Introduction

DR LOVE: I’m Neil Love from Research To Practice, and welcome to What Urologists Want to Know About the Management of Bladder Cancer. This is the first of two satellite meetings we’re doing during the American Urologic Association Annual Meeting that’s being held virtually, this morning we’ll be talking about the management of bladder cancer from the perspective of medical oncologists towards urologists.

We have a great faculty today, Dr Arjun Balar from the NY Perlmutter Cancer Center in New York, Dr Ashish Kamat from MD Anderson in Houston, Dr Guru Sonpavde from Dana-Farber in Boston, and Dr Rob Svatek from the UT Health Science Center in San Antonio.

And we want to make this very clinical and very relevant, and in order to do that we actually recruited 4 physicians who worked with us over the last few weeks, and we’ve recorded cases and edited them and we’re going to be presenting cases from these docs, Dr Gordon Brown is a urologist from Sewell, New Jersey. Dr Hafron is also a urologist from Bloomfield, Michigan. Dr Ibrahim is a medical oncologist who’s presented cases in many of our medical oncology programs. And Dr Morris is a urologist from Nashville, Tennessee.

Here’s where we’re heading. We’re going to start out just sort of chat a little bit about personalizing continuing education, and then we’re going to dive into our program with our cases. We’ll start out talking about non-muscle-invasive disease, then localized invasive disease in terms of neoadjuvant/adjuvant therapy. And finally, we’re going to have a pretty big section on metastatic urothelial bladder cancer, but again we’re going to come from the perspective of the urologist.

So just to kind of get warmed up a little bit here, I thought we could call this millennial Monday, and the reason I got that idea, well, you know what, let me ask the audience a question. Audience, I want you to think about 2007, and I’m going to tell you in a second why I’m asking you about 2007, but audience I want to know what you were doing in 2007. Were you in clinical practice the way you are right now? Or you hadn’t gone into clinical practice by that time, you either were in your residency, or maybe you were in high school? I’m kind of curious about the age spectrum of our audience. And interestingly enough, actually almost 50% was not in clinical practice 14 years ago in 2007. Now why did I bring this up?

Understanding the Millennial Physician — Jason Hafron, MD

DR LOVE: Well, when I did the session with Dr Hafron, I looked through his bio, I saw this really interesting paper, I’ve never seen anything like this in the medical literature, this is Urologic Clinics North America. And he wrote this paper about dealing with the millennial physician, particularly fellows in training, etc, younger physicians.

One of the things he brought is the experiences that these people went through that we all went through, but what age they were when this happened. How did it affect them? He picked out 2007 also because of the recession, but I picked out because that’s when the iPhone came in. This is my son who’s now 15, and this was when he was about 6 when he got his first iPhone. And you really wonder what life like when you as a 6-year-old, or in the case of millennials, maybe in high school, have this incredible device sort of fall in and how that affected the way they live, how that affects the way they learn, how that affects as the way they interact with you.

So I want to start out and let you listen to just a few seconds of Dr Hafron talking about some of the things that he was trying to bring out in this paper.

DR HAFRON: What they did and how they were trained is totally different. And I’m trying to say it’s not a negative, it’s a positive. Millennials value work-life balance. They value quality of life. They have to a lot of offer. I think a lot of our older partners get frustrated with them.

Millennials really respond to mentorship. And then I think what really stands out with them is their digital natives. This is a term commonly used with millennials. Is that their attached to their phones, their attached to digital media. I think they’ll bring a lot to medicine with the digital experience and how they use their phones and technology.

DR LOVE: Ashish, I’m curious about your thoughts about this. And I want to ask you also, if you were going to talk to a urology resident and maybe encourage them to get more involved with bladder cancer, work with you in the clinic, work with you in clinical research, what is it about taking care of bladder cancer patients, do bladder cancer research, Ashish, that you find attractive and compelling in your career?

DR KAMAT: So, Neil, interesting you would ask that, because obviously I have kids that are in college now and I do mentor college kids from Rice and UT, for example, but also we have residents and fellows. And one of the things that I find is, that those that have elected to select a career in medicine in Urology actually are in it for the right reason. So from my perspective, getting them to understand what’s great about taking care of bladder cancer patients, the fact that we can clearly make a difference. It’s a field, when I went into, I was actually in some ways discouraged by being told nothing happens in bladder cancer. There’s no advances. But now there’s so much going on.

It actually is very stimulating for these young minds to see what’s going on and how they can actually truly make a difference in the lives of our patients.

DR LOVE: Guru, I’m curious your thoughts on this. What is it about this field that you find compelling and attractive to be involved with in terms of bladder cancer?

DR SONPAVDE: In terms of bladder cancer, I think that there’s just a lot more unmet needs than many other more common cancers like colon, lung, prostate, breast, where we have a lot more going on. These are the big volume cancers. They tend to get a little more attention from everyone, including industry. So I think that there’s more opportunity in learning the biology of bladder cancer and also making therapeutic advances.

DR LOVE: Rob, any thoughts that you have about it? And I’ll mention another thing, too. I can remember doing Think Tanks where we get 8 investigators, when we were doing live things, together. Where we would do a breast cancer think tank, we might have all 8 as female investigators. And I notice kind of a lack of gender balance in urologic oncology. Maybe that’s partly tied into Urology. I don’t know. But any thoughts on that? And also, Rob, what you like about bladder cancer?

DR SVATEK: So, what I like about bladder cancer. I think the patients are a unique population. They tend to be older. This is a disease; the median age is in the late 60s or 70s. They’ve got great life experiences. I’ve learned a tremendous amount from my patients and they’re highly compliant. They’re just easy to get along with. They’re wonderful people. And the science is remarkable, too. We, as urologists, give chem, we give immunotherapy. And as Ashish comment on, it’s changed dramatically over the last 10, 15 years.

With regard to the gender discrepancy, I think that’s changing, as it needs to. We’re seeing more and more women interested in bladder cancer and in oncology. So I think it’s needed. And hopefully, that will continue to increase in the future.

DR LOVE: So, Arjun, Ashish in the chatroom says you were in high school in 2007. I’m not sure if that was true. But just kind of curious what your thoughts are about this discussion we’re having here.

DR BALAR: I’m going to stay mum on the issue, but if that polling question were asked to me, I definitely was not in clinical practice in 2007. I’ll just leave it at that.

So the issues you asked about, why is it that I chose bladder cancer. So I think back to my fellowship training. I chose bladder as a field because of my mentors at the time, Dean Bjorin and Matt Milowsky at Memorial Sloan Kettering and they were just absolutely wonderful people who then drew me into the field. But why did I stay in bladder cancer? It is because of what Rob just mentioned is the patients. A bit of a rough and tumble crowd who are just kind of shoot it to me straight, doc. Just tell me what’s going on. And you have really open and honest conversations. They accept the diagnosis. They accept their treatment options. And have had very frank and open conversation.

I’ve learned so much from my patients. And I think many oncologists and physicians can say that. and I don’t have another comparison. I guess I treat a lot of patients, bladder cancer, and kidney and prostate as well. But I see mostly patients with bladder cancer. But I have learned so much from my patients.

DR LOVE: And it’s interesting you mention mentorship — and actually Dr Hafron in his paper talks a lot about the fact that he thinks that millennials like the mentorship relationship. I think a lot of that stuff might apply to people of that age group, but then they have their own personal experience. And as he says, the digital background being really important.

Case: A man in his late 70s with bacillus Calmette-Guérin (BCG)-refractory non-muscle-invasive bladder cancer — David S Morris, MD

DR LOVE: All right, let’s go and make some rounds here on the cases that these docs picked out, and we’re going to start out with non-muscle-invasive disease and of course the big issue there is checkpoint inhibitors, specifically pembrolizumab. We’re going to talk about non-muscle-invasive, but we’re also going to talk about IO toxicity, autoimmune toxicity, which, of course, can be seen in metastatic disease or if you’re using it in the adjuvant setting. We picked out a few cases, interestingly I think in the setting of non-muscle-invasive disease to have complications, a little bit different implications than when you’re taking care of somebody with metastatic disease.

Let’s start out with our first case. This is a 79-year-old man with BCG-refractory disease. And Dr Morris decided to try pembrolizumab and got a pretty unpleasant surprise. Here’s Dr Morris.

DR MORRIS: Presented in the office on our interval visits between the infusions and was noted to be jaundiced. So we started high-dose steroids at that point for an immune-related AE and have been following serial labs.

So this is one of our early experiences of pembrolizumab for BCG-refractory disease, different than some of the experience on clinical trials, and unfortunately here we are with an immune-related AE.

DR LOVE: I can’t imagine what it was like to have him walk in jaundiced.

DR MORRIS: So we thankfully had built out a program, and I think many centers are trying to do this with advanced practice providers, if they have a 2-minute blurb that they give the patient in terms of what to look for, and really the high-level things to call.

DR LOVE: So, Guru, medical oncologists have used a lot of checkpoint inhibitors. I kind of get the feeling maybe even more than chemotherapy is being administered nowadays, infusion rooms are filled with people getting checkpoint inhibitors for head and neck cancer, lung cancer, you name it, even breast cancer nowadays. And one of the issues with urologists utilizing these drugs is medical oncologists often have an infrastructure already around them. Dr Morris was talking about trying to build that. What are some of the broad issues that you’ve developed for example at Dana-Farber, to pick up these toxicities, that sometimes hospitalists and ER docs are not that aware of.

