Hi, everyone. Welcome to our Fireside Chat with ALX Oncology. We have CEO Jason Lettmann with us. So great to have you, Jason. I guess for the audience who are less familiar with the story, maybe just tell us a little bit about ALX and what you're working on and what's coming up.
Sure. Well, thanks, Lee. Thanks to Cantor for having us. Appreciate it, as always. So ALX is the leader in CD47. We were founded about ten years ago, and really, we're taking a unique approach at the time, which is, how do you separate the "don't eat me" signal, provide CD47 blockade of the "don't eat me" signal, while combining with an anticancer antibody, for example, to drive the "eat me" signal? That was, and still is, very different than the approaches that others were taking, which was, in essence, to use CD47 as a tumor-associated antigen.
That, as we'll talk about, has run into challenges just in terms of getting that therapeutic window right, and by bifurcating the signal, we've been able to drive efficacy in a way that's unique and different, and also do so in a way that is safe, which has been a particularly major issue for the CD47 space.
Okay, so I felt like I asked this question last year. It's just, you know, there are some setbacks in the CD47 space. Obviously, we're seeing a lot of data coming out from your competitors, but on the other hand, you're also generating some pretty nice data yourself. So maybe just big picture, talk to us about why should we, or investors, for that matter, should still be looking at CD47?
Yeah, I think it really comes down to the data. You know, I think if you look at what we've generated, we now have nine ongoing clinical studies, and when we've gotten the combination right, that's combining with anti-cancer antibodies, ADCs, or checkpoints, I'd argue the drug has worked. And it's been very meaningful in terms of what we've seen. I think the field, ourselves included, ran an experiment in combining with Azacitidine, which is not an Fc active antibody, and mechanistically is just far more speculative, where it just didn't work. And so from our perspective, again, when we have the right combination agent, we've seen a very strong signal, and that's across both solid, like gastric cancer, which we'll talk about, as well as heme malignancies, like NHL.
Yeah, I mean, that's what drives a lot of our enthusiasm in the space.
Yeah, great. So I think we should probably talk a little bit about your gastric data. I think you just shared recently, that's the ASPEN-06.
Right.
Maybe just, you know, sort of walk us through the data because I thought that's a very meaningful data set for the space.
Yep.
And then also there is some controversy. So what are some of the key learnings that we can sort of draw from that data set?
Yeah, sure. ASPEN-06 was a randomized study in second- and third-line gastric cancer, and here we are looking at the combination of evorpacept plus trastuzumab plus RAMPAC, or the chemo backbone, or TRP, versus TRP. And the reason why it's important is it's the first study, the first randomized study in solid tumors with a CD47. So, obviously excited about it going into the data and to see the signal that we saw, you know, again, the first CD47, frankly, period, to show activity in solid tumors. And I think that goes back to the mechanism and the design here of evorpacept. You know, I think for us, what we're excited about is the delta that we've seen. So we've seen in the ORR, we saw a 40% response rate on the treatment side versus 26% on control.
I think in a second- and third-line gastric population, it's a very strong signal. Again, our safety was outstanding, and I think that it's really important when you think about a combination agent. And then last, but certainly not least, we saw a DOR of north of 15 months. And again, I think that was really impressive to see durable responses. It's indicative of an IO mechanism, and you know, again, you know, we're excited about what we're seeing.
So I wanted to get your thoughts on the question of whether you should use fresh biopsy, because the data are obviously stronger in patients-
Yeah
... that have fresh biopsy. Maybe just talk a little bit about that, and just from a drug development perspective, assuming you're moving to Phase III, is there a thought that you may wanna mandate, you know, fresh biopsy here?
Yeah. I think, again, for us, mechanistically, we need to block the "don't eat me," and then we need the positive signal of the "eat me." And we need both of those to essentially activate and drive ADCP, so drive a macrophage into phagocytosis. And when we don't have the "eat me" signal, meaning when we don't have Enhertu expression, for example, our drug is not gonna work. We were not designed to deliver single-agent activity. And so I think in the context of gastric and what we're seeing, fresh versus archival, is a fresh biopsy is indicative of strong Enhertu expression. And in those patients where, again, we've validated the Enhertu expression, we saw an over 30% delta-
Mm-hmm.
in terms of ORR. So when that signal is strong, and we combine it with the evorpacept to block the don't eat me signal, we are getting an incredibly strong signal. You know, I think people look at it and say, "Oh, it's a subgroup," but it was a pre-specified analysis that we've been looking at the whole time. It's also a bit unique to gastric, but it's super important, and it's right on mechanism for us.
Yeah, and from our, you know, conversations with doctors, it seems like it's also very important because when they use on HER2, for instance, they want to look at, you know, fresh biopsy to confirm-
Right.
