&reg;, which is focused on bladder cancer. In today&rsquo;s

&reg; presentation, my colleagues and I will review 4 clinical cases. We will discuss an individualized approach to treatment for each patient and will review key trial data that impact our decisions. Additional insight will be provided by Dr Thanos Papakostas during a separate interview.

I am Arlene O. Siefker-Radtke, a professor from the University of Texas MD Anderson Cancer Center in the Department of Genitourinary Medical Oncology. And I&rsquo;m very privileged today to be joined by my colleagues who are well known in the field of urothelial cancer.

We have Dr Betsy Plimack, who&rsquo;s the chief of the Division of Genitourinary Medical Oncology at Fox Chase Cancer Center in Philadelphia, Pennsylvania.

We also have Dr Tian Zhang, an assistant professor in the Division of Medical Oncology of the Department of Medicine at the Duke Cancer Institute in Durham, North Carolina.

To complete the group, we have Dr Gordon Brown, the director of Delaware Valley Urology&rsquo;s Center for Advanced Therapeutics and the program director of robotic surgery, Jefferson Health, in Stratford, New Jersey.

Thank you for joining us, and let&rsquo;s get started with our first case.

All right, Arlene. Thank you for the introduction. Welcome, everybody. I look forward to a productive dialogue over the next 90 minutes or so. Our first case today is going to be about a patient who has non-muscle invasive BCG [bacillus Calmette-Gu&eacute;rin]-refractory bladder cancer. This 74-year-old man presented to his primary physician with a chief compliant of gross hematuria. He&rsquo;s got a medical history that is significant for 20-pack years of smoking, hypertension, and coronary artery disease. In his initial evaluation, he obtained a CT [computed tomography] urogram, which revealed right bladder wall thickening, and underwent transurethral resection of a bladder tumor [TURBT], which demonstrated multifocal carcinoma in situ [CIS] on the left lateral wall.

He subsequently underwent induction BCG weekly for 6 weeks and that initial surveillance, cystoscopy at 3 months, had a negative evaluation by cystoscopy and negative cytology. Subsequently he underwent maintenance therapy, weekly 3 times, and unfortunately presented with repeat evaluation, with persistent red patchy erythema, or I should say recurrent erythema in the bladder, and a TURBT, which was positive for recurrent carcinoma in situ. So here we have a patient, 74 years old who has what would be described as BCG-refractory carcinoma in situ, the persistence of CIS or recurrence of CIS after adequate BCG therapy.

Case 1: Non-Muscle Invasive, BCG-Refractory Bladder Cancer

Thank you so much, Gordon. This really sounds like the typical case that presents to a lot of urology offices. What would you typically offer this patient?

Yes, this is something that we see commonly in our clinical practices on a day-to-day basis. Our management of this patient population has changed a little bit over the last 12 to 24 months in a couple of different aspects. 1) The limitation of BCG [bacillus Calmette-Gu&eacute;rin] supply nationally has forced us really to reevaluate and further risk stratify patients for appropriate use of BCG within our clinical practices. And to that end, we&rsquo;ve tried to relegate that use primarily to those patients who have high-risk localized disease. For example, those patients who have high-grade T1 disease or those patients who have CIS [carcinoma in situ] at the time of diagnosis, larger Ta high-grade disease at the time of diagnosis. All of those patients are preferentially given BCG, at least as a BCG induction.

The additional aspects that have changed our clinical practice here are the multitude of new therapeutic options, both on clinical trial primarily for patients with refractory BCG disease in the community. As it relates specifically to ongoing therapy for a patient like this, they&rsquo;ve obviously demonstrated progression of their disease to adequate BCG therapy.

So the question becomes, potentially, what are some of the next steps? We oftentimes look to the use of additional intravesical chemotherapies, potentially look to the use of valrubicin. We also look potentially to discussion around early cystectomy in some cases, and also look to clinical trial enrollment certainly for this patient population.

When would you consider additional BCG induction or maintenance? Never in a case like this?

Showing rapid progression of his CIS within the first 6 months really defines that patient as a BCG-refractory patient. Going on to additional BCG, if the supply was available, it potentially puts him at risk for disease progression. This is really somebody who we would consider going on to subsequent novel therapy, clinical trial enrollment, or additional intravesical options.

The challenges with maintenance BCG at this point are that the supply simply isn&rsquo;t there for us. So we&rsquo;ve had to look to other options, specifically intravesical chemotherapies, either gemcitabine alone, which we normally would deliver as 1 g of gemcitabine and then 50 cc of saline as an induction course plus a month of maintenance course. There have been some recent data published by Michael O&rsquo;Donnell, MD, looking at the combination use of gemcitabine with docetaxel in sequential fashion, similarly looking at the use of induction plus monthly maintenance. That&rsquo;s of course in the BCG-naїve setting. But those options I think become reasonable in the BCG-refractory patient with a limited supply of drug available to us.

Case 1: Treatments for NMIBC Refractory to BCG

When there&rsquo;s no clinical trial, intravesical therapy with gemcitabine, or gemcitabine/Taxol, what do you think is used most frequently or is the current standard?

I think currently the standard probably would be, based on the published data, a combination of gemcitabine and docetaxel based on Michael O&rsquo;Donnell, MD&rsquo;s literature. Historically, up until just recently, we&rsquo;ve used gemcitabine as a standard of care. I think that that paradigm has shifted now to the use of sequential therapy with gemcitabine and docetaxel in the same patient population.

So we are seeing the standard starting to change over time, moving from gemcitabine to gemcitabine/paclitaxel. But I have to ask you, in the setting of a BCG [bacillus Calmette-Gu&eacute;rin] shortage, I understand they&rsquo;re recommending only use of a third of a vial or partial vial use to allow BCG to be available for more patients. Do you think that that could have impacted this patient&rsquo;s care?

It&rsquo;s possible. The current AUA [American Urological Association] and SUO [Society of Urologic Oncology] recommendation as it relates to BCG therapy really relegates the use, as we discussed to those patients who are at highest risk of recurrence and progression of their disease over time. And those patients who have low risk or those patients who have intermediate-risk disease really should be precluded from BCG use. In the setting where we have an initial patient who has high-grade disease, whether it&rsquo;s T1 or CIS [carcinoma in situ] and they&rsquo;re BCG-naїve, they should be prioritized to undergo induction therapy. If the supply is available, we can dose reduce to one-half or one-third dose and follow-up.

There&rsquo;s no suggestion that on this patient per se that they had a dose-reduced regimen going forward. I guess if we&rsquo;re assuming they were treated in the current climate, we&rsquo;d have to assume so. However, the data would suggest that we can dose reduce and still have tumor effect as it relates to that therapy going forward. It has made us, in a practical sense, reevaluate and risk stratify these patients fairly aggressively and identify those patients up front who would best be suited to undergo BCG therapy.

What&rsquo;s helped us with that is the use of advanced cystoscopic techniques where we&rsquo;ve been able to further stage patients more appropriately, and allow patients to undergo more complete resections of their tumor at the time of their diagnosis, and potentially find multifocal disease that was previously unidentified. There are some good data out there that were recently published by Yair Lotan MD in 2019, which looked at some recommendations on the use of blue light cystoscopy in not only the diagnosis but the surveillance of these patients over time. And they recommend in those patients who have high-risk disease that they have blue light cystoscopy at 3 months, and then at 6 months, and every 6 months thereafter during the course of their surveillance.

So use of that technology has allowed us, I believe, to further maximally treat these patients up front, which obviously is the cornerstone of their therapy, and to identify previously potentially missed multifocal disease, all of which has been demonstrated in both prospective trials as well as meta-analyses to reduce recurrence risk over time. The impact on progression has not really been demonstrated in any great degree yet.