DR SONPAVDE: I think the main thing is to educate the patients on what to expect and to notify us if they see anything unusual, just about anything. And not to self-medicate, for example, for diarrhea, you don’t want to patients going out and taking Imodium over the counter. For a cough, we don’t want them going out and taking Robitussin or some other medication for cough. So that’s the first one is to keep the channels of communication open between patients and the providing team.

And secondly, do you want to get into specifically liver function test elevation? So I think that in this patient there is a significant liver function exam elevation, and definitely this is Grade 3. And I think that we would need to hold the therapy and start treating this patient and see how it goes with the steroid treatment initially.

DR LOVE: And actually, this patient got high-dose corticosteroids. In the time I was talking to Dr Morris, still had not normalized liver function, something that seems pretty unfortunate in this situation particularly.

Rob, we hear if it ends in ‘itis’ you can see it. I saw a paper recently on ototoxicity with checkpoint inhibitors I never heard of before. So there’s a huge spectrum and a complete mindset change from chemotherapy. Any thoughts, before we get into the indications and use of the therapy, about the kind of infrastructure urologists needs around them to be able to administer this therapy?

DR SVATEK: I think it is certainly something that you need to consider if you’re incorporate that into your practice. I mean we here at UT Health, we work closely with our medical oncologists, and we have not gone so far as to start administration from the urologist side. And I think that I don’t have any plans to do that. I think our medical oncologists have the infrastructure, have the experience and history of doing this. But we have a close relationship. These patients are getting cystoscopy every 3 months with us, so we may be the first one to encounter the symptoms. So it’s a close relationship, open air of communication back and forth with the oncology team, patient education as well as your urologic education as well.

DR LOVE: So just to throw a question out to the audience before we go to our next case. I’ll ask Arjun to respond to this next case. But just kind of curious, audience, for urologists who have an interest in cancer such as these 3 urologists presenting cases today, do you think that they be administering checkpoint inhibitor? Do you think the checkpoint inhibitors should generally be administered by a medical oncologist? So audience, do you think urologists who’s interested in doing this, it’s okay for them to give a checkpoint inhibitor?

It’s almost getting to be almost 50/50 here.

Case: A man in his mid-60s with high-risk non-muscle-invasive UBC — Gordon A Brown, DO

DR LOVE: Anyhow, let’s take a look at another case, this is from a patient Dr Brown is taking care of, another BCG-refractory patient who got pembrolizumab and a different complication. Here’s Dr Brown.

DR BROWN: He tolerated it initially but developed hypothyroidism after his fourth dose, with a markedly elevated TSH, and his pembro was stopped. He was started on systemic steroids, and he chose to come off of pembro and go back onto intravesical therapy.

I’d like to have the panel’s opinions as it relates to the options for management of patients with high-risk non-muscle-invasive disease who are BCG refractory and refuse cystectomy. I’d like to know how we can operationalize more consistently the use of immunotherapies in our bladder cancer clinics amongst urology practices across the country.

DR LOVE: So we’ll talk in a second, Arjun. We know these kind of endocrine autoimmune problems, particularly hypothyroid probably is the most common complication you see with checkpoint inhibitors. But I’d like you to kind of go back through the work that you did and others on this strategy and what we know about it at this point.

This is the KEYNOTE 057 study. Arjun, can you comment on what was seen in this and what we see now? And we’ll talk a little bit about the updated data. But, bottom-line of what’s seen when you use pembro in this situation.

DR BALAR: So the KEYNOTE 057 trial is the landmark study that led to FDA-approval in January 2020, which just short of 100 patients were treated with BCG unresponsive carcinoma in situ, meeting the FDA definition put forth in a 2018 guidance. The FDA reviewed the data. The CR rate at 3 months for patients meeting the strict criteria was 41% and the median duration of response was 16.2 months. Essentially, when you follow these patients out about half of the CRs are durable past 12 months. Now many people will go back and forth and say, well, is this clinically meaningful or not? I think it’s meaningful for the patients who are in a CR. And if it’s down safely and smartly, then you can offer this to patients who are willing to take this approach, and those who don’t want a cystectomy and certainly those patients who are not candidates for a cystectomy and the FDA agreed. And so, I think, most importantly we have to have options for our patients. And so this is a reasonable option for our patients.

Now is it a world beater? I don’t think people will say that. But is it a step in the right direction? Absolutely so.

And I’ll comment on the case here. This patient who’s developed immune-related hypothyroidism, it’s about 5- to 10% of all immune-related cases. So it’s extraordinarily common. It’s the most common endocrine AE. It’s irreversible. We don’t treat with steroids. We actually treat with endocrine replacement therapy. And if the patient was in a CR, it’s all the more reason to continue treatment actually.

So this is a patient that I would still have that 3-month CISTO. If they’re in a CR, clearly on cytology you’d continue treatment and start them on endocrine replacement.

DR LOVE: So I will say one of these cases that were not actually presenting, was a patient who developed hypothyroidism, got high-dose steroids and had the therapy stopped, which I would say is not a typical way to involve this. If you look at the KEYNOTE 057 study, you see here on this slide that people obviously, and it doesn’t matter what you’re using it for, if you use these agents you are going to see, this is not like chemotherapy in terms of quality of life, but it can cause problems. usually if they’re recognized, particularly endocrine problems like this, very well treated, don’t usually need to stop treatment. But certainly you need to be aware of.

Rob, I’m just kind of curious what’s been going through your mind as we’ve been chatting these last couple of minutes? Any thoughts?

DR SVATEK: So I think that we’ve got to keep in mind that urologists have been giving immunotherapy for decades. I mean we’ve been treating patients with BCG, and we have encountered immune-related adverse events, most of these are cystitis, BCG-related cystitis. It can be treated with steroids. But we also deal with disseminated BCG infections. So we’re not completely removed from immunotherapy. The transition to systemic immune therapy is not trivial. And we don’t have formal training in monitoring or treating these side effects, but it’s not say that it can’t be done. I think the most important thing is, if you’re going to adopt this in your practice, that ideally it’d be done in consultation with a medical oncologist, and you have some form of formal training.

I personally, like I said before, don’t plan to do this. I think we get better care by sharing it with the medical oncologist. But more so, like I said, the training and the ability to recognize and treat are critical.

DR LOVE: So I want to go back to the issue of endocrine issues. Guru, we see hypothyroidism, as we mentioned, very common, probably the most common. Usually it’s picked up by bloodwork and that’s recommended as a routine in these patients. But occasionally, I’ve heard hypothyroid clinically. I’ve heard hyperthyroid clinically. Guru, what is your experience? And you can also see adrenal insufficiency, how you pick that up?

DR SONPAVDE: Actually, you need to have a high index of suspicion. Hypothyroidism is the most common event we see, but we do see a transient hyperthyroidism before it can actually change or transform to hypothyroidism. You can see that there are adrenal insufficiency, as well as hypophysitis. These are really challenging to pick up. You have to have a high index of suspicion. Look out for extreme fatigue, headaches with hypophysitis sometimes. Look out for electrolyte abnormalities that are consistent with adrenal insufficiency.

So I think that all of these need a close eye kept on. You need a really high index of suspicion to detect this early.

DR LOVE: We had a medical oncologist who was walking around the hospital one day, saw the wife of a patient and said what are you doing here? And the patient was in the ICU. He went over there. They hadn’t called him. He was in the ICU in a difficult situation. He said this patient has adrenal insufficiency, give him corticosteroids. He was out in 24 hours.

So, Ashish, I’m going to let you answer this question because you responded in the chatroom to Steven, who asked the question which I don’t know anything about, but you apparently do. He says, do you think that nadofaragene or IL-15 will replace pembro in BCG non-invasive — BCG refractory? So what is nadofaragene and IL-15, Ashish?

DR KAMAT: So nadofaragene firadenovec is gene therapy that’s directed towards bladder cancer. It was initially developed by Colin Dinney and Bill Benedict here at MD Anderson and now it’s been sort of taken over by Ferring and FerGene. The data were published, very similar to KEYNOTE 057, various similar response rates. They take completely intravesicle therapy and it’s given once every 3 months. It’s not FDA-approved yet. There’s some regulatory hurdles that have to be cleared. And then IL-15 essentially is a way to supercharge BCG essentially, if you look at that way.

Both of these have the potential to be used in clinical practice once they’re approved. And I believe the question was asked from the framework of intravesicle therapies, urologists understand how to do those. There’s no systemic toxicity that we know of at least. And will they replace pembrolizumab? And my answer is, they’re unapproved yet. Once they’re approved, it essentially will be personalizing what’s appropriate for the particular patient. I don’t think pembrolizumab will go away, but it will be used for selected patients. In this BCG unresponsiveness realm.

Personally, I would use it for someone that is a high risk of micrometastatic disease, because I would like to get some of its systemic effect. But clearly, that remains to be seen in longer follow-up with these patients.

