where we might land in the next 5 or 10 years. And Monty, I’d like you to comment on that and also answer a question from the audience, “Any particular treatments that need to be discontinued if a patient develops COVID? For example, asymptomatic COVID.” These agents that we’re talking about, immunotherapy, chemotherapy, erdafitinib, enfortumab. Do you stop them even if they’re asymptomatic? How do you think that one through?

DR PAL: Yeah. I’ll start with that one. It’s a tricky question. I’ve really been on the conservative side there, and I’ve really held therapies by and large if somebody’s diagnosed, just because you never know how those pulmonary symptoms are going to pan out. So by and large I’ll wait for a patient to recuperate before I reinstitute treatment.

So Neil, you’d asked me to put together a little diagram that illustrates my future vision for the field, and this is something I really scrambled to put together here, but it defines these buckets of disease states that I usually review with my fellows; non-muscle invasive disease, muscle-invasive bladder cancer, and metastatic bladder cancer. And as I said before, I used to tell my fellows, don’t worry about that left-hand side. We’ll never be involved.

But the truth of the matter is I really see things moving forward. We’ve talked already today about checkpoint inhibitors like pembrolizumab and their use in non-muscle-invasive bladder cancer. I certainly see a lot more of that in the future. I also think there’s a lot of exciting trials ongoing right now looking at some of these FGFR inhibitors in that non-muscle-invasive space. So I certainly see things segueing in there, and that’s what those yellow lines are meant to indicate. Those are the theoretical applications. The green lines are what we’re using now in current state.

When it comes to these antibody-drug conjugate we’ve talked a lot about their application in advanced disease. Monica and Brenda have these great cases where they’ve had success using some of these entities, but I really do see that segueing from the metastatic setting into the muscle-invasive setting first. And who knows, maybe down the line, as you predicted, leapfrogging into non-muscle-invasive disease, and lumping them in with TAR-200 and others.

So it’s the same game of leapfrog that we see across other malignancies. I think all of these therapies are going to be used earlier and earlier in the continuum.

DR LOVE: So we also asked Brenda to speculate a little bit about where oncology nursing might be headed, in particular the amazing advances we have in communication and how we might be able to integrate that more into oncology. We already talked a little bit about that along the way, apps that patients can use, so many — and telemedicine of course. Brenda, what are some of your fantasies about how we can provide better care in the future?

MS MARTONE: Well, I think, and everyone will agree in this room, that everyone should be OCN or AOCN certified. I think that adds a high level of — it just reinforces how much experts we are. And then I also think that we will continue to play an integral part in the management of oncology patients. And I might be a little bold, but in terms of where I think oncology nurses are, sometimes we always say — I think we’re right next to the patient, in the middle of the wheel, and I think we all kind of reach out to all the different disciplines that are involved in their care and help coordinate with all those different disciplines. We see all these complex toxicities or potential monitoring that needs to be placed — or be in place to help keep our patients safe.

So I think we do a lot of communication with nurses, nurse navigators, and basically I think we — I think what we help our patients do is be with them during treatment and know that they can always reach out. And again, with all these apps everybody’s got some sort of MyChart. I think being responsive back to patients when they reach out gives them more permission to keep us informed. And then I also think just proactively reaching out to a patient regardless, if it’s MyChart or if it’s just a phone call, this gives that patient and family a lot of permission to reach out to us and maybe ask us those questions that they didn’t feel comfortable asking at the visit or were embarrassed to ask or of course just popped into their head after they left. And so I think communication, and I see oncology nurses being central to that.

DR LOVE: How about your thoughts here, I thought it was interesting, in terms of technology being harnessed, Brenda? Could you comment on that? I think it’s very interesting thoughts.

MS MARTONE: I really would hope that there would be a way that we could integrate like circulating tumor DNA into the management of patients as a way to kind of monitor. These are just wish lists, but as a way to monitor patients’ response to treatment. And I think maybe trying to find a better way of screening, if there is one, to identify those non-muscle-invasive bladder cancer patients before they become muscle invasive, either imaging or some study that — or test that can be used as screening.

And I think globally we aren’t all privy to having clean water and clear areas to actually bathe or wash our clothes. So there’s a lot of dirty water, and we know that a lot of bacteria is in that water, and sometimes that can be a precursor to bladder cancer. So I think anything we can do to screen patients to keep them from becoming muscle invasive is very important.

DR LOVE: Monica, anything you want to add to that, particularly in terms of nursing functions, moving forward how we can do things better, how we can educate better?

MS AVERIA: I think continue on with education, continue on with owning the patient and owning your job. I think if you pass it to someone else you might miss an opportunity to help the patient and make a difference on the particular side effect that they’re experiencing, which can ultimately affect them from continuing the treatment.