Case 1: Impact of the BCG Shortage in Bladder Cancer

With blue light, are you able to detect papillary lesions better, or is it most helpful for carcinoma in situ, which sometimes is, at least to my understanding, less easily detected on a routine cystoscopy?

It&rsquo;s actually both, Arlene. When we look at the data, there&rsquo;s a meta-analysis that was published by Dr Maximilian Burger in 2013 in the

which looked at the prospective trials, 6 of which were run and included in that meta-analysis. And they took that data and they found that white light alone misses about 24% of papillary tumors, and this is about 27% of carcinoma in situ. So the addition of blue light cystoscopy as an adjunct to white light cystoscopy dramatically increases the sensitivity of that diagnosis. And that allows us to do a more complete resection and allows us to make sure as best as possible those patients are visually NED [no evidence of disease] prior to the institution of intravesical therapy.

Also in the setting of patients who have T1 disease, for example, if we go back and do a re-resection, which we routinely do for those patients who have high-grade T1 disease, it allows us to ensure at the time that our resection is complete, again making sure maximal therapy locally has been achieved.

It sounds like the blue light cystoscopy is a real advantage. Is that used often across the United States, or is it a technology that has limitations, whether it&rsquo;s cost or access to care?

It is a technology that I think changes the way that we manage bladder care patients, potentially both in the diagnosis as well as the surveillance of this patient population. However, the widespread use of this has some challenges, frankly, with respect to the adoption of it. Specifically, the logistics of having this instilled and having these patients undergo blue light surveillance is a little bit challenging, even though it&rsquo;s FDA approved in the office setting. 2) There are upfront costs associated with it, which makes widespread adoption somewhat challenging, especially in smaller urology clinical settings. As we see this technology become more widely accessed, I think that hopefully the price points will come down and the logistics will be a little bit more efficient to allow patients to access this technology in order to appropriately diagnose and stage them.

I believe a lot of academic centers use it. I&rsquo;ve heard our urologists using blue light. How about you, Betsy, are you using it at Fox Chase Cancer Center?

Our urologists are using it at Fox Chase, and I think it&rsquo;s a tool like any other. It is helpful in certain circumstances, but it&rsquo;s not the only tool that they use when evaluating a bladder cancer patient.

I think we agree. At Duke Cancer Institute our urologists also use this in the operating room.

OK. So it sounds like the academic centers have it, but we&rsquo;re still waiting for the community urologists, due to a variety of reasons, to have access to this new technology that&rsquo;s helpful for our patients. Clearly, if you can start detecting new lesions, that might even impact how you think about previous trial end points from other trials. A trial of BCG [bacillus Calmette-Gu&eacute;rin] and BCG failures that had lower recurrence might now have a higher recurrence. Is that impacting clinical trials that are ongoing today?

The answer is yes. Ashish Kamat, MD, obviously looked at just this question. And he, with a consortium of bladder cancer experts, redefined how we consider the BCG-refractory/relapsed continuum with more contemporary definitions of specifically stage progression of disease early on. For example, those patients who had Ta high-grade disease now, within 3 months, if they were to have T1 high-grade disease, obviously that would be a BCG-refractory type patient.

So, looking back on those studies retrospectively, I think imposing that new definition is helpful in  reevaluating both our previous studies, but more importantly it allows us to level set a very well defined definition of where we&rsquo;re going for our contemporary studies and studies to be held in the future. Because now we all agree on a specific definition as it relates to progression of disease in that BCG setting. It allows us a framework in which we can work more effectively and better interpret the data as they come through.

Case 1: Use of Blue Light Cystoscopy in Bladder Cancer

Given our ability to better interpret data, I&rsquo;m sure the new and novel agents coming through the urology clinics are very exciting to the field. What do you think is going to be the next great advance in the treatment of superficial bladder cancer?

Well, I think there have been a couple of promising trials that we&rsquo;ve been engaged in, and certainly I think have been reported out on recentlyone being the KEYNOTE-057 data, which looked at the use of pembrolizumab in patients who had high-risk non-muscle invasive disease. They recently reported their data at about 15.8 months follow-up. This was a phase II single-arm trial that looked at pembrolizumab at 200 mg Q3 every 3 weeks for up to 2 years. These patients were surveilled with cystoscopy every 3 months initially, for 2 years, then every 6 months for 2 years. If they recurred then they went into a survivorship arm of that trial.

The primary end point of this trial was really to look at CR [complete response] in this patient population. Understand this was a heavily pretreated patient population. On median, these patients had had 12 rounds of BCG [bacillus Calmette-Guerin] intravesically. They recently reported data on the first arm, which was the arm looking at the combination of patients who had CIS [carcinoma in situ] plus/minus a papillary tumor. About 65% of these patients had CIS alone, roughly 25% had CIS and Ta disease, and about 10% had CIS and a T1 lesion.

And when they reported on their data, they see their complete response rates at 12 months of follow-up of about 40%. This trial was predicated based on the results from the PURE-01 trial, the neoadjuvant trial. And as we&rsquo;ve seen in other disease states in oncology, we&rsquo;re seeing some of these successes potentially move a little further, more proximal in the disease state. And the toxicity in this trial seemed to be pretty manageable, which is going to be important to us in the clinic. For the most part, these patients are asymptomatic to begin with. I think the grade 3 immune issues in this trial were about 3%, and the overall AEs [adverse events] were somewhere in about the 28% range for grade 3/4 of treatment-related AEs.

The real question becomes what&rsquo;s the durability of a treatment like this in this patient population? And we&rsquo;ve seen recurrence rates, we see about 53% of those patients still having persistent CRs at their recent report. So that holds a lot of promise in terms of potentially changing the landscape of the management of patients with high-risk superficial disease.

Do you think we&rsquo;re going to see an FDA approval of pembrolizumab based on these data, or do we have to wait for larger studies?

I think you&rsquo;re probably going to see an FDA approval of this because we juxtaposed these results to what&rsquo;s currently available for the same patient population. There&rsquo;s a paucity of treatment options, short of cystectomy, in this patient population. And it appears that based on the preliminary data we&rsquo;re seeing, that the results are potentially disease changing and paradigm changing in terms of how we approach this patient population. So I do think it will become approved, yes.

OK. So we can perhaps anticipate that in our medical oncology clinics, or do you think the urologists are going to prefer to give pembrolizumab?

I think that that&rsquo;s an interesting discussion. We know that a handful of us are giving it on trial. I think if we&rsquo;re going to choose to do this from a urology perspective, certainly outside of an academic medical center, we&rsquo;re going to have to make sure we have the infrastructure available to support that endeavor. Although, for the most part, these are well tolerated drugs with minimal toxicity profiles. The toxicities that do occur are not insignificant and can be life-threatening. So I think this is not a space that I would want to see anybody dabble in but rather have confidence in what they&rsquo;re doing. And if they&rsquo;re not going to be doing it, I would advise them to get the patient to somebody who is going to be able to do it well.

How about agents outside of immunotherapy, is there anything else coming down that&rsquo;s looking good?

There is one other exciting piece of information that was recently reported in the high-risk superficial bladder cancer space. It was the results of the INSTILADRIN trial, which was just updated. Initially, this was a trial which was reported out in 2017 by Neal Shore, MD, FACS, who looked at the use of basically an adenovirus vector that harbors recombinant human gene for interferon.

This process or concept was really built out of the bladder cancer support work that you guys are doing at MD Anderson Cancer Center. And this was a phase II trial that looked at 40 patients. Their updates to that trial were just recently delivered at the SUO [Society of Urologic Oncology] section of the AUA [American Urological Association] 2019 annual meeting. What we see there is that we have 14 patients who are complete responders on that trial. Of those, 10 were still alive and around to be evaluated at 3 years of follow-up. And 6 of those patients remained NED [no evidence of disease] or CRs out at 36 months of follow-up.

