Introduction

DR LOVE: Good morning, everyone. I’m Neil Love from Research To Practice and welcome to Breakfast with the Investigators, as this morning we talk about the management of urothelial bladder cancer.

We have a great faculty today and we’re really going to make rounds with them and talk about some of the patients in their practices. As always, you have the iPads in front of you. It has all the slides. We may or may not go through all of them. There’s also a survey on the iPad. If you take that, you’ll get a lot more out of this meeting. Also, you can use the iPad to ask questions, present cases to the faculty as well and do the CME evaluation. To our many colleagues out there online watching in here today on Zoom, you have basically the same functions in the chat room, including the slides. And we are recording all the programs we’re doing here this weekend on video and audio. We know a lot of people end up listening to these programs while they drive around in their car or rake the leaves or go to the beach.

This is the 7^th of 9 meetings we’re doing here this weekend. We come here every year. We’ve been coming here for, I think, 14 years to this hotel in this room. We love this ballroom and just sort of hanging out here for the weekend. We’re working with 40 investigators this weekend. What a privilege and honor.

Tonight, we’re going to talk about breast cancer. You can imagine with that plenary session yesterday on HER2-low. It’s going to be very interesting to see how the faculty responded to that and a bunch of other data that’s coming out here. And then tomorrow morning, we’ll finish out with multiple myeloma and see whether or not our faculty is still into quadruple upfront therapy. And here’s the faculty for that.

We dedicate our work in general and our primary target audience is the general medical oncologists in community-based practice, the docs who are taking care of myeloma, CLL, lung cancer, breast cancer, everything else. And our hats off to them for keeping up-to-date. Amazingly, they feel more up-to-date now than before the pandemic because they’re getting so much online content. We were never able to simulcast our meetings here. So it’s really a great opportunity nowadays to get online content and get up-to-date.

So as I said, we’re really going to make rounds as we’ve been doing for all the breakfasts this week. We have different formats for the different meetings. Tonight, we’re going to focus on a survey of breast cancer investigators we just conducted.

Here’s where we’re heading and the way we lined up these cases. We’re going to start out talking about localized disease, non-muscle invasive, of course, just kind of coming into the medical oncologist’s purview the last couple of years, adjuvant therapy in muscle invasive disease, sequencing in metastatic disease and new strategies for the future. We were at the AUA meeting. We also did a urothelial bladder program earlier this month. So it was interesting getting the urologist’s perspective on all the things that are going on.

Current and Future Management of Localized Urothelial Bladder Cancer (UBC)

DR LOVE: So I guess one question I was curious about and, Betsy, this provocative situation of patients who actually are medically eligible for cystectomy, have non-muscle invasive disease, have BCG resistant disease and don’t want to go to a cystectomy which we know really is the only curative option in this situation. And most of the audience has not encountered that situation, but said in the right situation, they would do that. Any comments about — we’re going to talk about some other cases and some older patients often is a challenging issue. But this situation where you have a patient you think you could cure with cystectomy and they don’t — understandably, it’s a difficult procedure to go through. Any thoughts, Betsy?

DR PLIMACK: Yeah. So I think that conversation with this patient starts with we can cure you and the best way to do that is with cystectomy. And usually, you don’t have the pembrolizumab conversation until they’ve really thoughtfully declined cystectomy after understanding the risks and benefits. Pembrolizumab, I think we really need to see the long-terms results. We need it to cure people for it to be reasonable to offer in that setting. And if we’re not, I think we need to do trials to find better options, which we’re doing.

DR LOVE: And so we’re going to talk about a couple cases pretty briefly, but just to sort of give you a little sort of exposure to some of the things that come up when medical oncologists start getting involved with these non-muscle invasive situations. And, of course, Yohann, you see that history of psoriasis right away. All weekend, you can imagine the number of complications of IOs we’ve talked about already in our 7 meetings between all the different cancers. Right now, IOs are issues. But in any event, this is a younger patient. I guess would have been cystectomy eligible just like we’re talking about. What happened there?

DR LORIOT: Yeah. So this man was diagnosed with non-muscle invasive bladder cancer. He has a history of psoriasis and mild hypertension. And this patient had several high-risk factors or high-grade tumor, T1 and CIS. So a second TURBT was performed. No tumor cells. But here for this patient, we have to discuss what we have to do after the diagnosis. There are different options that we can discuss, BCG 1 year, 3 years, or upfront cystectomy given the number of high-risk that we found in this patient.

DR LOVE: Jonathan, what would you be thinking in this situation? Any trials that you have right now a patient like that could go in?

DR ROSENBERG: We actually have a trial of pembrolizumab for resected T1s, super high-risk patients where whom cystectomy would be the right option who are refusing. But it’s not that common, fortunately.

DR LOVE: So I guess he got some more BCG. Still has the disease. Then what happened? Well I guess what were you thinking at that point?

DR LORIOT: Yeah. So he’s doing well. Initially, the BCG worked well. But finally, the tumor has recurred. And in this situation, again, there’s different options to discuss. Maybe intravesical chemotherapy, cystectomy, pembro or maybe other clinical trial.

DR LOVE: I see he gets put on pembro. And maybe not a huge surprise, his psoriasis gets worse. How bad was it?

DR LORIOT: So the patient started pembro indeed. So initially, again, works well with no lesions. But at 6 months, the patient developed psoriasis and so we had to discuss whether or not we have to continue pembro here in this patient.

DR LOVE: Yeah, we had a case like this at AUA and the patient wanted to go to surgery and the dermatologic toxicity was so bad, it was actually delayed. And getting back to Betsy’s point of the only option here for cure is surgery. I guess that’s what happened with this patient.

DR LORIOT: Yeah, indeed we, of course, the pembro was stopped. The patient recovered quite soon. No lesion was found during the first 9 months. But finally, again, the tumor recurred. And finally, the patient proceeded with surgery.

DR LOVE: Right. And just to kind of get another sort of snapshot of these cases that are starting to come into oncology practice. We don’t hear too much right now in the community about cases. They’re starting to see them, but you all are seeing a lot more of these patients.

This is another patient with a dermatologic problem. I thought it was interesting. This patient was on a trial of low-dose RT, just 3-fraction with an IO, durvalumab. I guess kind of a priming abscopal type strategy?

DR PLIMACK: Yeah, that was the theory. Yeah.

DR LOVE: Wow. Really interesting. But yet, again, here you go again. We were talking Friday night in lung cancer about dermatologic issues. Heather Wakelee was saying at Stanford, they have 6 dermatologists who just deal with their patients. There are so many issues. This looks like a pretty bad rash.

DR PLIMACK: This was a bad rash. And we do have really good derm support. So we usually try to do a biopsy to diagnose, make sure it’s related to the immunotherapy. Here, it was quite obvious. The picture that’s shown is just her back, but that rash covered really her entire body sparing the face. So the good news is she did have a complete response to this investigational therapy, at least so far. She’s now on surveillance cystoscopies. But it took about 3 to 4 months of steroids with slow start, stop tapers to really resolve the rash.

