Kathryn Beckermann: Well, thank you, of course, for inviting me and always enjoy chatting. I know I'll, I'm sure, learn from our conversation as well, so thanks for having me.
Pedro Barata: Absolutely. No, great job. Congrats. This trial data was selected among many things that are basically presented at ESMO, and yours got selected for an oral presentation on it, which is quite remarkable. The bar is always high there, but I would guess, for our audience, because it's not known to many of us, this therapy ciforadenant, which I'm not even sure if I'm pronouncing it correctly. I'm wondering if you could just review the mechanism of action for this therapy and explain the rationale to combine it with Ipi-Nivo.
Kathryn Beckermann: Yeah. I think we've all been encouraged with the 9-year OS data from Ipi-Nivo and what we'd love to do is be curing more people. So we have known, based on that biology, that VHL kind of causes that metabolic switch, that one of the things that produces in the tumor micro environment is a high level of adenosine. Adenosine is broken down from ATP, and adenosine signaling in the tumor micro environment, in addition to affecting the cancer cell itself, decreases T-effector activity and actually can increase immune suppressive activity.
So the idea here is can we somehow modulate adenosine signaling on top of that backbone of Ipi-Nivo to improve our IO-based therapies? And this particular novel drug is called ciforadenant. You did a great job saying it. It's an adenosine A2AR receptor inhibitor. So there's two receptors for adenosine, and this is the A2AR inhibitor. There had been some prior preclinical data suggesting that high levels of A2AR also correlated with poor prognosis and kidney cancer, and so that's kind of the rationale behind doing this. And again, we felt like studying this in that front-line treatment option with our longest durable IO therapy was the way to go.
So I was so thrilled to be able to present. This was the very first interventional clinical trial that ran through the Kidney Cancer Consortium, so the trial design really came about with this wonderful group of collaborators all focused on kidney cancer who helped us designed somewhat of a novel primary endpoint. As you mentioned, it was a phase Ib, so we had an 8-patient safety lead-in, there were no safety issues, ciforadenant was dosed at 100 milligrams po bid with kind of that standard IPI-NIVO dosing, and then we expanded it for a total of 50 patients.
And so the idea, again, amongst the collaborators, was that we were trying to look for a new signal. Could we identify a primary endpoint that we could test early, but would give us that early signal of durability of IO? And we've seen in lots of retrospective looks as well, there's an FDA review out now actually showing that you can use a 12-week scan that correlates the depth of response, so the tumor shrinkage on a 12-week scan, can actually correlate with that 3-year survival. And so for our primary endpoint, instead of doing ORR or PFS, kind of the more traditional, we chose depth of tumor response. So we were trying to increase the percentage of patients who got a tumor shrinkage greater than 50%. And then CheckMate 214, that was about 32% of people.
Pedro Barata: Got you. Thank you for walking us through it. Super comprehensive and very helpful. And it's great to give a shout-out to the Kidney Cancer Consortium that you're part of and the work that's been done. It's never easy to run investigative studies, so kudos for that.
As we walk through the data, at least to me, I'll let you comment on that, but at least to me, a little bit less, so we're talking about 50 patients, some with a lot of sites of disease, including bone, if I recall correctly.
Kathryn Beckermann: Yep.
Pedro Barata: Almost half did not get nephrectomy, which is a sign of probably heavier-treated, more aggressive disease. Yet you do see those bars going down on the death of response and you do have response rates not far from 50%. I know your follow-up wasn't that long to assess median progression-free survival, but you got my eye on the correlators around RNA-seq. I'm wondering, tell us, what are the highlights from the results that you'd like us to take home with?
Kathryn Beckermann: Yeah, yeah. I think some of those points are the ones that I would highlight as far as our patient cohort, heavy sites of aggressive disease. And maybe something that we'll be factoring in as we think about writing this up is we did have a lot of patients who didn't get nephrectomy and we know that primary of disease is often hard to shrink. So does that play a role in ultimately our primary endpoint and how do we think about that going forward?
