Pedro Barata: Hello and welcome. My name is Pedro Barata. I'm a GU medical oncologist out of University Hospital, Seidman Cancer Center, Case Western Reserve University in Cleveland, Ohio. Today I'm being joined by Dr. Michael Serzan, a renowned GU oncologist out of the Lank Cancer Institute, Dana-Farber in Boston.

Michael Serzan: It's a pleasure to be with you, Dr. Barata.

Pedro Barata: Well, thank you for joining us and taking time from the busy 2025 annual ASCO to talk a little bit about what I think is one of the highlights in the kidney cancer arena this year. And that has to do with the presentation of the phase 1-- on one of the cohorts of the phase 1 study-- involving these novel HIF-2 inhibitors, AB521, or Casdatifan, along with cabozantinib for refractory patients with clear cell RCC.

I know you've been heavily involved, so maybe we'll start by asking you briefly. Tell us a little bit about that combination, doses, and what basically was presented here at ASCO.

Michael Serzan: The Casdatifan program is really building on the belzutifan studies that we've seen. We now know that belzutifan is approved in the treatment-refractory setting for patients with clear cell kidney cancer. And Casdatifan is a similar oral transcription factor inhibitor of HIF-2 alpha.

We've seen phase 1 studies presented at GU ASCO 2025. We've seen response rates anywhere from the 25% to 30% range in the treatment-refractory setting. However, relative to belzutifan, we're actually seeing slightly lower rates of hypoxia and potentially lower rates of anemia as well. One of the Achilles' heel of HIF-2 alpha inhibition is that it takes a little while for those drugs to kick in and take effect.

On the original LITESPARK-005 study, we saw a primary progressive disease rate of about 20%. And so the thought is, can we pair HIF-2 alpha inhibition with VEGF TKI inhibition to hopefully bridge patients to the response and get that long-term benefit from the HIF-2 alpha inhibitor?

And so that sets the rationale behind combining cabozantinib-- one of our tried and true workhorses, multi-kinase inhibitors-- with Casdatifan, one of our emerging HIF-2 alpha inhibitors, to see if we can longitudinally block both the transcription factor HIF-2 alpha and the downstream VEGF component, and hopefully improve the durability of response to that combination.

Pedro Barata: So, perfect summary. As you go back a few years, you got data with belzutifan that led to the approval of the agent in the refractory setting, as you said, out of the LITESPARK-005 study. And then you had monotherapy data with this AB521-- now you know the name-- Casdatifan.

And then combining what is accepted by many as the go-to TKI of choice in the refractory setting-- cabozantinib-- for patients who progress on a prior checkpoint inhibition. And it's interesting that both therapies leveraging HIF inhibition have been tested out along with TKI. So it appears there's interest in the field to explore combination strategies involving TKI or anti-VEGF along with HIF inhibition.

So I think the data are provocative: responses over 45% or so, minimal progressive disease. I know it's not a huge set of patients-- around 40 or so patients-- but what's your take on the data from efficacy, but also from the safety perspective? Specifically on the combination-- and with 60 milligrams of Cabo, correct?

Michael Serzan: Yeah, I think it's a great point. It's a hefty dose of cabozantinib. And we see, again, rather modest rates of grade 3-4 adverse events. Again, anemia and hypoxia, which we know are class effects of these HIF-2 alpha inhibitors. But very low rates of treatment discontinuation. Less than 10% for either of the two agents or both together-- telling us patients are able to stay on therapy for longer with dose holds and dose reductions as we get used to managing those toxicities.

You mentioned response rates in the 40% range. However, I'll also note the median follow-up is only 2.9 months. And I'm very intrigued to see, as we continue to follow these patients over time, are we going to see some of those responses go up and hopefully see greater durability when we use the combination?

Pedro Barata: You raised a very good point. I'm glad you brought that up. Very short follow-up, which tells us two things. One, you’ve got to wait to see how long-lasting those responses are. And the other piece of the story is, it appears that you're getting what you get from a TKI, which is time to response being relatively fast. With a short follow-up, you already have that response evaluation, where almost half of the people actually had tumor shrinkage of 30% or more, which is quite remarkable.

And of course, the primary progressor seems to be minimal, which is actually very encouraging. I agree with you fully. Where do you think we're going to go with it? There are other therapies out there, both obviously anti-VEGFs and, in this case, even the inhibitor. So what do you think we're going to go?

Michael Serzan: So there's a large phase 3 trial that has been launched, investigating this combination. It's for patients who have received prior anti-PD-1 therapy. And patients are randomized to either this combination of cabozantinib plus Casdatifan or cabozantinib monotherapy.

And I think this is a really important question for our field and a place where we really don't have a ton of data-- for patients who have had progression of disease on prior immunotherapy. What is the best approach? And I think the standard at this point is probably single-agent VEGF TKIs. But I really think the HIF-2 alpha combination has the potential to decrease primary progressive disease and hopefully extend the benefit that we get out of our VEGF TKIs in the second and later lines of therapy.

Pedro Barata: Now, you're raising a very important point, because it is the standard of care today. Of course, I think as we think of HIF inhibition and combination strategies, it comes to mind-- the LITESPARK data that has not read out yet. The combination of lenvatinib with belzutifan compared to cabozantinib. And it will be interesting to see what those results look like.

We got, I think, maybe a quick peek into-- not that trial, but that combination. Katy Beckermann presented very elegant data on the UMBRELLA study, which actually looks at that as part of one of the cohorts. So it's interesting to see. I'm very curious to see-- we're talking about PFS-- how the LEN-BEL combo looks in relation to a TKI monotherapy standard of care, as you pointed out.

And then the other thing that comes to mind is-- as we were chatting earlier today as well-- trying to move these agents early on. Belzutifan is being tested in frontline, and then AB521-- Casdatifan-- is also being tested with immune checkpoint inhibition in the frontline space. So it's going to be very interesting to see where we're going to be using perhaps these novel inhibitors, if they get approved, if the studies are positive, and helping patients.

In what setting? Is it going to be monotherapy in the refractory setting? Combined with TKI in the refractory setting? Perhaps in the frontline for treatment-naive patients? So it's really, really a lot of movement-- bringing these new MOA or new classes of therapies into the earlier stages for advanced clear cell RCC. Any final thoughts, Mike, you want to share with us today?

Michael Serzan: Yeah, as you mentioned, I think HIF-2 alpha is the way of the future for clear cell kidney cancer. And I think it's both because of its unique mechanism of action-- directly targeting the transcription factor that drives many kidney cancers-- but also because of its rather favorable adverse-effect profile.

It's easier to combine with other therapies than maybe some of our VEGF TKIs or CTLA inhibitors. And so I think the therapeutic window of this class of medicines is quite promising and therefore gives us a lot of options on when and how to best employ it.

Pedro Barata: Wonderful. Well, fantastic talk as always. Thank you for joining us and educating us on next steps for HIF inhibition in the kidney cancer arena. So thank you so much.

Michael Serzan: My pleasure.