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Pedro Barata: Hello, everyone. I'm Pedro Barata. I'm a GU Oncologist at Case Western Reserve University, Cleveland, Ohio. Happy to be here today with Francesca, Dr. Francesca Jackson‑Spence, famous clinical research fellow at the Barts Cancer Institute in London, also a PhD student.

And I have the feeling we'll see her a lot more than the last time we saw her, which is quite a few weeks ago during ASCO GU. Wonderful job, Francesca, on the CALYPSO trial and the ctDNA data. So welcome. Thank you for joining us.

Francesca Jackson‑Spence: Thank you for having me.

Pedro Barata: Yeah. No, happy to have you here and pick your brain on a couple of things you went through during ASCO GU and a little bit of the data we're looking to see following the original CALYPSO presentation. But some of the folks who are listening to this might not be completely aware or might have that trial in mind.

So do you want to walk us through a little bit of what you presented, and then maybe we'll get a couple of questions that are hot topics now? Is that OK?

Francesca Jackson‑Spence: Absolutely. So I presented the final overall survival data for the CALYPSO study. I'm going to share my screen because I have this trial study design, which will be easy for people to follow. So I presented the final overall survival data and ctDNA analysis for the papillary cohort of the CALYPSO study.

This was a Phase II study initiated from Queen Mary University of London, which is where I'm employed. And this was a Phase II study investigating savolitinib, a MET inhibitor, in combination with durvalumab, an immune checkpoint inhibitor, in advanced papillary renal cancer.

The CALYPSO study also had a clear‑cell cohort, but that will be reported separately. Today, I'll just focus on the papillary cohort. We enrolled 41 patients with advanced papillary renal cancer.

They all had measurable disease. Some patients had prior VEGF‑targeted therapy, some had not. And savolitinib and durvalumab were given as combination together. Treatment was until progression.

The original primary endpoint of confirmed response rate and the secondary endpoint of progression‑free survival has been presented previously by Cristina Suárez and that was published in the JCO at ASCO GU 25. I presented the final overall survival data and the biomarker ctDNA analysis. And that's what we're going to chat about today.

Pedro Barata: Yeah, Francesca. This is a fantastic, good study design. Do you want to walk us through what you presented recently, specifically the ctDNA data?

Francesca Jackson‑Spence: So original data that was previously presented showed a confirmed response rate of 32% from the savolitinib and durvalumab combination in the papillary renal cohort. But, interestingly, the response rate increased to 53% in the MET‑driven tumors. And this resulted in a randomized Phase III trial, SAMETA, for which results are awaited.

We also did a biomarker analysis. And I'll quickly talk through the methods before I present the survival data. We've got four types of biomarkers.

ctDNA analysis was conducted using FoundationOne Tracker. So they do FoundationOne Tissue testing in combination with Natera ctDNA analysis on the plasma time points. Twenty‑one patients were eligible for ctDNA analysis, of which 48% of our patients were positive.

We also looked at MET‑driven status. Now, interestingly, MET status is defined as chromosome 7 gain, MET amplification, MET kinase domain variations, and HGF amplifications. And 41% of patients were MET‑driven.

We also did PD‑L1 analysis, which was assessed centrally using IC and TC staining, and 66% of our patients were PD‑L1 positive.

Tumor mutational burden was also analyzed using FoundationOne testing. And the median TMB was low, at 2.52 mutations per megabyte.

Here is the final progression‑free survival and overall survival in the intention‑to‑treat population: 6.5 months for progression‑free survival and 18.3 months for overall survival. But, here, you can see, in the MET‑driven subset, the PFS increases to 13.9 months, and the overall survival increases to 27.4 months, with the MET‑driven patients performing better.

This swim‑lane plot shows the duration of response, how patients are responding to therapy, and when they're progressing. And the median duration of response was 11.3 months.

Here is an overview of our PD‑L1 and TMB analysis. And you can see that neither of these biomarkers appear to be relevant in determining outcomes for patients. Here's a quick overview of our methods of ctDNA analysis. I've briefly touched on this. We started with 42 patients recruited onto the trial, 41 of which received treatment with the savolitinib and durvalumab combination.