Case: A man in his late 50s with high-risk, BCG-refractory non-muscle-invasive bladder cancer — Dr Hafron

DR LOVE: So, Arjun, I would like you to listen to this case from Dr Hafron, it’s a 58-year-old man. I’ll tell you that there was another case we’re not going to show with Dr Ibrahim, it was a 60-year-old man, and the medical oncologist was saying I feel really uncomfortable giving pembro to a patient, a perfectly healthy 60-year-old doesn’t want to have a cystectomy. Kind of curious if you face that situation? But here’s the case. Again, another patient — I’m not trying to say all patients have problems, but of course, these are the ones that people want to present. Here’s Dr Hafron.

DR HAFRON: The last 2 treatments, the patient has developed a recurrent pneumonia while on treatment.

My question to the group would you stop the pembrolizumab for this recurrent pneumonia? Is this a true side effect of pembrolizumab? Or would you consider changing him from q 3 week dosing of pembrolizumab to q 6 weeks? Would that reduce his risk of pulmonary issues? And then lastly, if the patient were to fail pembrolizumab and still refuse cystectomy, what else is there to offer this patient?

DR LOVE: When you say he had pneumonia, did he have a positive culture, or could he have had inflammatory or autoimmune pneumonitis?

DR HAFRON: I think he might have had autoimmune pneumonitis because he was treated with steroids, and he responded to the steroids. But he also was treated with antibiotics. So I’m leaning towards it was a mild immune-mediated pneumonitis. The question is what to do now? Is that a contraindication to continue with pembrolizumab?

DR LOVE: So, Arjun, your thoughts? And I’ll mention that Dr Hafron on this case was working very closely with the medical oncologist. That was the person who started the corticosteroids. Good relationship; really offers a lot to the patient. So any thoughts about this pulmonary problem? Do you think this is likely to be related to the pembro? And what are your thoughts about using pembro in a healthier 60-year-old patient?

DR BALAR: So, I’ll address the second question first because I think that’s the more straightforward, which is, there’s no reason why you wouldn’t, right? A healthy 60-year-old who doesn’t want a cystectomy for BCG unresponsive CIS, that’s the same conversation as an older 80-year-old who may be a frail surgical candidate. The question is, does the patient want it and understands the risks and benefits?

There does not appear to be any better or worse side effect profile or safety profile based on age and medical comorbidities. I mean that’s the attractiveness of systemic immunotherapy with checkpoint antibodies, that’s what makes them attractive. So, I don’t look at it any differently.

Now back to this specific case, it sounds like Dr Hafron has done everything right. He’s got a medical oncologist partner. I assume that they even got a pulmonary consult. Pneumonia versus immune-related pneumonitis, those are 2 very distinct clinical presentations. The subsequent diagnostic workup and management are obviously very different. But even despite your best efforts, if you can’t tell the difference and you’ve treated them both aggressively and you had 2 recurrent episodes, and you’re not 100% sure but you think this might have been pneumonitis, I think rechallenge is probably not in the patients’ best interest and would probably permanently discontinue pembrolizumab.

I will say one thing though, appropriately treated pneumonitis requires 1 to 2 mg per kg of prednisone for at least a week followed by a 4- to 6-week taper of steroids and during that time, the patients are off of immunotherapy. So that’s a very extended period of time during which the patients are receiving treatment. And if the patient’s had 2 consecutive episodes, then you wonder, like, really is it even worth — if the patient had such a sufficient, long period of treatment off — set period off treatment that it doesn’t even make sense to even rechallenge at that point. Two episodes, I think you’re done.

DR LOVE: So, Guru, any comments about the pneumonitis that can be seen? Arjun in New York, and you all in Boston really were in the beginning of the COVID wave and I know that’s an issue, too, ruling out COVID in these patients. Not to mention what to do if they actually have COVID Any thoughts, Guru? And also, getting back to this 60-year-old, I think the issue, and I’m going to ask Rob to comment, too, that the oncologist, Dr Ibrahim, felt uncomfortable with is he knew there was a curative therapy this patient had and yet the patient was going for a therapy that probably, more than half the time won’t even benefit the patient. So that was sort of his ethical dilemma. So any comments about working up patients with pulmonary problems on checkpoint inhibitors and particularly where COVID fits in? And your thoughts about this strategy in a younger patient who really could go for cystectomy?

DR SONPAVDE: I agree with Arjun in general, which is that patients who have had recurrent pneumonitis more than once, it would be, I think, difficult to challenge the patient a third time. Patients who’ve had mild pneumonitis the first time and you want to rechallenge some of these well-selected patients a second time, I think that’s reasonable. Not all of them will have recurrent pneumonitis again the second time to give them their immune checkpoint inhibitor. But somebody who’s had it twice, that would be more challenging.

Regarding COVID, that is I agree on a case-by-case basis you have to look at COVID as the issue going on and to test for COVID if you suspect COVID. You hopefully have some other symptoms to clue you into COVID rather than just an immune phenomena from the immune checkpoint inhibitor.

DR LOVE: So, Rob, any thoughts about our discussion? And about this ethical dilemma that the medical oncologist felt about treating a patient with pembro when they really could go for cystectomy. Have you had patients like that, Rob?

DR SVATEK: I think it’s a great comment. The first thing that came to my mind when the case was being presented was, well, no one wants a cystectomy. I mean except for patients that have severe lower urinary tract symptoms; nobody wants their bladder removed. So I guess I worry a little about the conversation that you need to have before you decide and make certain that they understand the options available for you if you’re going to get a cystectomy. And then once the decision is made … I think there is response rate, but it is modest, right, and so that needs to be clear, that we’re looking at, what, a third or less are going to have long-term benefit from this. So that’s real.

Now the other thing is, that it’s buying you a little bit of time. And so, the other thing that you could say is well, let’s buy a little bit of time, see how you do, keep you under close surveillance. And so it is a long discussion, and it is important to hit each of those targets before you decide on the right therapy for this patient.

DR LOVE: Ashish, we were talking earlier on about why you all like being involved with bladder cancer. To me, one of the fascinating things is this procedure, the cystectomy. It’s hard to think of another procedure in oncology that really kind of matches up in terms of potential morbidity. I’m curious how you approach the decision of offering cystectomy based on age, Ashish. They say age is not a number, but I’m guessing you maybe haven’t done too many cystectomies on people in their 90s. Any comments about how you approach the decision of cystectomy, particularly in older, frail patients, Ashish?

DR KAMAT: So it’s ironic you would say that because one of my patients who’s 98 now, but he was 94 actually when I did a cystectomy, recently sent me a picture, his grandson made him a T-shirt that said, “Bladderless and proud of it.” He put it on up in a hot air balloon, took a picture and sent it to me.

DR LOVE: Wow!

DR KAMAT: But I agree with you, right. We have to factor in all these parameters. So one of the things that we saw in KEYNOTE 057 is that most of the patients who actually enroll in the study refuse or do not want radical cystectomy. It doesn’t matter what age they are. Very few are truly non-cystectomy candidates.

So with the advances we have now in cardiology, anesthesiology, our techniques of radical cystectomy — Rob and I are both surgeons, we could get very frail patients to a cystectomy today that we couldn’t maybe 15, 20 years ago, when this procedure still done commonly but all the refinements didn’t exist.

That being said, that doesn’t mean we should be pushing these patients to a cystectomy. If there’s any way in which I can save a patient’s bladder, that’s my option number 1 or 2. But we have to remember, in the non-muscle-invasive space we do have the option of saving the bladder up to a point, beyond which we’ve save the bladder at the expense of the patient’s life. And that’s that fine balance that all of us kind of wrestle with. Because there’s no true predictive marker as to which tumor is going to metastasize. They’re all clinical parameters. None of the gene expression profiling, none of the molecular studies to date, replace what we know about stage and grade being able to predict who is going have an adverse outcome.

Case: A man in his mid-80s with recurrent high-grade noninvasive papillary carcinoma — Dr Morris

DR LOVE: So I want to put out 1 more case and Arjun, I’ll ask you to respond to this, and this is my answer to the question of should urologists get involved with IOs? Should they get involved with other therapies that we’re going to talk about in metastatic disease? My answer is yes. Yes. And with a medical oncologist close as your partner. And this case is a good example of why because maybe this is the future. Here’s Dr Morris's presenting an 86-year-old man.

DR MORRIS: We did a Blue Light Cystoscopy in the office; had no clear recurrences and then he underwent a resection.

And so the question for the faculty, and this situation may not be the best example of it, but is Blue Light technology worth the extra cost for all populations? At 86 he is not very interested in a cystectomy and is not the medically most healthy person that could potentially undergo a cystectomy.

DR LOVE: What’s this trial he’s on?

DR MORRIS: He had a confirmed FGFR mutation and is now enrolled in a clinical trial with an FGFR inhibitor, an oral inhibitor now being studied in localized disease, not just muscle invasive urothelial cancer.

DR LOVE: Really interesting. Which agent is he on?

DR MORRIS: It’s erdafitinib.

DR LOVE: Wow.

DR LOVE: So, Arjun, oncology, we start out with advanced disease and start moving it up. We already have IOs in the adjuvant setting in bladder cancer. And here we have a trial hat’s looking at a fascinating therapy we’re going to talk about later in metastatic disease in a specific population with a biomarker. Any thoughts about this case?

