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Pedro Barata: Hi, I'm Pedro Barata. I'm a GU Oncologist at University Hospitals at Case Western University. It's my true pleasure to be joined today by Dr. Dan George. Dr. George leads the GU program at Duke University. Thank you so much for taking the time.

Daniel George: Oh, my pleasure. Glad to be here.

Pedro Barata: I'm really, really excited to be here talking to you about the updates coming out of ESMO, right? In the kidney cancer arena.

Daniel George: Yeah, I mean, I think just oncology in general, the pace is really picking up now. Every meeting we're seeing new data, ESMO this year, no exception.

Pedro Barata: Right. It was super exciting and so let's get to it. And one thing that caught my eye was really the adjuvant data. We've been talking about adjuvant for quite a long time. Some of these developments, particularly with TKIs and then some kind of bittersweet with immunotherapy or immunotherapies, but one thing that's really interesting is the concept of exploring an mTOR inhibitor everolimus in the EVEREST Trial. And by the way, kudos to the cooperative group who was able to pull that together. So let's talk a little bit about EVEREST. So we've seen the data before. We've seen kind of a subgroup analysis looking specifically for the high-risk patients with post-nephrectomy and a very high risk for recurrence. What are your thoughts about that data?

Daniel George: Yeah, this is really important, Pedro, because I think when I look at kidney cancer and particularly high-risk kidney cancer patients, it's not one block. These are a lot of different factors into these patients that make them high-risk. Grade, in particular, to me, grade G-4 is a particularly worrisome sign. And then as you mentioned, this high stage, particularly like T4 tumors and stuff like this.

So there are features and subgroups where I think we would say they're high-risk and then maybe even very high-risk. So these are important things. And then I think the other part of this is mTOR, because if we think about where the mTOR inhibitors started, it was really in the poor-risk metastatic patients that we saw the benefits, or in the TKI treated refractory populations. That's where these drugs got their FDA approval as single agents.

And so when I think about mTOR, I think of it particularly for patients that have an aggressive poor prognostic renal cell carcinoma and if you're going to treat in the adjuvant setting, that's exactly the population that we want to target. So to me, I think these subgroup analyses, they're hypothesis-generating, right? They're not definitive studies, but they show us a trend and evidence that yeah, there is activity of this drug in this setting. It may not rise to the level of where we're going to treat everybody like this, but I think it is something that probably deserves further study and understanding. And I hope in the future with biomarkers, we're going to be able to better precisely decide who are the patients that benefit from strategies like that.

Pedro Barata: Right. No, that's really well said. I think we're aware of efforts being made within the cooperative group where all the tissue was collected to see if they can come up with biomarkers to see who can really benefit from an mTOR. What do you see the future for mTOR inhibition in RCC?

Daniel George: Yeah, so I completely agree, and it's one of the good things about the cooperative groups is that we do a good job of collecting tissues like this and studying them, maximizing their use. When I think of mTOR, a lot of people think of this now as fifth or sixth line therapy, "I'm never going to get to it." But I think of it a little bit differently. I think there's probably 10% of the population out there that really does benefit from this and are probably going to be relatively less responsive to some of the other approaches. So understanding that group, and I think this adjuvant setting gives us a great opportunity to do that with the amount of tissue and outcomes that we'll have to figure out who that is. There's some obvious biomarkers to consider - alterations in mTOR, PI3 kinase, and the like, but there may be other features here.

Pedro Barata: PTEN, TSC, etc.

Daniel George: Yes, loss of PTEN, exactly. Yeah. So I think that's what we got to figure out. And are there combinations where we would consider mTOR or sequences? I think too often we think of these as sort of monotherapy blocks until progression. I think now with the armamentarium we have, there's an opportunity to think about sort of induction and consolidative therapies and maintenance therapies or combinations. So I hope that we don't give up on mTOR. I hope that the EVEREST study is worthwhile in helping us understand the pathway better, and I still see their value to the field of having agents like this.

Pedro Barata: Got it. I really want to pick your brain on the metastatic setting, but before we get there, let me just ask you as I have you here, let me take advantage of that. What are your thoughts? Where are we going in the adjuvant setting? Obviously, we now have pembrolizumab, which a lot of people are using based on the KEYNOTE-546 Trial, and we are going to probably see more survival data soon. Do you think the future will be pembro-based approach? Maybe combination approaches, something else? What are your thoughts about the adjuvant setting?

Daniel George: Yeah, yeah. So first off, I think the pembro data, despite the relatively negative results seen with other immunotherapy agents, I think the pembro data, the 564 study stands alone as enough evidence to me to use this drug in this setting in these high-risk patients. Now, I think in the future it's also a platform to build off of. And what I hope we can do in the future is begin to understand the subsets of patients where we really need to be able to do better. There will be a tail to those curves and there'll be patients that are cured just with surgery alone. And ideally, we're going to see a durable long-term disease-free survival benefit with pembrolizumab, but it's not going to be a hundred percent. We're already having patients relapse. How can we improve on that? And I think there are two strategies.

One is a LITE-SPARK study that's completed accrual, but that we'll be waiting for with belzutifan and pembrolizumab. And that should be coming soon in just another year or two. So I think that study will be really helpful in understanding where using a HIF inhibitor, a HIF-2 inhibitor in particular, again for clear cell selected patients that that could really demonstrate an over and above effect. And then I think the other is a cooperative group study we hope to be launching soon called STRIKE, which is a short-term approach with a combination of tevosinam along with pembrolizumab. I say short-term because we're going to use just six months of the TKI. And it's purposeful because we see the greatest benefits of those combinations in the metastatic setting of TKI and IO. The greatest tumor responses are in that first six months.


