Pedro Barata: Hi there, and welcome again for another video from UroToday covering great work done and presented at ESMO 2025 in Berlin. Today I'm super happy to be joined by the superstar Dr. Andrew Hahn. Andrew, welcome.

Andrew Hahn: Thank you, Pedro. I appreciate the kind introduction.

Pedro Barata: Absolutely. So just a formal introduction, although you're known to many now. So Dr. Hahn is an assistant professor at MD Anderson, part of the Department of GU-oncology. He's leading a lot of novel concepts on novel therapeutics in the kidney and prostate cancer arena. And today, Andrew, you're going to be talking to us a little bit about a very interesting, I think very practice informing, investigator-initiated study of lenvatinib/everolimus versus cabozantinib, which is arguably one of two of the most commonly used treatment options for patients with refractory clear cell renal cell carcinoma. So we needed this data, it is the first time we're seeing this comparison, head-to-head comparison, this phase two, and so kudos to the idea, because it's really informative in clinical practice for our patients. So why don't you remind us of the great presentation you did at ESMO on this topic?

Andrew Hahn: Yeah. Thank you for the kind introduction, Pedro. I appreciate it. So like you said, LenCabo, this was a randomized phase two multi-center trial of lenvatinib plus everolimus versus cabozantinib in patients with metastatic clear cell RCC, that's progressed on a PD-1 immune checkpoint inhibitor. And then for everyone, this has... You can find the full presentation online, I'm going to give an abbreviated version now and then this has been simultaneously published and is available on Annals of Oncology as well.

First line treatment for metastatic clear cell RCC consists of a PD-1 checkpoint inhibitor plus either a CTLA-4 checkpoint inhibitor or an angiogenesis targeted therapy. When patients experience disease progression on one of these first line PD-1 checkpoint inhibitor doublets, there's no consistent recommendation of what agent we should be using next. If you look at the ESMO guidelines, which are listed here, you see listed that we can choose a VEGF receptor systemic therapy that has not been previously given. And then we have this smorgasbord of options listed here that includes cabozantinib, that's level two evidence, and then lenvatinib plus everolimus with level three evidence. So given the paucity of head-to-head comparisons of all of these different angiogenesis targeted therapies, it led us to designing and running the Phase II LenCabo study.

So the LenCabo study, in order to be eligible, patients need to have metastatic clear cell RCC that had progressed on a PD-1 checkpoint inhibitor, and had received one to two prior lines of systemic therapy. They were randomized in a one-to-one fashion, 90 total patients, to either lenvatinib 18 milligrams plus everolimus five milligrams daily, versus cabozantinib 60 milligrams daily. At randomization patients were stratified by their IMDC risk group, and whether or not they had previously received an angiogenesis targeted therapy. The primary endpoint for the LenCabo study was progression-free survival. Key secondary endpoints included objective response rate, safety and overall survival.

I will go ahead and also say that this was, as alluded to, a multi-center investigator-initiated study. The statistical design was all focused on progression-free survival. The study was not powered to evaluate overall survival. So that all being said, here's the primary analysis of progression free survival from the LenCabo study. At data cut, 25 patients of the 40 who were randomized to lenvatinib plus everolimus had experienced disease progression, and 35 of the 46 who were randomized to cabozantinib had experienced disease progression. In the Kaplan-Meier figure, you'll see that there's a 49% reduction in the hazard for disease progression favoring lenvatinib plus everolimus versus cabozantinib. This result is statistically significant, and you can see that the median progression-free survival is 15.7 months with lenvatinib plus everolimus, compared to 10.2 months with cabozantinib.

When we shift the focus to objective response rate by RECIST, you'll see that with lenvatinib plus everolimus there were numerically more objective responses, 53% compared to 39% with cabozantinib. And good news for all of our patients is that very few patients experience primary progressive disease with either of these regimens. Now, there was no statistically significant difference in the objective response rate between the two arms. And then on the bottom right you'll see that there is a waterfall plot depicting the best percent change from baseline per RECIST criteria.