DR LOVE: Really interesting, that RT priming. Jonathan, you have, again, a young patient, 55 years old. What happened there?

DR ROSENBERG: So he initially presented with CIS and eventually received BCG and was unresponsive after maintenance. But he declined cystectomy at this point and then went on to intravesical chemotherapy which ultimately did not work. And this was actually becoming a T1 tumor. He was counseled repeatedly that cystectomy was the best option. Repeatedly refused. There was some concern that maybe there was some upper tract disease, but nothing that was biopsy-proven or obvious on imaging. And so at that point, following failure of gemcitabine and docetaxel in the bladder, we moved forward with pembrolizumab after he had recurrent CIS because he, again, refused multiple times for cystectomy which we felt was the right approach. And at the first restaging after starting pembrolizumab, his cysto was negative, but his cytology was positive. He had a repeat CT urogram, all of which have been negative for the upper tract previously, but now had ureteral disease on imaging and had a ureteroscopy that showed high-grade urothelial cancer. And so based on the likelihood that this was invasive based on the imaging and the high-grade pathology, he’s getting actually neoadjuvant chemotherapy prior to upper tract surgery. He may get a cystectomy as well.

DR LOVE: I thought it was interesting that you treated him for muscle invasive disease yet actually didn’t exactly document it.

DR ROSENBERG: Yeah. So for upper tract disease, you almost never document. And there’s 2 approaches. One is the adjuvant chemotherapy approach, a la the POUT trial from the UK where they get either gem/cis or gem/carbo. And we probably overtreat some patients if you pursue a neoadjuvant approach, but you actually have 2 intact kidneys at that point and better renal function and could more likely give them cisplatin. And so we tend to pursue a neoadjuvant approach where patients we can’t get cisplatin in, we use — they get adjuvant therapy.

DR LOVE: Yohann, we presented this case to the audience of a 74-year-old man with muscle invasive disease, T2N0M0. The audience all was thinking about neoadjuvant therapy. A little bit of difference in terms of the type of neoadjuvant therapy. What are some of the situations where you don’t use neoadjuvant therapy in muscle invasive disease? And what about choice of regimen, Yohann?

DR LORIOT: So if the patient is ineligible for cisplatin-based chemotherapy, basically there’s 2 options in terms of regimens, dose-dense MVAC and cis/gem. There is a trial called VESPER reported last year that suggests that maybe MVAC is better than cis/gem. OS there are not mature. But in Europe at least, we recommend dose-dense MVAC because the level of evidence is a little bit higher. So I don’t know, Betsy, what do you think?

DR PLIMACK: We do dose-dense MVAC also. I like that it’s quick. We get them to surgery fast. We can use growth factor to get them through. But both are good options and both are in the guidelines. I think long-term follow-up of VESPER will be important to see.

DR LOVE: So, Jonathan, this is based on Betsy’s case she is about to present. This patient got neoadjuvant dose-dense MVAC, goes to surgery. No residual disease in the bladder, but a positive iliac node. The audience says adjuvant nivo. Again, right now, Jonathan, what are the situations where you’re using adjuvant IO? Is it always nivo? And what about this particular case?

DR ROSENBERG: This particular case is a patient who has platinum refractory disease essentially, in my opinion, and based on the pathology, would have been eligible for the CheckMate 274, the adjuvant trial. And therefore, I would have recommended adjuvant nivolumab. The endpoint is based on progression free — event free survival, disease free survival. We don’t have the overall survival data yet. It’s still maturing. And so there are some people who feel like we shouldn’t be doing this, but I think in a high-risk patient who is very likely to recur, it’s appropriate.

Can I make one point about the VESPER trial? I don’t believe there were any patients over 70 that were accrued onto that trial, right?

DR LORIOT: No, no there were not. Yeah.

DR ROSENBERG: And so patients in their 70’s, I find it hard to give dose-dense MVAC. I know, Betsy, you, with 3 cycles, you’ve managed to get it through in your care. But we tend to use gemcitabine/cisplatin in the older patients.

DR LOVE: So I’m just curious. You hear different projections, Yohann, for this in different situations. In general, if you’re starting, let’s say, adjuvant nivo, what’s the chance you’re going to have significant enough autoimmune toxicity that you’re going to need to use corticosteroids? The audience says somewhere between 5 and as high as 20%. You think it’s that high?

DR LORIOT: I would say it’s more or less 10%, 15%, Grade 3/4.

DR LOVE: Still pretty high.

DR LORIOT: Yeah. It’s quite high, so we have to monitor the patient because we are in the adjuvant setting, so we have to be very careful here.

DR LOVE: Absolutely. And some of these people are cured and you don’t want to kind of introduce a new problem. So, again, we’ll hear this case in a second, Jonathan, but the patient goes on adjuvant nivo and unfortunately, actually has recurrence while still on the adjuvant nivo. FGFR wild type. We asked the audience what they’d be thinking. The most common answer here is enfortumab, but quite a few people say they’d use chemo and maintenance avelumab. What do you think, Jonathan?

DR ROSENBERG: When they relapse within a year, I generally find that you don’t get a lot of milage out of platinum chemotherapy. Again, I would have used enfortumab vedotin as my first choice in this scenario if they’re FGFR3 wild type.

DR LOVE: So, again, Betsy, we’ll come back to you. In this scenario, if the patient had an FGFR alteration, the audience says erdafitinib, but some people also say enfortumab. Others, again, stick with chemo and maintenance avelumab. How would you think it through if your patient had an FGFR mutation?

DR PLIMACK: So I still go with enfortumab vedotin first. I think it has a little bit better data for a response. Their responses are a little more durable, but really, it’s just a lot easier to give. Both are toxic, but I’ve had difficulty with erdafitinib. It’s hard.

DR LOVE: Yeah, I want to hear more about that. A lot of questions from oncologists about erdafitinib and phosphorous, et cetera. We’ll talk about that in a second. But here’s the case that this was just based on. Maybe you can just sort of review how you thought through these decisions in real-life starting out with the neoadjuvant treatment.

DR PLIMACK: Sure. So this was a gentleman who presented with muscle invasive bladder cancer. We treated him with 4 cycles of dose-dense MVAC. He did have a clinical complete response on imaging and also on cystoscopy. And he really didn’t want a cystectomy. So he declined that. We put him on surveillance. We did CAT scans and cystoscopy every 3 months. He got through 2 surveillance cycles, no problem. At the third at 9 months, he had biopsy-proven recurrent disease in the bladder as well as an iliac lymph node that was enlarged on his CAT scan. So we biopsied the lymph node, re-sequenced it. Interestingly, it maintained all the same mutations as his primary bladder tumor and acquired several more. So we talked about it at Tumor Board and decided to reinduce with dose-dense MVAC since the tumor was a little different genomically. He got 3 cycles this time. Did develop peripheral neuropathy at that point. His post-neoadjuvant imaging showed a complete response, but unfortunately, on pathology, which I think is on the next slide.

