Overview of interdisciplinary care in UBC

DR LOVE: I want to start out with you, Cristina, if you could talk a little bit about what your working environment is here. Do you have an interdisciplinary conference that you go to, Cristina, where you talk about bladder cancer patients or not necessarily?

MS SALABAO: I think one exists between us in the Brigham. However, I don’t typically go to it. I’ll go to some if it’s a patient that I’m following, but regularly no.

DR LOVE: And Andrew, how about you? Is there an interdisciplinary conference that you go to?

DR RUPLIN: There are.

DR RUPLIN: We typically hold them about twice a month or so and discuss some unique patients. I do try to attend them. We also do kind of institution-wide immunotherapy-related adverse events tumor board, as well, where we may discuss, particularly in this age of immunotherapy, some of these unique adverse effects that we get from patients.

DR LOVE: So Betsy, maybe you can kind of provide an overview of how you see interdisciplinary care of patients with urothelial bladder cancer and what your vision is of the team and how, if at all, your team meets together, particularly as it relates to the medical oncologist, the urologist, the radiation oncologist, the nurse practitioner, the pharmacist, Betsy. How do you even envision that team and how do they function at your place?

DR PLIMACK: So that’s a really good point because the best clinical care, I think, for bladder cancer patients is multidisciplinary. There are so many different aspects to care that require different specialists. So at Fox Chase we have an every-2-week case conference where we present cases where we have questions or management questions. We have radiology, pathology, urology, radiation oncology, and medical oncology present. It’s a great forum for learning too, so our, we call them APCs, so nurse practitioners and physician assistants, also attend. They present cases, as do our trainees, residents, and fellows.

So again, a lot of the questions we bring to case conference are around how to layer treatment, what to do first, what to do after that, how do we incorporate new data into our treatment regimens, and how do we incorporate clinical trials into what we recommend for patients.

DR LOVE: Jonathan, I’m interested in your environment at Memorial and how you envision the interdisciplinary team and what kind of functions your pharmacists and APPs have.

DR ROSENBERG: So I think one of the issues that we have is we actually don’t have enough APPs in our programs, unfortunately, and that’s a historical artifact I think, of the ways things had been set up here. And so the APPs in our program are primarily used as coverage or as ongoing care of patients, but not particularly involved in evaluation of new patients. And the pharmacists are mostly trainees, and we teach them about the disease, but we don’t actually have oncology pharmacists very actively involved in the actual clinic, unfortunately.

And we’re probably an outlier in that, but we’ve had a more limited role of different providers in our practice.

Counseling patients with newly diagnosed mUBC about prognosis and treatment options

DR LOVE: So let’s get into the issue of first-line therapy of metastatic disease.

And Betsy, and maybe you can talk a little bit about your global vision of this clinical scenario.

DR PLIMACK: Sure. So metastatic urothelial cancer is a tough diagnosis, and I think when we meet patients in the clinic for the first time we are obligated to tell them that we can’t cure this, but our goal is to treat it and to maintain control of the cancer in order to maintain quality of life.

And this slide is from the SEER database. It was accessed recently. But this dismal survival, less than 5% at 5 years for distant metastases, I really hope and believe is improving with time. We just haven’t made it to the 5-year mark with immunotherapies and the other therapies that we’ll talk about today. So again, it is a tough diagnosis, but it’s one that increasingly we have more tools to treat.

DR LOVE: Cristina, can you talk a little bit about some of the issues that come up in the patient who’s presenting with metastatic disease? What are some of the questions that patients ask you, and how you bring them into this scenario?

MS SALABAO: Sure. So I don’t typically see brand-new patients, so that conversation of disease and prognosis isn’t typically had by myself the first time. But some of the questions obviously are what are the treatments available? What are the side effects? How’s this going to impact my life and that type of thing, which I think is the bread and butter of APP practices, kind of expanding on some of the side effect management and expectations of how their everyday life may change versus maybe the details of the disease itself. Does that make sense?

DR LOVE: Sure. How do you see people coping with the situation, pretty dismal prognosis, not really a curable situation? And what do you do to try to strengthen their coping?

MS SALABAO: Sure. So it’s tough. I think just being an active listener and making sure that, as far as side effects, the things we can manage are optimized so it has as little impact on their quality of life. And also just to make them feel that the life that they have they’re able to do the things that they want to do and that type of thing. And of course we do reiterate here that it’s not curable, but we will do everything we can to manage the disease with as little impact on their life.

But I think that just forming those relationships with the patients that you have, open communication, that type of thing. Letting them know that no matter how silly their question may sound to them or seem to them it’s worth asking.

DR LOVE: So Jonathan, maybe you can put in perspective where we are today with systemic therapy of bladder cancer. It looks like there’s a lot that’s gone on in the last couple years. Can you comment on that?

DR ROSENBERG: Yes, so we’ve had a veritable explosion of new drugs and drug development in bladder cancer over the last 5 years. We’ve had the approval in the United States of 7 drugs,

Five of them are very similar, the immune checkpoint inhibitors targeting PD-1 and PD-L1, as well as an FGFR inhibitor followed by an antibody-drug conjugate, enfortumab vedotin.

DR LOVE: So I guess the other issue is that in the past we really didn’t have second-line therapy. Now it looks like we have second and third line, Jonathan. What do you say to patients in terms of what to expect in terms of survival in the metastatic situation and how does it vary based on kind of what their situation is?

DR ROSENBERG: So I tell patients that the average survival used to be between 1 and 2 years, and now we’re looking at north of 2 years for the average patient, with variability, obviously, shorter or longer. And there are a small subset of patients where they actually have very durable remissions, on immunotherapy in particular, although unfortunately it’s not as big a subset as we’d like. It’s probably on the order of 10% to 25% of patients who do extraordinarily well with immunotherapy.

And so it’s a complicated discussion usually revolving around the idea that we’re going to be sequencing therapies starting with, for most patients, chemotherapy, and then moving into other options, as well as integrating discussion around clinical trials when relevant and appropriate.

DR LOVE: Andrew, what’s your role as a pharmacist in the tertiary care center in terms of interacting with patients with metastatic disease and the health care team and the oncology team?

DR RUPLIN: My role usually comes after patients have met with a number of people prior to me, including their medical oncologist, where they do the major decision-making. Sometimes we have our nurse care coordinators meet with patients to discuss generals about chemotherapy and the experience that patients can expect to receive at our center. By the time patients have gotten to me we’ve usually obtained financial clearance and may or may not have scheduled their first visit for the administration of intravenous chemotherapy. Or, in the setting of oral chemotherapy, patients can be expected to start that relatively soon.

So when I meet these patients I’m often in an educational role in which we speak very specifically about what they can expect on the day of their treatment as far as what a day would look like for them, coming to the clinic, getting their infusion, premedications that they might get. And then of course everyone’s kind of favorite thing to talk about from a patient standpoint is they’re always very curious about what side effects they might experience, or we predict the will experience, based upon the published data

DR LOVE: So again, Betsy, thinking about the patient with newly diagnosed metastatic urothelial bladder cancer, they may present that way or they may have recurred after earlier therapy, and you can talk a little bit about how often that occurs, but I’m curious what are some of the other things you talk to patients about or assess in patients outside of related to specifically what drug therapy. That issue, in terms of their lifestyle, alternative strategies, complementary strategies. Also their attitude. What are some of the things you look into in these patients with newly diagnosed metastatic disease?

DR PLIMACK: That’s a great question. So that first visit, where you may be the first one to tell them that they have metastatic disease and that it’s not curable, is a really important one because on the one hand you have so much information to convey about prognosis, new therapies, all of the things Cristina mentioned about maintaining quality of life and being there to support them. But also, they’re not in the best position, necessarily, to absorb that information because it can come as kind of a shock with this diagnosis.

So a couple things that I try to do on that first visit. One is to gauge understanding. So when I describe the clinical scenario I generally ask, “Does anything I say surprise you?” And sometimes you get interesting results about what they thought before they walked in versus what you’re telling them. It’s nice to know if there’s a discrepancy there. And the other is to give them a lot of written information to go home with so that once the kind of digest what you said or what they think you said, they have something that they can go to or share with family to review what we go over. But it’s a tough visit where a lot goes on, and I think important to understand the patient’s side of things going into it.

Recent advances in the management of mUBC

DR LOVE: So Jonathan, you had an interesting slide in your talk that provided an overview of where we are today in terms of metastatic disease. Can you kind of talk about that? We’re going to go through all these things in great depth as we move forward here today.

DR ROSENBERG: Yeah, so for most patients standard first-line therapy is platinum-based combination chemotherapy. There are several different regimens which might be options, and they’re really tailored to the patient and their particular comorbidities. When patients have high levels of PD-L1 staining in their tumor single-agent checkpoint therapy is an option. The FDA has approved it for those particular subgroups of patients, but it’s not based on Level 1 randomized trials. And then for patients who are chemotherapy and they achieve a response, either stable disease, partial response, or even a complete response, there’s randomized data to show that if you go on a maintenance program of immunotherapy that you actually live longer by about 8 months than if you just observe the patients. And so that has now become a standard of care for almost all patients with metastatic disease who respond to treatment in some fashion.

For patients who have progression in the second-line setting, then immunotherapy is generally considered the standard though. So people who don’t respond to chemotherapy get immunotherapy as well. And so in some ways you can think about it as everybody gets immunotherapy no matter what. And then finally there are several new options, and hopefully more than just 2, coming up soon, for people who’ve progressed on chemotherapy and immunotherapy.

DR LOVE: So Betsy, maybe you can talk a little bit about how you think through the first systemic therapy that you’re going to give to a patient and also when you bring in local forms of therapy, either radiation therapy or even surgery, in a patient with metastatic disease?

DR PLIMACK: So that’s a great question. I think, unlike some other malignancies, focal therapy, radiation or surgery, in the patient with urothelial metastases is something we use relatively infrequently. And we are generally leaning on our systemic therapies as our first-line agents.

When assessing a newly diagnosed metastatic patient for first-line therapy, my first assessment is whether I feel like they can tolerate cisplatin-based chemotherapy because this has the highest response rate and sets the patient up, I believe, for durable efficacy down the road, either from platinum alone or from that followed by switch maintenance if they have a response. So that’s the first assessment, and we can talk a little bit about how we do that if it’s important, but determining whether a patient can receive cisplatin or not is important.

And then if they are not a patient who I think would benefit from cisplatin, then, as is different from the beginning of this year, since ASCO 2020, we increasingly are giving patients gemcitabine with carboplatin. Starting with chemotherapy, planning for a few cycles, and then following that, if they respond, with switch maintenance therapy. In the cisplatin-eligible group they would get cisplatin also followed by switch maintenance in the setting of response, with the 1 exception that I think complete responders to platinum might get away with platinum alone and benefit from a treatment break to ascertain that first.

DR LOVE: In younger, fit patients, Betsy, what’s your usual up-front chemotherapy and what are some of the variations that are used by other people?

DR PLIMACK: So I can’t tell if we’re outliers or not.

I think in this particular poll we probably are.

We use dose-dense MVAC chemotherapy as our front line for metastatic disease based on older efficacy data we think supports it.

Also we’re able to give it pretty well, with good side effect management because GCSF is involved. I think I see more of a switch maybe back to gem/cis because the trials are all looking at gem/cis backbones, in combination with chemotherapy, in switch maintenance.

I guess the advice was to just go with gem/cis, and so all the trials are homogenous in that way.

We’re hoping to see more data with the MVAC, both as a backbone for combinations and as a front-line therapy followed by switch maintenance types of approaches, but that’s pending.

DR LOVE: So I’m curious, Cristina, what are some of the issues that come up in patients who get both dose-dense MVAC as well as gemcitabine and cisplatin? And what are some of the things that you would typically go over with a patient, from a patient education point of view before they get started?

MS SALABAO: Sure. So obviously the side effect profile. I will say I don’t use the dose-dense methotrexate at all. We do typically gem/cis, and so things like neutropenia, kidney function, neuropathy, a bit of nausea and vomiting. Those are the main things that I like to cover on day 1 of treatment. The neuropathy thing is big, and when we start talking about enfortumab I guess you’ll see why, but I would say that and the neutropenia are the 2 biggest things that would cause like a hold or a delay in treatment, along with fatigue, nausea, that type of stuff. But those things are manageable compared to what you would actually hold therapy for.

DR LOVE: So Andrew, any pharmacy-related considerations in this situation, starting chemotherapy? Any drug interactions that you’re looking for?

DR RUPLIN: Certainly as part of my role I always personally evaluate all the medications that patients are on and compare it to the chemotherapy that they’re intending to receive. For the gemcitabine/cisplatin or the dose-dense or accelerated MVAC there aren’t too many very specific drug interactions that I’m looking for, particularly if the methotrexate dose is lower then I’d be concerned with some of our high-dose methotrexate regimens we use, and other disease states. So for those 2 regimens, particularly, I’m not really looking for anything in particular other than, for example, nephrotoxic meds given that we’re giving cisplatin, or anything that might interfere with whatever additional premeds we give, given that these are fairly emetogenic regimens as well.

