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Petros Grivas: Hello, I'm Dr. Petros Grivas. I'm a medical oncologist and a professor as well as the clinical director of the Genitourinary Cancer program here at the University of Washington Fred Hutchinson Cancer Center. I'm very excited today to host two amazing people, who really had this showcase of how teamwork and mentorship can show wonderful results at ASCO GU 2023. So I am very pleased to have Dr. Koshkin and soon to be called Dr. Jindal. I will let you guys introduce yourselves. Tanya, I'll start with you.

Tanya Jindal: Okay, great. Thank you for the introduction. My name is Tanya Jindal, and I am a senior clinical research coordinator at University of California San Francisco, where I work with the Genitourinary Medical Oncology group, and also with Dr. Koshkin here.

Petros Grivas: Fantastic. And I said soon to be called Doctor, because Tanya, you're applying for medical school too. So we're very proud of you. Vadim, we'll let you introduce yourself next.

Vadim Koshkin: Hello everyone. My name is Vadim Koshkin, I'm an assistant professor and a genitourinary medical oncologist at the University of California, San Francisco, UCSF. Where again, I work with our GU group, and specifically also with Tanya Jindal, who also joins us here today.

Petros Grivas: Fantastic. And just for the audience, Dr. Vadim Koshkin was a stellar hematology oncology fellow at the Cleveland Clinic, and he has made us proud with his stellar course so far his contributions. And one of the contributions he has made in the field of GU cancers is this really impactful UNITE study. Vadim, can you tell us more about how this started, and give us an overview of the UNITE study as a concept?

Vadim Koshkin: So UNITE is a retrospective cohort study, looking at patients with advanced and metastatic urothelial cancer, and specifically focusing on clinical outcomes, and now other outcomes as well, for patients treated with novel targeted agents, such as enfortumab vedotin, and now other drugs that are coming about.

This study started as a collaboration between several academic sites in the United States, and we have now grown to 16 different academic sites, and looking to expand even beyond that, and potentially internationally outside the US as well. But it started specifically as a collaboration between myself and Dr. Ajjai Alva at the University of Michigan. And this is right around the time when enfortumab vedotin first achieved FDA, attained FDA approval. This was in late 2019. And actually a few months later, actually at the GU ASCO meeting in 2020, we were talking about looking at potentially some of the real world outcomes with inpatients treated with enfortumab vedotin, which we're really starting to use on a lot of patients at that point.

The initial aims of the study were twofold. On the one hand, we wanted to really see if we can really replicate the impressive data and outcomes that we were seeing in enfortumab vedotin clinical trials, if we could really replicate them in more of a real world setting. If really, the impressive outcomes that we were seeing from trials would show up in for patients that we're treating in clinic, essentially.

And then, the other important question, or a series of questions that we wanted to answer, is whether the benefit, the clinical benefit, of enfortumab vedotin would also extend to patients, and specifically subsets of patients, that potentially were not included or underrepresented in clinical trials of enfortumab vedotin. So these are for instance, patients with worse performance status, patients with significant comorbidities, like baseline significant neuropathy, or diabetes, or significant renal function impairment. So patients, in other words, who would not have qualified for the clinical trial of enfortumab vedotin, but who we see in clinic, and we're eager to treat with this new drug.

Moreover, we also wanted to see if the same benefits, clinical benefits with enfortumab vedotin would extend to patients with variant histologies for instance, which again were underrepresented in clinical trials of the drug. Or specific subsets of patients. For instance, patients with FGFR3 alterations, for who another drug is available, which is erdafitinib.

And so, our first publication from UNITE came out in 2021 in Cancer, and it did show that first of all, I mean we were able to replicate pretty impressive outcomes with enfortumab vedotin in this more real world setting. So we still saw impressive responses, impressive median progression-free survival and overall survival, which really was pretty consistent with what was reported in Phase II and Phase III clinical trials of the drug now in this more real world population.