DR LOVE: Right.

DR PLIMACK: Yeah, he had no residual cancer in the bladder, but that lymph node shrunk, but still had tumor in it. So he was still lymph node positive pathologically. And he went on pembrolizumab on a clinical trial we had.

DR LOVE: And how did he do on the pembrolizumab?

DR PLIMACK: He did really well on the pembrolizumab actually. He didn’t really have major side effects. But after 8 months, unfortunately, he had a scan that showed more nodal disease in a different nodal, more distant nodal chain. So we stopped adjuvant therapy and we talked about options at that point.

DR LOVE: And then what happened?

DR PLIMACK: So we decided — we recommended enfortumab vedotin. We started that. He had a little bit of a rocky course really starting at the beginning with skin toxicity. So initially, we continued to treat through it with steroid premedication. This is something we’ve been doing, dexamethasone day before, day of and day after each treatment. Remember, treatments are weekly, 3 weeks on, 1 week off. So it’s quite a bit of steroids. That did mitigate it somewhat, but ultimately, after a few cycles, 3 cycles, we got him through. The skin toxicity was really prohibitive. Interestingly, it especially caused problems with the ileal conduit because you need the adhesive sort of seal for that conduit to work to collect the urine and with his rash, that was challenging. He also had appetite issues, weight loss and loss of taste.

DR LOVE: Before we go on, Yohann, just curious of your experience with tolerability issues with enfortumab and particularly in terms of dermatologic issues, quality of life, dysgeusia. What’s your experience?

DR LORIOT: Yeah, I think EV is a good drug, well tolerated, but we have to be a little bit careful if the patient develops rash within the first cycle during the treatment, meaning that we can have serious skin effect during the first cycle. So if the patient develops rash like this patient, we have to stop the EV, treat patient with steroid, refer maybe the patient to the dermatologist. So we have, yeah, for the first cycle, we have to be careful.

DR LOVE: So a question from actually the chat room, Jonathan. And, of course, we hear this all the time. Correlation with PD-1 levels and benefit, in general, in various scenarios from adjuvant to metastatic disease with IOs. Also, other markers, TMB. Betsy was talking about NGS. What do you get out of NGS? Do you see specific mutations, Jonathan, that are helpful other than, of course, FGFR?

DR ROSENBERG: At the moment, the others are all investigational. There are some mutations that might portend better outcomes with immunotherapy, ARID1A mutations, but that isn’t a reason to select a patient. TMB is clearly predictive of outcome with immunotherapy, but there’s no cut-off and so I don’t know what’s high versus not. It’s sort of like, you know, when you see it, TMB of 20 is high, TMB of 3 is low, but what about TMB of 12? And so —

DR LOVE: According to the FDA, TMB of 12 could get you pembrolizumab. Does it change your strategy, in general, about using IOs at all?

DR ROSENBERG: To me, at the moment, it does not. And PD-L1 status for patients who are cisplatin ineligible refusing carboplatin chemotherapy, I’d check PD-L1 to determine whether or not they can get a checkpoint inhibitor. But otherwise, I try to avoid checking PD-L1.

DR LOVE: And it looks like this patient did really well once you sort of got them through the dermatologic problems. Is that the case, Betsy?

DR PLIMACK: Yeah, he did great. The good news was we had a really good scan to offer him. And it was pretty clear at this time for a treatment break. So he’s on a treatment break now and we’re hopeful.

DR LOVE: How useful is dose reduction or spreading out the doses of enfortumab in, for example, dermatologic issues and these other quality of life things?

DR PLIMACK: Yeah, that’s a great question. So we do have tools to mitigate side effects. One are steroids to mitigate, for instance, rash. But also, we do dose reduce. I think we try to get folks at full dose, but reduced dose has been effective in my practice. And, again, it’s given 3 out of every 4 weeks. So dropping doses if patients are really having trouble is something we also do. Jonathan, I don’t know, you’ve given a lot of this.

DR ROSENBERG: It’s a drug that you can hold often for long periods if they’re in response without being too panicked that they’re going to recur and progress. Early dose reduction for significant toxicities like skin toxicity and holding doses is very important. That doesn’t affect the dysgeusia all that much, unfortunately.

DR PLIMACK: Right.

DR ROSENBERG: If you’re on the drug, you have taste changes and a lot of patients lose weight. I don’t think it’s really the drug, per se, I think it’s just that they don’t like to eat because the food doesn’t taste good. So it is a concern and a quality of life issue. But the palliative benefits and the pain reduction for metastatic disease are quite impressive. And patients love the fact that it works and their tumors shrink dramatically often.

DR LOVE: Yeah. So let’s just take a quick look at some of the data that sort of relates to these decisions. And, Yohann, Betsy was referring to the longer-term follow-up that we’re seeing of using IOs in the non-muscle invasive setting. We’re still waiting for data from a bunch of other trials looking at other IOs including atezo, durva, nivolumab. Where do you see this heading long-term? Also, we’ll talk, we’ll get to adjuvant in a second. But, again, getting back to non-muscle invasive disease, where do you see things heading? We were talking about this trial looking at RT plus durva. Where do you think we’re going to land in the next couple of years on non-muscle invasive disease, Yohann?

DR LORIOT: So I think we’ll have maybe the preliminary data next year for some of these trials, maybe POTOMAC, for example. So clearly, it’s quite difficult to give pembro for the patient who had BCG resistant tumor. So I think it would be more important to give upfront immunotherapy combined with BCG, but we will see the data.

DR ROSENBERG: It’s going to be problematic though when we don’t have enough BCG with all these, you know, if the future is going to be BCG plus, how are we going to give that?

DR LOVE: Yeah, that is a problem. And here’s the adjuvant study, the CheckMate 274. There’s been a bunch of adjuvant IO trials. We were talking Friday night in non-small cell lung cancer, a big atezo study. Actually, similar disease free survival. The same kind of discussions that are going on. Hazard rate of 0.70 for this disease. Seems pretty worthwhile. What about, again, we were talking about PD-1 levels and benefit, Betsy. It looks like the hazard rate is better when you have PD-1. Is it worth giving in a patient with a PD 0 tumor?

DR PLIMACK: Yeah. I think the benefit was shown overall for the full study and that’s how it was powered. So this isn’t something we’d use for decision making. But obviously, the decision of whether or not to do adjuvant is one with a lot, where you’re really weighing pros and cons and patient value. And so I think adding the biomarker does help us have that conversation.

DR LORIOT: And maybe just to let you know that EMA approved adjuvant nivolumab only in patients with high PD-L1 expression.

DR PLIMACK: Interesting.