DR BALAR: So to address your question head on, do I think urologists, can they and should they? I think they have to be because you may not have a choice. Because there are folks like Ashish and Rob, they work in tertiary care centers. We have medical oncologists who are highly specialized in bladder cancer, but most cancer care occurs in the community and most often the urologist is the most expert opinion for that patient with bladder cancer and they may not have a medical oncologist nearby who knows enough about bladder cancer to be available as an expert. And there’s no one better to take care of that patient than that urologist. So they have to take it on. They have that duty to take it on. The key is that they need to develop the infrastructure.

So in regard to this case, we are seeing much more of these systemic agents entering localized non-muscle-invasive disease. I am familiar with this study, at least peripherally; we actually plan on opening that study here, and there are going to be other FGFR inhibitors that are going to be in development in the near term as well, hopefully ones that are even better tolerated than erdafitinib. And so, I think there is a compelling need to use some of these systemic agents, especially as Ashish mentioned, to avoid a cystectomy safely if we can, to avoid micrometastases and eventually death that is actually due from metastatic disease, not actually just from the disease in the bladder. So I think this is part of a big wave of new therapies that we’re going to see in the coming years.

DR LOVE: So, Ashish, we’ve had the pleasure of working with your medical oncology person, Dr Arlene Siefker, talking about erdafitinib and FGFR. But could you comment a little bit on the Blue Light technology that he was asking about, Dr Siefker-Radtke, I should say. Can you comment a little bit about this technology? When it’s used? And particularly from a medical oncologist asking, what is this? And what role does it have in managing these patients?

DR KAMAT: So, when we look into the bladders of patients we look in with a cystoscope essentially, and traditionally these cystoscopies are done with what’s known as White Light technology. There’s a of enhanced cystoscopy techniques that are available nowadays, and Blue Light is one of those. So essentially, in short, it’s a substrate that’s put in the bladder. It’s taken up by rapidly dividing cells. It’s a porphyrin derivative that is then metabolized. And then when you shine a blue light into the bladder of these patients, any rapidly dividing cells, specifically cancer cells, will shine bright pink. So it allows us as surgeons to be able to see tumors that may not be visible to the naked eye, which is crucial when it comes to the margins of high-grade tumors or the margins of CIS, which, honestly, sometimes you can’t really see even if you’ve done 10,000 of these procedures. And it’s absolutely worth it. It’s almost like someone today asking me, well, do you want to watch Tom Brady throwing a football on standard definition televisions when you have 8K TVs available, and I would be like, why would you? So why would you today any urologist taking care of any patient with bladder cancer want to be looking in their bladder with old technology when you have new technology available?

Now Blue Light’s not the only thing. So if you have narrow band imaging, all of those have not been studied as well in head-to-head comparisons, but use something, if you don’t have Blue Light. But if you are going into the field, absolutely use one of the enhanced cystoscopy techniques.

Case: A man in his mid-80s with muscle-invasive bladder cancer who declines cystectomy — Sulfi Ibrahim, MD

DR LOVE: So I want to go on now and we’ll talk a little bit about neoadjuvant and adjuvant therapy. Of course, we’ve now had the approval of nivolumab as adjuvant therapy. But we’re going to start out with a case from the medical oncologist, Dr Ibrahim. Arjun, I’d like you to comment on this case, and then maybe Rob, you can comment as well. This is an 84-year-old man who declined cystectomy. Here’s Dr Ibrahim.

DR IBRAHIM: He was 84 years old, muscle invasive bladder cancer. He declined a cystectomy. I've treated him on a clinical trial with concurrent chemoradiation therapy. On the clinical study, there is a randomization to immunotherapy with atezolizumab or placebo. He was randomized to the arm getting atezolizumab. He's about 6 months post treatment and so far, so good.

DR LOVE: That’s a really cool study.

DR IBRAHIM: Yeah. I've treated a few patients, about 3 patients, on this same study.

DR LOVE: Really?

DR IBRAHIM: Yeah. Because it's the exact same scenario — 80 some years old patient who declines a cystectomy.

DR LOVE: It sounds like the PACIFIC trial in lung.

DR IBRAHIM: Yeah. I remember you had a conversation with Dr Arjun Balar, and he mentioned that there were a few studies at ASCO evaluating immunotherapy and concurrent chemoradiation for muscle invasive bladder cancer. And I remember he mentioned that is a promising study. I would agree because many patients decline a cystectomy and I think if you had something to offer instead of a cystectomy that would be a significant benefit to patients and an upgrade in standard of care.

DR LOVE: So, Arjun, in our midnight webinar last night on lung cancer, we were talking about the PACIFIC trial, where they had locally-advanced, unresectable, they get chemoradiation as a standard, but they consolidated afterwards with a year of an IO, durvalumab. And we were looking at these curves last night, they have 5-year follow-up, and the curves were staying apart. Can you talk a little bit about that kind of strategy in bladder cancer and where you see that heading?

DR BALAR: So I think if there’s one area in bladder cancer that’s been something I’ve been most passionate about, it’s that. It’s bladder preservation as a whole. I think our data from KEYNOTE 057 was published earlier, and that led to an FDA approval, but that’s non-muscle-invasive. But what I’ve been working on since 2014 has been muscle-invasive disease. And we presented data from our first investigator-initiated study of hypofractionated radiation and twice-weekly gemcitabine and pembrolizumab, which was just as ASCO 2021. It’s only 54 patients, but a high rate of bladder preservation. We look at a composite endpoint of bladder intact disease-free survival which looks very promising at 1 year at over 80%. Historically, we see rates more in the range of 60- to 70%. Bottom line is that we have randomized, Phase IIIs that are now ongoing, SWOG 1806. We have the KEYNOTE 992 study. Our randomized studies of chemoradiation with or without immunotherapy. Dr Ibrahim is talking about the SWOG study that involves atezolizumab and KEYNOTE 992 is a multinational study sponsored by Merck.

Each one has a little bit of differences, some nuances, hypofractionated radiation, some of the chemotherapy therapies and regimens are a little bit different. Whole bladder radiation only versus pelvis included. So there are some subtle differences and tweaks that can allow for differences. In the toxicity profiles honestly of radiation, which I think is an important consideration, Western Europe and the UK is much more advanced when it comes to how they do bladder radiation. That’s the bottom line. And we have a lot to learn in the US about we do bladder radiation. But I think this is something that’s going to significantly impact, I hope, how we treat patients with muscle-invasive bladder cancer. And hopefully — right now were a highly surgically-driven country where most patients, muscle-invasive disease, are getting cystectomy — I hope that it’s more like 20% or more are offered bladder preservation, hopefully in the form of chemoradiation along with immunotherapy because I think this is going to be practice-changing in the next 4 to 5 years.

DR LOVE: So, Guru, in a second I’m going to let you explain what the abscopal effect is and whether you believe that it actually exists. But just to come back to Rob first. Any thoughts about this strategy of chemoradiation to start with in patients who aren’t eligible or don’t wish to have a cystectomy? And about these new strategies that start to include immunotherapy on the back end?

DR SVATEK: As a urologist, we see the radiation failures. And so, one of the things that we always like to think about is when you have a trial that’s agent versus placebo and there’s no cystectomy comparative group, it calls into the question the overall value versus the standard which would be a cystectomy. That said, in my practice, there is certainly role for trimodal therapy. And I tend to agree with Arjun, I mean we do need a move toward a situation where we can preserve more bladders. I think key things are that who are the candidates for this? I mean patients have to have adequate bladder and bowel function. Patients with severe lower urinary tract symptoms at baseline may have poor functional outcomes after radiation. And the tumors really need to be confined at the bladder. And when you have tumors with extension in the ureter beyond the intramural tunnel, that would be a contraindication.

So I think proper selection is important. Patients with diffuse CIS, that’s also a patient where you wouldn’t want to consider radiation. But in properly selected patients, trimodal therapy with maximal debulking surgery, TUR, and chemoradiation is an appropriate thing. And I’m excited about these immunotherapy combinations. And I’d like to hear what Guru thinks about the abscopal effect.

DR LOVE: So, Guru, this is like do you believe it exists or not. But people are still trying to explain why the PACIFIC trial had such great results. And one hypothesis is that there’s something about chemoradiation that’s dislodging antigens, whatever, potentiates immunotherapy and then they bring up the abscopal effect. So any thoughts about the biology, Guru?

DR SONPAVDE: I believe, Neil, that the biology is there for an abscopal effect; however, the schedule of radiation that seems to be the best at producing an abscopal effect might be different, which could be the hypofractionated schedule of radiation. Which is actually not the schedule being given in some of this chemoradiation plus/minus PD-1 or PD-L1 inhibitor trials. So I believe it does exist. I think it’s a small subgroup of patients that we don’t have a biomarker to recognize. So I think, hopefully, we’ll get there at some point.

Selection of Patients for Neoadjuvant Therapy — Dr Morris

DR LOVE: So another question, and Arjun, actually in the chatroom Mayer wants you to share your choice of chemo when you use RT and bladder conservation. But before you comment on that, I want you to listen to Dr Morris who has another question, this is about the use of neoadjuvant therapy in bladder cancer.

DR MORRIS: Most urologists know that neoadjuvant is a better delivery point for chemotherapy, but yet historically it’s just really underutilized, in even the best academic centers, and certainly in the community. Is there a patient group where it really makes the most sense to push and sell neoadjuvant chemo? We’ve typically done it for T3 disease, clinically trying to maybe downgrade them to make it more resectable, but we all know that if we can get a pathologic T0 at cystectomy that’s kind of the best outcome for the patient. But it’s really hard to balance that mixture of how well you heal from chemotherapy and what the delay might be to cystectomy for a small marginal improvement in terms of percentages postop versus people getting adjuvant therapy. So guidance on the best candidates to get into the office for consideration for chemo before surgery would be helpful.

