David McDermott: Glad to be with you, Pedro.
Pedro Barata: Wonderful. I'm really excited about our conversation. First of all, congrats, you always do an amazing job. Great presentation. You have fantastic work, and you always get us to think about biology around kidney cancer. And perhaps today, we'll spend a little bit of time just talking about anti-cyclins, right? But many of us know therapies like palbociclib, abemaciclib, and others as MOA in other solid tumors.
David McDermott: Right.
Pedro Barata: But then we're reading this in kidney cancer and we all think, "Why?" Right? And then we find your name behind that, leveraging that and understanding whether or not that makes sense from a scientific perspective, and whether or not combinations might make sense as well. So let's start from the beginning.
David McDermott: Yep.
Pedro Barata: Tell us why we should be thinking about that from a biology point of view for RCC.
David McDermott: Okay. So the story goes back a little bit. It's mostly preclinical until today. And it goes back to how do we build on HIF-2 inhibition in kidney cancer 'cause as we know, single-agent belzutifan has been with us for a little while. We're using it in the third and fourth line. How can we do better than single-agent belzutifan, not by targeting the microenvironment with say VEGF and PD-1, which we learned just today is producing exciting improvements and outcomes in some of those spaces. But how can you actually target the tumor with sort of a double hit targeting HIF-2 and then what else makes sense. And so the Kaelin Lab has been, which helped develop the whole field of oxygen sensing and the role of HIF-2 in that process and connecting it to kidney cancer, they started to think about what other genes are synthetically lethal with VHL mutation. And what they found was one of those that came out of their screens was CDK4/6 or cyclin D1. And then the next question is, how can we target that? And in their models, actually CDK4/6 inhibition with palbociclib actually had single-agent activity. Admittedly, mouse model, VHL mutant, but the single drug was active, suggesting there was some synthetic lethality.
So if you're missing VHL, if you block CDK4/6 signaling, you get a tumor response. So that was interesting. In that same study, which they published several years ago, they then looked at the combination of HIF-2 blockade with CDK4/6, and they thought they were seeing synergistic activity, obviously, once again, mouse models, with that combination. So at the time, this is early days, five or six years ago, we brought that data to Merck. They liked the idea so much that they made it their study, which is fine. And then so we launched what's now called the LITESPARK-024 study. Essentially, that was focused on studying that combination, tumor-targeted combos, building on HIF-2 in clear-cell kidney cancer.
Pedro Barata: Wonderful. So it sounds super simple.
David McDermott: Well.
Pedro Barata: Amazing rationale to justify the next step, right? It's a beautiful story of translational efforts, right, bringing it to the lab to patients?
David McDermott: Yes. It turns out though, as you know, mouse cancer easier to solve than human cancer. So the human story is messier.
Pedro Barata: Not always.
David McDermott: Correct.
Pedro Barata: Matching.
David McDermott: Right. So a couple of things. So before this study, there was a parallel look at just CDK4/6 alone, a small study of abemaciclib, which Brad McGregor led. Fortunately there, 11 patients, no responses. The abema approach sort of ended there.
Pedro Barata: As monotherapy?
David McDermott: Correct. So we've yet to show in VHL-mutated kidney cancer that single-agent CDK4/6 has any activity.
Pedro Barata: Right.
David McDermott: So that's one weakness of this story. However, this trial had a different focus. So in this study, everyone gets full-dose belzutifan. And in part one, we gradually ratcheted up the dose of palbo. We felt we could get to full dose without any DLTs. So we were about to launch a randomized phase II trial of belzutifan versus belzutifan-palbo when the regulatory agency, the FDA, came back and said, "Well, you need to study more of these doses in more detail."
Pedro Barata: Right.
David McDermott: So we went back and studied three dose levels with 20 patients on each dose level. And the results are somewhat confusing. If you just focus on the toxicity side of things, there was significant grade 3 toxicity, not dangerous tox. It's mostly anemia and hypoxia, which you see with belzutifan. The one thing that seemed increased that was related to the palbo, it was neutropenia, which seemed to increase as you went up on the dose, but there weren't a lot of dose-limiting tox. We thought you could give full doses. There weren't any treatment-related deaths. The efficacy story was complicated-
Pedro Barata: Right.
David McDermott: ... but it didn't stop things. What sort of stopped things was the efficacy story. So if you just focus on response, even if you look at the top dose level, the response rate there was only 21% with the combo, which as you know, is very similar to what you see with belzutifan alone.
Pedro Barata: Right.
David McDermott: But if you want to make the positive argument, which I would try to make today, if you look at things like primary PD rate, which as you know with belzutifan is pretty high, 34% of patients grow through it, here it was only 5% of patients. So maybe that's a signal. If you look at disease control rate, also north of 70%. So most patients getting some stability of their disease.
Pedro Barata: Right. Right.
David McDermott: And if you think back to how palbo actually works in breast cancer, it's not producing a high response rate, but it's improving progression-free survival. So if you are a believer-
Pedro Barata: Right.
David McDermott: ... you look at the progression-free survival of the high dose level in this trial and you say nine months, which is what we saw, might be greater than five months.
Pedro Barata: Five months, which is the median-
David McDermott: Right, which is one of the issues with 005, which is PFS isn't that long.
Pedro Barata: Okay.
David McDermott: So you might say, "Well, let's do the randomized trial."
Pedro Barata: So let me ask you this.
David McDermott: Go ahead.
Pedro Barata: This is a fantastic setup. And you did mention the selection on VHL-mutated tumors.
David McDermott: Correct.