DR LOVE: That’s interesting because Saturday night, same thing in upper GI cancer. We were talking — in the US, it was approved regardless of PD-1 although they didn’t see much benefit. Eric Van Cutsem was there and said the same thing in Europe. Because a lot of the investigators here aren’t using it, but it is approved. Anyhow.

I know you all aren’t urologists, but we were at the AUA meeting and we were talking with the urologists about this intravesical, the pretzel, delivery system. I think right now, it’s being used with gemcitabine. It’s put in every 3 weeks. Really interesting. Also being — it’s pretty easy to put in. It’s continuous dose locally. And I’m not really sure to what extent systemically. I don’t think very much. I think this is really fascinating, combining it with a PD-1 agent. Jonathan, any thoughts? The whole idea of IO plus chemo you see throughout oncology and, again, lung cancer, standard of care first line. Kind of in a way, if you think about it, this is sort of like that, but it’s local delivery. Any thoughts about sort of this strategy? I know it’s kind of in the urology world, Jonathan, but any comments?

DR ROSENBERG: I think it’s fascinating to combine a high-dose intravesical chemotherapy with continuous delivery along with systemic chemotherapy. The question is probably, is gemcitabine the right intravesical chemotherapy to use with immunotherapy? And it’s not clear based on the metastatic disease trials combining immunotherapy with gemcitabine chemotherapy. It didn’t work so well in bladder. And so we’ll see if this — they may need a different drug in their pretzel.

DR LOVE: Actually, I think they’re looking at erdafitinib.

DR ROSENBERG: Right.

DR LOVE: It sounds really interesting.

DR ROSENBERG: And that might be really interesting based on the combination data with the FGFR inhibitors.

DR LOVE: Right. And I guess you see more FGFR in non-muscle invasive. We had a case actually, Yohann, at AUA of a patient who was on a trial of erdafitinib systemically and had a complete response in non-muscle invasive disease. Again, any thoughts about targeted therapy in the non-muscle invasive setting like erdafitinib?

DR LORIOT: The mutation, FGFR3 mutations are found in up to 50% of non-muscle invasive bladder cancers. So it could be very important to investigate this drug in this setting. Yeah.

DR LOVE: So, Jonathan, this study I guess was updated at the GU Symposium. It got a lot of attention when Dan Petrylak initially presented it. Neoadjuvant therapy with enfortumab. Any comments on this and just the general strategy of neoadjuvant or even adjuvant EV and, of course, plus IO? Everybody is really interested.

DR ROSENBERG: Neoadjuvant enfortumab, I think, is a really useful agent to be testing in cisplatin ineligible patients who go right to cystectomy. We know that the metastatic disease response rate is very high. We see here pathologic complete response rate of 36%, similar to what we might get with cisplatin. So there’s additional trials. There’s another cohort accruing neoadjuvant and adjuvant. And all the randomized trials incorporate adjuvant enfortumab, which I’m worried about toxicity for patients post-cystectomy, but we’ll see how that goes.

DR LOVE: Any particular reason you’re concerned or just the general setting post-op?

DR ROSENBERG: Cystectomy is a tough procedure and we know that about one-third of patients can’t get platinum-based chemotherapy after surgery and I imagine that number is not going to be dramatically different than with enfortumab, but we’ll see.

DR LOVE: Betsy?

DR PLIMACK: And just to add to that and this is a point Jonathan and I have discussed and he made at the podium the other day is that giving adjuvant after you’ve given the same thing neoadjuvant makes sense in almost no situation. If you got a CR to your neoadjuvant, why would you give more? You’ve gotten a CR. The bladder’s out. If you have residual disease after giving EV, why would you give more if it didn’t work in the first place? And so really, we’ve given neoadjuvant followed by cystectomy followed by observation or adjuvant, but a different agent. And so to do it with the same seems to not make sense. So we’ll see what the trials show, but we wish they were designed differently. Is that fair to say?

DR ROSENBERG: Yeah. The one thing that gives me pause is the breast pembro study where the non-responders did better even if they continued pembro than if they didn’t continue pembro. And I think that’s the one — so maybe the checkpoints might be different, but we’ll see.

DR LOVE: Right. Yeah, that’s true. You’re talking about triple-negative.

DR ROSENBERG: Right.

DR LOVE: Of course, now standard of care. We’re going to talk about that tonight. Now also, PARP, you know, patients getting PARP and an IO. It’s really an amazing time in oncology in general.

First-Line Treatment for Patients with Metastatic UBC (mUBC)

DR LOVE: So this is based on a case we’re about to see. 81-year-old patient. History of coronary artery disease, creatinine clearance of 40. Has disease recurrence after nephroureterectomy and has a CPS of 20 and an FGFR3 mutation. And, Betsy, the audience is saying they’re thinking pembro in this situation for this 81-year-old man. Any thoughts?

DR PLIMACK: Yeah. I was trying to understand this case because he had a nephroureterectomy. Is the bladder in place? Is the recurrence in the bladder? But we’re talking metastatic disease here, right?

DR LOVE: Yeah.

DR PLIMACK: Okay. Develops metastases. Usually, I would go with chemotherapy before immunotherapy first line metastatic.

DR LOVE: Maybe because he’s 81? What kind of chemo in an 81-year-old?

DR PLIMACK: So carbo/gem, I think an 81-year-old can try. Obviously, you give 1 cycle and you can see how they do. I don’t usually use an age cut-off. And, again, there are toxicities and early deaths with first line PD-1. The label has been changed accordingly. So I think we would go with carbo/gem.

DR LOVE: We’ll talk about that. And, of course, when we present a case on paper, we know that all the subtleties of evaluating an individual patient, you know, this is in general kind of what you’re thinking through. But let’s get into the real-world, so to speak. And, Yohann, this is based on your case of an 81-year-old man. What kind of condition was the patient in, incidentally?

DR LORIOT: So this patient did not receive any perioperative systemic therapy, so no adjuvant chemotherapy based on the POUT trial that we should recommend. The patient was doing well but, as you know, he had creatinine clearance of 40 mL. 81-year-old. And the patient had only retroperitoneal lymph nodes. There were no lung mets, no liver mets. So the first question is should we do anything else in terms of molecular management? So in the practice, I would say not really, but we did. And the patient had had PD-L1 expression and FGFR3 mutation which is not common. For this patient who declined chemotherapy which we should recommend, and did. The patient received actually immunotherapy, 6 cycles of atezolizumab and achieved complete response except 1 lymph node in the mediastinal.

DR LOVE: So just to be clear though, you offered chemotherapy. The patient didn’t want it. So you kind of followed Betsy’s algorithm except the patient didn’t really want to do it.

DR LORIOT: Absolutely.

DR LOVE: High PD-1, gets atezolizumab. And then, Jonathan, it sounds like there’s an oligo lack of response or — this is a progression or just didn’t respond?

DR LORIOT: Actually, response on all the lymph nodes except 1, the mediastinal.

