Belzutifan Plus Cabozantinib Shows Manageable Safety with Promising Antitumor Activity In Treatment-Naïve Advanced Clear Cell RCC, The LITESPARK-003 Study - Toni K. Choueiri

October 16, 2022

Alicia Morgans is joined by Toni Choueiri in a discussion on integrating therapies earlier in the treatment landscape for renal cell carcinoma (RCC), specifically highlighting the HIF-2α inhibitor and the phase 2 study of belzutifan plus cabozantinib as first-line treatment of advanced RCC, the LITESPARK-003 study. This was an oral presentation at the 2022 ESMO meeting. Belzutifan, a first-in-class HIF-2α inhibitor, has shown antitumor activity and favorable safety in heavily pretreated advanced RCC and in patients with von Hippel-Lindau disease-associated tumors. Cabozantinib, a multikinase inhibitor that targets VEGF, is approved for advanced RCC. LITESPARK-003 was designed to assess the use of belzutifan plus cabozantinib for treatment-naive patients with advanced RCC.


Toni K. Choueiri, MD, Jerome and Nancy Kohlberg Professor of Medicine, Harvard Medical School, Attending Physician, Solid Tumor Oncology, Dana-Farber Cancer Institute, Director, Genitourinary (GU) Oncology Disease, Center, Dana-Farber Cancer Institute, Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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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: Yeah. 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 presented also, an update in previously treated patient, with a combination of cabozantinib and belzutifan, and the update looks good. The numbers are maintained, the responses are durable, and there was 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 group, the combination of the VEGF inhibitor cabozantinib and the HIF-2α inhibitor belzutifan, that's the LITESPARK. And the result were quite exciting, I would think. Compelling result was 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 best response, this is certainly a study that we need to watch closely, need to watch the update, and the next generation of studies with HIF-2α inhibitors.

HIF-2α inhibitors are being integrated in 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 patient to the control, pembrolizumab/lenvatinib, and in each arm at 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, combine the lenvatinib with the HIF-2α inhibitor, belzutifan. So this study is also accruing.

And finally, even earlier, 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 patient with high-risk renal cell cancer of clear cell histology, get randomized to pembrolizumab as the control now. The factor control. Versus pembrolizumab plus the HIF-2α inhibitor belzutifan. Primary endpoint being disease free survival, and 1600 patient plan. 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 outcome 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, remain 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 patient. This is for some time now, the enrollment was slow. But to 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 is seems that, to be combinable with immune checkpoint inhibitor and VGF inhibitor. Well, VGF inhibitor has been harder, in some situation, to be combined. So that's one of the advantage is tolerability.

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