Mechanism of action, efficacy and side effects of immune checkpoint inhibitors

DR LOVE: So Jonathan, maybe you can talk a little bit about where we were before the Virtual ASCO Meeting just a few months ago when we saw the JAVELIN 100 study in terms of what kinds of research had been done trying to bring in checkpoint inhibitors into the management up front and what had been seen.

DR ROSENBERG: Well so there were Phase II trials that led to the approval of single-agent atezolizumab and pembrolizumab for patients with high levels of PD-L1. Initially the approval was broad, but then the results from 2 Phase III randomized trials, KEYNOTE-361 with pembrolizumab and IMvigor130 with atezolizumab both showed that for patients whose tumors did not express high levels of PD-L1 that they actually did substantially worse, and that they restricted the labels.

We then also saw the results of IMvigor130, which while technically was a positive study the results were not clinically particularly meaningful, with a modest PFS advantage. And that study combined immunotherapy with chemotherapy. And there was a lot of effort to look at 3-drug combinations of a checkpoint plus gemcitabine and platinum, and those have not proved to be resounding successes as of this time. And that the standard of care still remains platinum chemotherapy, and for patients who can take it, cisplatin-based chemotherapy is still the standard.

And at our institution we tend to use more gemcitabine and cisplatin for patients who we know are not curable, people who have visceral disease, liver metastases, poor performance status. But for younger, fitter, healthy patients and for people with lymph node-only disease we often use dose-dense MVAC, similar to what Betsy talks about.

DR LOVE: So Betsy, I’m curious what you say to patients in terms of what to expect from benefit in the first-line situation, again, before the JAVELIN strategy, what to expect in terms of tolerability issues from these different chemotherapeutic approaches and efficacy? Do you see any patients who have very prolonged responses, for example?

DR PLIMACK: Yeah, so 2 different questions you just asked there. One is what do you tell the patients to expect, and there I think we’re obligated to talk about averages and what we see collectively in the data. Right now when patients ask about prognosis, the latest data we have is still about a year and a half, but I’m confident we’re going to see that go to 2 years once we get longer-term results from, for instance, JAVELIN 100 data. I usually couch all of my estimates and prognosis with optimism because I think the trials we have and will have in the future really are pushing that number towards more and more months for patients.

But are there outliers? There are. I mean we know, actually, from the JAVELIN data that Dr Grivas presented at ESMO, if you look at just the patients who had a CR to their prior gem/cis or gem/carbo chemotherapy, of those, in the best supportive care arm, a lot of them have not recurred yet, now months later. So we know that that treatment, even if curtailed after a certain number of cycles, can lead to durable responses. I think we need to learn more from the JAVELIN data set to know whether we should roll that into telling patients what to expect.

I do have a handful of patients in my clinic, I know Jonathan does too, who had metastatic disease, got a platinum-based chemotherapy, and are disease-free now years later. But unfortunately, it’s not as common as we would like. We would like to investigate ways to make it more common.

DR LOVE: So I’m going to kind of try to integrate where checkpoint inhibitors come in in this scenario of metastatic disease. And Jonathan, I’m curious how you explain to patients the way checkpoint inhibitors actually work and what your own vision is of how they work.

DR ROSENBERG: So I tell patients that they rely on the immune system to attack the cancer instead of a drug killing cancer cells directly, that it’s an indirect effect. And I also explain to them about the side effects in the same way, that these are agents that can stimulate the immune system, which we hope will attack the cancer cells, but in fact will sometimes misfire and allow the immune system to attack normal body parts, which is how we account for the side effects that patients see. And so it ends up being a reasonably straightforward discussion with patients as they realize that the drugs themselves are not the toxic thing, but it’s how the immune system reacts to the drug that causes the side effects for the most part.

DR LOVE: So I’m curious, Cristina, again, how you explain to patients what checkpoint inhibitors are and what you discuss with them in terms of potential toxicity or side effect.

MS SALABAO: Sure. So I say pretty much the same thing that Jonathan had mentioned as well, kind of it revs up the immune system. Personally I just tell my patients to report anything new, but obviously I go over all the itises, shortness of breath, diarrhea, bad rashes, that type of thing. And for the most part that explanation actually goes over really well, especially when you compare it to the chemotherapy that they’ve probably gotten before. It’s less of a clean burn and more of a selective kind of management technique.

DR LOVE: So again, Andrew, any thoughts about checkpoint inhibitors from the pharmacist’s perspective? What are some of the issues that you’re trying to keep an eye on?

DR RUPLIN: Again, largely I agree with what’s been said already, and that’s also the way I do tend to educate my patients is using that same kind of description of how the mechanism contributes to the toxicities in these agents. Certainly, we do have patients who get the toxicities and in particular I feel that the endocrine toxicities are really quite common. And I see a substantial number of patients who do require thyroid replacement therapy, so from a pharmacist’s standpoint it is fairly common that I have been consulted by some of my nurse practitioners, and in some cases our medical oncologists, for recommendations on adjusting some of these medications as well. But otherwise really emphasizing the risks, from my standpoint the endocrine toxicities, the colitis, and then more rarely but very severely in some cases the pneumonitis that patients can sometimes get and we have seen and sent people to the ICU for.

Design, results and clinical implications of the Phase III JAVELIN Bladder 100 trial evaluating first-line maintenance therapy with avelumab and best supportive care (BSC) versus BSC alone for patients with mUBC who had not experienced disease progression after induction chemotherapy

DR LOVE: So Betsy, people talk about “practice-changing trials” and this one, the JAVELIN Bladder 100 study, I think is widely viewed as one of those. You actually did the discussion for this. Can you talk about what they looked at in this study, what they saw, and why it’s changing practice?

DR PLIMACK: Sure, so this is a really interesting study design that the investigators used here in that this is chemotherapy followed by immunotherapy as a “switch maintenance” design. Now we have data from large, randomized Phase III trials using immunotherapy after progression on prior chemotherapy. This trial is different. This trial selected patients who received prior gem/cis or gem/carbo and had a response rate or stable disease. Once they achieved that they were then enrolled in the study, and you see the endpoints are measured based on the time of enrollment. They were randomized 1:1 to receive avelumab versus best supportive care.

And here are the results of the trial, as I framed in my discussion. Avelumab plus best supportive care led to a median survival of 21.4 months, whereas best supportive care alone following chemotherapy, 14.3 months. And again, the longest overall survival, regardless of how it performed compared to the control in any Phase III metastatic urothelial trial, including first line. Many will say well best supportive care, there’s no treatment in that arm. This actually was felt to be appropriate when the trial was designed because generally we do give platinum-based chemotherapy and then build in a break, or best supportive care during a treatment break. And patients in both arms were allowed to receive, of course, subsequent therapy as per their practice where they were treated.

DR LOVE: So Jonathan, I’m curious what your thoughts are about this study and how it affected your practice. And we’ll look in a second at what your colleagues are saying as well, but how did it affect the way you approach these patients?

DR ROSENBERG: So it’s had an immediate effect, frankly. I think, as Betsy pointed out, we would traditionally observe patients following the end of chemotherapy, and depending on if they’ve had a response, if they’ve had tumor regression or stability, give them a break from treatment, reimage in a few months and see where they stand. And so now I think we’ve shifted almost entirely to instituting immune checkpoint blockade in people who are responding to treatment or have stable disease. And so it’s been a very rapid uptick.

I would note that the survival numbers, the duration of survival, is actually measured from the end of chemotherapy and only in the people who did pretty well. And so those are numbers that don’t apply to everybody, but only apply to the people who will go onto maintenance therapy. And so for the people who had progression on chemotherapy, unfortunately, the outlook isn’t as good. And they’re moving on to immunotherapy as we’ve seen in other clinical trials, such as KEYNOTE-045 testing pembrolizumab in the post chemotherapy progressive disease state, and those outcomes, unfortunately, are not quite as exciting.

Selection of first-line therapy for patients with mUBC

DR LOVE: So Betsy, how has this affected your approach to first-line therapy in metastatic disease? Are you routinely using IO maintenance?

DR PLIMACK: So it’s really affected it in 2 different ways. One, we generally now, instead of giving a treatment break we will recommend the maintenance for patients who have stable disease or respond to their platinum-based chemotherapy. But the other way I think it’s affected practice is this really kind of gives support to starting with chemotherapy first in order to then achieve that really nice overall survival in your responding patients, for sure, from avelumab or subsequent checkpoint inhibitor. So it seems like priming with some chemotherapy yields superior results than starting with a checkpoint.

I will say there’s some other nuances to the Phase III trials with pembrolizumab and atezolizumab in the front-line setting, the randomized Phase IIIs, that give me pause recommending checkpoint front line, and you’ll see that in some of the surveys that are coming up. It’s not something I recommend routinely anymore, even for PD-L1-positive patients.

DR LOVE: So just to clarify though, Betsy, because we asked about first-line strategy. You said dose-dense MVAC without checkpoint.

DR PLIMACK: Yeah, so the reason I left it that way is because it really depends on the response or lack thereof that’s achieved. So a patient who has a complete response to dose-dense MVAC, which per the literature is 10% to 20%, those patients may not need subsequent therapy. And I think I would have a discussion with them about subsequent checkpoint in the maintenance setting, whether or not they want to try it. Maybe give them a chance to get away with platinum alone. Again, small subset, but in the CR group that’s where they are. So that’s just why I start with MVAC and then have a second-line type conversation.

For a patient with PR stable disease on MVAC I would absolutely layer in a checkpoint inhibitor there as maintenance. And for those who progress, they’re really outside the JAVELIN 100 data, and we look to second line based on a variety of trials that I’m sure we’ll discussed in this session.

DR LOVE: So Jonathan, these are the results of this 1 question. We asked people what their overall strategy is. We’re hearing there’s a little bit of granularity in Betsy’s response, based on the type of response. We went back to these people and checked, but in general I know Dr Balar, actually is not doing that. Any thoughts about where this controversy comes from, Jonathan?

DR ROSENBERG: I think some of it is the limitations that the answers we could give. I think the assumption is in someone who’s doing well you move on to a maintenance immunotherapy, and if they’re not doing well you move on to second-line immunotherapy. And avelumab is also approved in that context, although probably not the most commonly used.

So what I would say is that perhaps, with the possible exception of people who have complete responses, that almost everybody’s going to get a checkpoint inhibitor after they finish chemotherapy. And if they get it because they’re doing well, they get avelumab, and if they get it because they’re not doing well, they’ll get pembrolizumab, for the most part, based on Level 1 evidence with those 2 agents. And so I think there’s different ways that people could have answered it. The first treatment they get would be chemotherapy, for I would say the vast majority of patients, and then the second line is not really second line anymore, in fact, because there hasn’t been progression, probably for 70% of patients who would have stable disease or a response on front-line chemotherapy.

DR LOVE: Jonathan, what’s the difference between going to second line versus going to maintenance? Is it which checkpoint inhibitor you use or how you use it?

DR ROSENBERG: Well I think the intents are somewhat different as well. So as a maintenance therapy you’re trying to build on the response you’ve gotten, whereas for someone who has progression you’re trying to induce a response in someone whose cancer is growing. There are 5 agents approved for patients who had progression on front-line chemotherapy, including avelumab, but also pembrolizumab, atezolizumab, and durvalumab and nivolumab. And the only drug at the moment that has Phase III Level 1 evidence in support of its use is pembrolizumab, and so that’s, I think, most people’s choice in a patient who’s progressing rather than one of the other agents.

DR LOVE: Interesting.

DR ROSENBERG: But any of them are actually reasonable. Very similar.

DR LOVE: So Andrew, any questions you’d like to pose to Betsy or Jonathan about kind of what we’re talking about here?

DR RUPLIN: I think for me, certainly I work with Dr Grivas, so we’ve also been early adopters of the use of avelumab maintenance after platinum-based chemotherapy. And I guess from my standpoint as a pharmacist is when I’m evaluating individual patient’s chemotherapy regimens for safety and whatnot, and giving that go-ahead that we can proceed with that, is I’m always also reviewing what the primary literature is for the use of these agents, the lines of treatment and whatnot. So I suppose my question is, and one thing I haven’t really answered yet, is now that we have this JAVELIN Bladder 100 data will there be a role for pembrolizumab after the use of avelumab therapy? Or might we consider going towards something else, like enfortumab vedotin or a different non-PD-1-based therapy after a patient has received platinum-based therapy followed by avelumab maintenance?

DR LOVE: That’s a great question. Betsy, would you ever rechallenge someone with a checkpoint inhibitor who’d had it previously?

DR PLIMACK: I would say rarely. I have done it, typically in the context of a clinical trial evaluating reinvigorating the response to checkpoint. Typically though, of the 5 approved checkpoints for urothelial, sequencing one after the other isn’t something we have evidence for or typically do, and mechanistically I’m not sure there would be benefit there. The other thing is fortunately we have other agents to go to, such as enfortumab vedotin or erdafitinib, which I know we’ll talk about.