DR LOVE: So this didn’t respond. It didn’t progress. It just didn’t respond. So, Jonathan, of course, the issue here, are you going to do local therapy to that 1 lesion not responding? How do you think that through, Jonathan? And what do you do when you have an oligo recurrence?

DR ROSENBERG: So some of this depends on timing, in my opinion. And if someone’s been on treatment for a long time and they have oligoprogression, I’ll give local therapy. If they’re within usually the first 6 months, I’m not sure it’s that worth it to give local therapy because if that lesion is not responding, there’s probably other disease. And so I use tincture of time to help me evaluate whether or not I’m going to pursue local therapy. But I do have some notable cases where patients had oligoprogression after a year or 2 on checkpoint inhibitor and you zap that 1 lesion however you want to do local therapy, surgery, radiation or ablation, and some of them are still in remission now years later.

DR LOVE: Yeah. This patient had, it looks like they really had a great response to IO. Would you say this is sort of typical of what you see or is this a much better kind of response than you typically see to IO monotherapy?

DR LORIOT: I think for the patient with low tumor burden, I would say it’s quite common. If the patient has only lymph node disease, immunotherapy does well actually. So in this patient, we continued immunotherapy with excellent tolerance for the patient, but a new CT scan showed lung mets here as you can see. So, again, the patient declined the chemotherapy. EV was not available in this setting, at least in Europe. And the patient was enrolled in a clinical trial with an FGFR inhibitor. And after 3 months, the patient achieved a complete response on lung mets.

DR LOVE: So it’s interesting the EV wasn’t available. If it had been, would you have been — was that what you would have done?

DR LORIOT: Probably, yes. Because the patient declined chemotherapy. Otherwise, chemotherapy I think is the best option to offer to this patient in this setting.

DR LOVE: Which FGFR inhibitor did the patient receive? And what happened? How did the patient tolerate it?

DR LORIOT: Erdafitinib.

DR LOVE: And what happened?

DR LORIOT: Complete response and well tolerated within the first, I would say, 4 or 5 months. And after, the patient developed some nail toxicity which is very common with this drug as you know.

DR LOVE: And what do you do about it, the nail toxicity?

DR LORIOT: The different tips, the first is to refer the patient to the dermatologist very soon. So there’s a lot of things that you can treat in the nail. There is some emollient that you can recommend to the patient.

DR LOVE: So, Betsy, what about the — we’re about to do, believe it or not, I never imagined that we’d do this, we’re doing a program on ophthalmic issues in oncology and there’s so many eye things going on, particularly with the ADCs. But erdafitinib has an issue too in terms of central serous retinopathy. What’s your experience with it? What do patients tell you, incidentally, who have it?

DR PLIMACK: So the patients don’t tell me. The ophthalmologist tells me. We do do monthly retinal exams in our patients on erdafitinib. I have treated very few patients, but most of them have gotten CSR at some point.

DR LOVE: But you look yourself with the —

DR PLIMACK: No, no. We send them to ophthalmology.

DR LOVE: Oh, you send them.

DR PLIMACK: Yeah.

DR LOVE: Right.

DR PLIMACK: Medical oncologists do a lot, but we’re not doing that in exams yet.

DR LOVE: Yeah, we don’t do that. No.

DR PLIMACK: And usually, it’s just a finding on the exam.

DR LOVE: Right.

DR PLIMACK: And I think there’s a photo of it in one of the subsequent slides. But if it doesn’t affect visual acuity, you can actually dose reduce and continue treating. But the ophthalmologist also measures acuity. And usually, the changes that the ophthalmologist measures are not perceived by the patient yet in my experience. And so we intervene before it leads to acuity issues. So it is manageable, but it’s an interesting toxicity to a new drug.

DR LOVE: Yeah. Also, the sort of psychologic issue to patients. What we hear, belantamab in myeloma has ophthalmic issues. Tisotumab just approved in cervical cancer has ophthalmic issues. And we hear that a lot of these are kind of not that hard to manage but, again, a little —

DR PLIMACK: But you need your ophthalmologist.

DR LOVE: For sure.

DR PLIMACK: Sometimes at cancer centers, you don’t have one on hand like we have derm.

DR LOVE: And it’s not that easy outside of cancer centers to get an appointment with an ophthalmologist.

DR PLIMACK: Right.

DR LOVE: So that gets to be an issue sometimes with these.

DR PLIMACK: Yeah.

DR LOVE: The myeloma drug has a black box warning, so you have to send them, et cetera. Anyhow. Jonathan, this is a question I was really curious to see what the audience had to say because there’s so much excitement about the whole idea, in general, of antibody drug conjugate with IO. It’s very exciting. But we asked the audience, there’s been such exciting data with enfortumab plus IO pembro, whether or not they would consider using it right now if they could, you know, kind of putting aside reimbursement issues. And actually, a few people in the audience have actually done it, but most would like to do it and they would do it in the right patient. I guess we can talk about kind of what the “right patient” is in a second because you did it with your patient.

Then the other thing we were curious about is whether or not they’ve combined erdafitinib plus an IO. And I’ll ask Betsy about both of these things in her own practice. And the audience, again, says that they would consider it. I’m not exactly sure what the scenario would be. So before we go on to Jonathan’s case, Betsy, any preliminary thoughts? Have you? Would you consider or use pembro or an IO plus enfortumab?

DR PLIMACK: So I don’t think we would get it reimbursed, so I don’t think I would use it off trial. Also, I think we do need to see the results of the studies. What we have seen is very encouraging. I know the definitive trial enrolled very quickly because there was so much enthusiasm for the combination. So I think it will be in the future. I think in a future program, we’ll be talking about giving it and how to give it. But right now, just in a clinical trial.

DR LOVE: Yohann, any thoughts? And also, what should we be thinking about in terms of tolerability issues? We’ve been talking about enfortumab. We’ve been talking about IO. What about when you combine them?

DR LORIOT: Probably you can expect some additive toxicity indeed. So I think the rule is to try to monitor the patient very carefully, again, because we know that EV can do some toxicity, pembro as well. So in the context of clinical trial, we have to follow the patient, once again, closely. But, yeah. The recommendation, general recommendation is to follow the patient very, very carefully.

DR LOVE: We were saying that, to me, the fall of 2021 was antibody drug conjugate time, in general, in oncology. So many things. Last night, we were talking about first line treatment of diffuse large B-cell now has an antibody drug conjugate, polatuzumab. So many interesting things going on with ADCs. So, Jonathan, how about your 71-year-old lady? What happened with her?