Again, that&rsquo;s compelling. That&rsquo;s something that from a urologist&rsquo;s perspective we might be a little bit more comfortable delivering on a consistent basis in the clinic, this intravesical therapy. The response rates seem to again dwarf anything that&rsquo;s available in the clinic setting to manage this high-risk patient population. So that&rsquo;s very promising. They have now just completed accrual of a phase III trial with the same therapy, again looking at primary end points of complete response in that patient population.

It sounds like we have several promising options coming through that our urologists are going to be interested in giving, and also our medical oncologists will be perhaps pulled in to help and assist, especially with pembrolizumab. Any of your thoughts? Are you getting referrals yet, Betsy or Tian, for pembrolizumab?

So far we, as a group, only really advocate giving this as part of a clinical trial. I think, Gordon, some of the points you raised are really critical to reemphasize. One is this is a curable patient population, so we have to, in my mind, be curing them with this or at least some of them, if it&rsquo;s going to be relevant and approvable and come into practice. Maybe we are. I agree, the data are encouraging, but long-term follow-up is really important, especially for that end point. So we&rsquo;ll have to see. As we can show, there are a number of trials for patients looking at immunotherapy, and I think right now our role is to populate those trials so we can learn the best combination, whether it works with BCG, in what setting, and how many rounds of BCG they need before we should switch to and achieve benefit. And the more we emphasize populating those trials, the better we&rsquo;ll be positioned to use it in the most relevant way.

I absolutely agree, Betsy. There are multiple cooperative group trials as well as industry-sponsored trials of atezolizumab, pembrolizumab, and durvalumab in this space. I think it&rsquo;s really important to populate those trials and learn from our patients. And it really highlights the multidisciplinary approach to our bladder cancer patients that we take in clinic. And so I do think we work side by side with our urologists, particularly in muscle invasive disease, but now maybe we&rsquo;ll be seeing some of our non-muscle invasive disease patients, too, going on study.

Great. I think this is a fantastic case regarding the multidisciplinary approach that we use for bladder cancer and how we&rsquo;re using this to make these advances. I encourage everyone who&rsquo;s listening, please refer your patients for these clinical trials because there are so many promising new agents being studied.

Case 1: Novel Agents in Superficial Bladder Cancer

I&rsquo;d like to move on to case number 2, which is a 68-year-old Caucasian man who was referred to urology after an evaluation for gross hematuria. As anticipated in most bladder cancer patients, he has a past history of hypertension and COPD [chronic obstructive pulmonary disease] from smoking with a 30-year smoking history. He has a cystoscopy from one of D. Brown&rsquo;s colleagues showing a nodular 8 cm mass at the left urethral orifice. And on transurethral resection, has a high-grade urothelial carcinoma invading into the muscularis propria. His PD-L1 [programmed death-ligand 1] score by CPS [combined positive score] was greater than 10.

However, on imaging, we had some unfortunate news where he had both enlarged pelvic lymph nodes and lung metastases. A bone scan was negative, but his creatinine clearance calculated by Cockcroft-Gault was about 42 mL/minute. So he&rsquo;s now been diagnosed with a metastatic bladder cancer with borderline or poor kidney function.

Case 2: Cisplatin-Ineligible Metastatic Bladder Cancer

First, I wanted to ask Gordon. We have a patient who was presenting with metastatic disease and as often happens, they often have the CT [computer tomography] scan before the diagnosis. When would you go toward the bladder to make the tissue diagnosis versus the metastases?

Well, I&rsquo;m a urologist. I would at least go toward the bladder. But in all seriousness, Arlene, I think that oftentimes the medical oncologists, especially in our system, prefer to get tissue from the metastatic site as it relates to tissue typing and genetic analysis to maximally refine their therapeutic options. However, sometimes that sample is less than adequate, or more sample is required, in which case certainly we would go and resect this patient and get as much tissue as would be required to be suitable for any analysis based on the size of the tumor.

Are you being referred patients who already have a tissue diagnosis but they just need more tissue for special stains?

Yes, we are. And some of those things, oftentimes, will bypass us that have evidence of locally advanced or metastatic disease as identified by their primary physician or somebody else initiating their work-up, and will go right to my medical oncology colleagues. However, the challenge is, as it relates to that volume of tissue, we can overcome pretty quickly from a local therapy perspective. And we can also address their local symptoms if they exist, which is another piece of this here, which I think remains to be spoken about.

Due to Dr Gordon&rsquo;s thoughtful application of cystoscopy, we had copious tissue, PD-L1 [programmed death-ligand 1]positive, no specific targetable mutations present. What do you think, Tian, what would you offer this patient?

We&rsquo;re discussing a metastatic patient now, ineligible for cisplatin based on his renal dysfunction. And so usually in this setting, I offer immunotherapy as a monotherapy. We now have 5 agents approved targeting PD-1 [programmed cell death protein 1] and PD-L1. And so the question and the label change that happened last summer really was around using PD-L1 positivity in this patient population. I think as we are seeing more from IMvigor130, the data that were presented last month at ESMO [the European Society for Medical Oncology annual meeting] really showed us that the monotherapy atezolizumab patients do better when they&rsquo;re PD-L1positive at baseline. And those patients certainly do better on the monotherapy than the PD-L1&ndash;negative. And so that really provides a framework and the data for which we saw the label change. So in this first-line cisplatin-ineligible patient, I do reach for our PD-1 inhibitors first.

What do you think, Betsy, would you agree or would you do anything different?

I agree and I wouldn&rsquo;t do anything different. I&rsquo;ll speak to a couple of scenarios, not with this patient but that which we frequently see, and one is when they come to us, they have widespread metastatic disease, and we don&rsquo;t know their PD-L1 status. So here we&rsquo;re fortunate, due to your great collaboration with urology, that it was already sent, and you have it at your initial consultation. But often then we&rsquo;re asked, should we just make our best guess and go with immunotherapy, or should we play it safe and go with chemotherapy, or should we wait? And that&rsquo;s a common challenging decision that we have. Typically, if we can wait, I do. I&rsquo;ll send tissue and try to wait so that we know and can choose immunotherapy versus chemotherapy. But in my practice, if there&rsquo;s no time, we would start with chemotherapy with gemcitabine and carboplatin.

OK. So luckily we have information first before having to treat.

But I&rsquo;m curious. What if this patient had extensive liver metastases, would that alter your chemotherapy choice or treatment choice?

I think based on the data, it shouldn&rsquo;t, right? There are no clear data that having liver metastases, patients do poorly. Again, I think this speaks to the point of where you&rsquo;re getting your biopsy though. I think in that case I would feel most comfortable treating based on PD-L1high from a liver metastasis, so that I know that the clonal evolution didn&rsquo;t deplete the PD-L1 status on the metastasis. But I&rsquo;m always more nervous treating patients with liver metastases regardless really of what we choose.

I think sometimes the location of that liver metastasis may impact my decision. If it&rsquo;s really close to the common bile duct or something that looks like it&rsquo;s starting to impinge, we may be trying to get to an earlier response, so that we avoid hyperbilirubinemia or biliary obstruction. And so in those patients, maybe we would be choosing chemotherapy first to try to get a response quicker rather than the immunotherapy.

Arlene, how do you approach liver metastases?

