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Sam Chang: Hi. My name is Sam Chang. I'm a urologist in Nashville, Tennessee, at Vanderbilt University Medical Center, and we are very, very fortunate to have Doctor Amanda Nizam, who is an assistant professor at the Cleveland Clinic. I guess the Cleveland Clinic, that's all we call it. She is a medical oncologist and assistant professor there, and I would say her middle name is “superstar.” That's how I describe her.

We're at ASCO GU 2025, and she gave a presentation looking at actually the real-world first-line therapies and side effects associated with that in locally advanced and metastatic urothelial carcinoma. So we've asked her today to give us a summary of that presentation. And we look very, very much forward to it.

So, Amanda, thank you so much for spending some time with us. And we look forward to your thoughts and your data that you've collected from the [Flatiron]. I'm not-- or Flatiron. I'm not sure.

Amanda Nizam: Flatiron, yes.

Sam Chang: So tell us a little bit about that data set, and then what your findings were.

Amanda Nizam: Yes. So thank you, Doctor Chang, for having me. And, as always--

Sam Chang: We'll stop right there, Sam.

Amanda Nizam: Thank you, Sam, for having me. Always a pleasure to join you today to discuss all the exciting science going on in the genitourinary oncology field.

This study that we looked at—we looked at contemporary first-line treatment regimens used in locally advanced and metastatic urothelial carcinoma, using the Flatiron de-identified database, which looks at real-world data, large data sets using natural machine language processing to abstract unstructured data such as those for toxicity. As you know, those are not codified very well in a structured format in medical records.

So that is what we used for this, to identify about 5,300 patients.

Sam Chang: So more than 5,000 patients?

Amanda Nizam: More than 5,000 patients, diagnosed and initiated first-line treatment for locally advanced or metastatic urothelial carcinoma between January 2016 and October 2023. We followed those patients from the date of treatment initiation of first-line therapy to the earliest of 90 days, which was either the last dose of the first-line regimen, or date of subsequent therapy (next treatment), or death.

In addition to looking at crude incidence, we also adjusted for time on treatment, which is very important when you’re looking at toxicities.

Sam Chang: Over time as possible side effects start showing up.

Amanda Nizam: Exactly. So we adjusted for crude incidence and also time per 1,000 patient-months on treatment.

Sam Chang: OK. So what were the key findings in terms of, I guess, different regimens—obviously would have different side-effect profiles and concerns? What do you think are the highlights when you looked at that real-world data? Because I think, for clinicians, that really still carries the most weight: “OK, we have trial patients, and they have a certain degree of... sometimes we overread, sometimes we underread, patients are trying to stay on trial.” Tell us what you found.

Amanda Nizam: Yeah. So, big picture—why did we examine this? Because we've had a very exciting time in urothelial cancer. There's been a lot of different therapies that have come about. And as you mentioned, looking at patients’ safety profiles of different regimens can help guide treatment decision making, especially as we look at it patient by patient, because every patient has different comorbidities, especially in the real world outside of clinical trial settings.

So we examined six different regimens. We looked at enfortumab vedotin plus pembrolizumab, which is the most contemporary approved regimen. And then we looked at single-agent immunotherapy, so atezolizumab and pembrolizumab—since those were previously approved in the first-line setting. And then we also looked at cisplatin and carboplatin, with and without avelumab maintenance therapy.

So we have basically a seven-year period that we looked at, and those are the regimens that patients were started on. The reason to look at this, again, was not to do a head-to-head comparison, but to look at patients in the real world and see the profiles that they were exhibiting with each different regimen, see if there were major differences that would help guide perhaps clinicians in choosing treatments or—

Sam Chang: As they counsel patients.

Amanda Nizam: Exactly.

Sam Chang: Because patients will say, “Well, am I going to get nauseated all the time? Is my hair going to fall out?” All these different things, because obviously efficacy is important, but for so many of our patients, the quality of life and the concerns regarding certain side effects may impact others differently. So great.

Amanda Nizam: Exactly, yeah.

Sam Chang: As you go through, let’s look at probably the hottest one, the most recent: when you look at the combination of EV and pembro, what kind did you find there?

Amanda Nizam: Yeah. So, interestingly, overall in the overall cohort we looked at—before we stratified by those six different regimens—fatigue was the most common, about 71% of patients. Anemia, 48% of patients, and nausea, 48% of patients, and those are crude incidence rates. When we adjusted for time on treatment, the relative rates of some treatment-emergent adverse events were different.

So it’s probably a more accurate way to look at the incidence by taking into account the time on treatment. So interestingly, when you look at the EV-302 reported safety from the trial, and then the enfortumab vedotin plus pembrolizumab cohort in our study, I do want to caution that it was only about 198 patients in our study.

Sam Chang: So, obviously, it makes sense.

Amanda Nizam: Because it’s the most—

Sam Chang: That’s the most recent one.

Amanda Nizam: —recently approved, exactly.

Sam Chang: So 5,000 plus patients, a couple hundred that are on this current regimen, but obviously, I don’t want to say the most exciting, but probably the one that’s garnering the most attention these days. What did you find there then?