Pedro Barata: So was that selection based on somatic VHL versus germline? And would that explain the better results of belzutifan even if it was given as monotherapy? What are your thoughts on that?
David McDermott: Okay. Also, it's a great question. So as you know, belzutifan works much better in germline-mutated kidney cancer. So patients with VHL mutations at germline, we are not developing belzutifan, at least currently in VHL-mutated patients.
Pedro Barata: Right.
David McDermott: We assume most of them are-
Pedro Barata: Right.
David McDermott: Okay? But the response rates are much lower, so the biology obviously is much more complicated. It's a much more heterogeneous tumor than in patients with VHL disease.
Pedro Barata: Right.
David McDermott: Here, we did not require patients to have a mutation. We didn't sequence some of them ahead of time. So it's conceivable that some patients came in without a mutation, possibly. It's also possible that by the time you get to a third or fourth-line kidney cancer, it's a less responsive group of patients.
Pedro Barata: Right.
David McDermott: And they've sort of shown this. Neeraj has shown this with Mike Atkins where, as you know if you bring belzutifan up in the paradigm, treatment paradigm with fewer prior treatments, it's probably more active, which makes sense to a certain extent. So it's possible we didn't pick a great population. We were essentially focusing on the belzutifan approved population.
Pedro Barata: Right.
David McDermott: And if you want to make a positive argument, we saw manageable tox and at the top dose level, some suggestion of increased activity. But then when you combine it with all the other dose levels where the activity wasn't so great, which we probably wouldn't have expanded had we not been encouraged by the regulators and you look at the Abema story where there were no responses, the decision was made by the sponsor not to do the randomized trial.
Pedro Barata: Okay.
David McDermott: So that said, you could say, "Well, we could stop everything right there."
Pedro Barata: Right.
David McDermott: But what I would like to argue is that tumor-targeted therapy has a future. This trial suggests that at least part of the Kaelin data was in the right direction and that we should try to build on HIF inhibition with other agents in the future. And as you know, there are a lot of other ways of targeting-
Pedro Barata: Cyclins.
David McDermott: ... cyclin D1 that are either entering phase I, pure CDK4 inhibitors, macrocyclics that target cyclin D1, for example. There are ways to get at this pathway that may help solve two problems. One is the tox, which is somewhat dose-limiting, but also efficacy. You might be able to get more out of this, which I think for our patients will be important-
Pedro Barata: Yes.
David McDermott: ... because tumor-targeted therapy is so important in other cancers, not so much yet in kidney cancer, but we should try to keep it alive, is my argument.
Pedro Barata: This is fantastic, fantastic conversation. Maybe since I have you here and since we have a lot of updates on kidney cancer at the meeting, so from what you've seen and connected to our conversation, have you seen any synergistic potential for belzutifan-
David McDermott: Yes.
Pedro Barata: ... with either a TKI or IO that can convince you that the role for bel should not be monotherapy, it's combinable from a safety piece. There's not a lot of overlapping toxicities. Have you seen anything suggesting, you know what, the data that we know is so strong for a synergistic activity that we'll leave the cyclin story aside because we're probably going to have a role for bel in a different combo. Or you say, "You know what, yes, they might be additive, maybe not synergistic based on what we know. Therefore, we have a rationale to continue to pursue different combinations who can indeed provide that synergistic activity."
David McDermott: Okay. Complicated question, several questions in one. I think in the adjuvant setting where we're looking at the O22 trial, LITESPARK-O22, which as you know, is pembro versus pembro-bel, my sense of that benefit there is it feels mostly additive benefit, not synergistic. At least we haven't seen that yet. What would we like to see if we were seeing true synergy? You'd like to see a flattening of the DFS curve, which we haven't seen yet. Now maybe with more follow-up, we'll see it. You want to see a clear signal on overall survival, which we haven't seen yet. Maybe we'll see it in the future. It's still early-
Pedro Barata: Sure.
David McDermott: ... in that case. In the second-line space, where you're combining VEGF with HIF, with len and bel versus cabo, maybe there's a hint of synergy, but it's hard to find. You see certainly an additive benefit with a lengthening of median PFS, for sure.
Pedro Barata: ...Response in PFS.
David McDermott: And there's a trade-off there with managing the tox, but if you're experienced with belzutifan, you can manage around the tox, I think. A hint of... Synergy is a complicated word, but to me it means deep responses, complete responses, ability to stop the treatment. There are more complete responses with the len-bel combo than cabo. The numbers are small. It's like 4 versus-
Pedro Barata: 5 versus 1% or so.
David McDermott: ... Right. So you have to squint to see it. So it's a step forward, proof of concept, getting to the question of what creates VEGF resistance. In the preclinical models, getting back to that, what people have shown is that increased HIF-2 expression probably drives VEGF. And this LITESPARK-11 is sort of proof that if you're targeting the pathway in two separate locations, you can get additive benefit.
Pedro Barata: Yes.
David McDermott: But to your point of synergy, hard to define, we're probably not seeing it with today's data.
Pedro Barata: Yet?
David McDermott: Yet.
Pedro Barata: This is wonderful because obviously justifiable, there's a lot of excitement around HIF-2α as an MOA, belzutifan is maybe the first-in-class used in clinical practice, maybe not the only one in the future-
David McDermott: Correct.
Pedro Barata: ... which is great, right? So it sounds like a lot of amazing research like yours with cyclin stories. Beautiful. So, thank you so much for taking the time to be with us and congratulations again.
David McDermott: Glad to be here, Pedro.
Pedro Barata: Sure.
David McDermott: Thanks for having me.