Well, it&rsquo;s a difficult choice at this point. Historical data have suggested the liver metastases patient doesn&rsquo;t always respond as well to an immune checkpoint inhibitor. I don&rsquo;t think we&rsquo;ve done a deep dive into the IMvigor130 data to look at all the different subsets and of course, nor should we use those to provide definitive recommendations, although we all use them to try to guide us in our choices. Because we know if we pick the wrong strategy for a patient with explosively growing disease, they may not have time to get on a better treatment. So patient selection does matter.

I don&rsquo;t know, if they had vigorously growing liver metastases, I might choose a chemotherapy regimen first, just because they grow quickly, and sometimes a single-agent immunotherapy is like holding a garden hose on a 3-alarm fire. We just can&rsquo;t generate enough of immune response to make an impact. I&rsquo;m certainly looking forward to seeing more of the IMvigor130 data to try to understand, are there groups where the benefit is greatest, node-only, which has typically had the best benefit overall from an immune checkpoint inhibitor? Or will we see in PD-L1high that it&rsquo;s still looking quite good in the setting of a liver metastases patient?

Case 2: Factors in Treating Cis-Ineligible Bladder Cancer

We&rsquo;ll have to see. If we did have to give chemotherapy, what if we didn&rsquo;t know PD-L1 [programmed death-ligand 1] status, and they&rsquo;re rapidly progressing, what chemotherapy would you choose?

I would still probably go with gemcitabine and carboplatin. The carboplatin is renally dosed, so whatever creatinine they come in with that day, you calculate their creatinine clearance and you find your carboplatin dose. So I still think that a gemcitabine-based, platinum-based and combination in that setting would be my first-line go-to.

Yes, definitely if truly CIS [cisplatin]-ineligible. I&rsquo;ll throw in 1 other caveat with this case is that the sort of labeling of this patient of cisplatin-ineligible is based on a calculated and estimated creatinine clearance. If this patient had ureteral obstruction, I would send them to Gordon for perhaps a stent placement to try to optimize renal function. And typically I will try to get a 24-hour urine creatinine clearance to really be sure a patient is cisplatin-ineligible before making these decisions. As I&rsquo;m sure we can all comment on, cisplatin-eligible patients have a whole other realm of therapy available to them. We use dose-dense MVAC [methotrexate, vinblastine sulfate, doxorubicin, cisplatin]. There&rsquo;s also gemcitabine and cisplatin, and I think for the first-line treatment those are still standard of care for patients who can get platinum, cisplatin.

Gordon puts a stent in. Creatinine clearance goes up to 47 [mL/minute], and we get Betsy&rsquo;s 24-hour urine, and she feels confident it&rsquo;s at least 47. Would you give split dose cisplatin or would you give carboplatin?

So 47 mL/minute is a tricky number. I wish you had said 50. That&rsquo;s sort of our threshold, especially in a 24-hour urine, which you typically get more points with in the 24-hour urine test than you would with the estimated. So assuming this patient, Cockcroft-Gault formula, is 42, let&rsquo;s say we get him to 50, I would definitely give platinum with split dose. And there are different ways to give the split dosing. NCCN [National Comprehensive Cancer Network] Guidelines has some chemotherapy order sets and recommendations around that. But that really allows you to give the platinum over 2 days, the same amount of hydration really to protect the kidneys, and we&rsquo;ve had success with that. That would be my approach in that setting.

OK. It is something we&rsquo;ve done at MD Anderson Cancer Center. We will use split dose cisplatin down to a GFR [glomerular filtration rate] of 40 mL/minute. And again, you have to be selective in your patients. You can&rsquo;t really give this in a patient with a diabetic nephropathy. Those are the patients whose kidney functions won&rsquo;t handle it. If the kidney is obstructed, you have to unobstruct the kidney with either a stent, or a nephrostomy tube is my preference because it does seem to do a better job of improving kidney function. But we&rsquo;ve seen some data from IMvigor130 about chemotherapy plus immunotherapy [I/O]. And will this be a game-changer? Will it start changing people&rsquo;s approaches who prefer cisplatin at split doses over carboplatin? I&rsquo;d be curious as to what you think about the chemotherapy plus I/O group of patients. And we&rsquo;ll start with Betsy.

The IMvigor130 trial is a randomized phase III trial conducted internationally. There were 3 arms. Arm A was atezolizumab plus chemotherapy. The chemotherapy was gemcitabine plus either carboplatin or cisplatin. Arm B was ATEZO [atezolizumab] monotherapy, and arm C was placebo plus that same chemotherapy. One important piece in understanding these data are that cisplatin-eligible and ineligible patients were enrolled, and the decision of whether to give CARBO [carboplatin] or cisplatin was a separate differentiator. So patients who were eligible for cisplatin didn&rsquo;t always get it. Sometimes they were given carboplatin. The reverse was generally not true. It&rsquo;s important in interpreting these data.

The baseline characteristics are typical of the patient population we see, and the end point for progression-free survival in the intent-to-treat arm comparing arm A, which is atezolizumab plus the chemotherapy, versus arm C, which is placebo plus chemotherapy, showed a progression-free survival advantage of 8.2 months for the atezolizumab plus chemotherapy arm versus 6.3 months for the chemotherapy alone arm. There are overall survival data as well, and comparisons were made between all of the different arms, which we can talk about later. But I think these data suggest that perhaps we should be thinking about combining atezolizumab with chemotherapy in the frontline setting. The key questions I think that these data raise but don&rsquo;t answer are what to do with a cisplatin-eligible patient versus cisplatin-ineligible patient.

We know carboplatin and cisplatin aren&rsquo;t the same. And so when we&rsquo;re adding atezolizumab, does that same benefit benefit the cisplatin-eligible group as the cisplatin-ineligible group? Or is it limited to one or the other? They did do a forest plot, which suggests that more of the benefit is seen in the patients who get cisplatin, again different from eligible or ineligible. But very interesting data; in my mind, don&rsquo;t quite change practice for this particular patient in your clinic right now.

Looking at the trial, where I think they said upward of nearly half of patients who were cisplatin-eligible actually got carboplatin, or it was a relatively high number. How confident do you feel in that forest plot? Do you think there could be a little bit of cherry picking going on in the cisplatin arm, or do you think we&rsquo;re seeing a real difference in the cisplatin, I/O versus carboplatin? I guess we haven&rsquo;t seen much, but what do you think?

Arlene, I think when we&rsquo;re looking at this data, 52%, as you mentioned, of the cisplatin-eligible patients actually got carboplatin, would those patients have done better overall, would their progression-free survival been longer had they received cisplatin? That&rsquo;s a key question that I think we&rsquo;re all emphasizing. What I like about the data though is that in that atezolizumab plus chemotherapy arm&hellip;13% of patients actually achieved a complete response, which is very nice to see. I think what we&rsquo;re seeing is an early rescue of stabilizing disease with the chemotherapy effect. And then as we get on into the later parts of the study where atezolizumab is given as maintenance, we&rsquo;re seeing that durable effect of treatment.

And so perhaps the combination in a subset of patients may be beneficial to rescue these early progressors, people who won&rsquo;t get on to a second-line therapy if they fail first-line. But in a disease setting where unfortunately we don&rsquo;t have a lot of refractory lines of treatment options for these patients, I&rsquo;m hesitant to use all of my active agents up front in a combination like this unless we see overall survival benefit later on.

It sounds like you&rsquo;re waiting until you see an overall survival benefit before you change your clinical practice. How about you, Betsy?

I absolutely agree. Again, if you&rsquo;re using 2 agents up front that you would normally use sequentially, there has to be a signal of overall survival, otherwise it&rsquo;s better to use them sequentially. It&rsquo;s cost-effective; in terms of adverse effects, it kind of condenses those, so I agree.

Do you think there could be any reason why giving chemotherapy with immunotherapy would be less beneficial? Do you think that chemotherapy could be impacting the immune response, and what we&rsquo;re actually seeing as the impact of maintenance treatment with immunotherapy?