DR LOVE: So, Arjun, first, would you share the type of chemo you use in chemoradiation? And then address this question to neoadjuvant therapy.

DR BALAR: So there is no optimal chemoradiation regimen and that’s because really the purpose of chemotherapy along with radiation is radiosensitizing. That being said, when I have conversations with patients, I say hot, medium, or mild, based on the fitness of the patient to receive that chemotherapy. Weekly cisplatin is probably considered the most effective, most aggressive standard because it has the systemic effect that has been shown to have effect on micrometastatic disease and perhaps improve cure rates, along with definitive local therapy. So the purpose of the chemoradiation is to treat the bladder, and also the chemotherapy it also treats systemic disease. Your best effect with that second part is with cisplatin. So, weekly cisplatin at 35 per meter is probably your best bet.

Then, after that, 5-FU/mitomycin is — the BC2001 study, the UK experience — highly effective. That’s your second option. I would call that medium. And then your mild is probably twice-weekly gemcitabine. It’s something that’s really attractive and I’ve used that quite often, especially in my very elderly, frail patients, 27 per meter twice per week with 2 days between. And you can dose de-escalate based on tolerance. Most patients just have problems with a little bit of myelosuppression and platelet counts during the latter weeks of chemoradiation. But those are kind of my go-to — weekly cisplatin and 5-FU/mito and twice-weekly gemcitabine.

Now, to address the question of neoadjuvant chemoradiation, who should or should not. I feel like, after 20 years, the fact that we’re still asking this question is just striking, right. All patients with muscle-invasive bladder cancer should be offered neoadjuvant chemotherapy and that’s because you can’t pick them out of should or should not because clinical staging is woefully inadequate, because the rate of upstaging is hard to predict at cystectomy. And so, all comers, all of these patients should be offered neoadjuvant chemotherapy. And single institution experiences will say, oh, well, listen I’m really good at picking out the minimally muscle-invasive. And look at this survival curve where I picked these patients out and look how well these patients do over time with surgery alone. But what you can’t say is that well, how much better could these patients have done if they’d also received neoadjuvant chemotherapy, right? That’s what randomized trials hold us accountable to is really good quality science, prospective randomization showed us multiple times that if patients with muscle-invasive disease, irrespective of his clinical T2a, or T3b, that if you randomize patients neoadjuvant chemotherapy followed by surgery, or surgery alone, that patients consistently do better if they get neoadjuvant chemotherapy followed by cystectomy. Period. End of story. That’s it. There’s more conversation.

So all patients should be offered it. And that argument of, if it’s a small incremental benefit, that’s also flawed because if you look at adjuvant chemotherapy in colon cancer, if you look at adjuvant chemotherapy in breast cancer, the average benefit is about the same across all 3 solid tumor subtypes. So now that we have adjuvant nivolumab approved, we need to take this to the next step. Adjuvant nivolumab should not replace neoadjuvant chemotherapy. It should supplement neoadjuvant chemotherapy. What we should now see is that all patients should be offered neoadjuvant chem, that’s what we should have been doing for the last 20 years. Patients who have persistent muscle-invasive disease or greater after neoadjuvant chemoradiation should then be offered adjuvant nivolumab. That is the only way we are going to improve cure rates after definitive local therapy, otherwise, those patients who are undergoing cystectomy are undergoing a morbid procedure with major impact on quality of life, permanent impact on quality of life and then still suffering metastatic recurrence for no good reason.

We have to increase the value of the treatments we’re giving patients and replacing 1 adjuvant treatment to replace a neoadjuvant is not the right answer.

DR LOVE: So I know Ashish, you’re jumping out of your seat. Of course, MD Anderson, to me, is the heart of neoadjuvant therapy in oncology, breast cancer, many other diseases you all really pioneered that and continue. There was a question in the chatroom you responded to, Ashish, the question from Germana was, what’s your opinion about neoadjuvant chemo after partial cystectomy? You answered neoadjuvant chemo should be used whenever there’s a risk of mets. So, yes, even partial when appropriate. Do you agree with Arjun’s enthusiastic endorsement of neoadjuvant therapy for everybody, Ashish?

DR KAMAT: So let me answer that diplomatically and say, no. I don’t.

DR LOVE: Alright, that’s what I want to see.

DR KAMAT: But again, on the boards for urology training and medical oncology, the right answer, yes. Anyone with muscle-invasive bladder cancer going for radical cystectomy should be considered for neoadjuvant chemotherapy. However, at MD Anderson, we have our selection criteria which we’ve published for the last 20 years, validated in multicenter series. But again, it is single center. It’s not been replicated in a few other places in the US and internationally, but not in Phase II randomized studies. That being said, I do want to emphasize one thing that came up in Dr Hafron’s presentation, patients have no adverse surgical consequences after neoadjuvant chemoradiation. There is no increase in complications. No increase in hospital stay. There is no increase in any adverse event. And back in 2013, we actually convened a panel at the SEO asking this question of the SEO members, why are you not sending your patients who should be getting neoadjuvant therapy for neoadjuvant chemotherapy? And the first comment was very similar saying, it’s only a 5% benefit. Why would my patient want a 5% benefit? It’s a 5% benefit in life. It’s not a 5% benefit in anything else. It’s alive or dead, 5% benefit, number one. Number two, a reason was, well my patients have a lot of complications after neoadjuvant chemotherapy. Well, get a better medical oncologists is what I would say. And number three, surgical complications, and that doesn’t make any sense. In multiple randomized studies, it’s been shown that neoadjuvant chemotherapy, and even neoadjuvant IO therapy, does not increase complication rates if you allow for a washout.

So we recommend a washout of 4 to 6 weeks after the last dose of any cytotoxic agent before taking the patient to the OR for potentially wound healing issues and things of that nature.

So I just wanted to address those.

DR LOVE: Very important. Actually, last night in our lung program we were talking about this wild paper in neoadjuvant IO/chemo in lung that was done. Dramatic downstaging. I mean changed the kind of procedure they have from pneumonectomy/lobectomy. There’re still trying to process that, and it would be interesting.

And they were also talking about they thought that probably preop IOs weren’t going to be a problem. It doesn’t look like it. But still, really interesting.

All right, audience, let’s see if they’ve convinced you. So here it is, do you generally agree with what you just heard from arjun and Rob, that neoadjuvant therapy, in general, should be the standard of care for people with invasive bladder cancer? Yes or no? Let’s see if they talked you into it, because I’m pretty sure that isn’t the standard that’s been in the audience prior to that. I don’t know if we asked them in them in the pre-meeting thing. But wow! I think you should run for office, Arjun, you got 100% of people supporting — you and Rob completely convinced everybody.

Case: A man in his late 70s with Gleason 4 + 3 adenocarcinoma of the prostate and urothelial carcinoma — Dr Hafron

DR LOVE: All right, let’s do one more case. We actually had a question in the chatroom. Every time we do a solid tumor program, people ask about ctDNA. So, Guru, when you comment on this patient, a 77-year-old patient of Dr Hafron where he issue of adjuvant or post-neoadjuvant therapy comes up, I also want you, if you could, to please try to comment on that. Here’s Dr Hafron.

DR HAFRON: My question to the faculty is, he’s already received 4 cycles of adequate chemotherapy, would you consider adjuvant, immunotherapy, or would you observe this patient with N1 disease following surgical resection?

The prostate cancer was adequately resected. His margins were negative. His PSA is actually 0 six weeks after surgery. Clearly the pathology shows that his lymph node positive disease is transitional cell carcinoma.

What are the indications for adjuvant treatment with IOs today? If you were to go with an IO, how long do you have to treat these patients?

DR LOVE: Incidentally, Nicholas in the chatroom says, the problem in the community is NOT the medical oncologists, which I think Nicholas is, but it’s the surgeons who operate without having the medical oncologist see the patient. We’ll just let you mull on that.

Guru, what are your thoughts? I should mention this patient, obviously also had prostate cancer, but the dominant lesions seemed to be urothelial, at least that was what was in the nodes. Neoadjuvant chemotherapy preop. What would you be thinking about post-op in terms of IO, specifically nivo, Guru? Would you generally treat a patient like that? And any thoughts about this concept in terms of ctDNA, maybe even coming into the adjuvant/neoadjuvant space.

DR SONPAVDE: So this patient fits the criteria for which nivolumab was used in the adjuvant CheckMate 274 trial. As you know, adjuvant nivolumab is now FDA-approved in patients like this with residual muscle-invasive disease or higher state of disease post-neoadjuvant cisplatin-based chemotherapy. It’s also, of course, approved in cisplatin ineligible patients in the adjuvant space if they have extravesical disease or beyond that have not received neoadjuvant chemotherapy. And of course, if they’re cisplatin ineligible, or cisplatin refusing patients.

So in this patient, yes I would offer nivolumab. The duration of therapy in CheckMate274 was 1 year. They gave treatment every 2 weeks on the trial. This was the older formulation. But now, as you know, the every 4-week formulation is also available.

