So LITESPARK-024 came out of preclinical work from the Kalin lab, which has done so much to help us understand the HIF2 pathway in kidney cancer and in other areas, and helped in the development of Belzutifan as the first in class HIF2 inhibitor. And they were asking the question, like, what might improve HIF2 blockade as a tumor-targeted therapy in kidney cancer? At this meeting, we’re hearing a lot about combinations with HIF2 blockade, both with PD-1 in the adjuvant setting and VEGF in the second-line setting...
So LITESPARK-024 came out of preclinical work from the Kalin lab, which has done so much to help us understand the HIF2 pathway in kidney cancer and in other areas, and helped in the development of Belzutifan as the first in class HIF2 inhibitor. And they were asking the question, like, what might improve HIF2 blockade as a tumor-targeted therapy in kidney cancer? At this meeting, we’re hearing a lot about combinations with HIF2 blockade, both with PD-1 in the adjuvant setting and VEGF in the second-line setting. But their question was different. It’s like, how do we target the tumor in a combination way to improve outcomes in patients? And what they saw in their VHL mutant mouse models was that if you combine CDK4-6 inhibition with palbociclib with a tool compound for HIF2 blockade, you saw actually synergistic improvements in the mouse models. So the question was, could we test this in humans? So we developed a study that had two parts. Part one is what I’m reporting on today, which is looking at essentially a dose escalation. All patients started at the standard dose of Belzutifan at 120 milligrams per day. And then gradually we increased the dose of palbociclib to get up to the top dose. So we did three dose levels. We smoothly got up to the full dose of both agents. The FDA then weighed in and wanted us to then expand all three dose levels. So we enrolled a total of 60 patients at all three dose levels. At the top dose level, we saw interesting efficacy. At all dose levels, we saw some significant toxicity, a lot of grade three toxicity, mostly things that we’ve seen before like anemia, hypoxia, neutropenia was the only one that seemed dose related. As you increase the palbo dose, we saw more neutropenia. No new tox, all the tox was measurable, and we defined the randomized phase 2 dose as the full dose of both agents. On the efficacy side, if you just focus on the highest dose, the response rate was not higher with palbo and belzutafan than you might expect with belzutafan alone. It was only about 21%. But if you look at the primary progression rate, which was 5%, and the disease control rate, which was over 70%, both of those are better than what you’d expect with belzutafan alone. Because one of the weak parts of the LightSpark 005 data set is that so many patients have primary progression when they start on belzutafan. So that was much lower. PFS, admittedly, in a single-arm study of only, in this case, only 19 patients, was nine months, which is also greater than you’d see with belzutafan alone. So this suggested that the combination might be more efficacious than single-agent, but because the toxicity didn’t seem to outweigh this increased efficacy, the sponsor decided not to go to the randomized portion of the study. So we’re just reporting on the first part. But I think the first part is interesting because it supports the hypothesis that the Kalin lab developed in their models, which is that if you combine CDK inhibition with HIF2-alpha inhibition, you see more efficacy. And now it’s up to us to try to build on this, and potentially we could build on it with new HIF2 inhibitors or new inhibitors of the cyclin D1 axis, which are in clinical development, and several companies have those. So hopefully we can come back to this work as sort of a proof that maybe tumor targeting in kidney cancer has a future, and this would be the first study to move us in that direction.
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