DR LOVE: Yeah, we will get to that. Again, Cristina, any questions you want to put out there?

MS SALABAO: This is just a broader question, but at what point are you using like Oncopanel^TM or any other kind of like genomic testing throughout this process? When do you order that? Do you wait for progression?

DR LOVE: That’s a great question. Jonathan, we’re looking for genomic markers in many solid tumors right now, as Cristina verbalized there, do you use any kind of genomic evaluation? And if so, when? And what is it that you can pick up that’s going to be useful?

DR ROSENBERG: Certainly at the diagnosis of metastatic disease. For research purposes we’re actually sequencing a lot of patients earlier in the course of their illness and muscle invasion. But I think for anyone diagnosed with metastatic disease we need to assess for the presence of FGFR3 mutations, which is linked to benefit from erdafitinib. And so my practice is to make sure that they’ve had sequencing done during first-line therapy that will then set us up for treatment options down the road and understanding whether they might be a candidate for a targeted therapy, either with erdafitinib, another FGFR inhibitor, or clinical trials. But there are several FGFR inhibitors in late-phase trials currently.

Choice of up-front therapy for older patients with mUBC; role of PD-L1 expression in selection of therapy

DR LOVE: So I have a question. I’m going to throw this to Betsy, which is how do you think through first-line therapy in an older patient who is not a great candidate for chemotherapy or cisplatin-based chemotherapy?

How do you evaluate whether you give somebody cisplatin or carboplatin, for example, Betsy?

DR PLIMACK: Sure. So that’s an age-old question, and I think different centers do it a little differently, but there is general consensus that creatinine clearance, typically measured with 24-hour urine being the gold standard, has a cutoff of about 50 for most folks, 60 for some others. And below that, really, we know that cisplatin can be nephrotoxic and cause additional toxicity. So that’s the main one. And the other parameters kind of fall into the range of other comorbidities, age, frailty scale, those kinds of things. There are checkboxes you can check to determine if a patient is eligible or ineligible or cisplatin, but the main objective criteria I think we use is creatinine clearance.

DR LOVE: So maybe you can also go, Betsy, into the issue of the PD-L1 level of the tumor and how that affects the way you’re going to approach these patients as first-line therapy.

DR PLIMACK: Right. So up until ASCO we were routinely sending out, what Cristina mentioned, the next-generation sequencing for PD-L1 and all the other markers that come with the test that we get the results from as a send out. And we’re doing that before selecting first-line therapy because for cisplatin-ineligible patients we were routing them towards front-line checkpoint inhibitor therapy. I will say I don’t do that anymore, so I do not select patients for front-line checkpoint inhibitor therapy really ever anymore. A lot of that is based on careful review of the ESMO data from the 361 study showing that there is a curve inflection where patients kind of do poorly at the beginning with primary immunotherapy even if they’re PD-L1 high.

So again, if one is going to give a checkpoint inhibitor in that front-line treatment-naïve setting, I think PD-L1 status is critical. I would only give a checkpoint to someone who’s PD-L1 high. I think there’s a risk of increased death for the other group, the group that is not PD-L1 high. But then the JAVELIN data really supports using chemotherapy in that space instead. And that has kind of solved that issue for us, where we start with chemotherapy and then allocate to immune therapy either, as Jonathan said, in the salvage setting or in the switch maintenance setting, agnostic really of PD-L1 status in that setting.

DR LOVE: And Jonathan, when we look at this slide from the survey you can see, supporting what Betsy’s saying. And here we say the patient’s not a candidate for cisplatin, therefore a candidate for carboplatin. And rather than looking for PD-L1 level and giving checkpoint first line, it looks like people are thinking about using a maintenance strategy, including you Jonathan. Can you kind of talk a little bit about that?

DR ROSENBERG: So most people, I think, are switching towards that paradigm. I do think that the data from IMvigor130, using atezolizumab, looked better than the data from KEYNOTE-361 with pembrolizumab. However, the use of atezolizumab, I think, is less common these days as a first-line therapy. My own feeling is that there are people who are somewhere between carboplatin eligible and platinum ineligible, and for those patients, if they’re PD-L1 high and they have certain clinical features like lymph node-only disease for example, I might offer them an immune checkpoint drug. But they have to have high levels of PD-L1.

I think most other patients are able to tolerate at least some chemotherapy, although patients are often in their 80s and have multiple comorbidities, and quality of life during chemotherapy is often suboptimal. And so it does become difficult to treat patients with platinum-based chemotherapy when you add on COPD and heart disease and diabetes and peripheral neuropathy and renal insufficiency, et cetera. And they often don’t tolerate as well as we’d like them to.

MS SALABAO: I just wanted to ask, what are people’s thoughts on split dose cis/gem?

DR ROSENBERG: I use it all the time for people.

DR PLIMACK: I feel like it varies.

DR ROSENBERG: Yes. We use it all the time for people who are candidates for cisplatin but borderline so; tends to be people with decreased GFRs but who are otherwise good candidates for cisplatin-based chemotherapy. People who have some hearing loss and tinnitus, which make them also at risk for quality of life problems down the road are people also that we consider it. But other people don’t, and I think it’s certainly not the standard to do. But if I had a choice between giving split-dose cisplatin and carboplatin I’ll give split-dose cisplatin any day.

DR LOVE: So Cristina, can you explain what split dose is and what you’ve observed with it?

MS SALABAO: Yeah, so again, for our practice it depends highly on the provider who wants to do it. And instead of giving these bigger doses every 3 weeks you split them up to more tolerable doses. And it’s actually Dr Sonpavde who is a big advocate for that. He kind of falls in the same school of thinking as Dr Rosenberg. He’d rather give cisplatin in a split-dose format versus carbo.

DR ROSENBERG: I tell patients I’m amortizing. They think about it like their mortgage and they get it.

DR LOVE: Betsy, can you comment on this slide from our survey looking at how people manage older patients not eligible for platinum and talk about the answers of the faculty and your answer?

DR PLIMACK: Sure. So it’s always funny. I always chuckle when I’m like the outlier among my friends here, who are obviously super-smart people. So the reason I give gem instead of a checkpoint to someone who is platinum ineligible is really two-fold. I mean one is this is an extremely small group of patients, especially in my practice. As one of my colleagues who’s on your slide set, the real definition for platinum ineligible should be I don’t feel like giving the patient platinum, right, because it is in the eye of the beholder to some extent.

But assuming this is a patient for whom any platinum, including carboplatin, would be inappropriate, I would give gemcitabine alone. And the reason for that is I know there’s a risk of early quick death with checkpoint inhibitor therapy in the front-line setting, and this is an already frail patient. So I don’t want to really risk that, and that’s what we see with the curves. Granted, it’s compared to a platinum-containing regimen, but in my clinical practice I’ve definitely seen very prompt progression with checkpoint inhibitor therapies in frail patients in the front line, especially in PD-L1-negative patients.

And the second is that the response rate of gemcitabine is actually higher in this setting than the response rate to a checkpoint. The checkpoints were getting in the 20s, and gemcitabine as front line, based on really old data, is a little bit higher, in the 30% range. So I don’t feel like I’m subjecting them to a less-effective therapy.

And the third is I hope, even though this is not evidence based, that a little bit of chemo will still prime their system for subsequent checkpoint if in fact we can get them there.

DR ROSENBERG: So I have a similar, but not entirely the same view. I think that there are many patients where this is like a volcano, and chemotherapy is the only way you can control it, and those patients need chemotherapy. And that if you can so-call cool the patient off a little bit, then you can actually think about giving them immunotherapy. I don’t know that it’s actually inducing an immune response, but it’s probably slowing the disease down enough that you actually can give immunotherapy time to work. And I completely agree that it’s very appropriate in many patients like that.

Mechanism of action, activity and tolerability of enfortumab vedotin for advanced UBC

DR LOVE: So let’s talk about some of the new innovations that have come out in the management of bladder cancer, and that’s really the main purpose of what we want to focus on here today. I want to begin with enfortumab vedotin, and Jonathan maybe you can comment a little bit on kind of what kind of molecule this is, how it works, and what we know about it clinically.

DR ROSENBERG: Enfortumab vedotin is an antibody-drug conjugate, meaning that there’s an antibody linked to a cytotoxic. And this is something that’s used in several diseases in oncology, and this is the first drug in bladder cancer of this type that was FDA approved. And it’s targeting a molecule called nectin-4, which is highly expressed on bladder cancers. It’s also expressed a little bit in the skin, which accounts for some of the off-target toxicity. And the idea is to selectively deliver the cytotoxic to the tumor with an improved therapeutic efficacy than just giving the naked cytotoxic as an injection, which would likely be fatal due to the toxicities. And it’s conjugated to MMAE (monomethyl auristatin E), which is a microtubule disrupting agent. And so it is an intravenous therapy that’s given once a week 3 out of 4 weeks in patients with refractory disease.

DR LOVE: So Betsy, can you talk a little bit about what we’ve seen in terms of tumor response with this agent?

DR PLIMACK: Sure. So enfortumab vedotin, I mean I think a lot of us are really excited by these data that you’re showing here. One is so many patients see disease shrinkage. Remember, this was in the pretreated setting, so most of these folks had prior platinum-based chemotherapy and prior immunotherapy. And so to see a waterfall plot like this is really impressive. You can see there is a small cohort of patients who decreased their volume by 100%, which in some cases constitutes a complete response. It’s very unusual to see in this line in bladder cancer. And the swimmers’ plot, you can see those arrows with ongoing response. This is a slide of early follow up that we’re using here, but the ESMO data presented by Dr O’Donnell suggests that this can be maintained for some patients.

DR LOVE: And we should point out that the swimmers’ plot which is on the left, I guess you see how long the patients have been on therapy. And you can see many of these patients, in this particular point in this particular trial that Jonathan reported, had already been on it for more than a year. And then on the right is the so-called waterfall plot. And each one of those represents a patient, and when that goes down that means the size of the tumor’s going down, and you can see most of them do respond.

Jonathan, what’s been seen in terms of tolerability issues with this agent? Side effects?

DR ROSENBERG: So the most common side effects that I tell patients about are some fatigue, some cytopenias, primarily anemia, but mostly rash that occurs fairly frequently, as well as neuropathy, which I view almost as a sign of success. It’s often a time-dependent phenomena, so you have to be on it for a while to get neuropathy. And so the patients who tend to have good responses tend to be the ones who get neuropathy as opposed to people who come off quickly.

All these side effects are managed by dose interruptions and dose reductions and occasionally perhaps altering the schedule, instead of 3 weeks on, 1 week off, sometimes 2 weeks on, 1 week off or every other week. But those are really for the exceptional patients. For the most part, holding the dose for a few weeks, sending people to dermatology for skin problems, potentially consulting a neurologist for neurologic issues, although I haven’t felt them to be that helpful, unfortunately, are things that you can do in addition to the dose reductions.

DR LOVE: So Cristina, I’m kind of curious how you explain what enfortumab vedotin is, the antibody-drug conjugate. I’ve heard people talk about it being a trojan horse, that we’re trying to bring in the toxin just to the cancer cell. What do you say to your patients, and what do you discuss with them in terms of potential tolerability issues?

MS SALABAO: Yeah, so I say almost exactly that, is we’re kind of trying to trick the body and the cancer into getting this medication to where it needs to go. And I will say, of the patients that I’ve seen on it, most people have tolerated it fairly well, as in to the point where we don’t need to dose reduce, but they do have some of the skin changes. I’ve had people with some dry eye, which is a side effect, as well.

And I think that those are the biggest 2 other than the neuropathy, which even that I don’t see that often, and it could be just because of how long the patients have been on it. Maybe they had not been on it for long enough. But generally, other than they have to come in and see me every week for 3 weeks, they’re doing well, they should feel well, and that’s what I usually say. And then the only other thing that I try to educate them on is blood sugar, but that I’ve never actually seen outside the clinical trial.

Dose and schedule of administration of enfortumab vedotin; associated peripheral neuropathy, hyperglycemia and ocular toxicities

DR LOVE: So Andrew, can you talk a little bit about how enfortumab is actually given? And again, some of the tolerability and drug interaction issues.

DR RUPLIN: Absolutely. So as is visible on this slide here, our standard of administration would be days 1, 8, and 15 of a 28-day cycle. This is a weight-based dosed drug, so 1.25 mg/kg is the first or initial dosing strategy, with of course a recommended cap at 100 kg for all dose levels. This particular agent is administered over 30 minutes, so patients do generally tend to enjoy that, particularly patients who’ve had prior cisplatin-based chemotherapy where they had a much longer infusion, and they realize they only have to sit in the chair for about 30 minutes for this.

The side effects that I counsel patients on have really been said here already. Some of them do certainly tend to be somewhat surprising for patients, given their prior treatments. So when we talk about the neuropathy, which may not be unique to them, but some of the ocular toxicities, the skin rashes, the hyperglycemia, which Cristina I know you had said you hadn’t seen. there’s at least 1 patient I can think of who we have held treatments for them because their blood sugar did exceed 250 mg/dL on our prechemotherapy blood test. Overall speaking though, I feel like this agent has been fairly well tolerated and with the flexibility of the available dose reductions, I think it’s fairly quite easy to keep patients maintained on this treatment despite the overall fairly common incidence of some of these side effects that were reported in the EV-201 trial and are visible from our own experiences.

