Combining Radioligand Therapy with Cabozantinib and Nivolumab in Advanced Clear Cell RCC - Eric Jonasch

January 27, 2025

Eric Jonasch discusses a phase Ib/2 trial examining the combination of lutetium-177 girentuximab with cabozantinib and nivolumab for advanced clear cell renal cell carcinoma. The study explores using radioligand therapy targeting carbonic anhydrase IX to enhance immune response through increased DNA damage and STING pathway activation. Set to begin enrollment in early 2025, the trial incorporates comprehensive endpoints including clinical outcomes, SPECT imaging, and F-AraG PET to track activated T-cell response. The researchers hypothesize that this novel approach could improve complete response rates beyond the current 10-16% seen with IO/TKI combinations. Dr. Jonasch emphasizes the potential broader implications for radioligand therapy in RCC treatment, suggesting its role could expand based on demonstrated biological synergy with immunotherapy and monotherapy activity.

Biographies:

Eric Jonasch, MD, Oncologist, Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX

Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Wellstar MCG, Georgia Cancer Center, Augusta, GA




Read the Full Video Transcript

Zachary Klaassen: Hi. My name is Zach Klaassen. I’m a urologic oncologist at the Georgia Cancer Center in Augusta, Georgia. I’m delighted to be joined on UroToday by Dr. Eric Jonasch, who is a medical oncologist at the MD Anderson Cancer Center. Today, we’re going to be discussing an SUO 2024 presentation entitled “Phase Ib/2 Study of Combination 177 Lutetium Girentuximab Plus Cabozantinib and Nivolumab in the Treatment of Naive Patients With Advanced Clear Cell RCC.” Dr. Jonasch, thanks so much for joining us on UroToday.

Eric Jonasch: Yeah. Great to be here. Thanks for the invite. This study is a trial in progress. The study is actually about to start enrolling patients. The manufacture of the lutetium girentuximab is being set up at MD Anderson as we speak. But the idea here, the hypothesis, is that we know that the combination treatments of IO/IO or IO/TKI in individuals with advanced renal cell carcinoma result in complete response rates somewhere in the 10% range, maybe up to 16% with lenvatinib and pembrolizumab. And what patients really want is to have an increase in that complete response rate.

We’re conceptualizing that by using relatively low doses of radiation, which are going to be delivered via antibody—girentuximab is an antibody against carbonic anhydrase IX, which is found on the surface of tumor cells—and it’s tagged to lutetium 177, which is a beta emitter. This is going to result in some increase in DNA damage, which will then result in STING pathway activation in the tumor cells, which is going to result in an increase in elaboration of CCL5 and CXCL10 and other chemokines that are going to result in more immune cell infiltration. So we hope to make the tumor hotter, which will then improve the treatment with nivolumab and cabozantinib.

So one of the questions which arises here is, why not use nivolumab and ipilimumab instead, which would be more of a clean immunological combination that we would then use together with this? And that was because, when this trial was conceived, the toxicity of ipilimumab/nivolumab was considered perhaps to be a little too high. In 2025, I think we would probably be ready to consider that as one of the doublets to use together with this.

This is a trial that’s basically for individuals with previously untreated metastatic renal cell carcinoma. It’s also very rich from an endpoints perspective—both obviously clinical endpoints (our hypothesis is that we’re going to increase the complete response rate) and we’re also looking at SPECT imaging. So we can use the lutetium girentuximab as a way then to look at the tumor cells and the change in the avidity of the SPECT imaging over time as we hopefully decrease the number of tumor cells.

The other thing we’re using is F-AraG PET. AraG is a compound that is taken up by activated T cells, but not by non-activated T cells. And so we’re also going to be doing PET imaging to look at the F-AraG levels as a function of treatment. We would expect that F-AraG levels will increase over time if we’re getting a response and we’re getting a treatment effect, and we’ll then see the SPECT imaging go down.

So it’s a complex study, but one that also has biopsies at various time points. We expect to launch enrollment in the first quarter of 2025. This will be a multicenter study. We expect accrual to take about a year and a half or so, and we hope to get some results in the next two to three years.

Zachary Klaassen: Great overview of that study. As somebody who treats a lot of kidney cancer from a surgical perspective, it’s exciting to see that RLT is coming into the trial phase for advanced clear cell RCC. You addressed it a little bit in your presentation about the choice for nivolumab plus cabozantinib. I’ll maybe rephrase the question: is it possible we could see this with lenvatinib plus pembro, maybe axi plus pembro? How was it sort of selected that this would be the go-to right off the bat for this trial?

Eric Jonasch: It’s a combination. Cabo/nivo is a combination that our center is very comfortable with. The data for cabo/nivo are good. But absolutely, any of the other doublets, including ipi/nivo, would be reasonable here. And it’s really a question of whether or not you’re potentiating immune responsiveness in any of these doublets.

Zachary Klaassen: For sure. And I think you mentioned the timeline—probably a couple of years before we see data. Let’s fast-forward maybe three to five years down the road. This trial has already presented; perhaps there are phase III trials. From a high level, where could you see radioligand therapy fitting into the treatment landscape in the first line, or even beyond for the second or third line in metastatic RCC?

Eric Jonasch: I think it really is going to be a question of whether monotherapy radioligand treatment has any activity, and whether it be a beta emitter with lutetium, or whether it’s going to be with an alpha emitter with actinium—that I think is going to help decide whether, for example, an agent like that would be a monotherapy in the refractory setting.The second question is, does it actually potentiate an immune response? And if it does, then we could see it as a helper in the earlier line setting together with immunotherapy. So I think it really ends up being whether or not we’re seeing any type of biological synergy with other agents and monotherapy activity.

Zachary Klaassen: Yeah. Excellent. I think CA9 is such a good target for clear cell RCC. We have a population of maybe 20% to 30% of non–clear cell. A majority of those may be papillary. Could you see a target for RLT even in the papillary RCC space as well, potentially coming down the line?

Eric Jonasch: Yeah. It’s going to be a question of what you would be targeting. For example, CD70 is expressed at reasonable levels in papillary renal cell carcinoma. We know, for example, EGFR is potentially expressed in that patient population as well. So I think in general, the idea—and we’ve seen this in oncology—you find a particular surface protein that’s expressed robustly, and then you have some way of delivering payload to interact with that particular receptor. And I think in RCC—clear cell renal cell carcinoma—the real question is, what should that payload be? Because we know that tubulin inhibitors and various other things like that are probably not what we need for renal cell carcinoma. But the broad concept is a good one, and we just need to take advantage of it and find the right thing to deliver.

Zachary Klaassen: Yeah. Absolutely. Well said. Maybe just a couple of take-home messages for our listeners today. It’s an exciting trial in progress that we’re discussing.

Eric Jonasch: Yeah. So I think first of all, the study is testing the hypothesis that we can enhance immune responsiveness by using relatively low doses of radioligand therapy together with an IO/TKI combination. I think the second point is that we are in, I think, the infancy of understanding how to use things like antibodies—whether they deliver radiation or they deliver drugs, or perhaps even bispecific antibody–type treatments. These types of regimens and agents are likely going to find their way into the treatment of renal cell carcinoma, and we just have to make sure that these trials happen.

Zachary Klaassen: Yeah. Absolutely. We look forward to seeing these results in a couple of years, and in the meantime, we thank you for your time and expertise.

Eric Jonasch: Thank you so much.