Amanda Nizam: Yeah. So interestingly, if you look at the crude incidence rates and also the treatment-adjusted rates for time on treatment, I would say they were greater than what we saw reported in the clinical trials specifically for EV plus pembrolizumab. Interestingly, in the real world, hyperglycemia and peripheral neuropathy were, I feel, underreported. And we think they are underreported because, especially grade 1, even when you get up to grade 2 neuropathy, they can be very hard to assess and report outside of a clinical trial setting. Oftentimes, those symptoms can be vague, and they're harder to measure. So we feel that those were underreported.

Sam Chang: And hard to identify. Exactly.

Amanda Nizam: Exactly. But again, small cohort since this was recently approved. But in general, big themes: we saw obviously more myelosuppression with the cytotoxic chemotherapies—the platinum-based regimens—nausea. And then with enfortumab vedotin plus pembrolizumab, we see more unique toxicities like the rash, diarrhea, and weight loss as well. And then I would say most patients in the overall cohort had received immune checkpoint inhibitor monotherapy, and those profiles were pretty consistent with what we’ve seen from trials in terms of immune-mediated toxicities.

Sam Chang: The different “-itises,” OK.

Amanda Nizam: Exactly. Yeah. So when you look at these, the big-picture takeaway from our study is that each regimen may have unique toxicities that we should be aware of and that can be affected by the time the patient is on treatment—especially peripheral neuropathy, as you know, as that has more of a median onset of about three months, compared to rash, which is more within four weeks. Exactly. So each different regimen is important. As you know, EV plus pembrolizumab is not approved in most places in the world yet, unfortunately. And oftentimes patients will still get platinum-based therapies with or without immunotherapy.

Sam Chang: Yes.

Amanda Nizam: Exactly. And I do want to say GemCis plus nivo was approved, but we didn’t have enough follow-up data or numbers to report that.

Sam Chang: Actually, yeah. And especially if you look at the treatment over time, very, very difficult to measure. So as you look at this real-world data and the safety profiles as you counsel patients, tell me kind of how you integrate the safety profiles and then what you explain to each patient.

Amanda Nizam: Yes. So first we go off of the clinical trial data, because that is the most robust level one evidence. So I discuss the toxicity rates based on the trial reported data. But then I talk to my patients about their specific comorbidities, and we look at that. So, for example, patients with pre-existing neuropathy or uncontrolled diabetes would not have made it to the trial—they would not have qualified for the trial—whereas in the real world, we can still put those patients on therapy and just be extra cautious. Especially with diabetes, we can get their diabetes under control and get them on the appropriate treatment.

So we look at that. We take patients’ comorbidities into consideration when we're choosing treatments. Obviously, if you’re looking at level one evidence, EV plus pembrolizumab is the gold standard in the United States and wherever it's available, just based on the efficacy data we've seen, especially with updated data here. But then there are very few patients that cannot get EV plus pembrolizumab. But again, you have to look at each patient’s scenario. They may not be able to tolerate indefinite therapy or indefinite immunotherapy and may want a more finite duration of therapy, where platinum plus immunotherapy may be more doable with their circumstances.

Sam Chang: With their certain comorbidities that exist or as they develop. And I guess for patients understanding the overall profile of any treatment—this is what we're looking at—but being able to hone in on, “OK, this treatment is more likely perhaps to cause these side effects,” versus “this treatment” really makes it actually—I know you can’t directly compare—but just telling them numbers regarding “this is what seems to be most common, over time we’re more concerned about this” for each of the regimens, I think really is very, very helpful for these patients. Now we look forward—what next? I mean, what are you thinking of in terms of utilizing this real-world data or other data sets? What are you looking at next in terms of research?

Amanda Nizam: Yeah. So the big thing, as you know, the perioperative space is also undergoing quite a paradigm shift, and we’ll see more data this year—hopefully by the end of this year. So we're going to run into questions about sequencing, especially with a lot—because the de novo metastatic, locally advanced, is pretty rare in urothelial cancer. So we're going to see a lot of patients who are previously treated who may have lingering side effects, especially with the use of antibody-drug conjugates with overlapping toxicities. So if you're going to be using those in sequence, it's going to be very important to understand toxicity.

Sam Chang: Right. Additive versus—

Amanda Nizam: Exactly.

Sam Chang: Versus, perhaps, even multiplicative. I think I just made that word up. But adding that on top could make it much, much worse or a little bit worse. So that data, I think, would be incredibly important, just as you say, because we have more options now than we ever did before.

Amanda Nizam: And following more long-term data on this, especially with the more contemporary regimens that were more recently approved, just to see how people are doing there in the real world as a complement to clinical trial data—because obviously real-world data has quite a bit of limitations.

Sam Chang: No, no, no. And really, really good point. I'm going to throw a plug in: as you do your study, it would be also really helpful and great if, in those patients that perhaps don’t get a second line—and obviously it’s limited by death and outcomes—but if you could also then follow those patients long term that haven't continued therapy, how their side effects change, evolve, worsen, stabilize versus those that continue therapy. I think that would be great, as patients try to determine, “Gosh, can I come off? Can I not?” etc.

So, as always, I learn every time that I get a chance to speak to you, and it's not often enough. So hopefully we can do this again in the future, and thanks so much for spending some time.

Amanda Nizam: Thank you so much for having me.