In terms of ctDNA, there is exciting data with ctDNA to assess minimal residual disease in the post-operative muscle-invasive bladder cancer space where it looked like in the adjuvant atezolizumab trial, which was overall a negative trial, unlike the adjuvant nivolumab trial, it looked like patients who had MRD-positive disease by ctDNA, and this was tumor informed ctDNA, so the tumor was profiled and then select genes for profile in the plasma for ctDNA. And so, patients who were positive seemed to benefit from atezolizumab, while in the overall trial, atezolizumab did not improve outcomes.

Now the reason I’m hesitant to apply this to the adjuvant nivolumab situation is that in the nivolumab situation, we have a positive trial, the median DFS improved by 10 months, right, 11 months versus 21 months. So this is a situation where we’re looking at who did not benefit? Because most patients benefited if the median DFS benefit was improved by 10 months. So I’m hesitant to use it in the adjuvant nivolumab situation. I think we need more data to examine this platform, or maybe another more enhanced platform in this situation.

DR LOVE: So, Rob, when you look at the curves from the CHECKMATE 274 study, maybe it depends I guess on the scale, but here, maybe it’s not as impressive as you might think, but if you look at the HR, the hazard rate of the total population, there at .70. What that means is that at any point in time on this curve there was a 30% education in risk of relapse for these patients. And then if you look over on the right with the PD-1-positive patients, the hazard rate’s even better, which means lower, so .53, 47% reduction in recurrence.

Any thoughts about how this strategy is working into your practice right now, Rob?

DR SVATEK: Yes, I think it’s a meaningful difference. I mean you’re essentially increasing the disease-free survival by like a 100%, from 11 months to 21 months. So, that’s remarkable.

It’s interesting that it was so different than the other adjuvant trial that was published. But nevertheless, I think this is a meaningful effect.

And if you look at that Kaplan-Meier curve, the split occurs right away. I mean basically a like month 4 or 5, you see that split. Which is interesting. You might have thought it might have taken a little bit longer.

So I think this is a game-changer for the field.

The issues are cost. I mean it’s drug every 2 weeks for a year. And do you continue it after a year? So, those are some of the things to think about. But I think this has absolutely changed how we manage the disease and it’s one of the things that I think is exciting about this field.

DR LOVE: So I see an interesting thing in the chatroom which I’d like to bring out here, which is the question and Ashish you responded to it, here’s the question, do variant histologies factor into your decision to do neoadjuvant versus not neoadjuvant? Can you comment on the issue of histology, Ashish?

DR KAMAT: Sure. I replied in the chat, but essentially, yes, variant histology is an important factor to be considered. In most of these studies that we do, whether it’s neoadjuvant or adjuvant or whatever, the variant histology is capped at a certain percentage and that’s clearly because when you design clinical studies that’s what the person designing or the company designing it wants to do. So we don’t have actual randomized data on that. That being said, we know for sure if a patient has small cell bladder cancer, even if it’s a T1 disease, that patient needs to be on adjuvant chemotherapy. You don’t have to wait for it to be muscle-invasive.

On the other hand, if a patient has T4 pure squamous cell carcinoma, neoadjuvant radiation prior to cystectomy is much more beneficial than chemotherapy. These patients don’t respond quite as well to neoadjuvant chemotherapy as they would to radiation, and then surgery afterwards. Yes, surgery is harder, but the benefit is a lot higher.

And when it comes to the other variants, for example, lymphoepithelial-like carcinoma, a lot of these patients that go on neoadjuvant chemotherapy end up having absolutely nothing on cystectomy. So there’s a thought that maybe they didn’t a cystectomy. Certain patients with predominant micropapillary might have a different benefit profile. But in general, other than those extremes, I think all variant histologies do benefit from neoadjuvant chemotherapy.

DR LOVE: So in a second we’re going to move on and talk about metastatic disease, particularly some of these new agents.

But one other practical point about checkpoint inhibitors, Guru, and Rob was mentioning the issue of the patients coming in to receive treatment. And of course, this last year and a half we kind of had a real swing away from bringing people into the clinic and maybe swinging back now a little bit in the other direction, but because of COVID. And, of course, during the pandemic, Guru, one of the things that happened was we saw the approval of pembro given every 6 weeks at a higher dose. Nivo, as we were mentioning, q2-weeks, but then people use it q4. Again, I think people are trying to keep patients out of the infusion rooms. I’m curious about your experience with these, particularly pembro, in the lower dose, q3 versus q6, do you see more toxicity? And how do you generally approach intervals between IOs, Guru?

DR SONPAVDE: So, Neil, the answer is I tend to start with q3-week pembrolizumab just because I want to keep a closer eye on them, on their laboratory assessments, LFTs, symptoms, that the patients might not be reporting promptly. And so, I tend to go every 3 weeks for 2 or 3 months at least, before a switch to the q6 weeks. I have a lingering suspicion that if you start with q6 weeks, if someone has an immune event, do those events take longer to recover? I’m not sure we have seen any data on that. I think the pharmacodynamically, chemotherapeutically, they’re similar. I’m not sure how soon the drug washes out me giving it q6-week dose. So, that’s just my lingering suspicion, not that I have any data to support that.

So the bottom line is, I like to start every 3 weeks and go 2 or 3 months at least, before I switch to q6 weeks.

Urologists’ Questions about Second- and Later-Line Therapies and Management of Side Effects — Dr Morris

DR LOVE: So, we want to talk about metastatic disease and also get into the issue of these new therapies that are now available. We now have a tyrosine kinase inhibitor, 2 antibody drug conjugates in metastatic disease, in addition to the IOs that we’ve had for a while, as well chemotherapy followed by IOs, specifically avelumab maintenance. We’ll comment on that as well. But I just want to start out with a couple of comments about the issue of metastatic disease in general, and the kinds of questions that we’re hearing from urologists, particularly about these new therapies. Here’s Dr Morris.

DR MORRIS: I think urologists have a lot of questions about metastatic disease because most of our experience is up through cystectomy. Most urologists have no idea other than ask their friendly local medical oncologist which should be the third-line therapy of choice.

So I don’t know if there’s something to at least pave the road for what the discussion would be with the medical oncologist, so they’re at least aware of it? Just like we talk about chemo before surgery it might help us to talk a little bit about what could come after they had chemotherapy.

DR HAFRON: I think that the biggest challenge urologists have with these agents is expected adverse events and side effects management of these patients. I frequently will work with endocrinologists more often than I ever have. I will work with the oncologists. I try not to make it a turf war and just work together to do what’s best for the patient.

DR LOVE: So, Arjun, just to being, and we’ll get into some more details about these new agents in a second, but more of a macro view of management of metastatic disease 2021 compared to maybe 2 years or 3 years ago, how all these new options are affecting the way particularly how patients get sequenced. And also, you heard the kinds of questions that are coming from urologists. And sort of broad view of how metastatic disease is going nowadays?

DR BALAR: This is a really a moving target. So where metastatic disease is today as of September 2021, I think right now platinum-based chemotherapy, either cis or carbo, is probably the preferred standard for the majority of patients. And I think the pendulum is swinging a little bit away from first-line immunotherapy use, a little bit of reluctance to use it because the response rates are lower, and then there’s a fear of progression of patients receiving first-line IO if they don’t respond and not being able to subsequently be rescued with chemotherapy. And there’s a lot of experience that’s really needed to use first-line immunotherapy.

So, outside of the very platinum-ineligible patients and certain patients who really just want immunotherapy, we’re using a lot of just first-line gem/cis or gem/carbo. Some people really believe in the maintenance strategy with avelumab, others don’t. But in either case, systemic immunotherapy is going to be the more or less de facto standard in second line or line 1.5, however you want to do it.

And then in third line, where we sit right now, very firmly established, is enfortumab vedotin. We have data from the EV-301 study that shows a survival benefit, hazard ratio of .70, .73 against single-agent chemotherapy. And then also along with that regular approval that came with that, so accelerated approval turned into a full approval, the label included enfortumab to be used as a second-line agent.

So this is a neat little wrinkle that happened. Cohort 2 of EV-201, it’s hard to walk through all of this data, but the bottom line is that enfortumab vedotin, I think this is kind of the new kid on the block. It’s an antibody drug conjugate that targets Nectin-4. The payload is monomethyl auristatin E. But its activity throughout its development program has been very consistent, response rate of between 40- to 45%. The safety and tolerability, it’s been highly consistent, and I think what the FDA saw was that it’s such an effective option, especially in patients who might receive, let’s say first-line platinum, you might, per the NCCN guidelines, we often have to reach for immunotherapy, but sometimes we don’t want to reach for immunotherapy because the response rate is 20%, we want to reach for a cytotoxic. Now we actually can with enfortumab. So it’s actually available as a second-line agent. You don’t have to go through immunotherapy to reach for enfortumab.

And then erdafitinib, which is also available as a second-line agent and beyond, but only for patients with FGFR2 and FGFR3 alterations. And then lastly, sacituzumab govitecan, which received accelerated approval earlier this year in April, that’s also technically approved as a third-line agent, so after platinum, after immunotherapy. Response rate is 27% on a basis of a single-arm study, TROPHY U-01. There is the TROPiCS study, that’s the randomized Phase III that’s currently ongoing. But that has a unique safety profile, non-overlapping with enfortumab vedotin. Different target, different payload.