The patients actually have HER2 expression. So I do agree with you on that. Now, in terms of the phase three, obviously, you're still sort of probably thinking through that, but in terms of whether you guys are gonna use, you know, fresh biopsy, is there a plan there?
Yeah, I think it's really important for us to ensure that we have strong HER2 expression.
Mm-hmm.
And so, you know, whether or not we mandate fresh, and I think your point, Lee, is a great one. We know Daiichi in their DESTINY study is doing just that.
Yes.
So they know how important it is, clearly. I think for us, it's just how do we enrich the population to ensure that we have enough, if you will-
Mm-hmm
... HER2 truly positive patients? So whether that's, you know, mandating it or trying to, you know, tweak the inclusion criteria to get that right, I think are things that we're working through, but I think there's no question that we now understand the importance of that, and that's why you do a randomized phase two, right?
Mm-hmm.
I mean, now we know how to build a registrational study to win.
And on PFS, obviously the data set is not mature enough. But just curious in terms of the trends and the separation of curves that you're seeing so far, I wonder if you can just make a comment. You mentioned, Jason, that you've seen pretty long DOR. Obviously, that bodes really well for PFS. So maybe just setting the expectation for us, when are we gonna see PFS data, and what should be the bar?
Yeah. So I mean, typically, ORR, DOR, PFS in gastric has been highly correlated. I think you know, you look at this study, we finished enrollment Q1 of this year. So when we shared the analysis in July, you know, the curves were immature at that time. And again, keep in mind, we're developing an IO agent where we're trying to show, you know, long-term separation of those curves. So we think getting into first half of this year at a medical meeting is the right time in which to share updated PFS. You know, I think at that time, looking at it across the population will be important, but also looking at this group of about 50 patients that have fresh biopsies is gonna be important as well.
And that's what we plan to do, and I think we're gonna continue to let the data mature, and then when we get to that point, share that in the first half of next year.
What do you think the PFS benchmark is?
Yeah. Well, so I think right now, if you look at the RAINBOW study, the DESTINY study, five, six, six-ish months is kind of where they came in.
Mm-hmm.
HER2 got their label off barely a two-month delta in terms of PFS, and so that's how we think about it for us, too. You know, I think in gastric, the need is incredibly high, so if we can see a PFS delta in that range, I think that would definitely be suggestive of a drug that could change standard of care.
Great. Now in terms of the next steps, obviously, you've talked about moving into phase three. Are you committed to that? And then, you've mentioned sort of accelerated approval pathway before. Is it off the table, or is it still possible?
Yeah, I think it's really a question of what is the comparator for second and third line gastric. Right now, it's RAMPAC-
Mm-hmm
... which is, you know, our control, if you will, and it's also in HER2.
Mm.
I think there's a question as to how HER2 will progress. Certainly, as we've seen in breast, it's moved to up and up lines, and that may happen in gastric as well. So I think that's important, as well as looking at the maturity of the data. Of course, when you think about a registrational study, PFS, OS metrics are a lot more important than ORR. So understanding how our data matures is what's gonna inform our phase three. But internally, for us as a team, what we feel we now know is that when you combine evorpacept with an antibody, the drug is effective, and it's safe. And so that gives us a whole lot of conviction into pushing into other bigger commercial opportunities in solid, whether it's colorectal, head and neck, breast.
I mean, those are probably the top three that we're looking at because, again, with data like we've seen across the spectrum of antibodies, we think the signal is very strong.
Now, in terms of the competitive landscape, it sounds like Enhertu is moving into front line. So how do you think that's gonna impact? I guess your strategy in second-line or third-line gastric, and maybe you can talk a little bit about, you know, the commercial opportunity here. That would be great.
Yeah. Well, I think, you know, if HER2 were to move into the front line, you know, you think about a second or third-line gastric patient, you're essentially back to RAMPAC. RAMPAC was established as standard of care, you know, 2013. And so that's, that's tough, and I think that conversation with FDA would be an interesting one to have, which is, right now, standard of care is now back to RAMPAC. We just did a randomized study of about 130 patients versus TRAS plus RAMPAC, and does the data support, you know, offering this as an option for patients? You know, I think that's, you know, obviously, we don't try to speculate or play FDA. That's-
Yeah, sure.
- not good for anybody. But, again, I mean, I think we have randomized data and a very strong signal with a drug that's safe, so, I certainly wouldn't say it's off the table.
So in terms of when you would approach the FDA to discuss some of the options that you just talked about, like, do you have to wait for the PFS data?
Yeah, I think we wanna get to a place where we feel that the data's mature.
Mm-hmm.
I think that makes sense from a regulatory strategy perspective, just like it does with the street and external stakeholders. That's what we would plan to do.