We were able to do FoundationOne Tissue testing on 32 patients. And 21 patients had sufficient baseline tumor and sequential plasma time points for us to do a ctDNA analysis. This slide looks confusing, but it's actually very straightforward, so I'll talk you through it. First of all, this is an overview of the individual 21 patients included in the ctDNA analysis. Forty‑eight percent of patients were ctDNA positive at baseline.

Interestingly, only one patient had trackable MET alterations in the plasma. Being ctDNA positive was associated with a reduced likelihood of responding to therapy. We can see that 89% of the non‑responders in red were ctDNA positive at baseline, compared to just 22% of the responders in green. And here, in the middle, if you look at the circles, you can see many responding patients in green who are ctDNA negative, and many non‑responding patients who are positive. And there was no correlation with prior VEGF‑targeted therapy, MET status, or PD‑L1 status.

ctDNA status at baseline was prognostic for overall survival at baseline, when we compared ctDNA positive with negative. Ability to clear ctDNA, so going from ctDNA positive at baseline to ctDNA negative on treatment, was also associated with improved outcome. However, only two patients cleared their ctDNA with the combination.

And these results, we hope, will be validated in the randomized Phase III study, SAMETA, which has now completed enrollment. We're very excited about this. This study assesses the savolitinib and durvalumab combination, which was tested in this CALYPSO study, versus sunitinib alone or durvalumab monotherapy. And we're really excited about the results, which should be coming soon.

Pedro Barata: Wonderful, Francesca. This is super important data, so thank you for walking us through this, and also generated quite interesting discussion right during ASCO. So I guess one of the things that came to mind is, as you probably know, so two things.

One is the MET story. Actually, JCO has been liking the story quite a bit. And it's quite relevant. Toni's data with savolitinib monotherapy was initially published in JCO, now the CALYPSO, and we're looking forward to the SAMETA trial, as you said.

And what's interesting is we have been thinking that kidney cancer is probably not the disease for ctDNA because of the lower tumor shed compared to other tumors, like urothelial carcinoma. So, nonetheless, you show us that about half of the patients in your trial—of the 41, 20‑ish patients—got positive ctDNA at baseline, which is interesting.

And I think that's important because you're using a commercially available assay. And it's interesting to see if in the future we're going to have more studies looking at ctDNA. I would argue that what you've shown may be slightly surprising to some of us. Looking at the clearance and the prognostic value of the ctDNA is important, and it's interesting.

So one question that I'll have for you is, when you look at the patients—I know we're not talking about a huge cohort—but when you look at the patients with positive ctDNA versus those who didn't, did you find a pattern, whether the patients had the highest tumor burden or patients would have maybe more aggressive location of mets, like visceral disease, including liver or even CNS? In prior studies, for instance, I can tell you, for example, ctDNA cannot perform as well for patients with brain metastases, for example. So I'm wondering if that's something you can share with us about what have you learned from the ctDNA testing of this population?

Francesca Jackson‑Spence: Absolutely. I think it's important to emphasize that numbers are small. So we only have 41 patients in this cohort, 21 in the ctDNA analysis. So the number of patients with things like brain metastases are small.

On initial assessment between the two groups, actually, it was pretty comparable between the groups in terms of location of mets, prior therapies, and other biomarkers, like I mentioned, PD‑L1 and MET status as well. But we are going to do a deeper dive into actually assessing the burden of disease, which we'll publish in the manuscript. But the initial number of sites of mets is comparable between the two groups, which is interesting.

Pedro Barata: Right. I'm just curious. Since you've worked in a place that—or you're working in a place where biomarker‑driven research is really an important flag, I guess—and you're doing an amazing job on that. In the US, I can tell you that a lot of patients are not getting genetic testing.

You use FoundationOne study for NGS. Here, you're describing MET status. I can tell you, most patients are not getting genetic testing in the US. And I'm wondering if that is the case in England and in other places.