So I agree with your earlier statement as compared to lung cancer docs and even kidney cancer doctors, we have a lot of different drugs, but importantly each one of the drugs has a different target, different mechanism of action. They’re really non-overlapping. So we really do have a lot of options in bladder cancer now.

DR LOVE: And we are going to go through these, give a little bit more granularity to what we’re talking about. Interesting, people want to get checkpoint inhibitors because generally speaking, better tolerated than chemo. You have the possibility of a triple or homerun, who knows what might happen where you don’t usually see that with chemotherapy.

Guru, Arjun mentioned sacituzumab, the antibody drug conjugate, actually already approved in breast cancer, being used a lot in metastatic disease. A lot of antibody drug conjugates out there. There’s tisotumab in cervical cancer. There’s 2 in HER2-positive breast cancer, T-DM1 and T-DXd. Brentuximab in lymphomas has been out there for a while, particularly Hodgkin lymphoma. Can you kind of explain what an antibody drug conjugate is, Guru? You don’t usually see chemotherapy side effects, but the true action is coming through chemotherapy. What are these agents?

DR SONPAVDE: So antibody drug conjugates are essentially conjugates of a monoclonal antibody that binds to a surface membrane antigen found on a tumor cell mostly, although, also in some other normal cells sometimes, conjugated with a toxin. And therefore, when this ADC or antibody drug conjugate, binds to the cancer cell, the drug gets internalized and then the liposomal degradation leads to release of the toxin, which then has the antitumor effect.

So in the case of enfortumab, you would have the MMAE auristatin, the tubulin toxin being released. And in the case of sacituzumab govitecan, you would have the SN-38, that’s a topoisomerase1 inhibitor being internalized and released and having the cytotoxic effect. So basically you can think of it as targeted chemotherapy, right.

DR LOVE: Yeah, we heard the term Trojan horse applied as well to these kind of agents. Really kind of makes a lot of sense.

Case: A woman in her early 70s with metastatic UBC, PD-L1 30% — Dr Ibrahim

DR LOVE: Let’s go through a few cases and start to see the way this actually plays out in clinical practice. This is a 70-year-old patient of Dr Ibrahim who’s on enfortumab and in contrast to other patients he’s had on enfortumab, this woman actually is having some side effects. Here’s Dr Ibrahim.

DR IBRAHIM: She’s had approximately 4 cycles of enfortumab vedotin. Her disease is responding. She has toxicity on the enfortumab vedotin which haven’t encountered in other patients that I’ve given the drug to. So she has mild ocular toxicity which is not the issue. She has mild conjunctival erythema which resolves with a dose hold. The major issue is, she has like a scaly rash on her upper extremities. It is quite pruritic and bothersome to her. It hasn’t responded much to topical steroids and even to low dose systemic steroids.

So my question is what is the optimal management of the dermatologic toxicity with enfortumab vedotin?

DR LOVE: How many people have you treated with enfortumab?

DR IBRAHIM: Ballpark? Five. It’s been good. I don’t recall a single patient who did not respond. But this is the only case where I found significant toxicity. I generally have thought of it as a well-tolerated agent that most patients respond to.

DR LOVE: So, Arjun, I’m curious how you explain to patients what an antibody drug conjugate is? And what your experience is with enfortumab? Do you see typical chemo effects like hair loss, nausea and vomiting? What do you see?

DR BALAR: So Dr Ibrahim’s experience is, to some degree, actually somewhat typical for EV. So, antibody drug conjugates, as Dr Sonpavde mentioned, it’s antibody, highly specific for cell surface antigen, in this case it’s Nectin-4, in this case it is linked with a protease cleavable linker to monomethyl auristatin E, which is a highly potent microtubule disrupting agent. Nectin-4 is highly overexpressed on urothelial cancer. Actually, has minimal expression on normal urothelium. It does some have some expression on the cornea of the eye, which is why we see some of the ocular toxicity. So some of the corneal irritation, that conjunctival symptoms, is actually pretty common. And steroid eyedrops are actually very effective, Artificial Tears, and usually it’s not much more than a nuisance.

The skin issues are important and those develop chronically and can be a big problem over time with continued exposure. After topical steroids, high potency steroid creams, even sometimes systemic corticosteroids. The other things that help with the itch is dual antihistamine blockade, so Claritin, Pepcid, that sort of thing, is very effective. The same things that we use with immune-related rash with, let’s say pembrolizumab and other checkpoint antibodies.

And then what I’ve done is leverage our experience at NYU and other places, I’m sure Guru does the same thing, is that we reach out to our dermatologists. And what I’ve seen increasingly used are other monoclonal antibodies like dupilumab, which is an IL-4 antagonist, that is used in eczema. Very effective also reducing itch and some of the eczematous components of the rash. And then also what I’ve seen used is phototherapy. That, plus some dose reductions and dose holds can help patients get through it.

Now this is for some of the nuisance type of rash that can happen. That is differentiated from high-grade toxicity like Stevens-Johnson syndrome, toxic epidermal necrolysis. This occurs early in the course of treatment during cycle 1-ish. Those are high-grade events. Exceedingly rare. There are case reports of it. They don’t happen often. But those are potentially life-threatening and obviously, this is not the case that Dr Ibrahim is talking about. Those are different. And for those patients, they should never be rechallenged again.

DR LOVE: You said, Arjun, that his experience was fairly typical. He said most of his patients, if not all, have responded to some extent. Actually, I’ve heard the same thing about sacituzumab in breast cancer. It’s so hard when these new agents come out to get a real feel for that. When you start a patient, Arjun, on sacituzumab, are you kind of expecting they’re going to respond?

DR BALAR: So, with EV. So if you look at the waterfall plots with EV, 85% of patients have at least some decrease in their SLDs. So you’re going to get at least stabilization of most patients of their cancer. And what I’ve also experienced is symptomatic benefit, reduction in disease-related pain. A lot of my patients come off of narcotics completely, often by cycle 2 or cycle 3. And so I’m expecting clinical benefit. Yes, absolutely.

And so, that’s why these patients have toxicity. You don’t develop toxicity from chronic therapy unless you’re on therapy chronically. And that’s because they’re on treatment, cycle 4, cycle 5, right. They make it that far on treatment.

DR LOVE: That’s a great point. So, Guru, this is a slide that sort of provides a schematic of these 2 antibody drug conjugates. Can you talk a little bit about how they’re put together? How they’re different? And how they work?

DR SONPAVDE: So, enfortumab vedotin targets the surface membrane antigen called Nectin-4, while sacituzumab targets Trop-2 as you show there. And there’s also a little bit of a difference between the linker type and the drug antibody ratio. The drug to antibody ratio is around 3.6 for enfortumab, while for sacituzumab it’s higher, it’s around 7 or 8 molecules per antibody molecule. And so there’s more drug.

It’s also a hydrolysable linker in the case of sacituzumab. So there’s hydrolysis in the environment. So there are slight differences, but at the end of the day they’re both antibody drug conjugates that try to deliver the toxic agent specifically to a tumor cell.

DR LOVE: And here is the schematic of what you’re talking about. This is the big New England Journal paper that compared it to standard chemotherapy. You can see that rash and pruritis was noted, as Arjun just went through. But also sacituzumab was just approved this Spring in April, as another antibody drug conjugate. This is the TROPHY-U-01 study looking at that. Each one of these on the left is a patient who’s on therapy and you can see how long they’re on therapy for. On the right is a similar, it’s called a Spider plot, as well.

Just to go back to this, Ashish, any experience with your patients receiving antibody drug conjugates? And any questions you have about that you’d like to verbalize to Arjun and Guru?

DR KAMAT: So, we have first, have had patients on these trials — on these agents as part of these trials from the metastatic phase. There’s also, as you know, a trial that myself and others are leading looking at antibody drug conjugates in the earlier stages of disease. So, for example, EV in intravesicle formulation. There’s a Phase I/II study currently ongoing and recruiting. One of the advantages of that obviously is the prevalence of Nectin-4, which is the target, and the potential lower toxicity when it’s instilled in the bladder as opposed to giving systemically.

So, yes, personally, obviously, has a surgeon I don’t treat metastatic disease, but my medical oncology colleagues definitely do. but the mechanism of action of these agents is such that because it delivers that payload if you have the target and you have that payload that actually can kill your tumor cells, there’s the potential to use them not only in non-invasive disease, but also in muscle-invasive organ confined disease, as what we alluded to earlier, trying to get away from having to remove our patients bladders.

DR LOVE: So, Arjun, I know if I want to get an investigator in myeloma excited, I say the word bispecific. If I want to get a urology investigator excited about bladder cancer I say enfortumab plus IO. We’ve seen chemo plus IO as a very important strategy in lung cancer, head and neck cancer, in a way enfortumab plus IO is kind of a similar strategy except you’re using an antibody drug conjugate. Any thoughts about where that’s going? And Arjun, after you answer that, maybe you can also walk us through the biology and pharmacology of erdafitinib. But first, enfortumab plus IO, Arjun. Is that going to be moving up? And what do you think the future of that strategy is going to be?