DR ROSENBERG: Yeah, she had a muscle invasive bladder cancer, received neoadjuvant gemcitabine/cisplatin. Didn’t tolerate it very well with renal insufficiency, cytopenias and dose reductions. And stopped after about 3 1/2 cycles. Her post-chemo CT scan looked fine, but unfortunately, her pathology was terrible with 7 out of 20 lymph nodes involved. Margins were negative. At the time, we strongly encouraged her to enroll into AMBASSADOR, pembrolizumab versus observation, but also declined that. She was kind of done. And then about a year after the end of chemotherapy, her imaging showed sclerotic lesions and lytic lesions in the spine, but no extraosseous disease anywhere else. And so she wasn’t eligible for any clinical trials. She did not have any actionable alterations.

DR LOVE: Could I just ask before you go past that? ATM, you know, has been thought about as a mutation, I don’t know what kind of exact mutation it is, but as long as we’re bringing it up, do you see DDR alterations, BRCA? And would you use a PARP inhibitor in a patient with bladder cancer?

DR ROSENBERG: Right. So complicated question. ATM is potentially a platinum sensitivity mutation. Obviously, it was not — didn’t do this lady very well. Platinum didn’t really help her. There are trials with PARP inhibitors and as single agents, they don’t seem to have activity, but in combination with checkpoint, it’s possible they do in patients with DDR alterations and homologous repair. About 20% of patients will have one of these mutations, maybe 15. And there’s ongoing research with it. I presented a trial at the GU Cancer Symposium this year of olaparib and durvalumab that showed a PFS benefit.

DR LOVE: So maybe you can kind of describe the clinical situation at this point and see how Yohann would be thinking about what to do with a patient like this. At this point, there’s bone only mets. How symptomatic was the patient?

DR ROSENBERG: I would say moderately symptomatic. Mild pain and fatigue. Her imaging didn’t show any acute need for radiation. There wasn’t really a focal spot. And my own experience and the data suggest that single agent checkpoint in patients with bone mets is suboptimal, I would say, in terms of response and palliation. And we talked a long — she would have otherwise been eligible for cohort K of EV-103 if she had measurable disease. And after a lot of discussion, we decided to proceed with EV/pembro. We were able to get compassionate use for both drugs and she was able to proceed with that.

DR LOVE: Yohann, a lot of times, we kind of say, okay put aside reimbursement because you know that’s always complicated, but just in terms of clinical science, so to speak, how would you be thinking through this clinical situation? And what do you think about the idea of sort of outside of label considering EV plus IO?

DR LORIOT: In terms of level of evidence, I think we should recommend immunotherapy here, so at least pembrolizumab. But I do agree with Jonathan. We know that immunotherapy is not doing well with bone mets. So probably in this patient, I would recommend clinical trial, maybe EV/pembro in clinical trial. Otherwise, EV because we know that EV is quite active on bone mets. Yeah.

DR LOVE: Betsy, again, would you be tempted to add an IO or are you sticking with EV?

DR PLIMACK: Yeah, I think it’s great, Jonathan, you got this for your patient. I think she would have otherwise been eligible for the trial except we couldn’t measure her response. This is someone who would be appropriate for this. But it’s rare that we can actually get that through. So I guess I would just say we can’t wait to see the Phase III data.

DR LOVE: Yeah, that’s one of the most anticipated strategies, I think, in all of GU oncology. So wow, really interesting. So the patient gets put on therapy and develops acute back pain that you deal with locally with kyphoplasty. I don’t know how often — I don’t hear too much about kyphoplasty. I hear it all the time in myeloma, but it’s interesting in this patient. We hear good stories about relief. This patient had good pain relief?

DR ROSENBERG: Yeah, she did.

DR LOVE: Did you think it was like a mechanical thing or disease progression?

DR ROSENBERG: Well at first, I thought it was disease progression, but then reviewing the images and talking with the interventional radiologists and radiation oncologists and neurosurgeons, they felt it was just mechanical. And her pain went away within a week of getting the kyphoplasty. And so we saw a lot of sclerosis of the bone lesions consistent with treatment effect and sort of a flare response almost. And her alk phos, which had been rising rapidly, declined pretty quickly back down towards normal range. I don’t think that was just from the acute fracture, I think it was probably bone disease. And her KPS went up and she felt better. And, again, you can’t measure things easily in bone.

And as a side note, the poor woman was claustrophobic and I couldn’t get her to do a PET CT or an MRI unless she was completely anesthetized which was not good to do repetitively. So she continued and actually, unfortunately, after cycle 6, developed more pelvic pain and back pain and imaging showed new disease, new pelvic disease, new epidural disease. And she got palliative RT and declined. I think it’s important even though EV/pembro looks so promising with a 73% response rate, it is not a panacea and it doesn’t work spectacularly well for everyone. The median survival on the trial was 2 years in patients who couldn’t get cisplatin-based chemotherapy. This woman did not do that well. Didn’t have any significant real toxicities to speak of. But it’s not a cure-all unfortunately either.

DR LOVE: So, Betsy, when I talk about this being kind of the year of ADCs in general oncology, I always refer to urothelial bladder cancer and tell everybody, hey, 2 ADCs for you guys.

DR PLIMACK: Yeah.

DR LOVE: You’ve got 5 lines of metastatic disease therapy. We mentioned that a couple times. Really unbelievable. We used to have nothing to talk about in bladder cancer and now we can barely get through it in an hour.

DR PLIMACK: I know.

DR LOVE: Anyhow. So my question is if the patient hadn’t deteriorated that rapidly, what would have been next for you?

DR PLIMACK: Here, this is a tough one because this is a patient with a lot of, even before rapid deterioration, a lot of symptoms, a lot of issues. She got really good drugs. What concerns me, she had plasma, cytoid and micropapillary on pathology. So this is when you’re up against a lot. I think I would, you know, best supportive care would be on the list of things we’d talk about. Sacituzumab govitecan is the ADC that you’re referring to. I think that’s hard for patients who are really weakened from disease and treatment, hard to give, but certainly an option on the list. And then you can always cycle back to other chemotherapeutics. But it’s tough at that point.

DR LOVE: Yeah, we saw some data, we’re seeing data here on saci in ER-positive breast cancer, but it has been used for a while now in triple-negative. And we hear a lot of people responding, pretty well tolerated from what we see. We’re going to talk about it tonight in our breast meeting.

So we saw some follow-up earlier at the GU meeting of the JAVELIN study. Looks like fortunately, we’ve seen this in some of the longer IOs like the locally advanced lung. Now, they’re at 5 years, the curves are still apart. So hopefully, this strategy will continue. And we talked a little bit about enfortumab. Jonathan, maybe you can go through some of the recent datasets on enfortumab and kind of how that’s sort of setting the stage for this next time.

DR ROSENBERG: Yeah, so we presented the long-term results of EV-301 showing that 30% of patients were alive at 2 years compared to 20% in patients with — in third line setting. This is the EV/pembro data I was alluding to. A 45-patient cohort with a response rate of 73% and the majority of patients had tumor reduction on imaging. It didn’t clearly matter if they were PD-L1 positive or negative. And there’s a randomized Phase II cohort that I’m hoping will be presented soon, but not at this meeting, of EV alone or EV/pembro with the intent of getting accelerated approval in the United States for the combination. So we’ll see what that data shows. And if that supports it, hopefully the FDA will approve it.