So when we look at that, did we improve upon compared to historic CheckMate 214, we hit right on the percentage of patients at this early time point, which is 9 months, a pretty similar percentage of patients achieving that depth of response, 32%, 34% of patients who got at least 50% tumor shrinkage. When we look at the more classical ORR, which I think everybody has memorized at this point from CheckMate 214, there we had a 44% ORR. So I think in a high-volume of disease, early time point of follow-up, we were certainly meeting the CheckMate 214 numbers, and I think what we're curious to see with longer follow-up is, do we see any more patients who achieve that 50% response? And then also a question of, well, if it's modulating the immune suppressive microenvironment, maybe we keep more patients on it longer. So will durability, in fact, be better?
We still have 19 patients on trial. So that was another highlight here. Again, kind of an early median follow-up of 9 months. Our median PFS, also pretty in line with CheckMate 214, about 11 months. So again, I think kind of hitting those standard numbers that we know from CheckMate 214 and awaiting longer follow-up to see if this adenosine modulation can either enhance delayed tumor shrinkage or allow for improved durability, that we'll have to wait for longer follow-up to see.
And then, yes, thank you for bringing up the correlates. I think, again, another highlight of working with the Kidney Cancer Consortium was the enthusiasm around trying to not only learn from our patients and their clinical responses, but obtaining tissue. And this group of investigators was so great, we went back two or three times if a tissue didn't pass to get more tissue and they were really great.
So we did RNA-seq and we looked at two different signatures. One being probably the best known of the two that we looked at is that IMmotion151 signature, which we're using in another prospective trial called OPTIC. And basically that trial takes RNA sequencing and says, "Can we use the biology of the clusters?" So one cluster being angiogenesis and another cluster being an immune effector cell. And in our study, it was very exciting to see that the patients who were in the immune effector cluster, which was only 4, so quite small numbers, but all 4 of those patients achieved an objective response rate in this pure IO backbone regimen. So I think another exciting way to say we should continue to develop biomarkers and move this forward for prospective trial design.
Pedro Barata: Yeah, thank you. That's a fantastic summary of the data. And just to highlight that it's actually an oral medication that patients take on top of Ipi-Nivo, if I recall from your data. Patients did quite well on therapy without major side effects, and very few patients actually end up coming off because of adverse events. And I predict many are probably related to Ipi-Nivo. Is that a fair summary?
Kathryn Beckermann: That's exactly right. I think the most common treatment-related adverse events that we saw were related to what we classically see with Ipi-Nivo, the increased LFTs, fatigue, and rash. We had 5 patients out of the 50 that came off for treatment-related toxicity, no treatment-related deaths. So again, we've seen other triplet therapies in kidney cancer that have had a lot of toxicity, so it was very nice to see that we didn't increase toxicity here.
Pedro Barata: Got it. So Katy, final question before letting you go. Clearly, to me, at least, the signal that you identify with this triplet is at least as good as the CheckMate 214 Ipi-Nivo, perhaps maybe a little bit more favorable because the patients don't seem to be the same in terms of aggressiveness of the disease. Where do you think this might go from here? Should we expect a larger study or are you waiting to look at that maybe the tail of the curve, which I think that's what you're getting at, with that depth of response, and see if there's an increment value on top of Ipi-Nivo to decide what to do, where to go afterwards?
Kathryn Beckermann: Yeah, I think that's right. I think we know that total tumor shrinkage, on average, takes 7 to 10 months, and so still kind of wanting some longer follow-up, see if we increase our percentage of patients getting that primary endpoint and perhaps start to look at kind more durable responses if there's any benefit with the adenosine modulation.
And then going next steps, I think, will certainly largely depend on that. But I believe a lot of excitement remains around adenosine modulation. There's, again, all kinds of novel therapies being developed truly to target various aspects of this. So I mentioned that ciforadenant is an A2AR receptor inhibitor. There's an A2 β receptor inhibitor. There's targeting of the degradation pathway from ATP to ADP to adenosine. So I, as a field, hope we continue to see additional trials targeting this pathway.
Pedro Barata: Got you. Well, this has been fantastic. Again, congratulations, Katy. Great.
Kathryn Beckermann: Yeah.
Pedro Barata: Well done.
Kathryn Beckermann: Thank you.
Pedro Barata: Again, academic effort from the Consortium that you led for this effort. I'm looking forward to see a longer follow-up to see if you can answer that question. Would be fantastic to get more patients in remission, right?
Kathryn Beckermann: Yeah.
Pedro Barata: And so it's a great effort here put together by multiple institutions, so well done. Congratulations and thanks for joining.
Kathryn Beckermann: Thanks so much for having me.