DR BALAR: Yes. So I don’t consider myself a betting man, but if I were this would be where I’d put my betting chips on where I feel the first-line bladder cancer space is going to be heading in the next 2 to 4 years. We try not to put too much weight on early phase trials and the response rates that we see. But the 45-patient experience of EV/pembro from the EV-103 program, first line, cis-ineligible patients who were treated had a 73% response rate, 91% of patients having some decrease in their tumors and the median duration of response of over 2 years. The data was just updated at ASCO, really argues that there is something special there.

It’s actually no different than, I would say than our first experience with axitinib plus pembro when that experience was first presented and then ultimately led to KEYNOTE 427. And we know how all that turned out with 3 new standards of care with TKIs plus PD-1. I envision something very similar with EV plus pembro.

Now that being said though, we do need to test this out in randomized trials. And EV-103, Cohort K, and EV-302 are doing just that. those studies are enrolling and they’re enrolling well. And so we should see data very soon.

So I think most of us expect a couple of things. One, that EV/pembro will become the standard of care for first-line bladder cancer very soon for most patients. There will be room for IO therapy alone in selected patients who may not let’s say be candidates for EV for a variety of reasons. And then for patients who just want EV/IO monotherapy.

And then holdout that IO therapy, let’s say with CTLA-4 plus PD-1 may also have a role based on CheckMate 901, which is enrolling patients as well. That’s a higher dose of CTLA-4 at Ipi, 3 mg/kg. I think that’s something we have to look out for, especially in the biomarker-positive patients. So I think that’s something exciting.

EV plus pembro is also being tested in the muscle-invasive disease setting as well.

DR LOVE: Before you go on, just to clarify, so you’re saying first-line therapy of metastatic disease, so EV/pembro, so you have EV, which we just talked about, sort of chemo but not really, and pembro, which of course we talked about, instead of cisplatin-based chemo followed by avelumab maintenance? Seems like a very different experience.

DR BALAR: Yes. So remember, EV/pembro, just think of it this way, it’s kind of got built in maintenance anyway. So most patients on the EV experience, if you look at all the studies, patients stop treatment at 5, 6 months, 7 months for a variety of reasons. And so, they’re going to continue a pembro tail anyway. So maintenance is more or less built in.

And I think avelumab maintenance, while I think it is an important standard of care, my opinion, that’s mine, I think it’s a flash in the pan.

So there’s much more work to be done. And I think moving immunotherapy to just after chemotherapy rather than waiting for progression, I think is just an incremental step. I think this combination is much more meaningful in my view.

DR LOVE: Why don’t you just say what you think, Arjun.

DR BALAR: Just nibble around the edges right.

DR LOVE: Okay. Let’s talk. Certainly, Guru, biomarker-driven therapy is really the hallmark of oncology 2021. And erdafitinib, the tyrosine kinase inhibitor, fits right into that module. Can you talk a little bit about this drug and what it targets?

DR SONPAVDE: So erdafitinib is an oral pan-FGFR tyrosine kinase inhibitor and it’s approved, because of data we know in the post-platinum setting, patients with progressive disease who had somatic FGFR3 or FGFR2 activating mutations or fusions. Not amplification with it. There is some confusion out there regarding amplification of FGFR. So in this selected patient population, in a non-randomized study, the response rate was approximately 40%. And this is what led to erdafitinib approval in post-platinum patients.

DR LOVE: And just to be clear, when we talk about these abnormalities, it’s just in the tumor? So these aren’t germline abnormalities? These are mutations in the tumor. And how are they detected? What kind of assay is used, Guru?

DR SONPAVDE: So these are somatic mutations, Neil, so these were detected using a companion assay in the study using an RTP-CR of the tumor. However, in practice, we have used other similar next-generation sequencing platforms which assay many genes so that we have more information than just regarding 1 gene. So, it is somatic.

DR LOVE: So before Arjun comments on this, I put up some of the tolerability issues, which are pretty interesting with this drug, but before we go to Arjun, Guru, your experience in terms of efficacy. Have you seen significant clinical response with erdafitinib? We’ve had cases presented where patients have been on sometimes the earlier trials for a while. What’s your experience, Guru?

DR SONPAVDE: Yes, I have, Neil. So I have seen, my own experience, closely parallel what was seen in the study, approximately 40% response rate. I use it in the second line post-platinum setting in patients with progressive disease, often before the immune checkpoint inhibitor. Honest, of course, referring to the JAVELIN Bladder 100 switch maintenance avelumab paradigm where I’ve gone with avelumab regardless of the alteration. But I tend to use it very early, given that this is a specific agent, hitting a specific target. You want to use these drugs earlier rather than later I think.

DR LOVE: And of course, a minority of patients actually have this abnormality. But for those who do, you ask Dr Siefker, she also thinks about it second line, but there’s a lot of controversy about that. And part of it does relate to the toxicity profile. There’s some kind of unusual things that occur. Here’s a slide that sort of shows the development over time, particularly related to toxicities that cause dose interruption. What are some of the tolerability issues, Arjun, that come up with this drug and what’s your experience been with it?

DR BALAR: So the first point you made is that this is not that common of an alteration. So as oncologists, I personally have not had as much of an opportunity to use it. That being said, as Guru said, the clinical experience has reported out in the study has been my experience using it clinically in my patients. Diarrhea, fatigue, hand-foot syndrome, hair loss, the nail issues, it is a quality-of-life impacting drug. I mean I can’t really put it any other way. Diarrhea and the fatigue, it can be an issue.

The central serous retinopathy thing, I think you put up that slide, it’s a good one. Patients need ocular exams at baseline. I do it every 4 weeks. The reassuring part is that after 4 months or so, if it’s going to happen you will have seen it. If it doesn’t happen at that point, it’s not going to happen. And I think that’s the purpose of that slide is that you see it happen and then after that it really doesn’t. It’s an early event. Otherwise, it doesn’t really happen.

But I think the point though is that I think this is our first step for molecularly targeted agents in bladder cancer. We know have a reason to do next-generation sequencing. It’s the standard of care. Now our jobs are, as investigators, and hopefully drug developers that we work with, to develop better FGFR3 inhibitors. I think that’s what’s net on the horizon.

Case: A woman in her mid-50s with muscle-invasive bladder cancer — Dr Brown

DR LOVE: So I want to finish out with one more quick case and ask Ashish and Rob to respond to this. Get back a little bit more of a urology flavor here, just to close out. This is a patient of Dr Brown’s. the patient had high-grade T2 bladder cancer, status-post nephroureterectomy. Has recurrent disease, muscle-invasive disease in the bladder, getting neoadjuvant chemo right now and plans for cystectomy and urinary diversion. So, Ashish, I’d like you to start out the discussion. Here’s Dr Brown.

DR BROWN: She’s 55. She has T2 disease. So she had a history of high-grade T1, underwent nephroureterectomy, has a bladder recurrence with muscle-invasive disease, nonmetastatic. She’s getting currently neoadjuvant chemotherapy and is scheduled for radical cystectomy and urinary diversion.

In the setting of patients who have a solitary kidney with a recently-diagnosed muscle-invasive bladder cancer, how do you approach the use of neoadjuvant therapy? Is there a role for immunotherapy in lieu of their reduced GFR? I would also be interested to see what the panel’s opinion is on the choice of urinary diversion in solitary kidney. She’s desiring of a continent diversion, either Indiana pouch or Studer versus ileal loop. Would there be any thoughts as to concerns around a continent diversion in a patient with a solitary functional renal unit?

DR LOVE: Ashish, any thoughts about this case?

DR KAMAT: Sure, there are a lot of questions that Gordon through in there but let me address the neoadjuvant chemotherapy issue upfront. It depends on the patient’s renal function and GFR. right. Just having 1 kidney versus 2 is not what we look at. We look at what the patient’s GFR is. And if the patient can get cisplatin-based chemotherapy. And if she’s at MD Anderson, she meets the criteria for us selecting here for neoadjuvant chemotherapy, we’d certainly use cisplatin-based neoadjuvant chemotherapy. If she doesn’t meet our criteria for neoadjuvant chemotherapy, in other words if she’s what we call a lower-risk muscle-invasive bladder cancer patient, then we would not do the neoadjuvant chemotherapy.

Going to the choice of diversion, again it depends upon GFR. Our patients that have borderline GFR that elect to have a continent diversion, just have to understand that they have to be that much more careful when it comes to their renal function, diet, hydration, etc, because it does put extra stress on that renal unit to manage the urinary — the reabsorption of toxins that occur in a continent diversion. But again, if the patient has sufficient GFR, it’s not a contraindication for a continent diversion either.

DR LOVE: Final comment from Rob. Agree, disagree or in between with Ashish?

DR SVATEK: Well, Neil, we were talking about mentorship earlier, and Ashish was my mentor. So you’re not allowed to disagree with your mentors. No. So I tend to agree with everything that he’s taught me.

What a couple of comments are, we will sometimes do a 24-urine to get a more accurate assessment of function in someone like this. And I think that the other things to consider are some people with 1 kidney have better function that patients with 2, so their other comorbidities may play a role.

When we’re thinking about what type of diversion to use, sometimes it’s nice to have easy access to that upper track in somebody like this which may have pan-urothelial disease. And creating an Indiana pouch means that if she does develop a positive urine cytology, it’s going to be difficult for me to scope and see that ureter, so I’d rather have an ileal conduit if she were okay with that. But I agree that you can offer all 3 types of diversions.

It’s an interesting case. And it’s challenging. But I agree with what’s been said.