DR LOVE: So are there issues about the potential for extravasation that have to be considered in particular, Betsy, with enfortumab? I hadn’t heard that before, but we asked about it.

DR PLIMACK: Yeah, so that’s actually probably a really good question for Andrew. I haven’t had extravasation reported. I would say extravasation of anything we infuse is potentially a problem.

DR LOVE: Andrew or Cristina, is extravasation more of an issue with enfortumab than other agents?

DR RUPLIN: So in my experience at our center we have not had any patients have an extravasation event. To my knowledge, when we reached out to the drug company for information on, I think, 1 or 2 patients had had what was considered an extravasation event. We had asked them what their recommended management of this was. For the 2 patients who did have a “extravasation” really no major intervention was needed. So for me a major intervention might be defined as is there a need for a therapeutic antidote which we might use for some vesicants. The response that we had received was that in, I think, the 1 patient who had a “extravasation”, they used a cold compress. The patient had developed some cellulitis, so they simply treated what they assumed was a cellulitis.

But in my personal experience we have not had any patients demonstrate extravasation, in my opinion, or from what I’ve heard from other colleagues.

DR LOVE: So Jonathan, maybe we can talk a little bit about the peripheral neuropathy that’s seen with enfortumab. When do you typically see it? What type of neuropathy is done? Here’s a slide from the survey suggesting that most people will use dose interruption or dose reduction. Can you talk a little bit about the clinical scenario of neuropathy with enfortumab, Jonathan?

DR ROSENBERG: Yeah, in my experience it often starts in the third or fourth cycle and initially presents with perhaps some paresthesias, but actually quite frequently with numbness. It can progress to motor neuropathy in addition to sensory neuropathy in some patients, manifesting itself as generalized weakness or weakness in the legs. It is a difficult thing to manage, and it is not often reversible if you’re intent on continuing the patient on treatment. But by reducing the dose or holding the dose you can usually stop the progression, at least for some time.

And I have patients who’ve been on it for several years, with neuropathy, and we have played with the dose and the schedule a little bit. One thing I’ve actually found patients tell me is helpful is occupational therapy to deal with the consequences of the peripheral neuropathy, to really get their hands working again properly so that it doesn’t affect them nearly as much. The pain that they get often goes away, but the numbness, in my experience, generally can be persistent.

DR LOVE: Cristina, any comments about the issue of peripheral neuropathy with EV? Any alternative complementary strategy that you find useful?

MS SALABAO: I would just say that we have to be particularly vigilant just because of the probable treatment that they’ve had before with cisplatin. Again, I haven’t really had anybody with neuropathy to the point where we’d have to dose adjust or hold. And I know that there’re some complementary treatments as far as a think some of the B vitamins, but I don’t typically recommend them. I spoke to our pharmacist about that, and I think that the jury is still out as far as the research that’s been done. There’s nothing high quality.

DR ROSENBERG: I would agree with that statement.

DR LOVE: So Betsy, any comments on your experience with peripheral neuropathy in terms of how it presents, how you manage it? And also we asked in the survey the issue about hyperglycemia with enfortumab, if you could talk a little bit about that.

DR PLIMACK: Sure. So neuropathy’s just tough. I mean I just echo what Jonathan and Cristina said in terms of management. I think it’s really hard to mitigate, and in a patient who’s having a really nice response to therapy it’s a really hard balance to trend. I mean I can share an anecdote. I had an elderly patient who was really underreporting neuropathy to us because he wanted to stay on the EV. It was working for him. It was shrinking his lung mets. And it wasn’t until he could barely walk into clinic, we always ask about neuropathy, but we really asked him and learned it was much higher grade than we thought.

And so I think encouraging patients to be honest with you about what they’re going through so that you can build in the treatment breaks and try to mitigate it as best we can. But it’s just an issue with EV. And I think the longer it’s working for you, the longer you’re on it, the more your chance of getting. So that’s neuropathy.

The glucose management issue is really tricky. It’s not clear, and Jonathan may have more information on this, it’s not clear to me why some patients get refractory hyperglycemia with acidosis. We have seen it. It comes on precipitously and unexpectedly and is very hard to treat. So the glucose management recommendations are really an attempt, I think, to mitigate one of these severe acidosis reactions. But I’m not sure there’s a direct correlation because, at least in my experience, when that does occur, which is rare, it can be in the setting of reasonable glucose control at baseline that evolves into uncontrollable glucose later.

DR LOVE: So Jonathan, any thoughts about hyperglycemia? It looks like if you look at the survey that people will often hold the drug, institute diabetic therapy. You say skip a dose, start metformin, resume when better under control. We also ask whether or not people look at A1c levels, and in some cases based on that maybe not use enfortumab. So what about glucose control in enfortumab, Jonathan?

DR ROSENBERG: Yeah, so I’ve seen a couple of these cases, and there’s 2 forms of it, one is mild hyperglycemia that is manageable and then there is this acute hyperglycemia that leads to metabolic acidosis, and patients are often in the ICU. And in order to get those sugars under control they may need hundreds and hundreds of units of insulin a day. And the etiology is totally unclear, I think, to anybody at the moment. It is a very rare side effect for that to occur, but if you notice that there’s a trend with rising random glucoses that your detecting before patients have their treatment, I would suggest taking it seriously because it can happen suddenly. It often happens early if it does occur, and it’s apparently associated with obesity. And that’s about the most we know, which suggests that there’s probably some underlying insulin resistance and some other process that we don’t understand at the moment. It is not a common event, but when it happens you won’t forget it.

DR LOVE: So Betsy, a couple other tolerability issues that we asked about in the survey. One is skin-related events, and it looks like people have generally seen those to some extent. I’m curious what your experience is. But also, Betsy, the other issue is ocular toxicity. If you could comment on both of those issues.

DR PLIMACK: Sure. So these are unusual toxicities that are linked to EV that we do see. Rash can be severe, and in our experience we haven’t found a good mitigating strategy. Obviously, you can soothe the rash with topical treatment, but it’s not one that’s going to go away with that strategy. It seems to be dose limiting when it becomes severe. Obviously, if it’s a low-grade rash that the patient feels is tolerable, it can kind of coexist with treatment. But again, I don’t know that we know a lot about the etiology of the derm reaction other than that nectin-4 is in the skin, so it’s probably actually an on-target but unwelcome effect of the drug itself.

DR LOVE: Can you comment more on the ocular issues that occur?

DR PLIMACK: Sure. So in the clinical trial we had patients evaluated by an ophthalmologist regularly for evaluation of the eyes. And I don’t know that in clinical practice that’s something we continue, mostly because it doesn’t require an eye exam to have a patient report dry eyes. And it’s really dry, itchy, irritated eyes that we see with this agent. We can usually treat it with eyedrops, either steroid or just saline eyedrops. And if it’s severe we certainly send to ophthalmology. The key is that we don’t want it affecting visual acuity, and in my experience it typically does not and can therefore be managed.

Case: A woman in her early 70s with mUBC and a history of multiple sclerosis receives enfortumab vedotin after disease progression on neratinib/paclitaxel — Cristina Salabao, MSN, FNP-C

DR LOVE: Let’s talk about some of the cases you submitted. And Cristina, you have this 70-year-old lady who has a history of multiple sclerosis, which is interesting, if we consider checkpoint inhibitors with a patient like that. But what happened with this lady?

MS SALABAO: Sure. So as you can see her treatment history here, she had quite a quick progression, well I guess into that 2-year mark through several treatments. Anyway, she started enfortumab late spring/early summer and had a partial response after I believe 2 cycles. But she developed the skin toxicity. It was more of just like an unsightly discoloration that was dry, so we managed that with Eucerin^®. But she did actually complain of some blurry vision, so I did send her to an ophthalmologist, who diagnosed her with blepharitis, and she was treated. She did a course of tobradex, and I don’t think it really improved, and then continued with rewetting drops and steroid drops. But that was the first time that I’d seen some of the actual vision changes and not just like the crusty, dry eye side effect.

DR LOVE: So is she still on enfortumab now?

MS SALABAO: She’s not. She unfortunately progressed after 7 cycles.

DR LOVE: Seven cycles she progressed.

MS SALABAO: Yes.

DR LOVE: So you put together some notes on this case. Maybe you can kind of comment on that.

MS SALABAO:

so she at baseline, again, thinking about her treatment history, she did have peripheral neuropathy. It was maybe Grade 1, and so that’s why in particular for her I wanted to make sure that we were monitoring it. And she also has MS too. So that was a big side effect that I wanted to monitor closely with her. Thankfully, we didn’t need to make any reductions in dose or skip any days. And I will add, I don’t think the day elimination is actually listed in the prescribing guide, I think you’re supposed to just dose reduce, like hold and then dose reduce. But I think, again, it depends on the provider whether or not they eliminate the day 15. I’m not sure what our medical oncologists here prefer to do.

DR LOVE: So Jonathan, can you comment on that, the idea of eliminating the day 15 dosing?

DR ROSENBERG: So you don’t change the dose intensity all that much, but you do reduce the amount of drug that people are getting, obviously, per month, by doing that, about 20% or so. So the question is, is it related to peak dose or is it related to cumulative dose. I don’t think we really know yet. I’ve certainly thought about that. What I’ve also done with patients with more severe neuropathy is drop the day 8 dose and just treat every other week when I’ve had the opportunity to treat patients off study, to do that. And I found that I’ve been able to keep people on longer without necessarily reducing the dose. Although my general practice has been dose reduction before skipping doses because I actually think the exposure over time is more important than peak dose in terms of efficacy. Therefore, I don’t usually use that strategy very often. I find that dose reduction tends to work better.

DR LOVE: So I’m going to ask Betsy in a second how the fact that this woman also had MS might affect any of these treatment decisions and management. But first Cristina, how difficult a problem was the MS? Did she require biologic therapy or it wasn’t a big problem?

MS SALABAO: No, she did not. It was very well controlled before she started this treatment. She had regular follow up with her neurologist, I think. She maybe had 1 episode of vertigo that just kind of came out of nowhere that I attributed to something else, and she had the whole like kind of workup redone with her neurologist. But it really didn’t flare up. It didn’t really cause her any issues other than some of the baseline things that she had had going on, which again were very mild and very manageable.

DR LOVE: So Betsy, any comments about how this history of MS might affect your overall management? Of course MS is, I think, considered an autoimmune disease, and you wonder whether or not a checkpoint inhibitor might make it worse. It looks like she was able to get a checkpoint inhibitor. But how does that affect your approach to a patient if you know they have MS, Betsy?

DR PLIMACK: So it changes the conversation. A patient with a prior autoimmune disease, if it was severe, or any variety, MS included, is one that predisposes the patient to either a flare of that autoimmune condition or a new one. We know that from multiple studies. So it just changes the risk conversation, and based on that these are the patients who occasionally will get EV, for instance, before immunotherapy or get more lines of chemotherapy or get erdafitinib sooner.

So I had a patient who had bad MS on treatment, and we actually avoided immunotherapy. It was not something she ever wanted to risk because she didn’t want to have the MS flare. But again, I wish we knew how to counsel people more in terms of percent chance of having it as a problem. As this patient demonstrates, especially if it’s a mild, controlled case, you can get away with immunotherapy, and that’s an important piece of their treatment.

DR LOVE: I’m curious, Jonathan, how you think through patients with prior autoimmune problems. There’re lots of them out there in checkpoint inhibitors, but maybe some of these other drugs we’re talking about. How does that affect it? And also what about the patient with a history of transplant who may be on immunosuppressive drugs? Can you give, for example, a checkpoint inhibitor?

DR ROSENBERG: All these are good questions. So for patients it really does depend on the type of autoimmunity they have. I think I would be more scared of multiple sclerosis or scleroderma or active lupus than I would be of rheumatoid arthritis or psoriasis. Things that are generally of a more life-threatening nature that may be more difficult to control, if we get into trouble with the immune checkpoint drug, I’d be more reluctant to use a checkpoint inhibitor.

For a transplant patient, it depends on the organ transplant too. I think for a patient who might have a kidney transplant, let’s say, and if the kidney’s rejected and the patient goes on dialysis and they’re okay with that, it’s certainly something I would consider. But there are case reports, certainly, of patients who have had solid-organ transplants who’ve had good responses to immune checkpoint drugs and mild lowering of the immunosuppression and able to keep everything in balance. But my sense is that those are success stories, and we may not be hearing about the all the failures of that approach. I think there’s certainly a bias in the literature towards doing something successfully as opposed to warning about how it was a disaster.