During your conversations, is that the sense that you're getting? Or is this story not compelling enough to look after it? Or because drugs like cabozantinib might have MET activity, folks are still not buying into the story around genetic testing, and we need to do more? What are your thoughts about that?

Francesca Jackson‑Spence: That's a great question. So, currently, in the UK, we are also not doing genetic testing in kidney and bladder cancer routinely. Of course, we have the National Health Service, so that sort of testing is not offered to everyone, particularly for these cancer types.

I think there is such a movement towards biomarker‑driven research. We're doing these sorts of biomarker assessments in all the trials we're running at the moment. And I think there will be a shift.

We need to better select patients for therapy, particularly for cancers like papillary renal cancer, when the options are already limited because the bulk of the research is on clear cell, right? So, right now, it's not something we're routinely doing.

But I think results such as that from the SAMETA trial, which we hope will be positive, showing that MET biomarker—it may be something that we start to do.

Pedro Barata: So, Francesca, I have maybe a last question to tease you a little bit. And let's do an exercise. Let's assume the SAMETA trial is going to be positive.

And just a reminder, three‑arm study—savolitinib with durvalumab, vs. sunitinib, vs. durvalumab monotherapy—so assuming the combination will be positive with savolitinib and durvalumab. And then you have promising Phase II data with cabo/nivo, which has MET activity, and you have lenvatinib/pembrolizumab, also Phase II. At least one randomized trial is looking into cabo, which has MET activity, plus atezolizumab called PAPMET2 as a cooperative group‑based study. And, finally, you have at least another randomized trial that I'm aware of—well, we have more than one, but one is the PAXIPEM trial, a French/European study with axi/pembro. And then another one would be the zanzalintinib with nivolumab.

In the world, if we can fast forward three or four years, where you have savolitinib with durvalumab, and then you would have one of these two or three combinations with a TKI in immunotherapy, what are your thoughts? Do you think people will look at the MET and kind of say, you know what, I'm going to use this because I have a MET inhibitor? Or do you think people are going to prioritize more the PD‑1 inhibition instead of PD‑L1 and would say, you know what, I would go after a TKI that has MET activity, even though we will have no data to support one or the other? Or do you really think the data, the outcomes of the patients in each one of these trials, will drive what folks will decide?

I know we're speculating here, but, I guess, why not, right? So what are your thoughts? Assuming we'll have different combinations out there in a couple of years, how do you think it's going to play out?

Francesca Jackson‑Spence: I think, well, first of all, we have to wait for the results of the SAMETA trial, don't we, because we need to see what the trial results actually show. I think the differentiating factor here is that in the SAMETA trial, only MET‑positive patients—or MET‑driven patients—are included. And so that data is, therefore, in support of, if you're testing for MET, going for one that's proven to work in specifically MET‑driven tumors.

But I think it's difficult to speculate. We have different health systems going on. And I think individual clinicians also have their favorite drugs. I think, when it comes to using things like TKIs, there's that saying that Professor Powles loves to use, which is, "Pick one. And use it well." And so I think that's also going to have a factor to play. But I think we need to wait for the results of these trials.

Pedro Barata: So Dr. Powles taught you well because you actually got the answer, which makes sense. We’ve got to see what the data looks like. I do anticipate there being quite a buzz, specifically in papillary RCC, if we're going to have—which I think might be the case, we'll see what the future brings—more than one combo available.

But amazing job to actually proceed, as you said, with a confirmatory randomized trial to really look at the activity. And I really love the design because that's the way to truly understand the contribution of components, right? Because you really break it down. You have the PD‑L1 there, you have the PD‑L1 with the MET, and then you have the TKI, which was considered standard for a long time—sunitinib—and it still is in many places.

So, with that said, Francesca, wonderful conversation. Again, great job doing your presentation. And it generated a lot of interest, a lot of conversation, and discussion. And let's see what the future brings for the ctDNA, as you said. I'm looking forward to more work from you and your team. So thank you.

Francesca Jackson‑Spence: Thank you so much.