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Pedro Barata: Hello and welcome. My name is Pedro Barata. I'm a GU medical oncologist out of University Hospital Seidman Cancer Center. That's Case Western Reserve University in Cleveland, Ohio. I'm very happy to be joined today by Dr. James Geller. Dr. Geller is an authority and key opinion leader in pediatric oncology. He's actually the former chair of the renal committee for the Children's Oncology Group, COG. And he has played significant leadership roles. So far and will continue to do so.

He's out of currently University of California San Diego Children's Hospital. Former affiliation in Cincinnati, Ohio. So not far from where I am. And it was really great to-- we felt it would be important and very important to talk today about the AREN1721 study and presented-- which was presented at ASCO 2025, and the efforts around rare tumors and the experience in non-clear cell RCC. So welcome, Dr. Geller. Thanks for taking the time.

James Geller: Well, thank you so much for having me.

Pedro Barata: Absolutely. So thank you for joining us. Such an important effort. You basically looking at combination of immunotherapy and targeted therapy TKI axitinib and nivolumab compared to single agent nivo for these patients with TFE translocation RCC. We know it's a rare disease. We have some data. I think we're going to talk a little bit about that about other data sets, including very small numbers. What a huge effort. Do you plan for about 28 or so patients to enroll in this study?

I don't-- unfortunately, we didn't get quite there. But I'm curious, can you-- I know it took some time to design the study and to implement it, and a big effort from around the country. Let me just start by asking you, can you walk us through why the combination of axitinib with nivolumab and tell us the rationale to combine it against an IO and how was this study born, and how do you pitch it around the cooperative groups around the country?

James Geller: Well, thank you for the question and for the opportunity to discuss this topic. I think it's important to focus in on rare cancers, and in particular, adolescent young adult cancers that spill into the pediatric space and the adult space, such as translocation, renal cell carcinoma. I initially presented our pediatric data at a KCA meeting going back to 2012, and at the time, several of the adult oncology key opinion leaders came up to us and said, that peds data is interesting. We see this in adults, too. We should run a collaborative trial and the COG should help lead this and bring it forward.

At the time, the TKI of dialogue was axitinib and we had to develop some phase I data for that in kids, which we did. And we initially drafted a phase II axitinib trial, but by the time that was written, the era of immune checkpoint inhibitors had entered into the RCC space. So there was a strong push by the collaborative groups-- the cooperative groups, to make sure we built in a immune checkpoint inhibitor.

The selection of the specific immune checkpoint inhibitor was more related to pharma support and who wanted to be involved in the trial. And that's how we came up with axitinib-nivolumab as our combination arm. So this grew out of a axitinib monotherapy arm trial to a randomized axitinib versus nivo versus axi-nivo study. And then as time went on, when accrual was a bit of a challenge, we dropped the axitinib monotherapy arm based on the input from the champions of the cooperative groups to say that everybody needs to get an IO, immune checkpoint inhibitor. And there was a little bit of clinical bias towards feeling the need for their patients to have access to that. So we dropped the axitinib monotherapy arm. And we can talk about whether or not that was a smart move down the road. But that's how we got to where we are with the trial.

Pedro Barata: Got you. And, of course, I think you use standard dose in the combination flat dose of nivolumab and then axitinib 5 milligrams twice a day?

James Geller: We allowed axitinib dose escalation. And we allowed the Q4 weekly nivolumab as well. As we moved on, we made the amendments throughout to accommodate the trends and desires that are more relevant in the adult medical oncology community.

Pedro Barata: Got it. So can you just quickly so as you alluded to [INAUDIBLE] patients, can you just walk us through briefly the main efficacy signal that you identified?

James Geller: Yeah. So ultimately we had 13 eligible out of age 15 enrolled patients. 12 of the patients overall were accrued through the Children's Oncology Group. The average-- the median age was 16 years and there were four patients greater than 18 years old and nine patients 18 and younger. So this is a largely pediatric, adolescent cohort. The signal that we saw was fairly robust, despite having six patients on the combination arm and five patients on the nivo monotherapy arm and two on the axi arm.

And in part, it was robust because nivolumab by itself showed no activity really whatsoever. All the patients who had received axi did not experience progressive disease as their best response. But four out of five of those who had nivo monotherapy did. And the median progression-free survival of the combination compared to nivo alone was 10 plus months versus less than two months. So we saw robust signal despite the small amount of patients with a significant p-value, in part because one arm was completely inactive and the containing arm that was a combination arm showed some activity.

We're not surprised by that. I think there's plenty of single agent reports with TKIs and TRCC. We were not able to determine what the added value of the immune therapy was due to dropping the certain arms and the accrual level.

Pedro Barata: No. Fantastic summary. I agree with you. We have at least two data sets in the form of studies. Single-arm studies. We're talking offline about that one lenvatinib with pembrolizumab. The other one cabozantinib nivolumab. And we see some activity. The activity doesn't seem to match what we see in clear cell RCC where we see 50%, 60% response rate and PFS is usually close to a year and a half, not quite, maybe 14, 16, 17 months or so depending a little bit longer length, but absolute numbers, although we don't do comparisons across studies.