Case: A woman in her late 60s with mUBC receives enfortumab vedotin after disease progression on sacituzumab govitecan — Andrew Ruplin, PharmD

DR LOVE: So I want to get into another case. This is actually Andrew’s case of a 69-year-old woman who actually presented, got neoadjuvant therapy, started out in 2017, long history of metastatic disease, gets pembrolizumab along the line, actually gets sacituzumab, a drug approved in breast cancer. We’ll maybe talk about that, as well. It was on a trial. And then got enfortumab.

Andrew, can you maybe focus on that point? I guess it was earlier this year when she started the enfortumab, and maybe chat a little bit about what happened.

DR RUPLIN: Absolutely. So this patient, I will say, was our first patient in whom we did enfortumab vedotin after the FDA approval. So from a systems standpoint there was a lot to do with getting this on our formulary, developing an order set to actually order this chemotherapy with the appropriate lab parameters, call parameters, labs to be ordered, premedications, and all of that that goes into a chemotherapy treatment plan.

This patient, I’ve talked about before how in my practice one of these roles that I often do is education of the patient. So I did meet with this patient to do this counseling session on the use of enfortumab vedotin. And while there are a number of different resources I love to use to educate patients, I think at the time that we started using this agent in this patient, which I think the earliest we used it was late December of last year, there wasn’t much published out there as far as a patient-friendly education guide. So in that scenario I think we did actually teach her from the actual EV-201 publication on some of the side effects, how they administer the treatment, and what patients could generally expect from their treatment.

So I will say this happened very quickly. There was a large urgency to get this particular patient on this treatment as quickly as we could. So it was a very fast, from start to finish, of starting the process of getting the drug on formulary, ordering the drug, and then getting the treatment plan ready in our electronic health record to administer it to this patient, as well as education of our nurses and providers on how to manage and care for patients on this treatment, as well. It’s been very successful overall.

In the case, she had some dose reductions, as well as some discontinuations of some of the standard days of treatment for this treatment. But to date I think she’s doing relatively well overall, with some manageable toxicities, and she continues on treatment.

DR LOVE: I see that she had a rash and taste changes. What did she describe there?

DR RUPLIN: The taste changes was unique. We weren’t really expecting that one, but she described variously some of the decreased sensation of taste when she’s eating food, as well as almost like unpleasant tastes, not really describable, but just kind of a general unpleasantness of taste when she’s been eating food. So that unpleasantness of taste plus the rash was one of the more recent occurrences that led to the decision to drop some of the days of treatment with her. But again, overall, she’s been managing fairly well and tolerating fairly well. And she, as we’ve kind of talked about before, is very intent on remaining on this treatment for as long as she benefits, so she’s been willing to accept those dose reductions, but also the ongoing side effects that she’s been experiencing.

DR LOVE: Betsy, in a second, I want to hear about your 83-year-old man with chronic renal insufficiency, but have you seen taste changes, I guess dysgeusia, with enfortumab?

DR PLIMACK: No, but my first thought was we should COVID test her, right?

DR LOVE: Yeah. I was thinking that also.

DR PLIMACK: I’m sure you did that.

DR LOVE: I don’t know if that’s taste or smell.

DR ROSENBERG: It happens with the drug. I’ve had people who suffer with it, unfortunately.

DR LOVE: Are you saying with enfortumab or COVID, Jonathan?

DR ROSENBERG: Both, but enfortumab. Negative COVID, positive taste changes.

DR LOVE: Interesting.

Case: A man in his early 80s receives enfortumab vedotin for mUBC — Elizabeth R Plimack, MD, MS

DR LOVE: So Betsy, how about your 83-year-old man here?

DR PLIMACK: Sure. So this is a patient I met when he was younger than 83. He unfortunately got BCG for a localized bladder cancer but developed metastases after his surgery. So the metastases are the ones you see here. And when he presented his creatinine was 2.9.

DR LOVE: And can you talk a little bit about what happened? I guess initially he got pembrolizumab?

DR PLIMACK: So, right. He was treated with pembrolizumab outside, and then at 2 years on pembro he met criteria for progression and developed colitis from the pembrolizumab. And so based on that we stopped pembro. It was hard for him to let go of it. He had had such a nice response and tolerated it well up until the tandem criteria were met for stopping, and then he was started on enfortumab vedotin.

DR PLIMACK: He had a really nice response to treatment, and he was receiving standard dosing as per the clinical trial. There was a cohort in the clinical trial that allowed for patients with severe renal insufficiency, which is what this patient had. The trial did conclude that in a renal insufficiency cohort they could be treated with this, which is good because a lot of our urothelial patients do have renal insufficiency.

But the issue that we ran up against with him is what we were just talking about, where he ultimately developed neuropathy and again downplayed it to us in the clinic. And then when we noticed on clinical exam and evaluation of his gait that it was severe, he ultimately had to stop it.

Now, in the context of clinical trials we’re much more limited in terms of dose reductions, adjustments, dropping day 15 or day 8, all the things that we were just talking about as nuances of management of dosing to maintain patients on active therapy. So I think going forward when this happens, when I’m treating someone off study, I would be more liberal with dose reductions, treatment breaks, and perhaps spreading out the dosing, as Dr Rosenberg suggested.

DR LOVE: But he actually had an objective response to the enfortumab?

DR PLIMACK: Yeah.

DR LOVE: Where was the disease? Was it his lungs that responded?

DR PLIMACK: Right. So the lung tumor was much larger than the picture you just showed when he started on EV after he had had progression on the pembro. And yeah, they shrunk.

DR LOVE: It’s also interesting that he had that long period of time on the pembrolizumab when he got the colitis. I’m curious, Cristina, what your experience is with colitis in patients on checkpoint inhibitors and how you evaluate patients for diarrhea who are on checkpoint inhibitors. Of course lots of things can cause diarrhea. But Cristina any comments?

MS SALABAO: Yeah, so it’s kind of tough because the other population that I work with is renal, where some of our clinical trials use TKIs along with immunotherapy, and it becomes harder than when you have 2 agents that may potentially cause diarrhea to differentiate. I ask about severity and kind of look at what they look like. Do they look dehydrated? Do they look awful and terrible? And then if it’s to the point where they’re constantly running to the toilet, then we hold, and if it goes away in a day or 2, then we assume that it was some bad oysters.

But if it continues to persist, at that point in time we think about getting GI involved, getting imaging, steroids, that type of thing. But yeah, it is hard. It’s hard because you don’t want to stop for every little thing, but you also don’t want to push them over the edge. So good clinical judgment, and then just keeping a really close eye on people I think are the 2 biggest things that you can do to kind of help differentiate is this IO related or something else.

DR LOVE: So Jonathan, in a second I’m going to ask you to talk about your 88-year-old man. He actually got pembrolizumab, as well, but ended up getting enfortumab. But before we get into that, anymore comments about colitis and diarrhea with checkpoint inhibitors, Jonathan? How do you decide when to use corticosteroids? How do you deal with tapering corticosteroids?

DR ROSENBERG: So for patients who have very mild diarrhea we usually recommend diet modifications first and see if those help, with some loperamide. We sometimes use budesonide, although I can’t say that there’s good high-level evidence to suggest that it really helps reducing the severity of diarrhea. For people who have Grade 2 of 3 diarrhea, or 3 or 4 diarrhea, obviously we are pretty quick to institute corticosteroids. Often, as was alluded to before, the temporal nature of the diarrhea and any attributions are often very helpful. People who had a questionable meal, people who feel like it was related to some food indiscretions, often those just get better within a day. And so sometimes time is very helpful here.

For patients who require high-dose steroids, I usually wait a week or 2 until starting to taper, and then taper over the course of about a month. Depending on how fast they improve, perhaps a shorter amount of time before we start tapering. And it can be very frustrating and difficult for patients because they’re so invested in the treatment working and staying on treatment and not skipping doses. But colitis is one of those side effects that you can’t really mess around with.

Case: A man in his late 80s attains a stable response with enfortumab vedotin for mUBC — Jonathan E Rosenberg, MD

DR LOVE: So let’s hear about this 88-year-old man, Jonathan, that you took care of. Can you talk about initially how you interacted with him and a little bit about his treatment course?

DR ROSENBERG: So he was first diagnosed with metastatic disease. He was still working every day, going to the office, running a company, so obviously very high functioning, relatively unusual 88-year-old, physiologically probably more like a 75-year-old. He refused chemotherapy initially, even though he was PD-L1 low, and as predicted he progressed on pembrolizumab. He actually did not respond to chemotherapy either.

And so he was agreeable to starting enfortumab vedotin. And he’s tolerated it relatively well, but I did start at a dose reduction, which I have not generally done, at 1 mg/kg for this patient because of his advanced age. I figured that we could probably push him over the edge pretty quickly. And he’s been very tired, but otherwise tolerating it pretty well. And he’s had stable disease so far without any untoward major effects.

He actually had all of his seborrheic keratoses turn black, interestingly enough. They didn’t fall off, which I thought would have been a new treatment for seborrheic keratoses, and then with topical steroids they came back to normal. I’ve actually found that skin toxicity, for many patients, topical steroids actually work very well and our dermatologists, who I often refer to relatively early on in the course of treatment when the start developing skin toxicities, also are believers in corticosteroids.

DR LOVE: I just want to again come back to Cristina and Andrew. Any questions you’d like to pose to Betsy and Jonathan? Andrew?

DR RUPLIN: Dr Rosenberg, I was curious. How long was the longest term that a patient has been on enfortumab vedotin therapy so far in your experience?

DR ROSENBERG: I have someone who’s been on it for just about 3 years.

DR RUPLIN: Wow.

DR ROSENBERG: But he’s required dose reduction, dose holds, skipping doses, for neuropathy, but he is in a near-complete CR, effectively in a CR at this point, 3 years later.

DR RUPLIN: Beautiful. Thank you.

DR ROSENBERG: So whether he needs to be on treatment still is not actually clear, but it’s very hard to take someone off in that scenario.

MS SALABAO: Would you consider a treatment break?

DR ROSENBERG: I would, and I have effectively. I mean there have been times where we’ve held for a month or 2 while neuropathy improved. But the anxiety level for the patient, and particularly the patient’s wife, was something I could not overcome. So he’s still on treatment now, a year after the treatment break, and still in remission. I don’t think I’ve cured him, but I do think he’s in the best possible scenario he could be.

DR ROSENBERG: He had lymph node-only disease.

MS SALABAO: Sure.

DR ROSENBERG: And so his lymph nodes didn’t increase in size. They stayed the same.

MS SALABAO: Hard to know.

DR ROSENBERG: Hard to know if there was microscopic disease there.

Biologic rationale for, efficacy of and pharmaceutical considerations with erdafitinib for patients with mUBC and FGFR gene alterations

DR LOVE: Okay, so we’re going to loop in erdafitinib at this point, and then we’ll bring it all together.

And maybe we can start out, Jonathan, we have some slides that kind of reviewed erdafitinib. Can you talk a little bit about what it is, what we know about it?

DR ROSENBERG: So erdafitinib is targeting a transmembrane growth factor receptor for the fibroblast growth factor family. And it heterodimerizes and homodimerizes with other FGF receptors. And when they dimerize it leads to activation, and there are mutations, or fusions, in bladder cancer that lead to constitutive activation, permanent activation essentially, of the gene. And we know that this is an oncogene for bladder cancer, and that if you inhibit it it’s function in vitro that you have decreased growth and actually tumor regression, and so that’s the basis of targeting the pathway. And it’s more common in nonmuscle-invasive bladder cancer, but it is playing a role in advanced metastatic disease as well.

DR LOVE: So could you talk a little bit more about what we know in terms of what happens when you give it to patients in terms of clinical activity? It was approved more than a year ago. How do you use the drug and what do we know about its effect, both efficacy and tolerability?

DR ROSENBERG: So it is an oral agent approved on daily dosing, and you have to monitor phosphorous levels in order to determine whether you’re at the optimal dose or not. And if you’re at 8 mg, and the phosphorous levels are under 5.5, you can actually increase the dose. the response rate is about 40% in the Phase II clinical trial. And the drug is meant to be continued until disease progression. You need to watch for ocular issues, and you need monthly ophthalmologic exams.

And so I’ve found personally that there are some patients that tolerate the drug well, but that there are many patients for whom tolerability is more of an issue, with mucositis and stomatitis and skin rashes, or fingernail changes in particular, that are much more difficult.

In terms of the duration of the response and the overall survival, it’s similar, I would say, to enfortumab in this setting, with a PFS of about 5.5 months and OS of a little over 10 months. But it only applies to about 15% to 20% of patients compared to a drug like enfortumab, which might apply to 100% of patients in this group.

DR LOVE: Betsy, any comments on the waterfall plot here? Again, it looks like most of these are going down, so it looks like most of the patients are having their tumors shrink. What do you see clinically in terms of the efficacy, Betsy, with this agent?

DR PLIMACK: So I think it’s effective. I think the waterfall plot shows that. Obviously, this is for a subset of our patients that will be candidates for this therapy, so it’s not for everybody. I will say the curves you show there from ESMO, showing progression-free and overall survival, I was hoping to see a little bit better PFS with this agent. It seems like even though we do see that shrinkage, as showing in the waterfall plot, patients aren’t able to maintain that. I’m not sure if that’s related to, again, accumulation of side effects, tolerability, or just limited efficacy of this agent.