And then, we also saw that basically, the clinical benefits of enfortumab really extended across the board to most subsets of patients. So regardless of specific comorbidities, baseline renal function, and really, even regardless of presence of variant histology, we really saw pretty impressive responses to enfortumab, with the variant histology question in particular, even though numerically, the responses to enfortumab were lower in patients who had some component of variant histology, rather than just pure urothelial histology, numerically, it was in the low 40s response rate, versus well about 50 in this study. But the difference was not statistically significant.

So basically, from this initial analysis of the UNITE data, at the time, we concluded that basically, the drug is as active as advertised in clinical trials, and really its benefit extends even to these more potentially sicker subsets of patients, and also other subsets of patients that were not included in initial clinical trials. And beyond that then, we have subsequently pursued some other analyses, and I think that's some of the additional data that we'll talk about today.

Petros Grivas: Fantastic. Vadim, thank you so much for the very comprehensive overview. Kudos to you, Ajjai, and all the other UNITE investigators. I'm very, very pleased to see that, and also very honored to be part of this UNITE effort. So thank you for reaching out to me early on and discussing this project. I think it's a great segway to have Tanya give us an overview of your wonderful oral presentation that happened on Saturday morning at ASCO GU.

Tanya Jindal: Of course. So like Dr. Koshkin mentioned that we use this UNITE study to look at outcomes in patients treated with enfortumab. So in this analysis specifically, we wanted to look at biomarkers that were associated with outcomes to EV treatment since it was approved in 2019, and we still have limited, we don't have much data available regarding biomarkers.

So in this analysis, we looked at all patients with advanced urothelial carcinoma treated with EV monotherapy, and who also had next generation sequencing results available. We looked at some molecular biomarkers, which included tumor mutation burden, somatic alterations present in 10% or more of patients, presence of at least one DNA damage response mutation. A subset of patients were evaluated for response, and those included patients who had scanned after at least one cycle of EV. And then the main endpoints were looking at the observed response rate and some time to event based endpoints, such as overall survival and progression-free survival from enfortumab vedotin start.

So what we found was that the patient characteristics were pretty consistent for this patient population. So when we looked at biomarker focused outcomes, we saw that patients who had alterations in ERBB2 and TSC1, their response rates were higher compared to wild-type patients. Interestingly, when we looked at overall survival and progression-free survival, we didn't see the same, or we didn't see the differences translate over, and this might be due to the small sample size. However, we did find some other biomarkers that were associated with differences in overall survival and progression-free survival. Specifically, we saw that in patients who had alterations on CDKN2A, CDKN2B and MTAP, they had shorter progression-free survival. And in patients who had high tumor mutation burden, we saw a longer overall survival.

Petros Grivas: Thank you so much, Tanya. Really interesting data. And as you said before, and Vadim said the same thing, we need to evaluate biomarkers in the context of enfortumab vedotin therapy. We have not seen biomarker data from the clinical trials EV-201, EV-301, and it would be nice to have this exploration. The data is very interesting, of course, required to, as you said, and also you pointed out at ASCO GU, external validation and evaluation in larger studies. But I think it generates some very interesting hypotheses about how we can use biomarkers, think about biomarkers and use them in the sequence of therapy in advanced urothelial cancer. So it's a great start in the right direction.

Maybe I could ask both you and Vadim, what's the next step? Obviously, the manuscript from that great work will be important to see, I know you're working on it. But what else you envision in the future? Maybe Tanya, we'll start with you this time.

Tanya Jindal: Yeah, so like Dr. Koshkin mentioned earlier, we are expanding the study not to just look at outcomes in patients treated with enfortumab vedotin but also other therapies like sacituzumab govitecan, so our plan is to also look at outcomes in those subsets of patients, and also maybe look at biomarkers for that treatment.

Petros Grivas: That's great. And I think looking at that real world data in terms of clinical outcomes, response rates, investigator assessed, observed response rates, PFS, OS, median time to response, duration of response, and even toxicity data, I think are important in the world of antibody drug conjugates, the sequence of those agents and again, looking at some early hypothesis for putative molecular biomarkers and generate hypothesis to be tested in bigger trials. I think it's exciting. Vadim, you just orchestrate this big effort. What are your thoughts for the vision of the future?

