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Pedro Barata: I'm Pedro Barata. I'm a GU oncologist, a clinical trialist out of University Hospitals Seidman Cancer Center at Case Western Reserve University in Cleveland, Ohio. Today, I'm very happy to be joined by Dr. Chahoud from Moffitt Cancer Center, a kidney cancer leader there and a really great clinical trialist. And we're going to be talking a little bit about the STELLAR II data that you did a wonderful job presenting during ASCO. So congratulations, and thanks for taking the time.

Jad Chahoud: Thank you. And thank you for having me, Pedro. We're going to have fun talking about STELLAR-002.

Pedro Barata: Yes. So I'm biased because I happen to have that study at University Hospitals as well. And it's really interesting trial, in my opinion, from a lot of reasons. The STELLAR-002 is testing Zanzalintinib, known as XL092, along with the immunotherapy. And the data that you presented is relevant for patients with clear cell renal cell carcinoma because you presented data regarding a doublet with a PD 1 inhibitor, nivolumab, but also with a triplet and the LAG3.

So tell us a little bit about who are the patients that you present the data on on these two cohorts from the STELLAR-002 trial.

Jad Chahoud: So as you know, STELLAR-002 is a dose escalation, dose expansion clinical trial that is evaluating zanzalintinib, which is a novel, multi-target TKI that has-- one of its specialties, it has a short half life. So it helps us a bit more with the TKI-related adverse event that we usually face. It's easier to manage in the clinic.

And it's being explored in combination with the PD-1 checkpoint inhibitor, nivolumab, as an arm in clear cell RCC first line stage IV patients and PD-1 plus a LAG-3 inhibitor, relatlimab. So the steroid, too, has multiple expansion arms.

Today, I presented the expansion arm for first line clear cell RCC. So we have a second line non-clear cell. Second line clear cell RCC, as you know. You're one of the lead PI's on that trial as well. So today, we presented that data.

We had 40 patients in each of the different arms. So arm one we're going to call it was nivo plus zanza. And the other arm was nivo plus zanza. We had picked the good dose at 100 milligrams. So the treatment was every four weeks. There were 40 patients on each arm.

This was not a randomized controlled trial, so it was sequential enrollment. So we started first with the nivo-zanza arm. So you have a longer follow-up data on that. So the median time of follow-up for that arm was around 20.1 months. On the other hand, the median follow-up time for the other arm was 15.9 months.

So you would see some differences in patient characteristics as well because, it's non-randomized. But I think the patient population reflects a lot of the real world clear cell RCC patients that we see, even on both arms. So it had 25% of favorable risk. 75% intermediate and poor. And that's what drives most of our disease prognosis.

Yes, you may have some patients who had more prior nephrectomy with 90% of patients on the doublet arm versus 65% on the triplet arm. And yes, you may have some more bone mets on the triplet arm. Maybe less on the doublet. So some small nuances that usually happen with phase I, Phase II dose expansion cohort. But nevertheless, I think both cohort are representative of real world RCC patients.

Pedro Barata: So wonderful. And I don't know. You tell us, because I know you had a lot of patients in the Florida area who were able to enroll in this study. So you have, actually, huge experience from using these new TKI and these new combination. For us, and as you mentioned, using 100 milligrams with the ability to go down. Dose minus 1, dose minus 2, 60/40. You could even do 20 in some situations.

So how was that experience of talking to your research team, seeing these patients, the ability to adjust dose, if you will, associated with a shorter half life? I'm curious to get your thoughts about is it feasible, and does the data that you presented reflect what you've seen in your experience at Moffitt in regards to these patient population?

Jad Chahoud: Thank you for that great question. It gives me the opportunity to thank my research team, because they did a lot of heavy lifting. And they gained a lot of experience with this drug. And one of the easier things, yes, we had some dose reduction in a lot of the patients starting from the 100, and most of them settled on the 60 milligram dose.

Some are still continuing on 100 milligram dose with good responses, and we can talk about clinical activity later. But one of the good flexibility point is that when a patient would call our research nurses or nurses team with the side effects or whatever, stopping early on, patient would recover and feel safe.

And we didn't have to send any patient to the emergency room. We only had two grade 4 adverse event in each of these cohorts. So most of the grade 3, 4 adverse event data that's presented is mainly grade 3 manageable.

And one of the interesting things that I felt the patient tolerated better was the PPE. That's a bothersome symptom for the quality of life. The patient, especially if they're active and working, standing on their feet or whatever. We only had 5% of patients having PPE in both cohorts in total. So a good number in comparison to other TKIs.

And yes, you will have all the other common TKI side effects that we see. Hypertension. Blood pressure. Nausea. A little bit less nausea and vomiting. We had similar numbers that we expect with diarrhea, but a bit less in the nausea or vomiting that we would expect with what we know historically with IO-TKI's.