DR LOVE: So Andrew, what are some of the important considerations from a pharmacist’s point of view with this agent in a patient who’s going to be receiving this agent?

DR RUPLIN: Yeah. At our center I can speak to, from an operational standpoint, one of the first things we do have to do is the cumbersome US Bioservices supply of this medication. So it can be fairly lengthy for some people, but it’s not a traditional write a prescription, send it to a pharmacy or a specialty pharmacy and get it filled. Patients and the providers have to work with this US Bioservices form in order to get it filled. So that, in some people, can be quite difficult to get financial coverage for this medication and has caused delays in starting the treatment for some of our patients.

From a clinical standpoint, we do educate patients on the prophylactic measures that were described in the protocol of the trial and are also reported out in the prescribing information to help mitigate some of the issues with this drug, including the hyperphosphatemia. So we do recommend patients start with a low phosphate diet, and we do recommend that patients, to prevent skin toxicity, use moisturizing agents, and in some cases we may use like a urea cream if patients have hand-foot syndrome or the more severe skin toxicity.

Certainly, there’s always the question of well is the dose going to increase once we draw phosphate labs. Our standard is to do it at the 14-day range. I think the recommended standard is to do it between days 14 to 21. We do it a little bit earlier rather than later. And some of these toxicities can manifest beyond that 14-day window, so it is not necessarily uncommon that we have patients who have an increase in their dose based on their phosphate level, however then later go on to develop some of these side effects like the skin and the ocular side effects as well.

Monitoring and management of ocular, skin and nail toxicities and hyperphosphatemia associated with erdafitinib

DR LOVE: So Cristina, any comments about, from your point of view, how you manage these patients, particularly as it relates to some of these tolerability issues, phosphate, et cetera?

MS SALABAO: Yes, so I’ll echo the low-phos diet, and then also for the skin issues, again, recommend Eucerin typically or another thick nonscented moisturizer, keeping an eye on their nails, and then rewetting drops for peoples’ eyes as well. That won’t necessarily prevent some of the eye toxicities, but just for comfort.

DR LOVE: So Betsy, here’s some data actually you put together on tolerability issues with this agent. Can you kind of go back through this and reflect on your own personal experience with these various issues, and particularly as it relates to these ophthalmic issues?

DR PLIMACK: So the ophthalmic issue is different with erdafitinib compared to enfortumab vedotin, and even though both really require attention paid to the eyes, the EV ocular toxicity’s more surface. The toxicity seen with erdafitinib is a central serous retinopathy, which is a retinal issue. And so that really does require an ophthalmologist be following a patient monthly. What’s interesting is that with the way this toxicity is graded it’s really not until it affects visual acuity that it becomes higher grade and requires adjustments.

So in a sense, if one doesn’t have access to ophthalmology, just a little visual test in clinic for the patient could help catch one of these central serous retinopathy issues that leads to acuity issues. In the case of altered acuity you do have to hold and adjust the dose. But there are parameters for retreatment for patients who experience this toxicity. It doesn’t mean you have to hold it permanently.

DR LOVE: So Jonathan, of course we know that only a small fraction of patients who have this FGFR3 mutation will benefit, but for those patients, theoretically, you have a choice of either one of these agents, enfortumab or erdafitinib. We presented a few scenarios to the faculty to see kind of which one they would do first. So first, this is a patient who actually gets adjuvant chemotherapy after cystectomy and was found to have liver mets after that, but also an FGFR mutation. So when you ask, actually Betsy’s the only one who says checkpoint inhibitor, which you would think maybe would be standard. Dr Balar says enfortumab, and the rest of the faculty says erdafitinib.

Jonathan, can you talk a little bit about how oncologists think through these various options, for example in this situation?

DR ROSENBERG: So the FDA label for erdafitinib is actually for either post-platinum with or without a checkpoint. And so technically erdafitinib is within the label for this drug. It is a single-arm study. Pembrolizumab has randomized Phase III data, but the data suggests that if there are liver metastases that the outcomes are not as good as we’d like. And so it certainly underscores the desire to treat with an agent that might have a higher response rate, and that’s where I think people are thinking about erdafitinib, and that’s certainly why I was thinking about erdafitinib.

Due to the fact that the response rate in the liver seems fairly similar regardless of sites of metastases when they’re treated with erdafitinib, whereas with immune checkpoint it seems to be much lower in liver metastases.

DR LOVE: So I want to go through some of the tolerability issues that come up and kind of what our faculty has to say about this. So Cristina, we asked do they use preemptive steroid mouthwash to prevent stomatitis, and it looks like most people say no, Cristina, any thoughts about this issue of a steroid mouthwash?

MS SALABAO: Sure, yeah. We don’t do that here. I’ll recommend baking soda rinses and making sure they’re vigilant in monitoring whether or not these symptoms start to come up, but not prophylactically.

DR ROSENBERG: We wouldn’t start with steroid rinses prophylactically, but at the first sign of any oral toxicity we’re starting to use it because it often gets out of hand very quickly, in my experience.

DR LOVE: So yeah, and actually when we say to people what do you do when the patient actually does get stomatitis, Cristina, it looks like a lot of people are using magic mouthwash, dose interruption or reduction. That’s interesting, sugar-free candies, haven’t heard that one before, to promote saliva, salt and soda mouth rinses. Cristina, any thoughts about these strategies?

MS SALABAO: Yeah, so again if it’s mild, baking soda rinses. The sugar-free candy, sometimes we’ll use, more for like dry mouth, not so much like stomatitis, and then magic mouthwash. Some people like it, some people hate it, but it’s always a nice tool to have at least to numb things up so people can eat and sleep and be somewhat comfortable.

DR LOVE: So Betsy, another thing we asked about was dermatologic side effects that are seen. People talk about using local therapies, particularly steroid creams, also issues related to the nails. Any comment, Betsy, in your clinical experience and what you’ve seen in the data as it relates to these issues?

DR PLIMACK: I think the key here is to educate patients to really watch their nails and their nailbeds if they typically don’t care for their nails, to not pick at the area, not exacerbate it. But we’re still experimenting with different ways to help when they do get the nail toxicity, the paronychia and the onycholysis. I mean onycholysis is just really hard, and it did occur with some frequency in the clinical trials. Fortunately, I haven’t seen it in my clinic, but it’s not something easy to fix. So I tend to approach this with catching it early and holding the dose for a period of time until it resolves, and then restarting. I guess that’s borrowed from my experience with the VEGF TKI inhibitors, where that’s how we manage skin tox.

DR LOVE: I’m curious, Betsy, in terms of your global take of these 2 new drugs that have come into the management of this situation, erdafitinib and enfortumab. When we asked the faculty, most of them thought that in general enfortumab is better tolerated. What’s your experience?

DR PLIMACK: It really varies, I mean again, enfortumab is probably better tolerated early on. I think the toxicity you get with erdafitinib happens early, so if you were to take 2 patients, 1 on enfortumab and 1 on erdafitinib and see how they’re tolerating it at month 1 it might be different that at month 6, 7, or 8. I will say, based on the ESMO data, I’m not sure how many patients are on erdafitinib for that many months, and so maybe it doesn’t work well enough to keep patients on it long enough to see this accumulation of toxicity that we see with enfortumab vedotin.

Case: A woman in her early 70s develops rash, mucositis and nail changes after treatment with erdafitinib for mUBC with an FGFR3 alteration — Dr Rosenberg

DR LOVE: So Jonathan, you had this 70-year-old woman who got erdafitinib, and I see she had some nail changes and rash and mucositis. What happened to her?

You said you saw her 3 years.

DR ROSENBERG: Right. Yeah, yeah. So she was able to tolerate treatment again at a reduce dose with the nail changes once she saw the dermatologist and came up with a treatment plan. She needed antibiotics for paronychia. She had mucositis that was difficult to control, ultimately required dose holding and dose reduction. And the rash was the least of her problems.

I think we need to think about how we can best manage these folks. We’re doing things according to how we’d use other drugs, and obviously there’s similarities between classes and dealing with certain toxicities from VEGF TKIs maybe relevant, but they may not be because it’s actually not a VEGF TKI. It’s an FGFR TKI. And so I think we need to try to address some of these issues more systematically and try to get a handle of the best practices for doing this. And so certainly some clinical trials might be in order for supportive care to try to help us actually keep people on drug longer.

Case: A woman in her mid-70s with mUBC and an FGFR3 alteration receives erdafitinib after disease progression on cabozantinib/atezolizumab — Ms Salabao

DR LOVE: So Cristina, you have this 75-year-old lady originally diagnosed in 2011, and you put together the treatment course. This patient’s gotten chemo, they’ve gotten a checkpoint inhibitor, but also they were found to have an FGFR3 mutation. What happened when this lady got erdafitinib? How did she do?

MS SALABAO: So she tolerated it quite poorly. She had rash and nail issues that required dose holding and eventually did just come off due to progression as well. But she was sent to derm to see what they could do. They did, I think, antiseptic soaks, and she did either have or antifungal or antibiotic treatment, with some improvement. Really I think what improved her the most was holding the drug.

That wasn’t her, but it was very similar to that.

Just very painful skin on her hands and foot, and also these nails that were just flaking and just very painful. And she did require some holding of the medication for that.

But again, it got to the point where even holding, as soon as we restarted it there was a flare of these symptoms, and she ended up having to come off because of that, and also progression.

DR LOVE: So in a second I want to hear about, Andrew, your 60-year-old man. But Betsy, can you explain a little bit more about what central serous retinopathy is, how you diagnose it, and what the implications are?

DR PLIMACK: Sure, so I’m no expert, but it is where the retina detaches from the back of the eye, and there’s a serous accumulation there. It is detected based on a retinal exam, which does require an ophthalmologist. They are the ones with that equipment. And so it can be measured in millimeters to determine how significant it is. But again, the grading and what mitigates dose reduction is the change in visual acuity.

I have seen this, and I have seen it result in acuity changes and had it be present without acuity changes, and the management is different in those 2 scenarios.

DR LOVE: But this is generally reversible, Betsy?

DR PLIMACK: Generally reversible, and also so reversible that the drug, at least in the erdafitinib guidelines, can be restarted at a lower dose if CSR occurs.

DR LOVE: Interesting.

Case: A man in his early 60s develops hyperphosphatemia and central serous retinopathy after therapy with erdafitinib for mUBC with an FGFR alteration — Dr Ruplin

DR LOVE: So Andrew, can you tell us about this 60-year-old man? It looks like, again, he got chemotherapy, checkpoint inhibitors, as these patients often do, and then at some point here got the erdafitinib. Can you talk about what happened? I guess that was last December. Can you talk about what happened once the patient got started on erdafitinib?

DR RUPLIN: Yeah, absolutely. So this gentleman overall I feel has had a tumultuous but ultimately successful, experience with erdafitinib. He was started in December, and he is still on treatment, but he started at the standard dose of 8 mg daily. His follow up there, of course, showed that his phosphate was elevated. If you follow, I think, the recommended prescribing information for what to do based upon an elevated phosphate level, I think they actually use a threshold of 7 for a blood phosphate level for their recommended threshold for when to start phosphate binders. But we figured it was prudent to do it in this gentleman as well. So we did start on those phosphate binders and more or less had resolution of his hyperphosphatemia as a result of his erdafitinib.

Perhaps more interestingly is he did, about 2 months after starting it, go on to develop the central serous retinopathy. So he did have vision changes. We recommended him to an ophthalmologist. Unsurprisingly he had CSR on exam, so we had held it for a period of time in this gentleman.

He had a repeat exam done, which demonstrated resolution, so we did reinitiate at a lower dose level, 6 mg I think, is what he was restarted on and what we basically continued.

He did eventually go on to have a reoccurrence of the central serous retinopathy, and I think kind of interestingly what we did with this nuance was his CSR did resolve to about Grade 1, so on an examination he does have serous fluid in his retinas. However, it’s nonsymptomatic to him, and given its stability the ophthalmologist recommended that he would be eligible to continue his erdafitinib.

So in this gentleman now, he is still on it. He gets an ophthalmology visit once a month. Every single time he’s gone since then, including most recently in October, he’s had stable Grade 1 CSR. And he uses an Amsler grid daily to check his symptoms. So every single day he uses an Amsler grid, and if he has visual changes, he’s supposed to call us. But so far, so good. He still remains on 6 mg daily with just very close surveillance of his CSR.

DR LOVE: So can you explain what the Amsler thing is, so to speak? I guess you’re looking for a defect in the field of vision?

DR RUPLIN: From my pharmacist standpoint essentially there’s a grid, an XY grid, with a dot in the middle. And when the patient looks at the dot, if they see kind of like a bulging in the grid while looking at the dot, that would be a positive Amsler grid test. And in the trials, they did see quite high sensitivity and specificity for the Amsler grid with erdafitinib. I think it was 100% for the specificity and probably greater than 70% for the sensitivity. So we’ve been using it for pretty great effect in this gentleman, and I think 1 or 2 other patients that we’ve used erdafitinib in.