I&rsquo;m really glad you asked that question. I think it&rsquo;s hard for us to ever think that more would be not as good as a single agent. It&rsquo;s not logical. But I think to be scientific we have to examine that possibility, and again that&rsquo;s where the control arms are really important for this as we take a look. Part of the issue with control arms is you can&rsquo;t always mandate a specific sequence, which is really our question. Is combination versus sequential meaningful? There were some data on subsequent therapies in IMvigor130 that were collected. Hopefully we&rsquo;ll see that summarized.

Case 2: Combination Therapy for Cis-Ineligible Bladder Cancer

Luckily, there are additional trials that have accrued looking at more of a maintenance type strategy, as well, following chemotherapy. So we will gain some important answers to this question at some point in the next few years, as soon as these trials read out.

Matt Galsky, MD, presented the chemotherapy followed by pembrolizumab maintenance trial at ASCO [the American Society of Clinical Oncology] 2019 annual meeting, and I thought the data were compellingto keep a patient in a response, use these agents sequentially more in a maintenance fashion rather than giving them all combination-wise up front.

I think 1 other point on that is chemotherapy, there&rsquo;s a limit to how much we can give before building in a break or switching to something else. Immunotherapy seems to be if it&rsquo;s working so far, we can continue it as long as it&rsquo;s tolerated. And so thinking about those differences in terms of durability of response and ability to continue therapy are important. I think this underpins how we interpret these trials we just spoke about.

I think it&rsquo;s definitely exciting what we&rsquo;ve seen with immunotherapy and the duration of response that we&rsquo;ve seen with pembrolizumab showing a median duration of response second-line of over 2 years. With nivolumab, there are similar data. There was the landmark analysis of the CheckMate 275 data showing if you have a complete remission in the metastasis second-line state, you actually did extraordinarily well. So it&rsquo;s very possible that durability and depth of response may matter. So giving chemotherapy to induce a response followed by something to maintain it, it feels a little bit like we&rsquo;re treating leukemia now, or perhaps.

The key question in that setting though, in my mind, is how long do we keep these patients on that because these immune-related adverse events can really occur any time, even years into treatment. And so there are still not enough prospective data, I think, to inform us on when we can stop therapy, particularly for those patients who have complete responses or very deep partial responses and who are 2, 3 years into treatment.

It&rsquo;s certainly very exciting. What do you think, Gordon, is it time to give this neoadjuvant?

It&rsquo;s interesting. As you know, based on Bart Grossman, MD&rsquo;s initial data, which have changed our practice patterns as it relates to management surgically for patients with muscle invasive disease, the PURE-01 trial would suggest that we&rsquo;re seeing complete pathologic responses that are superior to dose-dense MVAC [methotrexate, vinblastine sulfate, doxorubicin, cisplatin] in some cases. So it would suggest potentially that yes, this might have a role there for the appropriately well selected patient in the neoadjuvant setting. That I think is not ready for prime time obviously, but it does raise some additional intellectual questions around which patient and at what time to institute this therapy. And it has really changed the landscape for how we manage bladder cancer.

Certainly there are several clinical trials that are now open and accruing patients, studying the same idea, chemotherapy with immunotherapy as a neoadjuvant treatment to try to enhance the clinical benefit earlier in the disease space. But there are other options coming up as well. Tian, did you see any of the interesting ESMO [European Society for Medical Oncology] data on any other frontline combinations?

Well, we were really impressed by the enfortumab vedotin with pembrolizumab trial that Chris Hoimes, DO, presented, the EV-103 study, where the objective response rate was somewhere around 70% in these frontline cisplatin-ineligible patients. And disease control; if you take everyone with stable disease or better, it was about 91%, 92%. So very impressive data early on for a single cohort phase II study, so we will need to see more patients and randomized to standard of care current controls. But I think it&rsquo;s very promising for an active agent like enfortumab vedotin.

It sounds like enfortumab is going to be a player in the future. What do you think, Betsy, anything else exciting coming up through the trials?

Sure. There are other metastatic trials looking at novel agents. I think sacituzumab govitecan, I hope I said that right, IMMU-132 showed again initial impressive data in terms of response. It&rsquo;s an antibody drug conjugate targeting a different marker than enfortumab vedotin with a different linker toxin and a different toxicity profile. I think as we think about these agents, the question I&rsquo;ll be asking is how different are they from one another? If one doesn&rsquo;t work for a patient, can another one then have success or not? Kind of the same questions we were asking around the slew of PD-1 [programmed cell death protein 1] and PD-L1 [programmed death-ligand 1] inhibitors in this space when they all came at the same time. So I&rsquo;m optimistic that these are different enough that we can have multiple treatment options for patients with urothelial cancer to look to.

Yes. Maybe we can be a bit more precise about our definitions, too. So enfortumab vedotin targets Nectin-4. Antibody drug conjugate gets into the cell and acts via MMAE [monomethyl auristatin E], which targets microtubule proliferation and extension and so really helps in the cell cycle. And then as you say, sacituzumab is more TROP-2 targeting, gets in and acts as more of a irinotecan, sort of topoisomerase inhibitor. And so very different mechanisms, both by which they target the cell and then also by which they impact cell proliferation. I think we&rsquo;re going to need to learn more about these agents and the differences in urothelial expression of these antigens on the cell surface, when it gets into the cell, how much that inhibits in urothelial cells and then also in normal tissues and the off-target effects. And they seem to be quite tolerable, but are there differences in their adverse effect profiles?

Case 2: Exciting New Treatment for Cis-Ineligible Bladder Cancer

How about any I/O [immunotherapy]-I/O combinations, anything that avoids the chemotherapy and potential toxicity?

I think there&rsquo;s the DANUBE trial: durvalumab versus durvalumab and tremelimumab; eagerly awaited results we haven&rsquo;t seen yet. So that question is being asked, again, typically with I/O-I/O combination, is the toxicity more challenging to manage? I think we learned that in renal cell and melanoma. And so again, we&rsquo;re going to have to balance whatever the toxicity looks like compared to the response, durability of response. And really there I think we&rsquo;d be looking for a long-term durability, which has been seen with I/O-I/O combos in other diseases.

And the CheckMate 901 study is still ongoing. In fact, I think they just added some patient numbers to enrollment, so we still have that open at Duke Cancer Institute, and we&rsquo;re still actively enrolling patients to that study. And so that&rsquo;s IPI/NIVO [ipilimumab/nivolumab] and also [nivolumab]/chemotherapy versus chemotherapy. I think a lot to learn in this space.

I think in the future we&rsquo;ll be seeing a lot more about chemotherapy I/O combinations, I/O-I/O, antibody drug conjugates. There&rsquo;s another one that I&rsquo;ve been working on called bempegaldesleuken, which stimulates lymphocyte production using the IL-2 [interleukin-2] pathway combined with immunotherapy. So I think the community should know there are so many great options. We&rsquo;d really appreciate referral of patients so we can get them these opportunities and hopefully find 1 that&rsquo;s going to enhance this durability of response, that chemotherapy alone hasn&rsquo;t really achieved.

Case 2: I-O Therapy for Cisplatin-Ineligible Bladder Cancer

Our third case is a 53-year-old man who went to his primary care provider for a gross hematuria that had persisted for a week after Bactrim treatment. Cystoscopy showed a 2.8 cm bladder mass. And on transurethral resection of the bladder, tumor pathology showed a high-grade invasive urothelial cancer with invasion into the muscularis propria. His imaging studies were positive for metastatic urothelial carcinoma in the retroperitoneal lymph nodes.