DR LOVE: Shilpa, any thoughts about Brenda’s thoughts in terms of new strategies, particularly the circulating tumor DNA? We hear a lot about that. We were talking before about the fact that there was another adjuvant trial looking at a different checkpoint inhibitor Monty mentioned that was negative, but when they went back and looked at circulating DNA they actually saw an effect. What is circulating DNA, Shilpa? Again, we hear almost — even in lung cancer, we didn’t talk about it, but it’s a big issue. What is it and how do you see it fitting into oncology moving forward?

DR GUPTA: I think it is a very important tool, and Monty has done a lot of work with this. In other diseases circulating tumor DNA is primarily like a liquid biopsy or a noninvasive way of detecting cancer cells in the blood. Many times we can’t always biopsy if we see a lesion, and that is also true for patients who’ve had definitive surgery and they don’t have visible disease on scans, circulating tumor DNA could be a good predictor to tell us that these are the patients at high risk for recurrence. And there are several studies now going on to see if they can precede the findings on scans.

DR LOVE: Is this kind of like analogous to, say, a PSA in prostate cancer, trying to find disease that you can’t detect with imaging?

DR GUPTA: Yes. I think it is, although I hope it doesn’t become like PSA where patients are obsessed with every decimal value. But I think this is the way to go, and it is starting out to really be incorporated in a lot of clinical trials to evaluate for minimal residual disease.

DR LOVE: Yeah. We had an interesting discussion about PSA anxiety in the first one of these meetings here when we talked about prostate cancer. Well, we’re about to end here, and we have a tradition that I spend a couple minutes at the end just chatting. Normally what I talk about is a fortune cookie that I picked up at an ONS meeting, I don’t know, 8 or 9 years ago, and I put the picture of the fortune cookie up and talk about it.

But this year something happened last night, and we changed the script. I want to talk about something else to close because I think last night there was a message that came through from someplace to me that said I ought to talk a little bit about this. And last night we had a program on AML. It was 8:00, which for a lot of us was 11:00. We had people there who had been with us since 6:00 in the morning, but we had a great time.

And towards the end Dr Eunice Wang, who you see down here in the lower right, an internationally-respected and known investigator in AML presented a case, very typical for what we were talking about last night, which is the revolution that has occurred in the management of older patients with AML. She presented a 90-year-old woman “one of her favorite patients”, “loves her life, knows what she wants”, who had been followed by a medical oncologist for myelodysplastic syndrome and had been treated with azacitidine when she was diagnosed with acute myelogenous leukemia.

The hematologist said, “Your 90 years old. I have never treated a 90-year-old patient with AML. I think really what I would advise would be for you to go to hospice.” And this woman thought a little bit about it and said hmm, I’m not sure I’m ready for that, so she and her daughter got in the car and made an appointment with Dr Wang, drove 3 hours to meet with her. She got put on venetoclax — actually low-dose ara-C, went into remission, went back to her oncologist, who then learned how to administer ara-C to the patient at home.

The patient did great for 2 years and really a shining example of what we were talking about last night, no transfusions, doing really well, and then Dr Wang mentioned that as she was about to get on the plane to come here she got a call that this patient was sick and had COVID. And she was very — you could see last night how worried she was about the patient because she had not heard from the patient. She tried to prescribe an antiviral, but they did not hear back, so she was very concerned.

I brought up the fact that I know — that I had worked with Dr Wang, and we did an interview, we did a Zoom interview last October, and I said, “Eunice, you don’t look too good.” And she said, “Well, yeah, I’m just getting over COVID.” And as it turns out she had gone to a medical meeting, the first time she really left Rochester, and she got symptomatic COVID, short of breath, very sick, according to her the sickest she ever was. And she was in bed for 2 weeks and recovered, and of course is doing very well. She said, “People said to me the 1 positive is now you’ll get a better understanding of what patients will go through.” And she said, “Absolutely.”

And I think everybody who was here last night at that point was thinking about the sickest they ever were in their life and how it affected them, including me. And I flashed back to quite a while ago when — quite a few years ago when I started to get a fever and a cough. This was way before there was ever a thought of anything like COVID, went to my doctor. He said hey, it’s just a virus. You don’t need to take antibiotics. I kept getting sicker and sicker, eventually ended up in an ER, temperature 105, had a community-acquired pneumonia. If I’d gotten antibiotics 5 days earlier it wouldn’t have been that bad, but I spent 24 hours in the ICU. They gave me antibiotics. I got better.

But last night I remember what I was thinking when I was sitting there in the wheelchair getting ready to get picked up to go home, which was “thank God for nurses.” Thank God for nurses. And I think a lot of people were thinking about that last night. And I just want to — I felt like somebody was telling me to say to you thank you very much. What you do is highly, highly valued. You should be very proud of what you are doing. You are doing a lot. So that’s my message to you. I was sitting here on this same stage 3 years later, I said, “Well, see you next year in San Antonio.” And it didn’t quite work out that way, though, did it?

But anyhow, hope to see you next year in San Antonio. Thank you so much. Have a great day. Thanks.