DR LOVE: So Jonathan, this is really kind of a wild case, really. Can you comment on it? And a couple of the questions Andrew put out there, which is what about the idea of continuing the erdafitinib in spite of the fact that it hasn’t completely resolved, the central serous retinopathy. Do you use these daily checks with these grids? And also how do you manage the phosphate thing practically, Jonathan? What’s your threshold, Andrew wants to know, to start phosphate-lowering agents?

DR ROSENBERG: So it’s a tough case. I’ve restarted with central serous retinopathy when symptoms have gone. There perhaps are some findings still. But I have to say, I haven’t run into it all that much, to be very honest. It hasn’t been as big of an issue in the patients I’ve treated. So I don’t have a ton of experience with that.

As far as the phosphate levels, I tend to start when it’s in the 6s or into the low 7s. I do find that some of the GI toxicity is actually probably from the phosphate binders as much as anything else. And so that is something that I have in mind, that if they don’t need a phosphate binder, and their calcium phosphorous product is not particularly high, that I try to wait a little bit before I add a phosphate binder. But you’ve got to start to be careful in the 6 to 7 range.

Case: A man in his late 70s with mUBC with an FGFR3 alteration attains a good response to erdafitinib — Dr Plimack

DR LOVE: So Betsy, you have a great case writeup here for a 79-year-old man, former smoker. Incidentally, I’m curious how many of these people smoke? I mean bladder cancer has been considered maybe a smoking-related disease. Interestingly, also a retired volunteer firefighter. Can you talk, Betsy, a little bit about this patient?

DR PLIMACK: Sure. So this is a patient, 79-year-old, so older patient who developed lung metastases after being treated for a localized urothelial cancer. Even though he only had 1 kidney, I’ll point out, and his EGFR was greater than 60. And so he was first evaluated on the outside, where PD-L1 testing was not performed, but the decision was made to start with atezolizumab.

So he was on atezolizumab. At 9 months, interestingly, he had a really nice response in the lung, but 1 new bone metastasis. And so we did the somewhat unorthodox move to radiate that as an oligoprogression. And that did allow him to continue on atezolizumab for about another year. So he got 2 years total out of atezolizumab before his lung metastases grew.

These were the options we had to consider for this patient, again, after checkpoint.

And I guess consistent with what I talked about before, we started with gemcitabine and then added carboplatin. And I will say at this time we did not have any of the newer agents available to us, and so this was the treatment we selected. He did get quite a bit of time on this, and I think we got a little bit longer starting with single-agent gem because we didn’t run into cytopenias.

But it was at this juncture, you can see his lung met there is clearly much larger, that we biopsied this, and he was found to have an FGFR3 mutation. So we started erdafitinib at 8 mg daily.

DR LOVE: Anything you want to say about the lab results you have posted here, the NGS findings and the specific exon 7 finding, for example?

DR PLIMACK: Yeah, no. I mean I think most practitioners aren’t going to memorize all the different mutations, and there are many that are possible. It’s just if it is pathogenic it does meet criteria for this particular agent, erdafitinib. And again, there are a variety of different mutations or alterations one can have to meet criteria for that.

DR LOVE: So we talked a little bit about the hyperphosphatemia. This is his?

DR PLIMACK: Yeah, this is his case. So this is a patient who had both hyperphosphatemia and central serous retinopathy. So we started at 8 mg daily, and then we checked it promptly at 3 weeks, and his phos was almost 8. So we held erdafitinib. His phosphorous decreased. You can see the package insert is actually great for this drug. I would recommend folks turn to that for guidance because they have really clear dose modifications in there. And so we had the option of restarting him later at the same dose or a dose reduction. We elected the dose reduction, (1) because he had such prompt hyperphosphatemia, and (2) because he also had, at this point, central serous retinopathy.

So here is a picture, not of my patient, but he brought in a printout that looked almost just like this from his ophthalmologist, of the central serous retinopathy. Our patient experienced it at month 2, and he had no changes in visual acuity, both by his report and also as measured on ophtho evaluation.

DR LOVE: So where that line is going through there’s like that dark pocket. Is that the what’s pushing on the retina?

DR PLIMACK: Yes.

That’s the accumulation of central serous retinopathy.

So the good news is he had a really nice response, and we maintained him at 6 mg daily. His eye exams remain stable, and his phosphorous remains stable. So he’s a success story with this drug.

DR LOVE: So Jonathan, any comments about this case?

DR ROSENBERG: No. I think this is the type of benefit you’d like to see from erdafitinib, and it’s great that she was able to get him the drug and tolerate it with a dose reduction.

DR LOVE: Betsy, what prompted you to choose erdafitinib in him as opposed to enfortumab?

DR PLIMACK: I think he had had a lot of chemotherapy by that point, and enfortumab vedotin is not technically chemotherapy, but I think of it that way because a microtubule agent is the toxin. Patients do get chemotherapy-type side effects, the ones we just talked about, neuropathy, cytopenias, and so we wanted to give him a break from that particular set of toxicity.

DR LOVE: So Jonathan, one of the things we asked in the survey was generally speaking in people who can get both, in other words people who have the mutation, which one comes first. And it’s actually interesting, it’s kind of split here. I guess a few more people go with enfortumab. How do you decide which one to sequence first, Jonathan?

DR ROSENBERG: That’s a great question. My philosophy had been use the targeted agent in a patient with a mutation, which would mean using erdafitinib first in a patient with FGFR mutation. However, my experience has been that people tolerate enfortumab more predictably, and that the side effect management, albeit that it is chemotherapy like, in a sense, is a little more straightforward then erdafitinib. And while patients like having an oral medicine, my own experience is many of them can’t eat particularly well, or their fingernails were falling off, and so they’re not particularly happy with erdafitinib.

And so I have switched now more to start with enfortumab, and then use erdafitinib later in patients who progressed on enfortumab or don’t tolerate it.

Biologic rationale for the combination of enfortumab vedotin and pembrolizumab; efficacy in the first-line setting for patients with advanced UBC

DR LOVE: Let’s talk a little bit about where things might be heading in the future and near future. And Betsy, it seems like everyone wants to go combinations nowadays, but one combination that seems pretty interesting that I hear a lot excitement about is enfortumab plus a checkpoint inhibitor. And this is a trial looking at pembrolizumab. Can you comment on the idea behind that strategy and what we know about it?

DR PLIMACK: So this is Jonathan’s data, so it’s interesting that you’re asking me to comment first. I’m sure he can give you more of the backstory. But I believe the 2 were combined up front because they both work, and we wanted to see what this looked like in the up-front first-line population of patients. So again, this was a small substudy in a large basket study, and I think the early results were impressive. I imagine they then expanded accrual, and this is 43 patients, but I think it’s expanded to further, I believe. Jonathan can weigh in.

We just don’t see results like this very often. You can see here nobody progressed on this particular waterfall plot, and so far the results appear to be durable. So again, I’m not sure I can speculate what exactly why combining these 2 particular drugs up front leads to this market efficacy, particularly when chemotherapy combos studies were not effective, or at least not more so in this space. So I’m excited to see larger studies which are underway looking at this combination.

DR LOVE: Jonathan, any comments about this? First of all, theoretically why you think there’d be benefit, what the current thinking is, and what are the trials out there that are going to really test this?

DR ROSENBERG: So there’s thought that the combination of enfortumab with pembrolizumab takes advantage of the idea that the MMAE, the cytotoxic agent, leads to immunogenic cell death, and that that potentiates the immune response. Whether that’s true or not remains to be seen, but in the laboratory there’s evidence that those things might be happening. And there was evidence of this in lymphoma with MMAE-containing antibody-drug conjugates when combined with immunotherapy. It is possible that it’s just additive, but there’s certainly plausible thought here that there could be some degree of synergy between the 2.

There is an expansion cohort that is accruing, randomizing patients to enfortumab or enfortumab plus pembrolizumab in the same patient population in order to understand the true contribution of components, how much dose single-agent enfortumab actually do for you in terms of response rate and durability. Because we’ve never tested it in untreated patients. And so that study will hopefully see some results sometime in the not very distant future, but probably not in the next couple of months.

The combination of enfortumab and pembrolizumab is moving forward in a randomized Phase III trial comparing it to standard gemcitabine and platinum chemotherapy for first-line treatment for metastatic urothelial cancer. So that study is accruing within the US and internationally as well.

DR LOVE: Just to get back to these data, Jonathan, one of the things that’s interesting about it is it looks like people with all PD-L1 levels responded. Is that kind of the way you interpret this?

DR ROSENBERG: Yeah, it seems to me that there’s not a real selection that’s possible based on PD-L1 levels, which may go along with the fact that there’s something happening immunologically within the tumors, perhaps it’s making cold tumors hot. We don’t have any evidence specifically of that at the moment, but that’s one possibility, that you are taking tumors that might not respond to immunotherapy and actually between the MMAE-targeted antibody-drug conjugate and immunotherapy you’re getting more than the sum of the parts as a result.

DR LOVE: So Betsy, what are some of the trial concepts and experimental concepts in bladder cancer, in general, that include these agents but also others, just checkpoint inhibitors in general. What are some of the key questions that are being asked in the trials that are out there right now in urothelial bladder cancer, Betsy, that you’re excited about?

DR PLIMACK: So I think one of the key questions I’d love to understand is why resistance develops to the checkpoint inhibitors and can we use other immune strategies to mitigate those. I know there are a lot of trials that have the potential to answer that question, I guess, if they’re effective or not and what we’ll learn from those. But it’s always disappointing when a patient achieves a response to checkpoint inhibitor and then loses that response, and understanding that biology, I think, is going to be key to maintaining immune responses long term.

I think in terms of ongoing clinical trials right now, you hit upon the one I’m most excited about, which is EV plus pembro in the front line. We have that here as part of a randomized trial randomizing front-line patients to EV/pembro versus EV, and I think that’s really very compelling. And always just novel agents.

Emerging data with the antibody-drug conjugates sacituzumab govitecan and trastuzumab deruxtecan for mUBC

DR PLIMACK: And we haven’t talked too much about sacituzumab govitecan. That’s percolating up. I think there’s some toxicity/efficacy balance issues with that drug, from what I see in the data, but we are always eager to try truly novel therapies in this disease. I mean that’s how EV came along, and erdafitinib as well. They were brand new when we started testing them, and I think we should continue to be on the lookout for novel concepts like that.

DR LOVE: So Betsy, you mentioned sacituzumab, which actually is approved in breast cancer, what is it, and what do we know about it in bladder cancer?

DR PLIMACK: So sacituzumab govitecan is an antibody-drug conjugate, but the target is different, and the toxin is more of a topotecan variety, so similar to sacituzumab govitecan, it’s a little like chemotherapy. From what I understand, it’s been limited by gastrointestinal toxicity. And from the efficacy results we’ve seen, which again have been really a small cohort of an early-phase trial so far, there is definitely some signal, but it seems might be hard to maintain over time in the balance of the toxicities. But I will admit I don’t personally have experience with this agent. We don’t yet have clinical trials of it open here.

DR LOVE: There’s this antibody-drug conjugate out there that first started in breast cancer, then went to lung cancer, then gastric and colorectal cancer. My understanding is there is HER2-positive bladder cancer, right Jonathan?

DR ROSENBERG: Yeah, it is a small percentage, probably 10% of patients have mutations which are potentially activating, and a smaller percentage might have amplifications.

There’s been a reasonable amount of effort trying to target HER2 without tremendous success, anecdotal responses, some studies show maybe adding like trastuzumab to chemotherapy looks a little better than what you might expect with chemo alone.

There was a randomized trial of lapatinib, which was negative. There have been trials of T-DM1 which haven’t been that promising. But there are some new antibody-drug conjugates that are very exciting.

Some of those are being tested in basket studies, or urothelial cohorts, and they may be truly very important for patients with HER2 amplifications, maybe mutations. It’s hard to know.

And so I’m not dismissing the pathway yet, but we’ve certainly been hitting it without a lot of success.

DR LOVE: So actually, Andrew, I was looking at a case that we hadn’t mentioned yet, this patient actually got EV, but it looks like he also was evaluated for the drug I’m talking about, which used to be called DS-8201, I guess must have had some kind of HER2-positive situation. Do you know anything about that in this case, Andrew?

DR RUPLIN: I can speak a tiny bit. Because I also practice in breast cancer, I do have some first-hand experience with some of these agents that were approved in breast cancer and have continued, in some cases, in trials in urothelial cancers.

The trastuzumab deruxtecan, I believe, which we are using in metastatic HER2-positive breast cancer. In bladder cancer I don’t really have experience with that.

Interestingly enough, both kind of patients that I submitted for the enfortumab vedotin cases, the one we just looked at was the deruxtecan conjugated to the HER2-targeting trastuzumab. And then the other patient who got enfortumab vedotin, earlier in her treatment her tumor was found to be highly HER2 overexpressing, so she was treated briefly with a triple combo of trastuzumab, pertuzumab, and actually the CDK inhibitor palbociclib based on some safety data on breast, given that her urothelial cancer was HER2 overexpressing. And then she too was on the IMMU-132 trial for sacituzumab govitecan.

