Read the Full Video Transcript

Alicia Morgans: Hi. I'm so excited to be here today with Doctor Umang Swami, who is joining me from the University of Utah, where he is an assistant professor of oncology at the Huntsman Cancer Institute. Thank you so much for being here with me today.

Umang Swami: Thank you, Dr. Morgans and UroToday for this opportunity to discuss our study.

Alicia Morgans: Wonderful. So let's just make sure that everyone knows. You have a great publication, Clinical Genitourinary Cancer, where you talked about the real-world treatment effectiveness of enfortumab vedotin, which is, of course, one of our newer antibody-drug conjugate treatments for urothelial carcinoma. Can you really take us through what was the question you were trying to answer and how did you go about trying to get to the bottom of it?

Umang Swami: Definitely. Thank you, Dr. Morgans and UroToday for the opportunity to discuss our study, “Real-world Effectiveness of Single-Agent Enfortumab Vedotin in Patients With Advanced Urothelial Carcinoma,” which was published in Clinical Genitourinary Cancer in December of 2024. So briefly, an introduction of enfortumab vedotin.

As we all know, it’s a fully human IgG1 kappa antibody-drug conjugate directed at nectin-4, a cell-surface adhesion protein, conjugated to a microtubule inhibitor, MMAE. It’s FDA approved for patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1 or PD-L1 inhibitor and a platinum-based chemotherapy or are ineligible for cisplatin-containing chemotherapy and have previously received one or more lines of therapy.

In the phase III EV-301 study, overall survival was longer in the EV group as compared to the chemotherapy group, which led to its approval in the late-line setting. And recently, in the EV-302 study, overall survival was longer with the combination of EV with pembrolizumab as compared to platinum-based chemotherapy, which led to its approval in the first-line setting. It is to be noted that this trial was conducted in previously untreated patients with locally advanced or metastatic urothelial carcinoma.

However, in the real world, many patients progress from localized disease and have prior treatment with platinum-based agents or PD-L1 therapy in either the neoadjuvant or adjuvant space. Also, many patients may not receive EV with pembrolizumab in the first-line setting. And in that context, real-world effectiveness of EV, particularly regarding the line of therapy and the impact of prior treatments, is lacking. So we tried to answer this question.

And to answer this question, we used the patient-level data from the Flatiron Health Electronic Health Record-derived de-identified database, and we looked at the patients treated from 2011 to September of 2022. The Flatiron Health Electronic Health Record database is a longitudinal database that collects nationwide data from 280 US cancer clinics or 800 sites of care, which includes community practices and academic medical centers. And this data is curated by a technology-enabled abstraction.

The main inclusion criteria for our study were diagnosis of advanced, recurrent, or metastatic urothelial cancer of the upper or lower urinary tract, receipt of single-agent EV as second line or beyond subsequent to its FDA approval (which was in December of 2019), and we excluded patients who had no documentation of first-line therapy.

Our endpoints were real-world time to next therapy, which was basically time from start of EV to start of a subsequent therapy or death. And our second endpoint was real-world overall survival, which was time from start of EV to death from any cause.

And we assessed real-world time to next therapy and real-world overall survival quantitatively based on line of therapy and presence or absence of prior platinum-based chemotherapy or PD-1/L1 inhibitor, utilizing Kaplan-Meier survival estimates accompanied by their respective 95% confidence intervals.

Here, this slide presents the baseline characteristics of the patients. Overall, there were 6,566 patients in the Flatiron Health cohort with metastatic urothelial carcinoma. And after applying all the inclusion and exclusion criteria, 371 patients were included in the analysis who received single-agent EV in second line or beyond.

Of those, 157 patients received EV in second line, 132 in third line, 62 in fourth line, and 20 in fifth line. The baseline characteristics like age, gender, ECOG performance status, receipt of prior platinum-based therapy, and prior PD-1 or L1 therapy were kind of similar. However, in the fifth line, more patients had a low hemoglobin—that is, they were more anemic.

Herein, we show the results of our analysis. So basically, the median time to next therapy in the cohorts based on line of therapy (second line, third line, fourth line, and fifth line) was between four months to six months. And the overall survival was between seven months to 11 months.

When we look carefully, it appeared that patients who received prior platinum therapy had a better outcome as compared to those who didn't receive prior platinum chemotherapy. But this can be due to a selection bias, because patients who are unfit or have various comorbidities may not receive platinum.

So to conclude, EV showed efficacy in patients with metastatic urothelial carcinoma across various lines of therapy and prior treatments. Real-world data from these 371 patients indicated median overall survival ranging from 7.2 to 11 months, and EV remained effective irrespective of previous platinum or PD-1/L1 inhibitor therapies, enhancing metastatic urothelial carcinoma treatment flexibility. Thank you.

Alicia Morgans: Great. Thank you. That was so, so interesting and really so effective with the slides. So thank you for sharing that. I wonder if you can share, from your perspective, how does this impact you clinically? Is this something that is meaningful as you're seeing patients at various stages of their disease course in your clinic?

Umang Swami: Definitely. So these data are very encouraging. As you know, many times the real-world patient population may not be reflective of the clinical trial population, and these data are very encouraging.

Because the effectiveness of enfortumab vedotin was present regardless of prior lines of therapy—whether they received prior checkpoint inhibitor, whether they received platinum-based chemotherapy—so it shows that if the patient is eligible to receive enfortumab vedotin, it should be given, and probably it retains its effectiveness in this real-world patient population.

Alicia Morgans: Wonderful. I think it's so incredible, this Flatiron data that you've used, because you can imagine that this is going to capture patients who are obviously being treated in the real world, and to your point, may more closely reflect the patients that we see in our clinics than a clinical trial population.

This was really—it says over 280 cancer clinics, about 800 sites of care—so a broad swath of the US. I wonder—one of the things I found striking about your work is that there were so many patients who have received EV. Do you have any thoughts on that and on how quickly this particular agent seems to have been taken up into our clinical practices?

Umang Swami: So the uptake of EV as well as EV with pembrolizumab has been quite rapid. There was a recent publication in European Neurology which demonstrated that the EV uptake in combination with pembrolizumab in the first-line setting has been tremendous. And I believe that this will ultimately translate into improved overall survival of our patients in the real world.

Alicia Morgans: Absolutely. If you had to pick any limitation of your study, what would you have people just be aware of as a limitation of this or other real-world analyses?

Umang Swami: So definitely, when we talk about the real-world data set, it has some inherent limitations, including a retrospective analysis. There is a selection bias with regards to treatment given by physicians to the patients. There is always some missingness which may be there.

And it needs to be noted that this is not a randomized controlled trial. So there is always some residual confounding which may be present, which can’t be accounted for. And these all are limitations with any real-world data set.

Alicia Morgans: Agreed. Well, wonderful. So I would love to hear, as the primary investigator on this project, what your take-home message is so that clinicians can really think about that as they go into clinic tomorrow.

Umang Swami: So my message is that if the patient has not received EV and has progressed on a platinum-based therapy or immunotherapy, then EV should be considered as the next line of therapy, because it has a proven survival advantage. However, if the patient has not received any therapy and is newly diagnosed with metastatic disease, then EV with pembrolizumab should be the first-line treatment option for the patient if they are eligible for it.

Alicia Morgans: Really, really important message. And certainly, really reflective of the transformations that have happened in terms of recent approvals, clinical trial data now demonstrating in this real-world data set similar efficacy, and certainly that ability to utilize this in our practices. So thank you so much for sharing your work with us. And we appreciate your time and your expertise. Thank you.

Umang Swami: Thank you, Dr. Morgans.