He went on to receive 6 cycles of cisplatin and gemcitabine, and then achieved a partial response from his initial chemotherapy. However, after about 8 months his surveillance CT [computed tomography] scan showed disease progression, including 1 new liver lesion. And his molecular testing results we are lucky to have back. His PD-L1 [programmed death-ligand 1] IHC [immunohistochemistry] was at 0%, but his

was positive for a mutation at S249C, and that was done by a RT-PCR [reverse transcription polymerase chain reaction] assay.

His ECOG [Eastern Cooperative Oncology Group] performance status is excellent, it&rsquo;s at 1; and his estimated glomerular filtration rate is 56; he also has adequate s hematologic and hepatic parameters.

Case 3: Relapsed Muscle-Invasive Bladder Cancer, FGFR3+

I&rsquo;d like to ask Gordon, is there anything else that you think we should look into for this patient before we move on to treatment?

No. From a urology perspective, I think he&rsquo;s been actually fairly well evaluated. He already has evidence of metastatic disease. As long as we have adequate tissue to interrogate as it relates to molecular marker evaluation, which has been done, and his local symptoms are controlled, I think we would not have much more to intervene with at this point for him.

Right. So moving on to treatment. We now have someone who&rsquo;s failed platinum-based chemotherapy with progressive disease, and we have a detectable mutation, but PD-L1 [programmed death-ligand 1]low. However, immunotherapy does not require presence of PD-L1 to be tested in the second-line setting. I&rsquo;m curious, Betsy, what would you recommend as the next line of treatment for this case?

mutation is very tantalizing. We now have a targeted therapy, erdafitinib, that targets FGFR. The response rates are impressive. But at the same time immunotherapy, as we just discussed, offers a possibility of potentially adverse-effect-free, potentially durable response and survival.

So do you go with the agent that&rsquo;s more likely to achieve a response based on the target being there? Or do you take a chance with immunotherapy where the target is not there, although again, not required in the second-line space, and we have seen responses in the second-line in PD-L1negative patients, going for a better quality of life and response?

And here&rsquo;s where I would really have a discussion with the patient I think and ask about their priorities. Also, informing this would be any threatening lesions or impending disease-related symptomatology that I see coming in the short term that would lead me toward erdafitinib. But I would say it&rsquo;s great to have both options. Again, it&rsquo;s not either/or necessarily. It&rsquo;s which one to try next usually.

I heard you say, if there was something threatening, I&rsquo;d take that to mean rapidly progressive disease or a lot of symptoms, would that cause you to choose erdafitinib versus immunotherapy?

I think it would. I think the response rate percentage-wise is higher there. The patient does have this alteration, so we know they&rsquo;re a candidate for it. And again, if it&rsquo;s not tolerated, we can dose adjust or dose reduce to get it to be tolerated more long term, and we&rsquo;ll always have immunotherapy as an option.

And I&rsquo;ll be honest, that has been my preference with the work I&rsquo;ve done on erdafitiniband for full disclosure, I was involved in that trial. But I have seen dramatic responses, even in rapidly growing liver metastases, with symptomatology improving within 1 to 2 weeks of starting therapy. So one thing that erdafitinib does have for that rapidly progressive patient, it does have that potential to improve symptoms.

That&rsquo;s really why we want this, the molecular testing, early, right? One thing I&rsquo;ve been stressing with our pathology department, with urology is in that high-risk patient, let&rsquo;s screen them early, let&rsquo;s get that molecular information so that if this patient becomes metastatic or we&rsquo;re dealing with a platinum-refractory patient, we have that information. And if this

mutation or translocation is actually driving their tumor, then these patients are actually less likely to respond to immunotherapy and more likely to respond to our erdafitinib, new standard of care for these patients.

Now in the trial that you presented nicely at ASCO [American Society of Clinical Oncology 2018 annual meeting], only 5% of these patients had a previous response to immunotherapy; whereas 59% of them responded to erdafitinib in this very refractory setting. So I think that the earlier we get the molecular testing, the earlier we would have our ducks in a row to know what next to treat the patient with.

Case 3: Treatment for FGFR3+ Bladder Cancer

When are you testing? Are you waiting for progressive metastases, first-line mets [metastases], earlier? What do you prefer?

As they are getting their cystectomyafter muscle-invasive disease we&rsquo;ve given them neoadjuvant chemotherapy and the surgeon, Dr Gordon&rsquo;s colleague, has taken out their bladder&mdash;I&rsquo;m sending the high-risk patients right at that point. So as we&rsquo;re thinking about adjuvant trials in that setting, I&rsquo;m also getting their molecular testing so that if and when they do recur, I have that information to drive the next decision making.

And if we&rsquo;re not seeing them until that metastatic point, then if I&rsquo;m seeing them with a new diagnosis of either de novo or recurrent metastatic disease, then I&rsquo;m grabbing the archival tissue and sending it off at that first office visit.

When you say &ldquo;high risk&rdquo; following surgery, what would you define as high risk when molecular testing is indicated?

I think of T4 disease, for example. And a lot of our women with vaginal or uterine involvement, I think of lymph node involvement, right? A couple of lymph nodes at the time of surgery is micro-metastatic disease, in my mind, and we really need to send that tissue off quickly.

OK. For node-positive or T4a or T4b tumors, you would do molecular testing right away without waiting for relapse.

I think we are moving toward that. The one issue that gives me pause, Bishoy Faltas, MD, published really beautiful data on clonal evolution of bladder cancer, and it doesn&rsquo;t stay the same. There&rsquo;s reason to believe that as disease progresses through years of therapy, or through the metastatic process, that the marker has changed. And so part of me always would wonder if we&rsquo;re using the bladder that&rsquo;s out of the patient, are we really getting information that&rsquo;s relevant to the tumor that&rsquo;s in the patient, which is what we want to treat?

So I&rsquo;ve been trying to time it where I do it right before I think I&rsquo;m going to need it, like one line of therapy before I think I&rsquo;m going to need it. In the case of a patient who got platinum chemotherapy and then immunotherapy, probably before the immunotherapy, we would send it off to be prepared. But it&rsquo;s tricky because I think probably in a perfect world we would be able to quickly biopsy the metastatic lesion right before making a treatment decision and have that information in a few days. We&rsquo;re not quite there yet. And so it&rsquo;s sort of a balance between timing and delaying therapy versus getting the most relevant information, which I do believe is probably a metastatic site at the time of initiation of erdafitinib.

I absolutely agree. And the only caveat is in my metastatic lesions, sometimes we don&rsquo;t get enough tissue for Foundation Medicine or Caris Life Sciences next-generation testing on the tissue itself. Sometimes we&rsquo;ve been depending on circulating tumor DNA tests, for example, to try to pick up on these rare allele frequency mutations. Sometimes it picks it up, other times it doesn&rsquo;t. I think the tissue is still gold standard if we can get enough of it.

How are we doing liquid biopsies in patients?

I have started to do them in patients who don&rsquo;t have amenable biopsy-able lesions. I would preferentially lean on those results again over a remote cystectomy sample, for instance. But it&rsquo;s early days and I think we don&rsquo;t know exactly how to interpret that. Or, more importantly to me, whether we&rsquo;re missing an

mutation in a patient who could benefit from erdafitinib; that would make me a little bit uneasy.

That&rsquo;s an interesting point that you raised. I don&rsquo;t know if you&rsquo;re aware, but there was some liquid biopsy data presented from the erdafitinib trial. Now the erdafitinib trial itself required tissue confirmation. So all patients enrolled had the mutation detected in tissue, and this was mostly archival tissue.