Now, gastric cancer obviously is more common in Asia, so any thoughts in terms of whether you wanna find a partner in that region?
Yeah, I think it's a great question. I think if you look at Asia broadly, as you point out, the gastric opportunity is significant. We've had a high level of engagement and interest from, from partners with an eye on Asia.
Mm.
You know, I think ALX's Asia office is not staffed at the moment, so we could use a hand. So we're definitely interested in talking about that. And again, I think it's a big opportunity that we're not set to really capitalize on. So it could be an opportunity for partnering, and we, to date, have done no deals. I mean, ALX is... We own evorpacept outright. We have not-
Mm
... encumbered the asset in any way.
Now, I want to switch to head and neck cancer. Obviously, this is a much bigger opportunity than gastric, and you're running two frontline studies. Maybe just remind us in terms of what prior data that you have shown and what are the trials that you're running.
Yeah. So in head and neck, this is testing a sort of the second big mechanistic hypothesis here, which is combining with a checkpoint inhibitor like Pembro to activate T-cells. So again, mechanistically different than what we're doing with antibodies to drive ADCP. Here, we're looking to essentially release two brakes, so it's sort of a dual checkpoint approach. What got us excited about frontline head and neck was our Phase Ib data. I think what we showed there was very consistent with what-
Mm
Pembro showed in the KEYNOTE studies, which was relatively modest benefit on ORR, but a very, very strong survival signal. So in our Ib, across both first and second line head and neck patients, we saw over 80% survival rate, which is very impressive. And even fast forward to new competitors like Bikara or Merus-
Yeah
... we feel our survival data stacks up very well, which is why, you know, we then launched two large randomized phase II studies, which will read out soon.
You sort of push out the top line readout to next year. Was that driven by maturity of the data? What was the driver for that?
I mean, again, our goal here, we have over 300 patients-
Mm-hmm
... frontline head and neck randomized patients, and what we're trying to show is both ORR and OS. Again, KEYNOTE-048 ultimately on OS, so we made the decision a long time ago to go for OS. That's taken us over three years to get here. So the last thing we would want to do is open the envelope early, so to speak.
Mm.
We wanna make sure we have mature data with the Kaplan-Meier curves showing separation, ideally, and we also just felt like it'd be a good time coming off the 06 data to reset expectations, and give us room in order to make sure we get both studies to the right maturity.
Maybe just remind us in terms of the powering assumptions for the OS. So if I recall correctly, you are looking at the twelve-month OS rate.
Mm-hmm.
Is that correct? So what is the sort of the delta that you're looking for?
Yeah, I think, again, we're looking to KEYNOTE to provide guidance on that.
Mm-hmm.
So if you look at the KEYNOTE Pembro-only arm versus our data, we did see a, you know, a relatively good difference on ORR, but we also showed a very, very significant difference on OS, and so that's how we are approaching the ASPEN-03 read. We'd certainly love to see an ORR benefit, but mechanistically, this is an IO agent, so we want to really power the study to show survival. ASPEN-04 is slightly different. Again, best I can tell, the only company running a large randomized study with chemo plus pembro versus chemo plus pembro. The others are focused on pembro alone. And there, they did see an ORR benefit, so much so that in KEYNOTE, pembro actually looked worse than the chemo arm on ORR.
So there, for us, it's really important for us to drive towards survival, and that's, you know, kind of reflected in how we're thinking about the statistical plan.
I wanted to ask you about the registrational strategy. Jason, as you mentioned, there are some other companies out there, right? Merus, Bikara, for instance. They're sort of going after maybe a phase III trial design based on maybe AA approval, on maybe a response rate. But you seem to think, well, I mean, in head and neck in particular, maybe OS is more important for approval. Maybe just expand on your view on that, and in terms of the, you know, registrational pathway, what is-
Yeah
the correct one? Yeah.
Yeah, I think importantly, ASPEN-03 and ASPEN-04 are designed with registrational intent, and so that's how we built those studies. I think, again, it's important to look at how standard of care in head and neck has been defined, and that's by the KEYNOTE studies, which again, did not show any delta on ORR, but ultimately won the day on survival. So when we set up those studies, it was to demonstrate that. Again, I think with over 300 patients coming, randomized data, and again, showing survival plus ORR, you know, we're excited about it. I mean, certainly the data from Merus and Bikara is exciting as well.
Mm-hmm.
But we think with this number of patients randomized, it's gonna be a powerful statement, and frankly, one of, if not the biggest readout in head and neck...
Yeah
Since the LEAP studies. So that's what's fueling our excitement about it.
Great, so I wanna talk a little bit about other combinations. Obviously, the antibody story is playing out nicely, but you're also doing, you know, combo with, for instance, ADC, and I thought your data at ASCO in bladder cancer was quite interesting, so talk to us about that, and in terms of, you know, whether you may have a path in bladder cancer, what are your thoughts on that?