DR LOVE: Yeah, Yohann, we were talking also about erdafitinib plus IO. We saw some data at ESMO on that. Any thoughts about the strategy of combining IO with this type of targeted treatment and where you see it heading?

DR LORIOT: Yeah, I think there is good rationale to combine FGFR inhibitors and immunotherapy. And last year at ESMO, we reported the preliminary data of the Phase I/II trial combining erda and cetrelimab and showed that very good response rate, more or less 70%. This is just preliminary. Probably we will report the full set next year with PFS, duration of response. But I think at this point, it’s quite encouraging.

Later-Line Therapeutic Options for Patients with mUBC: Novel Investigational Strategies

DR LOVE: So I want to go on and talk about another case to keep sort of the rounds thing going here. And, Betsy, you have a great writeup of a case that really goes through a bunch of issues related to erdafitinib. 79-year-old former smoker, retired volunteer firefighter, motorcycle enthusiast. Sounds like kind of an interesting person. What happened?

DR PLIMACK: So he presented with hematuria, was treated with BCG. But unfortunately, he developed metastases during his BCG treatment which is uncommon and unfortunate. He was metastatic. He had actually donated one of his kidneys so he only had one kidney, but his EGFR was greater than 60. He was treated elsewhere before he got to me. PD-L1 testing was not available at that time. He got atezolizumab as first line therapy as we were doing back then. Had a nice response. Developed a new lesion. We did radiate that lesion. So this is another case of oligoprogression in the setting of response. Spine is a little easier to radiate than the mediastinum, we talked about last time. But he had a nice response to that. When he did progress, again, genomic testing was not available at that time. We had a decision point as to what to do next. And these are our options, as you were saying. We can add sacituzumab to this list now. We have a lot more than we ever did before. So those are the ones we were considering.

DR LOVE: I’ll just ask Jonathan, how would you be thinking through the case at this point?

DR ROSENBERG: I would consider probably, he was platinum naïve, platinum eligible, maybe cisplatin wouldn’t be the best thing and wouldn’t really want to put him through that necessarily in a 79-year-old, but you could consider split dosing cisplatin and gemcitabine in addition to gem/carbo. And if you really, you really could give enfortumab if you felt they were platinum —cisplatin ineligible based on data from EV-201 and an FDA approval in the US. So there are a bunch of options. But I would probably do gem — in the interest of prolonging the number of options, I would give him platinum first.

DR LOVE: So, Yohann, in general, in a patient who is eligible for both, how do you choose what comes first, enfortumab or erdafitinib?

DR LORIOT: So for this patient, I would give carbo/gem, but if your question is to —

DR LOVE: In general, yeah.

DR LORIOT: In general, I think we have to base it on the level of evidence. So I think the level of evidence is still higher for EV than erdafitinib, for example, in this setting. But for this patient who is naïve, carbo/gem. Yeah.

DR LOVE: Again, in a patient where that’s the decision, you said the evidence is better. What about your clinical experience? What do you think it the best option, in general, both in terms of efficacy and tolerability, again, erdafitinib, which comes first, erdafitinib or enfortumab?

DR LORIOT: The safety profile is totally different, of course. So it’s a matter of discussion with the patient. You have to inform the patient regarding the safety with the EV and the erdafitinib. In my experience, it’s by discussion with the patient.

DR LOVE: And so, Betsy, you did start gemcitabine, but the patient progressed. So it got to the point that we’re talking about at that point. And, of course, you saw that the patient was eligible for erdafitinib. The CPS was 0.

DR PLIMACK: Right.

DR LOVE: If it had been positive, would you be thinking differently?

DR PLIMACK: Well he already had atezolizumab first line.

DR LOVE: So that’s out either way.

DR PLIMACK: This case is unusual. This is not how things would go now.

DR LOVE: Right.

DR PLIMACK: But this is how things went over time. So no, we would not rechallenge with a CPS 0 someone who progressed on prior atezo.

DR LOVE: So at this point, where was the disease? And how symptomatic was the patient?

DR PLIMACK: So he was not symptomatic from his disease. He had had a lot of prior therapy. He was ultimately symptomatic from the chemo side effects which got better when we stopped. But his disease was mostly in the lung. We did biopsy this lung lesion. That’s where we got the FGFR positivity. And so we did start him on erdafitinib. And we started him at the 8 mg daily dose.

As you can see here from the published data, this is Arlene and Yohann’s data, that we see central serous retinopathy and hyperphosphatemia. I circled those because that is indeed what we saw with this patient pretty quickly after he started treatment.

So here’s just how we monitored his phosphorous. And this is something on erdafitinib, obviously, Yohann’s treated more patients with this, very common to have high phosphorous. We do have to measure it. There are really good instructions in the package insert. So since you won’t be able to memorize these, just go to the package insert if you have hyperphosphatemia. And so per the package insert, we started at 8 mg, held it when the phosphate got high, waited for it to resolve which it did, and restarted at 6 mg daily and it rose, but not to the level where we had to hold again.

DR LOVE: Yohann, can you give us a little texture to how you approach the issue of phosphorus? Lots of questions from oncologists about this. Do you ever use phosphate binders? Do you change their diet? Just maybe a little bit of a feel of how you do it. Half the time, people are using it for the first time.

DR LORIOT: I think it’s a mix. You have to sometimes step down the dose, to give phosphate binder, I think for most patients, I would say. The diet recommendations. So there’s a mix of recommendations. So the take home message is that you have to be trained. So it’s not an easy drug to give. So you have to be trained. And maybe just to get some advice from a clinical center that are experienced with the drug.

DR LOVE: That’s one of the things that happened these last couple years. I think our connection has improved, particularly between the community, hopefully between the community and tertiary centers. Certainly, in general, we’re much more connected. So hopefully, again, people are often using this for the first time. They hear of central serous retinopathy, Betsy. Again, not something you deal with every day in oncology.

DR PLIMACK: Right. I know. So the 2 things if you’re starting someone on erdafitinib, you do need to monitor phosphorus which you wouldn’t maybe normally do and you do need to send them to the ophthalmologist monthly. They get acuity, so visual acuity testing and a retinal exam as I was discussing before. This patient’s retinal micrograph looked really just like this. This is from the internet, but.

DR LOVE: The little collection of fluid there, right?

DR PLIMACK: Exactly. And the one thing we have had conversations with ophthalmologists who aren’t oncologically experienced, they would normally treat this with like sort of a local therapy, injections and drainage, but that’s not what you want to do. You really want to mitigate it with altering the drug because long-term, you can’t have someone getting those injections long-term. So this patient did come with this. His acuity was intact. We did, again, this was all in the same time we were holding the drug and lowering it for low phosphorus. We did the same which was effective to mitigate the CSR.