Vadim Koshkin: Orchestrate is a big word. I think I have a lot of help and input from all the other investigators on it, including, of course, our present company with Dr. Grivas as well as many others. Dr. Bellmunt, Dr. Sonpavde, Dr. Campbell, Dr. Gupta from Cleveland Clinic. A lot of smart folks I think on this and involved in this project that I think helped us quite a bit.

But yeah, I think there are a lot of different directions to go in. I mean to start out, the data that was presented at ASCO GU that Tanya just discussed, that was for about 170 patients with biomarker data. And that's a great start, because again, as I think both of you have highlighted, there just hasn't been a lot reported in this space. Only now some biomarkers of response to enfortumab like nectin-4 expression in tumor samples is starting to emerge. But this was one of the first efforts more comprehensively to look at this. And I do hope we see also more of this data including from clinical trials and patients who participated in enfortumab vedotin clinical trials.

But I think, as some of our next steps here, we can do more powerful analyses on larger patient subsets. So again, this was 170 patients. We've now expanded the cohort further. So there are more analyses coming up looking at enfortumab vedotin and other biomarkers there. As Tanya alluded to, we're starting to focus on other agents as well, sacituzumab. And looking at also sequencing of therapies. As Dr. Grivas alluded to. In bladder cancer, in urothelial cancer for many years, and the many, many investigators that have before me, had a lot fewer options to work with. Now, we've suddenly with as dynamic a space as it has been over the last several years, and of course, Dr. Grivas here has been involved in a lot of this development of sacituzumab, of avelumab, of all these other drugs.

There're just so many questions now come up where you see a patient in clinic, and you have more than one option to offer them, you have potentially several options. So that brings up really relevant questions that you ask yourself that the patient is asking you, because they've read about the different options of which way to go. And I think, large real world studies, even retrospective studies like this one, can shed a lot of light on these questions, on the questions of sequencing of therapies.

Also importantly, and something that we've, data we've collected in UNITE but haven't reported yet, are on toxicities and adverse events of enfortumab, of other drugs as well. And I think real world toxicities and adverse events, at least as they're reported, are very different from often from what we see in clinical trials. So I think there's a lot of value to add there as well.

So I think a lot of these potential directions to go in. And also as new drugs get approved, as potentially we see other antibody drug conjugates like HER2 targeted antibody drug conjugates being developed and then come about, that's something we may look at in the more distant future, so to say.

Petros Grivas: Vadim, this is inspiring work and really, really commend you and applaud your effort. Again, all the investigators working hard on these studies, because it takes effort, time, and energy to enter the data. High quality data is important, so quality control. And as you said, high quality data and analytics like that can complement, of course, the start with this clinical trials. And obviously clinical trials have a high level of evidence, but I think real world approaches like UNITE can help complement the clinical trial data.

And as you said, with more centers and more collaborations, maybe you can have even higher sample size. And I think quality of data and sample size can help us reach even more destination steps of meaningful hypotheses, and help the field move forward. And we have, as you mentioned, antibody drug conjugates, two of them enfortumab, sacituzumab, we have erdafitinib an FGFR inhibitor, we have checkpoint inhibition, we have a tip in the database that you are part of. And it's exciting to see so many new agents to your point, Vadim, in the field of advanced urothelial cancer recently. So congratulations, and thank you so much to both Tanya and Vadim, for great work, leadership, and also for your time today. And of course, thanks to the audience for watching this, and hopefully we'll have more data for you in the future.

Vadim Koshkin: Yeah, absolutely. And from our part, again, I also want to say thank you to you, Dr. Grivas, and UroToday for our conversation here today. And of course, special thank you to all the UNITE sites, all my co-investigators in the UNITE sites. And of course, all of the patients who contributed, whose data we also analyze. I think that that's always also a very important thing too to point out. And thank you to Tanya as well, for working on this, and for really putting in a ton of work and a significant effort. And it's really great to see it bear fruit, and to see Tanya present this on the big stage. She really did a great job.

Petros Grivas: Wonderful. Kudos again, more to come. Excited about the field, excited about your work. Thank you.

Vadim Koshkin: Thank you.