The trial also collected tumor from doing the liquid biopsy, looking for circulating free DNA, and Ademi Santiago-Walker, MD at GU ASCO [the Genitourinary Cancers Symposium, American Society of Clinical Oncology], I think it was this last year or maybe the year before since time flies, she looked at the liquid biopsies. And when she detected the presence of the mutation and the circulating free DNA component, the response rate was actually over, I think it was over 60% of patients had a response, which speaks to that tumor heterogeneity that you were referring to, with having to be present to achieve the benefit.

But intriguingly, even when she couldn&rsquo;t detect it, and again, these were patients preselected by archival tissue, the response rate was still around 30%. So that tells me there&rsquo;s heterogeneity, but there are also limitations in the assay where we still cannot detect, or I&rsquo;m guessing we still cannot detect, a very small amount of active disease.

So I think circulating DNA is certainly a promising strategy. Archival tissue remains the gold standard. We&rsquo;re testing it earlier now rather than later, and the trial did allow people to have it tested at any point prior to needing therapy, so they could easily sequence on to their next line. But I&rsquo;m curious in the urology setting. Are you doing any mutation testing or testing any of the tissues in superficial or even neoadjuvant patients?

We&rsquo;ve tried to make it standard operating protocol, quite honesty, with our pathology department at the time of diagnosis. That, to be honest, has been met with a little resistance because of some of the infrastructure demands, etcetera. So we&rsquo;ve been trying to be selective in whom we request that analysis for. I think you&rsquo;re absolutely correct, in those patients who have node-positive disease at time of cystectomy, those patients who have T4 disease. Especially if you&rsquo;re looking to accrue them to a clinical trial in the adjuvant setting, those patients are ripe for testing at that point.

In the earlier stage of the disease and trying to risk stratify who may best benefit either from trial inclusion, or from off-label kind of indications and use of that, then the question really becomes, we only can go back to the insurance well so many times, to be quite honest with you, from a practical perspective, right?

So if it&rsquo;s really going to make a difference I try to get them on trial preferentially because all of their costs are going to be covered by the trial, and if they required additional testing as their disease evolved, should it, then we can obtain analysis at that point, based on their current insurance. The logistics are a little bit different in terms of disease state, whether they&rsquo;re on trial or off trial, in terms of how we utilize it.

Case 3: Molecular Testing in Bladder Cancer

I see we&rsquo;re moving even earlier in the disease space. And how do you feel about using FGFR inhibitors earlier? I know there are different frequencies where it&rsquo;s detected across disease state.

Yes. I believe it&rsquo;s detecting up to 70% basically of patients who have bladder cancer. I think it will naturally evolve into a trial in that space. The questions really become toxicity versus benefit, as it will with all these therapies earlier on and being able to avoid radical cystectomy in that high-risk patient population.

I think that that is compelling that you published, and I think that if the responses continue to show the similar responses in a superficial population with less toxicity potentially, then it would be a very reasonable approach in patients with high-risk non-muscle-based disease.

OK. So maybe a role in muscle-invasive disease. How about in urothelial tumors of different sites? Do you see any differences in mutation frequency, even in metastatic settings? Betsy?

Different sites like upper tract versus lower tract?

I think there have been a lot of studies looking at that. They&rsquo;re powered somewhat but not comprehensively in my mind. I think while there may be a propensity to a different mutational pattern in one versus the other, we&rsquo;re still in the clinic faced with defining that particular patient and determining what makes the most sense.

There&rsquo;s actually an interesting adjuvant study that&rsquo;s led by Monty Pal, MD, and others looking at one of the FGFR inhibitors, infigratinib, for upper tract disease. And the thought is if we&rsquo;re seeing more

mutations in the upper tract, then maybe these patients benefit more from adjuvant therapy early on as well. So that is an ongoing phase III, I think it&rsquo;s randomized to placebo, trial for patients with

mutated or translocated upper tract urothelial cancers.

Case 3: Mutational Patterns in Bladder Cancer

I think one of the issues in the adjuvant space that always comes up is toxicity. And the balance between toxicity and an efficacy that you can&rsquo;t measure in real time in the adjuvant setting really becomes a key conundrum in the clinic. Arlene, I know you have probably more experience than anyone managing toxicity to erdafitinib. What recommendations do you have for clinicians using it for the first time?

Well, when you look at the toxicity, there seems to be early effects, and then the cumulative effects, like you see with other TKIs [tyrosine kinase inhibitors], including the hand-foot syndrome. As far as the early effects, we do see hyperphosphatemia, but we actually increase the dose pushing to a level of hyperphosphatemia, because there was an early sense that this might contribute to the response, or benefit from treatment. And that&rsquo;s why erdafitinib has this up-titration schema where it used a phosphorous level of 5.5 on day 15. And if it was less than that, you went up from 8 to 9 mg dosing.

Now despite this up-titration, we don&rsquo;t see long-term phosphorous toxicity. And it&rsquo;s thought because there are homeostatic mechanisms that occur using continuous dosing that then allows the kidney to excrete more phosphorous. So we haven&rsquo;t needed to use, at least in my experience I haven&rsquo;t need to use, as much of the phosphate binding agents like a sevelamer, whereas other trials have utilized more. And perhaps it&rsquo;s a difference in schedule. When you give it intermittently, the homeostatic mechanisms allowing phosphorous excretion may not necessarily occur, or occur to the same degree, perhaps.

But we do see these long-term effects, we do see in patients who are receiving treatment, they get a hand-food syndrome, peeling of the skin, and paronychias. And that&rsquo;s been one of the most frequent causes of holding the drug, at least in my patients. And the patient that I still have on treatment today, more than 3 years on therapy, about every 3 months he requires a 2-to-3-week off period to allow hand healing to occur. And this is despite doing a lot of preventive maintenance to the hands. I tell them, baby your hands, use hand creams, especially the emollient cream.

Living in Texas, several of my patients found that when they were waterproofing their boots with mink oil that you can buy in a sports store, that that was working very well on their hands. And so they buy a $6 tin of mink oil. Mink oil, if you buy it as a beauty product for women, it can be $100 an ounce. So much cheaper when you buy it to condition your cowboy boots or baseball gloves. But the mink actually has, when I looked up the properties of mink oil, it says that it most closely approximates human sebum.

So it might be closer to humans, and then mink also, they&rsquo;re water animals, so perhaps some water protective effect in addition to the water protection for leather. I had several patients using the mink oil that they use on their cowboy boots, which actually seemed to have helped very well.

Now of course the one that everyone worries about is central serous retinopathy, and we&rsquo;ll hear more about that from our esteemed ophthalmologist who will be able to tell us more about that process.

When we look at central serous retinopathy, it&rsquo;s thought to be a potential class effect through inhibitors of the MAP kinase pathway. It&rsquo;s been observed with other inhibitors of MAP kinase as well. We did monitor for it for in these patients by doing baseline ophthalmology scans, and ophthalmology visits. And then we did Amsler grid testing looking for wavy lines because anything that might disrupt your retina would cause a bit of visual changes, or blurry vision. And then if a patient ever reported a wavy line, or a blurred vision or change in vision, we immediately held therapy and sent them to ophthalmology to make a diagnosis.

There were I believe only 3 patients who actually discontinued for central serous retinopathy. And in the patients I had who developed it, I was able to resume treatment in most of them. The 1 patient we didn&rsquo;t, it was a patient choice. He went on to alternate therapy and was having difficulty coming back and forth to Houston. So it was reversible, it did appear tolerable, it didn&rsquo;t result in any long-term vision damage. Now of course, when we treat thousands of patients, we&rsquo;ll have to see how that bears out, and that&rsquo;s why there&rsquo;s such close monitoring recommend currently by the FDA for

So I would say it would be good to have your ophthalmologist added to your Christmas basket list, because you&rsquo;ll probably be communicating with him before starting patients on treatment with erdafitinib.