So if that's where we're seeing the benefit and not the cumulative side effects of a whole year, then that's what we want to focus on. Then I think the second thing is to be able to keep that pembrolizumab going for a year. So that study's under development, it's approved through GU ASCO, through GU Steering Committee. So hopefully in the next year, we launch that study, but I think that's where the field will go. And then I think the other piece here is selection, and we've talked about it. I think ideally we're going to need either measures of microscopic disease progression or shedding or what have you, or other predictors within the tumor that really help us gauge who's benefiting from these approaches.


Pedro Barata: Well, great thoughts and I really think it's exciting times, right? Moving forward and kudos to the trial that you're involved with. That's fantastic. So I'm looking forward to it. And actually, we did speak about two drugs and let's talk about the same drugs in the metastatic setting, right? I think one of the highlights of ESMO on the kidney cancer, the presidential session was actually the comparison of belzutifan, a HIF-2 inhibitor, as you mentioned, against everolimus. We did talk about two, you did mention both of them. So let's talk a little bit more about that particular trial, it's a practice-changing trial comparing this novel mechanism of action belzutifan against our old standby everolimus. PFS is the endpoint. Yes, we did see OS. What are your thoughts about the difference that was seen in PFS? Are you ready to change practice based on that data, what is your take on that?

Daniel George: Yeah. It is a really important result. And obviously we'd love to see OS benefit and this study didn't achieve that at this point in time. And there's more follow-up to come and there very well could be a benefit in OS that will happen as that matures. And the reason I say that is because if you look at the rPFS curve, and this is again the LITESPARK-005 study that we're talking about. If you look at that progression-free survival curve, those curves really overlap for the first 40% of patients. And then they start to separate and they get really wide. And you see this tremendous tail to the curve of about 25, 30% of patients on the belzutifan arm. And you see the everolimus arm drop off. A hazard ratio of 0.42, almost completely driven by the bottom half of that curve. So then you flip over and you look at the overall survival curve.

We haven't hit that point yet, right? The survival curves are just getting down towards the median. We're not going to really see that separation for another few years, but it's going to happen. And the question is it going to look as dramatic as what we see in the rPFS curve or is it going to be somewhat less? Time will tell. But the thing that I like about this drug, and if you've used it as well, is the side effect profile. This is different from the tyrosine kinase inhibitors. It's not causing the hypertension, the hand-foot syndrome, the diarrhea that has hampered and limited our dosing in so many of our patients and their quality of life. So to be able to have a drug that offers a different side effect profile with again, continued benefit, proven benefit in randomized control trial, I think that's phenomenal, especially that degree of radiographic progression-free survival if we get the OS to follow, icing on the cake as far as I'm concerned. But already this is a welcome addition to our armamentarium and I hope will lead to an approval and access in the near future.

Pedro Barata: Right. So I mean, I think you summarize it brilliantly, right? So we're talking about patients who progress on immunotherapy, who progress on different TKIs and they actually seem to benefit clinically from belzutifan. Right? And I think you really highlight an important point, has to do with the safety and the tolerability of the drug. It's actually interesting. At ESMO, we did see data combining it with different TKIs. I like cabozantinib, we saw that data as well. So I guess my question for you is where do you see the perfect role for belzutifan? Do you see it as monotherapy perhaps later, or do you see it moving early on faster maybe combined with other partners given the safety tolerability profile, if you will, of that particular molecule?

Daniel George: Yeah, this drug is really specific. Our tyrosine kinase inhibitors block a lot of different things and angiogenesis involved in a lot of different biology. But this is blocking HIF-2. It's very specific. And what I think this really calls for is a biomarker. And there is a biomarker potential out there with imaging with a new PET scan that we saw earlier this year that really suggests that CA9 PET imaging could help us identify those patients that are likely to have upregulation of this HIF mechanism.

So coupling that approach could really help us identify even in this late refractory setting, who are those 30% or so patients that are likely to get a durable response to belzutifan? And early on, maybe in some of our favorable risk patients, who are the patients where that's really a driver, maybe even pre-nephrectomy? Does that help us identify the patients who are likely to benefit in an adjuvant setting, as I mentioned with pembrolizumab? So I think that, and I'm just putting that out there. I don't know, we don't have data yet. I think there could be other biomarkers for sure, and more context to look at.

But I think it's helpful to be able to think about who we would probably not want to think about using that drug in right away because it's not a key feature? And again, there could be activation of HIF without CA9, but I think it would at least give some pause to this and give us some precision towards how to enrich for the patients likely to benefit. So that's just an example of, I think that could help us because the armamentarium in kidney cancer is expanding, and rather than sort of put drugs on the sideline and park them like we talked about with everolimus, I'd rather find the niches of patients who can benefit from those and maybe have a different course, a different side effect, and quality of life profile and an enrichment for benefit.

Pedro Barata: Well, I think it's a fantastic way to conclude. We leave with a note that there are actually more options for our patients out there, right? It sounds like the future is bright. Look at us with great discussion coming out of ESMO. I'm pretty sure it's going to be the same in the months to follow. So thank you so much for taking the time to join us today and allowing us to share your thoughts with us about promising therapies.

Daniel George: Oh, my pleasure, as always. Thank you so much.

Pedro Barata: Thank you.