DR LOVE: So it looks like this patient responded.

DR PLIMACK: Yeah, he responded really well. He did. It was transient. It didn’t last. But it was nice. It was one of the first scans where he saw a really nice response.

DR LOVE: And what happened after that?

DR PLIMACK: So after that, he did progress. And during a treatment break, ultimately went on hospice.

DR LOVE: All right. Well I think we’re going to try to do one more case, but here’s a question. Maybe, Yohann, you can react to this. In general and, again, put aside regulatory issues and assume you could access anything you want. Someday maybe that’ll be the case. Who knows? But what would you recommend, in general, for a patient who has got an FGFR wild type metastatic disease, progressed on chemo, PD-1 antibody and enfortumab? The audience says sacituzumab govitecan. Yohann, what are you thinking?

DR LORIOT: Yeah, probably SG in this setting. We know there is no cross resistance between EV and SG. The preliminary data, there is no cross resistance. But the patient has to be fit enough to receive SG here. But generally, what I would recommend here is SG for this patient. Yeah.

DR LOVE: That’s interesting you call it SG. The breast people call it saci. I kind of like that.

DR PLIMACK: I did not know that.

DR LOVE: Yeah. Joyce O’Shaughnessy came up with that one. Anyhow. So, yeah. General oncologists have used this drug a lot in breast cancer, mainly triple-negative disease. And, Jonathan, you have a patient who actually received it. What we hear in breast cancer is more cytopenias. Not too much quality of life. I’ll be curious what you’ve been seeing here.

DR ROSENBERG: Yeah, a fair amount of cytopenias and some diarrhea and abdominal cramping. But it’s not out of the range of easily manageable for almost all patients. And quality of life is pretty decent if the diarrhea is not significant. And I find it pretty easy to give for patients except sometimes you’ll need growth factor and dose reduction in some patients. And you don’t get a ton of neutropenic fever either. So my experience has been pretty consistent with the data.

DR LOVE: This is a young patient who has metastatic disease, kind of the scenario we were talking about, status post chemo, IO and enfortumab and then gets some more chemo. And then finally, gets sacituzumab. Where do you see things, first of all, let’s hear about what happened with the patient once he started on treatment.

DR ROSENBERG: Yeah, so he did experience neutropenic fever. Was dose reduced.

DR LOVE: Did you give him growth factor upfront?

DR ROSENBERG: I did not give him growth factor upfront, but he did end up getting secondary growth factor prophylaxis. And he had a response showing increasing cavitation of his lesions after 3 cycles. And so we continued treatment. This is a gentleman that every time I’ve needed a new treatment, a new treatment was approved with the course of his disease. He’s had a long natural history. Atezolizumab was approved. He went on that. EV-201 was available. He went on that. Now sacituzumab was approved. He went on that. So he’s been a lucky guy. Unfortunately, after cycle 9 of treatment, he experienced disease progression. You can see the cavitary lesion filled in. And he’s doing well and asymptomatic. And we’re trying to figure out what to do because he has renal insufficiency and doesn’t have a trial option.

DR LOVE: Interesting. We were talking Friday night about the idea of the time capsule, you know, pushing people out with progression free survival so they can get a drug that gets approved. So many drugs are getting approved that you can keep people going for a year or 2. It’s not impossible. They’ll see another agent will be available.

DR ROSENBERG: It’s very exciting.

DR PLIMACK: Yeah.

DR LOVE: Anything else you want to say, Betsy, about your experience with sacituzumab? Again, I think most oncologists have used the drug in breast cancer, but what’s your experience with bladder cancer?

DR PLIMACK: Yeah, I think by the time we use it, there are cumulative toxicities. I don’t know if the renal insufficiency in your patient was from that. But neuropathies are common in patients who have been through this many treatments. And so they’re usually a little more frail. As Yohann said, they have to be fit to receive this. And there are side effects, GI and cytopenias, that you just have to watch for. So everything is manageable, but I think because of the space where we use SG, it’s tricky to balance risk/benefit there.

DR LOVE: So I’m just going to quickly go through. We’ve already talked about these data and you can take a look at it in the slides. We put it there for your reference for convenience. But I did want to ask about, in the final couple minutes, about a couple of new strategies that I think are interesting. Here’s some more data that, again, we put in your slide set, about erdafitinib. Again, these studies we’ve already talked about. But I wanted to ask, again, here’s the sacituzumab data. TROP2, I guess it sounds like a target that’s getting more attention, Jonathan. There’s a couple, I think, antibody drug conjugates with different payloads looking at that. What is TROP2? And where is it preferentially expressed?

DR ROSENBERG: It’s expressed primarily in tumors. And it is a cell surface antigen. And because it is restricted to malignant tissue, it is a good target for anti-cancer therapy. And sacituzumab govitecan is the first one. It incorporates SN-38, the active metabolite of irinotecan which gives this side effect profile primarily. And so when combined with immunotherapy, I would say the results were not as great as we would have hoped to see. It didn’t look that much better than sacituzumab by itself. You can argue how heavily pretreated these people were, et cetera. But this is really interesting, RC48.

DR LOVE: Yeah, that’s what I wanted to ask you about. Not to mention, HER2 is a pretty hot topic this weekend.

DR ROSENBERG: Right.

DR LOVE: Yeah, what about this?

DR ROSENBERG: So RC48 is an MMAE conjugated, antibody drug conjugate. It’s really RC48 vedotin. And the response rate in HER2 positive patients is very high, as you can see on this waterfall plot, in bladder cancer. And in combination with immunotherapy, the results are almost too good to be believed. 89% response rate or something along those lines. 70’s in some other data. So there’s many more clinical trials that we’re going to see. There’s some evidence that it has activity in HER2-low bladder cancer as well. And so this may be a very interesting and unique option. The one unfortunate thing is that it’s the same cytotoxic with the same toxicity as enfortumab vedotin. And so they may not be able to be used sequentially, unfortunately.

DR LOVE: So I guess, Yohann, the other thing, of course, at this meeting plenary is trastuzumab deruxtecan. Not just breast cancer, we were talking about it in lung cancer, HER2 mutant disease, GI cancers. Saturday night, we were talking about it in colon and upper GI. How commonly do you see HER2-positive urothelial bladder cancer? Does T-DXd work in these? Has it even been tested?

DR LORIOT: There was a trial combining nivo and the drug. And the overall response rate was more or less 35, 36%. So not so exciting to me. But as Jonathan said, I think maybe the RC48 may be much better. So we had a lot of abstract during this ASCO, at least 4. And the combination with immunotherapy was striking to me. So that’s something we have to follow very closely.

DR LOVE: Interesting. So I want to thank the faculty. Thank you for attending. Come on back tonight. We’re going to try to talk a little bit about HER2-low breast cancer and a whole bunch of other things. Have a great day. Thanks so much.

DR PLIMACK: Thank you for coming.