Case 3: FGFR-Targeted Therapy Adverse Events in Bladder Cancer

I&rsquo;d like to ask a few more questions. Have any of used erdafitinib, or any of the other FGF receptor inhibitors?

Yes, we&rsquo;ve had other FGFR inhibitors on trial. And then also I&rsquo;ve used erdafitinib as part of the expanded access protocol early on, and then now as standard of care. So I have a handful of patients. We&rsquo;ve been dealing with the nail bed changes, with the rashes. And as you say, taking some time off, and then going back to our small molecule inhibitor types of dosing schedules, we take a 2-weeks-on, 1-week-off approach for some of these patients who have really significant toxicities despite dose reduction. And then also paying really close attention to baseline ophthalmology scans and then periodic follow-ups.

I&rsquo;ve also noticed some dry mouth, stomatitis, mouth ulcers that also occur. Taste changes. My patients will say, &ldquo;You know, food just tastes off, and may have a metallic taste, or taste very different than I&rsquo;m used to.&rdquo; So we&rsquo;re dealing with getting dietitians into the clinic at their consult visits, and making sure that we&rsquo;re keeping up with their nutrition as well.

Great. And I know some of the trials that are ongoing, some of them rely on the presence of mutation, but some are using other strategies, including amplification or overexpression of

. Betsy, what are your thoughts about the use in non-

I think it&rsquo;s a pretty rare condition. We had the AstraZeneca FGFR inhibitor years ago in phase I, and I think we screened 62 patients to treat 2, and this was across tumor type. So prevalence I think will be an issue if looking at that. I think scientifically it makes sense, if you&rsquo;re overexpressing the target, to then hit the target. But I&rsquo;m not sure it will be clinically relevant until we can really find enough of those patients.

Well you know at ESMO [the European Society for Medical Oncology 2019 annual meeting], the BISCAY data came out as well, and specifically regarding the population with

-positive mutations treated with this AZD4547 drug that targets FGFRthere were 20% objective responses; I think it&rsquo;s pretty comparable to other FGFR agents we&rsquo;ve seen. I don&rsquo;t like to use

amplification on its own. Mostly from other data I&rsquo;ve seen that the amplification patients don&rsquo;t necessary respond quite as well as the patients who have the true driver mutations, or translocations that are driving tumor proliferation.

We saw in the BISCAY data a response rate probably about half what was achieved with erdafitinib. What do you think about any of the other FGF receptor inhibitors? Are there any others that are promising?

I think erdafitinib is the one to use right now. It&rsquo;s FDA approved. It&rsquo;s one we can use in the clinic, we have the most data on it. There are more trials cooking that will inform us better. And I think the prevalence of the mutation in the population that we&rsquo;re using it in right now, metastatic, has been defined. So I think until we see something significantly better than erdafitinib, it&rsquo;s something worth investigating in clinical trials. But I would agree with you. I don&rsquo;t think the AZD4757 has sort of met that bar that&rsquo;s been set by erdafitinib.

So perhaps a lower bar with some of the previous or early inhibitors that were given whether it&rsquo;s intermittent scheduling or just inhibitory concentrations that weren&rsquo;t quite as optimized, may make a difference. So not all FGF receptor inhibitors are created equal at the moment.

And any thoughts about the ideas of combining it with an immune checkpoint inhibitor?

We also saw data from the BISCAY trial combining the AZD4547 FGFR inhibitor with durvalumab. Certainly we saw more disease stability in patients who were treated with the combinations than with the FGFR inhibitor alone. Some more durable effects. The progression-free survival, for example, was 19% at 6 months, and then also for 1-year overall survival, that rate was 47%.

So I think it&rsquo;s promising in combination, and certainly active therapies in an active population where it&rsquo;s a target, hopefully will improve overall efficacy. We&rsquo;re looking at this in a less controlled population where it&rsquo;s still hypothesis generating and doesn&rsquo;t change my current standard of care, which is an FGFR inhibition alone. I also think that when we&rsquo;re talking about these combinations, we also need to be careful of any overlapping toxicities, and trying to tease out which drug is responsible for the adverse effects that we&rsquo;re seeing.

I think the caveat we talked about with the IMvigor130 data holds true here. I would rather give these in sequence to achieve the same results than give them together with overlapping toxicity to achieve the same results. So until we have a sense that we&rsquo;re helping people live longer or really denting the disease to a greater extent with combination versus sequential, it&rsquo;s nice to have multiple options for patients along the way, especially as their disease evolves both clinically and molecularly, as we talked about.

It sounds like we really need for that combination to meet the scientific rationale that it&rsquo;s, you can take an immunologically cold tumor and really warm it up to the immune system and knock it out of the park with a good survival benefit or dramatic response before we&rsquo;d be willing to move this forward in all patients in the clinic.

I would agree, and I don&rsquo;t think we&rsquo;re quite seeing that with the BISCAY data. The numbers are small, but I didn&rsquo;t quite see it in those data.

OK, so the first data not looking quite as good, although Tom Powles, MD, sort of indicated at his presentation that maybe the AstraZeneca compound wasn&rsquo;t quite as good at hitting the target compared to&hellip;.

I think the single-agent data support that hypothesis.

Some of the other agents. We&rsquo;ll be looking forward to additional trials coming down the road showing, does it make sense to give it in both an amplified and nonmutant state? And does it make sense to combine it in a thoughtful fashion, or is it even a thoughtful fashion, to combine it with immunotherapy? So please, I would again ask the listeners, if you have a patient with an

-altered tumor, we have lots of great trials for them. So always consider clinical trials in this space.

Case 3: Experience With FGFR-Targeted Therapies in Bladder Cancer

For our last case I&rsquo;m pleased to have Betsy Plimack present a patient with metastatic urothelial cancer that unfortunately has recurred.

This is a case of a 78-year-old man with some comorbidities. He had CHF [congestive heart failure] and chronic kidney disease, and he presented with a left upper tract urothelial carcinoma of the renal pelvis. This was resected surgically and he was set on a surveillance protocol. He had imaging per guidelines, but unfortunately 3 years later, now age 81, he developed metastatic disease to the lung, and this was biopsy-proven. At the same time, he had a concurrent non-muscle invasive recurrence in the bladder. His creatinine was 2.7 mg/dL and his Eastern Cooperative Oncology Group performance status was 1. He was felt to be cisplatin ineligible, and this was before the FDA label restriction, he was initiated on pembrolizumab.

He had an initial response to pembrolizumab that was durable, but after 2-1/2 years, he had progression with new lung lesions. At this time, he was initiated on enfortumab vedotin, also on a clinical trial. And we noticed an initial immediate response in his target lesions in the lung. However, in the 6th to 7th month he started mentioning neuropathy, and by the 8th month it was clear to us in the clinic that this neuropathy had become debilitating, and so we held the drug.

His neuropathy unfortunately did not improve, and he was then on a treatment break. And after 6 months of treatment breaks, his imaging did show progression in the lung.

So the question is what to do at this juncture. I will add that a fresh biopsy for

status was felt to be too high-risk due to the location and small size of his lung metastases. He did have non-muscle disease in the bladder, which was potentially accessible, but his primary upper tract tumor was quite remote at this point, now 4 years.

Case 4: MUC With Non-Muscle Invasive Recurrence

It sounds like this is one of these challenging real-world cases that we&rsquo;re starting to see more with clinical trials, patients who actually haven&rsquo;t received chemotherapy. Now he has neuropathy as well though, from the enfortumab vedotin. I guess I&rsquo;ll ask you, Tian, any thoughts as to what you would do for this patient?

Bladder Cancer