I can speak to, again, in breast cancer the tolerability that we’ve seen with some patients, and the biggest issue we’ve seen in some patients, is hematologic toxicity. Keeping in mind that the cytotoxic component, the govitecan, is cleared by the UGT1A1 enzyme, so in some patients who have mutation in this enzyme, we’ve seen profound toxicity with sacituzumab govitecan. Now we aren’t routinely screening all of our, not to get off topic, but our breast cancer patients for this UGT1A1 mutation, but if a patient were to have profound toxicity after even 1 or 2 infusions of sacituzumab govitecan, I personally am somewhat in favor of testing them for this mutation. Granted, there are dose reductions that we could implement more quickly and probably more cheaply than getting this mutational test done.

DR LOVE: Andrew, any other questions you want to mention?

DR RUPLIN: I supposed I had 1 or 2. Curiously, in my opinion, erdafitinib was approved by the FDA for the FGFR2 or 3 mutation, and I was curious what your thoughts were on whether it’s legitimate whatsoever to use erdafitinib in a patient with only an FGFR2 mutation. I think based upon the BLC2001 trial, those patients did not do particularly well at all if they only had the 2 mutation as opposed to an FGFR3 mutation.

DR LOVE: Jonathan?

DR ROSENBERG: Well, they did that based on the fact, as you probably know, that that was the way the study was designed, and it wasn’t designed to look at each mutation separately. However, I tend to agree with you, and I might prioritize a patient like that for a different treatment rather than erdafitinib, if possible, depending on what they’ve had previously.

Similarly, FGFR fusions didn’t seem to do so well with erdafitinib as well. But again, not really powered to evaluate that and designed to evaluate that question. And so the people I feel the most comfortable using it are patients with FGFR3 known driver mutations. And there’s a list of 10 or 12 that are in the package insert that I think I’d feel much more comfortable using compared to an FGFR2 mutation.

Approach to therapy for patients with mUBC during the COVID-19 pandemic; role of telemedicine in patient care

DR LOVE: I’ll start with Betsy, but I’m really curious what all of you have to say about this, which is how does COVID affect the management of patients with metastatic bladder cancer. And I know Jonathan, it will be very interesting to hear him, being in New York, but let’s start out with you, Betsy. It seemed like in the beginning people were really trying to keep people out of the clinic. They were trying to stay away from infusions. It was hard to get people in this hospital for surgery. I’m curious if you kind of went through a stage like that, and where you are now. And how this whole situation has affected the way you manage these patients.

DR PLIMACK: Yeah, I mean every aspect of our lives has been affected by COVID, and certainly the way we approach patient care. I will say it’s like everything with COVID, it’s evolved really quickly over time. In the beginning we were really trying to keep patients out of the clinic, and that meant treatment breaks if we were approaching that. That meant having people come in for their labs, go home, do a telemed visit and come back for an infusion to limit touchpoints in the clinic.

I think now what we’re really trying to do is just get back to the optimal care of patients as best we can. The way we’re doing that here is like keeping cancer care really separate from COVID care, totally separate hospitals for the 2. We’re fortunate enough to be able to do that. We’re doing a lot of testing, testing of all patients going for elective procedures, all patients getting admitted to our hospital. And that’s how we’ve been able to do that.

But we’re looking at cases going up again. I think we’re going to be stricter on our visitor policy, in terms of patients coming to clinic, using again more telemedicine for routine things. But I guess in bladder cancer one of the clearest ways that it’s affected our patients is patients with long-term durable responses to checkpoint inhibitors, we gave them a break from treatment, and we’ve had a chance to get a couple of scans on most of those patients, and they’ve been doing well. So hopefully they’ll experience treatment-free survival, meaning that they’ve achieved their response to checkpoint and can maintain it off treatment. But we’ll let you know next year.

DR LOVE: Cristina, of course Boston also is an early problem, huge problem with COVID, kind of went back down, seems like it’s coming back up. I’m curious about your experiences. Also I’m curious from all of you about your experiences with the positives and negatives of telemedicine. So Cristina, another think, Cristina, I’m curious about is increasing the duration between therapies, particularly checkpoint inhibitors. Are you going to go to every 6 weeks pembro, for example? So maybe just reflect back in general what are some of these issues that you’ve dealt with, Cristina.

MS SALABAO: Yes, Dana-Farber was not set up for telemedicine. We weren’t any at all prior to 8 months ago. And so I would say, for the most part, the transition has been smooth, but also I don’t only work with bladder. I also work with renal and prostate, and many of those agents are oral too. So for people who are on oral agents it’s been great. They get their labs done locally, do a telemedicine visit either over the phone or via Zoom, which a lot of people are really into. We get people from New Hampshire, Vermont, Florida is a big population down there too, and so they’re loving not having to come in.

For bladder it’s a little different. There are more infusions. So we’re not stretching anything out. I think 1 group in Dana-Farber is, and I’m not sure which group it is.

It might be GI or thoracic where they are able to stretch things out a little bit more. But the physicians here who see bladder like to stay on track with treatment. So I would say it’s been a mixed bag as far as COVID goes. In some ways it’s been really great and really convenient for people.

In some ways it’s been a real pain, especially like, for example today I have a cold, but given I had symptoms I couldn’t come into clinic even though I tested negative. And I think that this is going to continue, causing some staffing issues with people who are in direct patient care. So yeah, we’ll see. We’re doing this for the foreseeable future, I would guess another 6 months at least, so hopefully we’ll start to streamline it a little more.

DR LOVE: So Andrew, actually Seattle, I think, was really the first place. It preceded everything. I remember talking to a bunch of colleagues out there, and pretty interesting developments. And some cool publications have come out of that area too. Any comments about, particularly in some of the issues we’re talking about today. We’ve heard people talk about trying to avoid neutropenia, et cetera. What’s going on in Seattle?

DR RUPLIN: Yeah. I was going to say, from my pharmacist perspective, 2 of the big changes that I saw included kind of more liberal use of myeloid growth factors in patients throughout our clinic, not just our bladder cancer patients. In bladder cancer I expect generally less issues with like decreased leukocyte counts. Of course if they’re getting dose-dense MVAC they’re going to get growth factor support anyway. But frequently we’ve been using a lower threshold for when to initiate growth factor support in our patients here out in Seattle.

The other kind of big change that I’ve witnessed, and you’ve probably all seen this too, is of course the FDA approval of the 6-week interval dosed pembrolizumab, which was previously denied for approval many months ago. And then when COVID came out, I don’t know if there was just kind of a push by the general sense of trying to get patients out of the clinic or if there was some new data that the studies had seen, but the approval of that every 6-week dosing has been pretty beneficial in many of our patients. We’re not doing it in everyone, and certainly some patients have been fairly anxious about whether this increased dosing less frequently is more likely to cause immune-mediated side effects. But overall it’s been very helpful for some of our patients.

The last kind of component of living in Seattle and being a major medical center in Seattle is that we service a substantial number of patients outside of Washington, so including Alaska, Montana, Idaho, who come to use for their care. And previously, before COVID, they might actually literally fly to us for a day, stay a day, and then fly home. And that was their routine for their cancer care for months to years. Of course when COVID happened we were substantially more limited in plane flights and of course trying to utilize more telemedicine.

So I think our adoption of telemedicine has been overall fairly successful, but certainly I know many patients and providers have been very happy to somewhat return to clinic and have more patients in the clinic.

Impact of COVID-19 on clinical research and the care of patients with UBC

DR LOVE: Jonathan, I’m curious about your experience and your thoughts in New York City, and also how it’s affected clinical research.

DR ROSENBERG: So I’ll say a couple of things. I think one of the big differences between the beginning of the pandemic and now is that we have a much better sense of the prevalence of COVID in the community here. And while it may be going up, we also know that it’s not very high. We also have a lot more PPE available than we did at the beginning of the pandemic, and so it allows us to protect ourselves and our patients better and actually be able to see people, admittedly with face masks and face shields, but in an environment that seems safer, as well as a lot effort to screen patients prior to procedures and question them before they enter the building about symptoms.

The nosocomial transition rates are very, very low, making us feel more comfortable about seeing more patients in person. We’re still doing about half of our work with telemedicine, but for patients who need to come in, we can come in and see them more safely, whereas back at the beginning we didn’t have face masks for the clinic because they all needed to be used in the hospitals. And so we really couldn’t see anybody safely at that point. That may be a slight exaggeration.

As far as clinical research has gone, it’s been a real challenge. We’ve been able to put people on trial. We never halted all trials. But effectively if people aren’t able to come in and get treatments, then you’ve put a slow-down, at least, on accrual. It has started to pick back up, and I’m hopeful that when this is over, we’ll be back at similar levels. But I think it’s been a worldwide hit on clinical trial accrual and I imagine it’s an issue at all of the major cancer centers in the US.

DR LOVE: I’m curious too, Betsy, theoretically you could imagine that telemedicine could be an advantage to execute clinical research. I know there’re obstacles to it, but at least nowadays people are at least familiar with it. But one of the biggest obstacles for people coming in trials is they didn’t want to travel, like as we were just describing. Do you see more telemedicine maybe that’s going to be introduced into the execution of clinical trials in the future, Betsy?

DR PLIMACK: Definitely. I think in a couple of ways. One is we can really monitor toxicity more frequently if the patients don’t have to come for visits. So I can see phone calls or telemedicine encounters being built into clinical trial management and monitoring. There are occasionally trials where the treatment arm comes more frequently than the observation arm. Well you could allocate the observation arm to telemedicine visits.

And I will say with immunotherapy I find telemedicine pretty effective in picking up autoimmune adverse events because really you’re questioning people about a long list of symptoms, and typically symptoms are what tip us off that someone’s having an autoimmune adverse event. You do miss the physical exam. You do miss, in some cases, the vital sign gathering, which is hard. But I see telemedicine when it’s used in the right places as being a real advantage for our patients. And again, check-ins around CT scans and such can also be done remotely, which is good.

One of the things I’ve learned to appreciate with telemedicine visits versus our inpatient visits currently is the ability to read facial expressions and involve more of the patients family. We’ve had telemedicine visits with children from across the country on Zoom. We are able to do these visits without the impediment of a face mask and a face shield, which really, I feel like, get in the way of my ability to emote empathy to patients in some of these tough conversations. So we’re learning. We learned really fast, and now I think we’re learning how to fine tune telemedicine.

DR LOVE: Yeah, Cristina I’ve heard that comment before about how PPE makes it more difficult to kind of read the patient, so to speak, and takes away some of the intimacy. A lot of places are restricting or preventing visitors from coming in. I’m curious how this has affected the psychosocial aspect of care.

MS SALABAO: It’s difficult. I know I’ll call in or I’ll FaceTime family members. Unless they have like a cognitive disability that visitors are not allowed in with patients. And I think everybody understands. We have probably the most careful set of patients who have been self-quarantining since the beginning of the summer, and so they understand as well as we do that, we want to keep them safe, and they’re okay with it. But yeah, it does get tough when someone’s crying in front of you, and you want to like give them a hug, but you’re not supposed to. It is hard. You kind of have to work around it.

DR LOVE: So Andrew, we actually did a national survey of medical oncologists about a month ago about COVID. And actually, we went into all kinds of treatment practices and how they changed them, et cetera. But one question we asked, and I wasn’t really expecting the answer, was to what extent has COVID and this whole situation interfered with your ability to keep up-to-date? And a surprising number of people said substantially, which I thought was very interesting. We’re seeing now a shift in how we learn. Much more virtual learning, not the typical platform. Any thoughts about that, Andrew, keeping up-to-date in the COVID era?

DR RUPLIN: Yes, absolutely. Certainly, I think the major change has been what platforms can we use to do live education and live sessions. And certainly this adoption of technology has been very, very rapid, whereas previously, I don’t know how many people before this whole thing happened even knew what Zoom was, and now Zoom is basically a household name.

I think what I’ve appreciated is some of the summits and learning opportunities and organizational events that I’ve gone to now have fairly sophisticated online platforms, where you can join breakout groups and ask questions and record your attendance and things of that nature. So I think what has been really interesting for me is how much technology has, within specifically the health care setting, how health care has adapted to using technology that’s probably been used in other industries for multiple years, but healthcare has continued to generally lag behind in technology.

I think also from speaking briefly to the point of learners, there was a huge adjustment period of understanding how do we utilize our residents or students or pharmacy residents, medical residents, fellows, and how do we limit the number of people that are able to be in the clinic while still providing care and while still educating the next generation of healthcare practitioners and providers.

DR LOVE: This concludes our program. Special thanks to our faculty, and thank you for listening. This is Dr Neil Love for Newly Approved Agents in the Care of Patients with Metastatic Urothelial Bladder Cancer Who Progress on Immune Checkpoint Inhibitor Therapy.