So it appears that in this group of patients with this subtype-- RCC subtype, we see the activity is not quite there, but it is fair to say that there is an ongoing effort combining an IO TKI against sunitinib control, including also patients with translocation. So I think we'll have at least level 1 data. Of course, it wasn't power just for the translocation group. We'll see how many patients will end up there. Because on these two other studies I've just described, single digits. So you got 13 patients on this particular effort and unfortunately was not enough for your endpoint the way you designed it. But in the other, experiences with help of farmers support, we're talking 5, 6 patients or so.

So it's really hard to find these patients. And I agree with you, at least you're not in the United States. We can't ask this question for non-clear cell, what folks are doing and a good number of teams around the country are already offering an IO TKI combination. So I think you were ahead of the curve and in a form of how you design the study. So congratulations for that. But I really want to pinpoint on an aspect that you really brought up. which has to do with how hard it is for rare tumors to achieve the numbers that need to be achieved as far as sample size, to actually answer the question from the statistical point of view, particularly, with randomization is required?

So I'm wondering your thoughts. You learn a lot from working with different cooperative groups, including the SWOG alliance, and others. I remember-- I'm a SWOG person. I remember different teams bring it up in every single meeting trying to bring up raise awareness. But unfortunately, that was not enough on the adult side. Clearly COG did an amazing job on the children's side. So what are the lessons learned? And maybe I'll ask you another provocative question is, if you were to go back, do you think the field is ready for a different design where we don't use the same type of trial designs for rare tumors? What are your thoughts about that?

James Geller: Great questions, and I appreciate you asking them. Lessons learned. So the efforts that we did make to try and improve accrual included champions in each of the cooperative groups trying to raise awareness, letters of support from big centers, amending the protocol to accommodate the wishes of the evolving field. But it proved to be not attractive enough, at least in the adult cooperative groups, to enroll patients. There are many reasons for that. Some of them are logistic. Insurance covers these combinations for renal cell carcinoma. And not everybody diagnoses TRCC as quickly as we'd like.

There's awareness issues. But I think embedded in that is just because it's covered doesn't mean it's the right regimen. I think a lack of clinical equipoise did impact some of our practice. We want to believe immune checkpoint inhibitors are so robust and the thought that they're not part of the solution is difficult for us to get our heads around. I don't know what immune checkpoint inhibitors do for this disease. I have an idea of what TKIs do. And yet there was this bend that we had to have an immune checkpoint inhibitor.

So I think the key question going forward is going to be what do immune checkpoint inhibitors add, if anything? Because we do know there are toxicities to those drugs. They're not benign. So I hope that we can improve on our clinical equipoise and recognizing that this is a distinct disease and not just knee jerk into what we're doing for another group of patients. And think about these rare populations separately.

As to future trial designs, I can tell you that I can't speak for the Children's Oncology Group, although I've had conversations with its overall chair as both when I was as chair of the renal committee, but also as the protocol chair. And the appetite for COG to lead in this space where there's more adult patients than kids. TRCC accounts for about 50% of RCC in children and 1% to 5% in adults, maybe as high as 20% in adults younger than 40 years of age. But even though it's 50% of the kids, it's still vanishingly rare when it comes to numbers. So this is still a dominantly adult oncology disease in a younger adult population.

And if there's not a design, a novel design, or a combination or a novel drug, that's interesting enough to the adult cooperative groups, I don't think that COG can influence that. So lesson learned, that we really need not just buy in, but perhaps leadership from all the stakeholders to advance awareness and buy in and clinical equipoise. Whether we need to do a novel design, I don't know. The patients are out there. We just didn't get them on the study as well as we could have.

Pedro Barata: That's really well said. And yeah, we need to continue. I really think that stress out on one hand the importance of the cooperative groups. I mean-- again, I mean, getting 13 patients on this study is quite a remarkable effort, nonetheless, and actually better performance overall than what we've seen in some of the pharma-based efforts. So still, kudos to you for putting this data together. I think to your point around whether or not-- what is the contribution of the confidence in the form of IO? What is IO adds to TKI is a fantastic question.

I'm not sure efforts like STELLAR-304 will answer that because we are random-- the randomization is zanzalintinib which is a new TKI with nivolumab compared against sunitinib as a monotherapy. So to some extent, we'll look at how that patient population is going to look like. Again, the study has completed enrollment. It has not read out yet. And it has primary endpoint is PFS. But also looking at the OS. So it will be important to see how those patients do. And particularly, looking at the subset of translocation patients which were allowed. We'll see what happens there.

But to your point, I think we need to understand better the impact of immunotherapy in these type of tumors. And so with that said, I really appreciate your leadership in this. Really important I think the way moving forward, it still is collaboration between different cooperative groups. And I'm sure if you were to design the next study, you will take the lessons learned with you and you'll do it even better next time. And hopefully the community will stand behind your leadership and will help bring you more important questions or try to answer more important questions as they arise.

James Geller: Thank you very much. I agree that collaboration is the answer for these rare diseases, and I look forward to seeing more progress.

Pedro Barata: I look forward to seeing your paper as well. This amazing presentation at ASCO and fantastic presentation there. And, of course, it's always more difficult to put down as a form of the manuscript when the studies are not [INAUDIBLE]. But there's a lot you get to teach us with the experience around the study. So I'm really interested in reading the manuscript and learn some of that as well. Thank you very much for taking the time.

James Geller: Thank you for having me.