Read the Full Video Transcript

Tian Zhang: Hi. I'm Tian Zhang GU oncologist and Associate Director of Clinical Research at the Simmons Comprehensive Cancer Center at UT Southwestern in Dallas, Texas. We're welcome to an episode of UroToday, where we're rehashing some of the great work we saw at ASCO 2025.

Today, I'm joined by Dr. Martin Kurian. He is an Internal Medicine resident at University of Pennsylvania, working with Ronac Mamtani on a real-world EV and with or without pembrolizumab treatment-based toxicities and associations with survival in advanced urothelial cancer. Welcome, Martin.

Martin Kurian: Thanks for having me.

Tian Zhang: So describe your study that you presented at ASCO this year. What did you guys do and what did you find?

Martin Kurian: So this was a retrospective cohort study of around 120 patients with advanced urothelial carcinoma at Penn that were treated with either EV monotherapy or EVP combination therapy. We first examined the frequency of five common toxicities associated with these treatments and then we compared the relationship between each toxicity and survival outcomes.

To do this, we first performed an analysis without accounting for immortal time bias. And then we performed an analysis that did appropriately account for immortal time bias using a landmark analysis. In the landmark analysis, we only defined the toxicity as being present if it occurred within three months of treatment initiation, and then we counted survival from a three-month landmark time point after treatment initiation.

We did find it critical to account for immortal time bias in this study, because in retrospective studies like this one, if you simply compare patients who develop a toxicity such as neuropathy, versus patients who do not, without accounting for when that toxicity occurred, you can introduce this hidden bias where because a patient must survive long enough to develop the toxicity, and patients who die early, won't live long enough to develop the toxicity, they will be less likely to be in the toxicity group.

And this makes the overall comparison unfair, and can make it falsely appear that patients with toxicities do better from a survival outcome perspective.

Tian Zhang: And so accounting for that immortal time bias is really important to adjust for it and have the comparisons be similar. So really carefully done analysis there. I thought this issue of skin toxicity that you found to be associated with survival to be really interesting. What do you think is the underlying mechanism or what's driving that?

Martin Kurian: We also found this to be pretty interesting as well. We do know that, nectin-4 is the target for EV therapy, and it's expressed in urothelial cells, but it's also expressed in skin cells as well. But whether nectin-4 expression itself is predictive of response to EV remains a bit of a controversial topic, our results do suggest that perhaps early skin toxicity is a predictor of response to EV therapy. However, we do believe that more mechanistic data is really needed to further elucidate that.

Tian Zhang: That's fair, but it's interesting that some patients who have rashes are the ones that seem to have good prognosis. It reminds me of the days that we were looking at immune mediated toxicities associated with good prognosis and with checkpoint inhibitors. Awesome.

Well, turning our attention a bit to neuropathy I saw one of your findings was about neuropathy leading to dose hold in almost half of the patients, but only about 20% discontinued. So how do you think we should mitigate or prevent neuropathy in our clinical use of enfortumab vedotin?

Martin Kurian: It's really a great question. And as a resident in Dr. Mamtani's clinic, who is my mentor, I have seen that we do really struggle with this in practice. One lesson that I've learned is about the importance of using either dose interruption or early dose reductions to try to mitigate the effects of peripheral neuropathy that these patients experience. But despite these measures, it really does remain a significant issue in real world practice

Tian Zhang: For sure. And we see that all the time for patients on enfortumab vedotin was one of the early signals, I think, in the early trials that were done with enfortumab vedotin. It's something that we needed to monitor and watch early on.

And then so thinking through time to toxicity then, these rashes, neuropathy, hypoglycemia, they all seem to have some varying delays in our practices until they become clinically significant. What insights do you have on time to these toxicities? Do you see one group of toxicities arising before another? What comments do you have on those patients?

Martin Kurian: So one of the highlights of our study, was to better appreciate the real-world time to onset of these various toxicities. We did see that the earliest toxicities were skin reactions which on average happened less than one month after treatment initiation. On the other hand, neuropathy usually occurred much later after treatment initiation with the median time to onset of around three months.

And it's a little bit unclear why this might be one explanation for this may be related to the fact that again, nectin-4 is expressed in the skin and leads to a more direct and immediate effect after treatment initiation, leading to a skin reaction being a manifestation of that. Whereas toxicity leading to neuropathy requires a longer, cumulative, systemic exposure to the drug.

Tian Zhang: And we see that in our clinical practice quite a bit where those skin toxicities rashes and certainly happen even with cycle 1. It's good to prepare folks for that. But neuropathy tends to take a little bit more time. I generally quote our patients around four to six cycles in and to tell us early if they have numbness, tingling or any sign of neuropathic toxicity. Just motor changes. It's really important to identify these early. And to your point try to dose reduce hold treatment when needed.

Anything else you would like to add about the data that was really interesting that you guys presented at ASCO this year?

Martin Kurian: Just wanted to say thank you for the opportunity to really share these results and to stay tuned for the next step in our project, where we're going to hopefully combine these findings with some national data from the Flatiron database.

Tian Zhang: I think Flatiron represents a really nice database for time on treatment. And hopefully you'll be able to validate some of your findings in that bigger database. Congratulations again.

Martin Kurian: Thank you. Really looking forward to it.