Alicia Morgans: Hi, I'm thrilled to be speaking today at ESMO 2022 with Dr. Toni Choueiri of the Dana-Farber Cancer Institute. Thank you for being here with me today.

Toni Choueiri: Thank you, Dr. Morgans.

Alicia Morgans: Wonderful. I wanted to speak with you today about some of the work that was presented at ESMO this year, related to the LITESPARK program for kidney cancer. Can you share a little bit of those details?

Toni Choueiri: Yes. It was a pleasure bringing the HIF-2α inhibitor, belzutifan, into the therapeutic landscape in kidney cancer. We presented some updates from the VHL data. We also presented an update in previously treated patients, with a combination of cabozantinib and belzutifan, and the update looks good. The numbers are maintained, the responses are durable, and there were no signs of new toxicities.

But the most important one, I would think, in the oral session, was for the first time, an untreated patient with clear cell RCC of all risk groups, the combination of the VEGF inhibitor cabozantinib and the HIF-2α inhibitor belzutifan, that's the LITESPARK. And the results were quite exciting, I would think. Compelling results were a response rate of 57%, and the PFS of 30 months. This is really quite impressive. Nevertheless, the follow-up is short. So this is, in a way, an actuarial PFS that is not very stable.

But if you look at tumor shrinkage, the fact that no patient has PD as the best response, this is certainly a study that we need to watch closely, need to watch the updates, and the next generation of studies with HIF-2α inhibitors.

HIF-2α inhibitors are being integrated into the landscape of RCC, in the therapeutic landscape, in earlier settings. So for example, in first-line untreated metastatic RCC, there is a study by the name O12, that randomizes patients to the control, pembrolizumab/lenvatinib, and in each arm adds either a CTLA-4, or a HIF-2α inhibitor, belzutifan. This study is accruing.

There's another study in second-line or later, in the refractory setting, that uses cabozantinib as control, usually post-immunotherapy. And then, combines lenvatinib with the HIF-2α inhibitor, belzutifan. So this study is also accruing.

And finally, even earlier, there is the adjuvant study. So there'll be a lot of talks about ESMO 2022, and the negative adjuvant study. We have Phase III negative studies with immune checkpoint inhibitors, atezolizumab, nivo/ipi, nivolumab, neoadjuvant and adjuvant. But nevertheless, pembrolizumab is the only PD-1 inhibitor approved with positive results.

So building on pembrolizumab, LITESPARK-022 is a study in the adjuvant setting, where patients with high-risk renal cell cancer of clear cell histology, get randomized to pembrolizumab as the control now. The de facto control. Versus pembrolizumab plus the HIF-2α inhibitor belzutifan. The primary endpoint being disease-free survival, and 1600 patients planned. And actually, we have the study open and accruing. So certainly, HIF-2α as a target. This was in part, our colleague, Bill Kaelin, Nobel Prize in 2019, from Dana-Farber. Certainly, this is paving the way for improving outcomes in RCC, how you integrate HIF-2α inhibitor. A very, very thrilling and exceptional, really exceptional, time in kidney cancer.

Alicia Morgans: Absolutely. And so interesting too, just to think back, as you mentioned, for no patients to have progressive disease as their best response in this particular study. That, to me, is pretty striking. In a solid tumor, it's very unusual. So the power of that combination, whether it's in the work presented, or moving potentially, as you said, in studies all the way to the adjuvant setting, is really exciting.

Toni Choueiri: Absolutely. And now having such a 35-patient, but nevertheless, remains exciting. And there weren't many patients with poor-risk disease. So a lot of favorable and intermediate. So it is a population where you expect that cabozantinib, a single agent, even does well. But nevertheless, this could be sometimes, an alternative with non-IO. So certainly, this is something to look at. We were able to enroll patients. This is for some time now, the enrollment was slow. But having patients front-line untreated with IO and get responses, what's the biology behind it, is very special.

Alicia Morgans: Absolutely. So what is your message on this program, the LITESPARK program, and really, the future of HIF-2α in kidney cancer?

Toni Choueiri: I think, it's something that came to us, and we have driven it from late stage to early stage to benefit patients. I am quite, I would say, happy with the drug in itself, as a drug that is first and foremost tolerated. Most of the side effects include anemia, which is due to the drop in erythropoietin that happens fast. But also hypoxia, we have to be careful about it. But it seems to be combinable with immune checkpoint inhibitors and VEGF inhibitors. Well, VEGF inhibitors have been harder, in some situations, to be combined. So that's one of the advantages is tolerability.

We have to see the quality of life that comes. The first randomized trial of single-agent HIF-2α inhibitor versus a control, finished accrual, that study by the name 005, in previously treated patients, up to, I believe, three lines of therapies. Patients receive control, everolimus, post-VEGF, post-PD-1, versus belzutifan. This study will also have quality of life data. Will have more data about single-agent activity. So it's important, and hopefully, the results will come soon.

Alicia Morgans: Absolutely. Well, there's always more to hear, I think, when I talk to you. But I'm really glad for all the work that you, the team, and the whole group of people involved in the LITESPARK program, are really moving the field forward with this novel mechanism, and it's exciting. So thank you for your time and your expertise today.

Toni Choueiri: Thank you, Dr. Morgans, and thank you UroToday.