Pedro Barata: So that's reassuring, because actually this compound is being developed in different contexts, including non-clear cell that's just completed accrual for a phase III trial, also with the same combination showing clear cell frontline.

So let me just-- since I have you here to pick your brain on the efficacy data. And I'll make one or two comments. When we saw the clinical activity of these combination regimens, two comments or two things crossed my mind. One, it's definitely an active combination with a PD-1 as backbone. Not really surprising.

Zanzalintinib, based on the MOA associated with checkpoint, not surprisingly good and active. It helped a lot of patients. To me, it's good to see the low PD rate. Very low PD rate, I should say, particularly.

From another perspective, perhaps a little bit underwhelmed or disappointed as such, if you will, on the triplet with the LAG3 component. There's this excitement that came, I think, from the melanoma world, and we were trying to figure out if that's the case in kidney cancer world.

And at least in this effort, I didn't see a signal that I would love to see, or perhaps that did not match my enthusiasm when I saw the melanoma data. Would you agree with that? Is that fair? What are your thoughts on that?

Jad Chahoud: I think I completely agree with that, but with a couple of comments. So I was as well excited about Rela. Even before seeing the data, I was biased because patients on the triplet did not feel like on a triplet with ipilimumab. They felt better. So we had less complication.

Yes, we had some rashes. That is expected with relatlimab. And we know that, relatlimab. We know that from the melanoma world. The caveats that we could have are basically the shorter follow-up time that we have.

We have five patients that are still in partial response but could transition to confirmed partial. So that would increase it 10%. Still there can be-- still going to be in the 50% response rate. Not as great as we would hope for.

The last thing that also I remind myself of is, even looking at CheckMate 214 data. If CheckMate 214 was running today in comparison to IO-TKI's, we would have called it maybe a failure because of a response rate of 45%. Not the best PFS point.

And that's a reminder that immune checkpoint inhibitor benefit is more on the tail of the OS curve. So that's the only still sliver of hope-- is with longer follow-up, maybe we can see an OS signal on that tail of the curve for those patients.

And the reason why I'm saying that as well is that we see a high percentage of stable disease patients. And if you look at the spider plots, you can see that the stable disease and the responders have long, durable-- so they're still in response beyond the 12 month mark on both arms, which is maybe expected with RCC. But we hope with longer follow-up, if that holds on, then that could be a signal. But as you said--

Pedro Barata: As of now--

Jad Chahoud: As of now, the data is underwhelming and does not appear to be a slam dunk in objective response rate and PFS at least.

Pedro Barata: So you raised very good points. As you were talking, it crossed my mind that you're right. When we see a response, at least with the IO-TKI's that are available for us to use, duration of response is close to two years. Not quite around 20 months or so if I quote that.

So you're right. You don't have enough follow-up to appreciate exactly for how long patients stay without progressing. So on top of that, you also don't know the median the tumor control measured by progression free survival, exactly to your point.

And then, it sounds like you're right. Can you leverage on bringing a LAG3 into the combination strategy to bring those tail of the curves, those durable remissions, a little bit over what we are used to see? Which you normally quote in the 20% range or so. Certainly around those numbers. And can that number get much higher?

I know your fantastic point. And by the way, maybe we should highlight efforts from colleagues of ours. There's a study called ARCITECT running, a consortium that's basically looking into the addition of also LAG3 inhibition on top of ipi-nivo as backbone.

This is different, because you have a TKI with an IO, and you bring in another IO therapy. So there are definitely nuances. I think we're learning a lot more about triplets, to your point. And with COSMIC-313, cabo, ipi, nivo, we got data during ASCO PDIGREE, although it's basically what happened to the patients with step two. It's a little bit different information now, and the data you just presented.

I think we're learning a lot more. And apparently, these frontline spaces is going to change. We have that sense that it's going to change. How? Maybe new MOAs. Maybe different strategies. Maybe adaptive approach.

So to me, it's very good news. And there's A lot of hope. And there are a lot of new efforts and big, important efforts being put into these space. So that's good news.

Jad Chahoud: That's great news for the kidney cancer patients and us advancing kidney cancer patients' outcomes. Because the earlier you go, the better your shot at having patients push that long tail of the curve with long overall survival.

With efforts like CheckMate 214, we pushed the needle forward with the IO-TKI combination. We pushed the needle forward. And I think the field needs to try to continue trying to figure it out and getting more. And the best way of doing it is gathering information from all these amazing, large effort PDIGREE. 1,111 patients on an Alliance trial. That's a huge effort that is going to give us a lot of information to help guide the future of frontline therapy.

Pedro Barata: Wonderful. Listen, thank you for taking the time. Again, congratulations. Great job doing ASCO. Very important. Very promising. I'm sure everybody's going to keep the eyes and get a more follow-up up data as you see how these patients are doing and learn from that. So congratulations.

Jad Chahoud: I'm excited to be here with you and excited to see more follow up.

Pedro Barata: Thank you.