Yeah. So our ADC story, I think, has similarities to both the antibody and checkpoint combination modalities. An ADC, of course, is just an antibody with a payload. So our ability to enhance the activity of an antibody, whether it's Padcev or an HER2, we think is going to be similar. That's why we have two studies, one with Padcev, as we'll get to, in bladder, and then the second is with an HER2 in breast. In bladder, what we shared at ASCO was a single-arm study combining Evorpacept with Padcev in second-line bladder. This was pre-Padcev moving-
Mm-hmm
... to the front line. And what we showed at ASCO, which I think is really the first validation of an ADC plus CD47, we had an over 60% initial response rate. We had very strong durability, and, you know, I think it was early, but a signal nonetheless. And so we're excited about sharing more of that data. What we were seeing in those curves at the time was a nice, slow deepening of tumor shrinkage with a relatively durable response, which we think is unique to our mechanism. Certainly not what clinicians would expect to see with Padcev. And so when we get into next year, sharing more around PFS and how those curves are maturing is gonna be important.
That's why our guidance is for the second half of next year for more data with Padcev.
And then in terms of sort of other combination studies that you're running, maybe with some antibodies as well, maybe just walk us through some of the trials and the cadence of the data updates.
Yeah. So we have, I mean, on the antibody story, we have the gastric data coming, which is important.
Mm.
We shared data from NHL at AACR, which was a very strong signal. We had an almost 90% CR rate in second-line NHL. And so we're gonna continue to advance more on the more programs on the antibody side. On checkpoint, we've talked about the combinations with pembro and ASPEN-03 and ASPEN-04. For us, mechanistically, I think if we validate that mechanism, we'll be looking to push forward into other combinations with pembro, whether that's lung or take your pick. I think there's very large swings we would take at that point. And then the ADC story I mentioned, you know, it's-
Mm-hmm
...it's earlier than the other two buckets, if you will, but you know, running studies with Padcev and Enhertu, which are arguably two of the most successful ADCs on the market, I think it's gonna provide a validation for us as to what evorpacept could do with an ADC, and we'll have data from that coming next year as well.
... Okay, so I guess a question on perhaps strategic partnership. Obviously, you're combining with antibodies, ADCs, and the commercial opportunity could get to a place where it's gonna be, you know, fairly, meaningful.
Mm-hmm.
I guess to tap into sort of this potential opportunity, how are you thinking about, you know, maybe leveraging some partners, and what are your thoughts on when might be a good time to have that conversation?
Yeah. So we're having those conversations now. You know, I think a lot of the questions we've got from pharma is sort of, "Prove it, and then show me a story around biomarkers and patient selection, and that the biology is real." And this fresh versus archival story, I think, has been tricky for the street to understand, just because gastric is a bit of a weird space that a lot of the folks don't traffic in, particularly second line. But to be able to talk to pharma about HER2 expression and the importance of target expression in our combination has been really exciting. Because for us, they're seeing our drug work where Traz doesn't, for example. So that's led to us, I think, having really interesting conversations with pharma. This is a really broad program.
And interestingly, for me, you know, each pharma has a different angle-
Mm-hmm.
As to what they would do with evorpacept. If you are sitting on a large HER2 franchise-
Mm-hmm.
You would wanna talk about how can we combine this with our various HER2 agents in breast, for example?
Yeah.
Versus if you have ADCs in development, our data with Padcev and how you could potentially combine in what is an increasingly competitive ADC space is of interest. Or if you're, you know, Merck, et cetera, and have a checkpoint strategy, then that's a whole different thrust. So what's interesting, I think, is we have a lot of different strategic angles we can play-
Mm-hmm.
and we've done no deals to date that encumber us. So we're definitely looking and talking to partners about how we could do a deal that would help accelerate the program.
Are there any sort of near-term triggers that may get you to a place where you can maybe have a partnership? It sounds like you have a lot of data coming up right next year. So is that sort of a reasonable time point that could trigger some partnership?
Yeah, I think so. I mean, it's just a question of how quickly pharma can move.
Yeah.
I mean, we're usually not the limiting factor on that, but I think that some of these conversations have been going on for a while.
Mm-hmm.
And again, I think this story that's emerging around expression of our combination agent has really resonated. And yeah, I mean, I think we've provided them a playbook as to how you select patients and what indications you go forward with this drug. And so yeah, it's hard to comment on the pace of BD. I'm usually very wrong. But yeah, it's been we've had a lot of good conversations as of late.
Fair enough. I think we're out of time, so thank you so much, Jason.
Thank you. Appreciate it. Thanks.