Here's a summary of treatment-related adverse events. You'll see that lenvatinib plus everolimus was associated with a numerically higher incidence of serious adverse events, grade three or four adverse events, and treatment discontinuation at 20% versus 11%. Now it's worth noting that five of the eight patients who discontinued lenvatinib plus everolimus discontinued due to proteinuria, which is not something always discontinued in routine clinical practice. Now, cabozantinib had a numerically higher incidence of dose interruptions and dose reductions compared to lenvatinib plus everolimus. None of these differences were statistically significant and you can see the odds ratios and 95% confidence levels on the right.

In conclusion, among patients with metastatic clear cell RCC that's progressed on a prior PD-1 checkpoint inhibitor, lenvatinib plus everolimus significantly prolonged progression-free survival over cabozantinib. And as the first head-to-head randomized comparison of contemporary second-line or later treatments after checkpoint inhibitors, these results are relevant to treatment sequencing and inform oncology practice. All right Pedro, that's all I got for everybody. Open to some questions.

Pedro Barata: This is great work, and what a big effort that you guys put in and you enrolled this study quite fast between Anderson and Moffitt, so great work from the team, so congratulations. I'm just wondering, just I don't think what we've seen here is really surprising, right? Active regimen. Folks always ask the question, real-world application of lenvatinib everolimus, right, which so much dose adjustments. So perhaps what I'll ask you is outside of clinical study, if you think of a broad population with comorbidities, polymedications, et cetera, maybe talk a little bit about the comparison of the 18-5 versus 14-5 for lenvatinib/everolimus, and do you find the dose of 18-5 able to deliver, like you do see more adjustments, interruptions in the lenvatinib everolimus? What is your advice for the community providers out there in regards to these regimens specifically? Because it does work.

Andrew Hahn: Yeah, no, I think it's a great question. I highlight a few points here. My first point that I want to highlight is that, yes, there was more toxicity associated with, and not statistically significant, but numerically there was more toxicity associated with lenvatinib plus everolimus compared to cabozantinib. And it's likely related to the combination of the two different mechanisms of action here. That being said, when you really dig into what were the treatment-related adverse events that were taking people off of study, how do they compare between the two arms? What were the grade three and four adverse events? There's a lot of similarities between the two treatment arms, and the biggest one was actually proteinuria that was pulling people off of study, and that's us being very dogmatic on a clinical trial of obtaining UPCs every two months, and then the moment it went over two grams interrupting and then ultimately patients could continue lenvatinib plus everolimus off of trial, because this is available commercially.

And we saw some patients do that where they got censored and pulled off for proteinuria, and then the providers just said, "Hey, I'm comfortable with two and a half grams of proteinuria. If my patient's benefiting clinically from this medicine, I'll continue it off of study or I'll even go to lower doses." So I think when people, providers in the community are thinking of using lenvatinib plus everolimus, you need to know that you're probably going to need a dose interruption at some point. You're probably going to need a dose reduction at some point. And it's actually the same with cabozantinib. If you're starting at max dose with either of these regimens, these are regimens that are highly active but also have a lot of toxicity associated with them. So you need to be closely following up with patients, intervening with interruptions and then just reducing the dose down and finding that right dose for your patient. I think it is something that most community providers can do quite well.

To your point of 14 versus 18, our close friend Monty Pal has looked at this in a really large clinical trial. In order to enroll in this study to evenly compare the two groups, we used the full dose in the package insert in both arms, and you had to either get 18 of lenvatinib or 60 of cabozantinib is what we said. So the patients that were being referred reflected that, right? These were patients that the providers felt like could manage full dose, at least to begin with, and then dose interruption. I think it's very appropriate and I do it often in my clinic that with both medicines I'll start at a lower dose, especially if you've seen toxicity with prior TKIs and the patient's already walking into second or third line treatment with a number of ongoing adverse events.

Pedro Barata: Absolutely. And if I have you, Andrew, let me take a bigger picture. We heard very recently about the positive press release around lenvatinib with belzutifan versus cabozantinib as well. And so, also the adjuvant study, but that's a separate conversation. Do you think these data might challenge the way we see the setting for utilization of lenvatinib, but also for cabozantinib? In the absence of data with... So we have clear data for lenvatinib in the frontline. You're showing us that it's really active lenvatinib-everolimus combination, and then with this press release of lenvatinib/belzutifan versus cabozantinib, apparently the belzutifan/lenvatinib also has shown superiority in terms of PFS, regarding compared to cabozantinib. Do you think they'll make some of us move cabozantinib earlier on and maybe use less of lenvatinib/pembrolizumab and do more maybe cabozantinib/nivolumab? What do you think, if any, will be the impact in clinical practice for the community out there as they're managing advanced RCC?

Andrew Hahn: Yeah, Pedro, there's a lot to unpack in that question. It's a really good one as well. And you'll see we attacked some of this in the discussion. I think the easiest component to discuss and to frame is the comparison of second line or later lenvatinib/everolimus versus lenvatinib/belzutifan, because this is what... Let's present, we have the positive press release, we know PFS is positive from LITESPARK-011 with lenvatinib plus belzutifan. We previously didn't have any context to compare lenvatinib plus belzutifan versus lenvatinib plus everolimus. We now have context like LenCabo clearly gives us prior estimates to compare against. We have a hazard ratio of around 0.5 compared to cabozantinib. Cabozantinib performed exactly how we would've expected it to perform from other studies in this study.

So now when we have the actual data from LITESPARK-011 shown to us, we're going to all be asking ourselves this really important question, which is, does the data I see here justify first giving up everolimus altogether, and not including it as a treatment regimen either anymore for metastatic clear cell RCC? Because what's going to happen if you start using lenvatinib/belzutifan instead of lenvatinib/everolimus. And then the second thing is that you are going to give up one of belzutifan's great strengths, which is its tolerability and alternative side effects compared to these angiogenesis targeted therapies, when you combine it with lenvatinib. So in my view, when I see this data, the bar is going to be high for me to start adopting a lot of use of lenvatinib plus belzutifan. I'm going to need to see a very impressive hazard ratio for PFS. I'm going to also be looking very closely at what the objective response rate data looks like, as well as overall survival.

And I think that a lot of us are thinking this way in this space and it's going to be really fascinating to watch this comparison. I think LenCabo provides really helpful data to everyone to contextualize the results. Now the question of how does this shift cabozantinib use? I think you're inevitably, with these two studies, going to see cabozantinib getting pushed in one of two directions here, which is going to be going later after lenvatinib combinations, or moving earlier into the first line setting, as you said, as people try to think of treatment sequencing. In my practice, and I think when you think of the LenCabo study, LenCabo is looking and post-nivo/ipi, post-pembro/axi, and post-adjuvant/pembro, we're really not commenting on post-nivo/cabo in this space. So we're not really giving a direct commentary there.

I still think nivo/ipi is really appropriate for a ton of patients, and for those patients this data is relevant to my clinical practice and it's changed the way that I practice in that situation. There's always going to be a group of patients who just need the most effective, highly active first-line treatment you have, because you're worried they're not going to have opportunities in second line or later. In that one, I think you're still going to be thinking about lenvatinib plus pembrolizumab and nivo plus cabo.

Pedro Barata: Well said. No, great insights, Andrew. Great insights. And I agree, we're living exciting times. A lot of movement, right, in the kidney cancer arena. And those are usually good problems to have for patients. So we'll see what happens as we actually see the details of all the data's going to be reading out soon. So again, congratulations, a very important investigative study. I'll invite the audience to actually take a look at the paper as well for the full details. And well done, and thanks for joining us today.

Andrew Hahn: Thank you, Pedro. I appreciate the opportunity.

Pedro Barata: Sounds good, thanks.