Everyone, good afternoon and welcome to day 2 of the 2024 Bank of America Healthcare Conference. Thanks for joining this session with Erasca. Excuse me, my name is Alec Stranahan, and I'm Vice President and Senior Biotech Analyst covering Erasca here at B of A. I'm pleased to be joined by David Chacko, Chief Financial Officer and Chief Business Officer. David, thanks for joining us.
Yeah, thank you for the invitation. Happy to be here.
Yeah, perfect. So I'll just jump into questions. I have a few here, but if anyone in the audience has a question, feel free to raise your hand and we'll pass you a mic and you can get your question answered. But David, you know, maybe just at a high level for those less familiar with the story, could you walk us through your approach to shutting down the MAPK pathway as well as the key assets you're pushing forward currently?
Sure. So our approach is to really comprehensively shut down the RAS/MAPK pathway. This is a pathway that's responsible for anywhere from a third to half of cancer that's diagnosed annually. So it's a super important pathway. Our approach is to take three complementary strategies around shutting down the RAS/MAPK pathway. The first strategy is to target key upstream and downstream nodes in the pathway, for instance, RAF with our naporafenib program that I'll talk more about in a second. Number two is to target RAS directly. And then number three is to target key escape routes that cooperate with the RAS/MAPK pathway. Using that framework, we've assembled what we consider to be one of the deepest modality agnostic pipelines in the industry going after this pathway. And so our lead program is naporafenib. That's a pan-RAF inhibitor.
We in-licensed this in December of 2022 from Novartis. And I know that we'll be talking more about that. We also have our ERAS-007 program, which is our ERK inhibitor that targets the terminal node of the pathway. We also have ERAS-801, which is a CNS penetrant EGFR inhibitor, for glioblastoma that targets EGFR both in the vIII mutation but also wild type. And then we also have a number of other programs behind that as well.
Perfect. And maybe it'd be helpful, just to hear your philosophy regarding clinical development. You know, what's your approach to de-risking assets, looking at different combinations of either internal assets or combinations with other approved therapies, and also which indications you end up pursuing? And how is this maybe changing at all as you move ahead with NAPRA and 801?
Yeah. So, you know, combinations are very important. I think the RAS/MAPK pathway is such a wily set of targets that if you hit it at one node, in most cases, it's almost an invitation to resistance. And so the importance of combinations, you know, really can't be overstressed. So for instance, with naporafenib, we're actually combining it with trametinib as a MEK inhibitor. The profile of naporafenib is such that it has very good potency against BRAF and CRAF, which are two of the isoforms that you want to hit, but relative sparing against ARAF. And while we think that that may help from a tolerability standpoint, it does allow for some potential escape. And so the advantage of having trametinib as a MEK inhibitor on board is that it can mop up any of that oncogenic signaling that can get through.
So that's one example. Another example is our ERAS-007 combination in BRAF colorectal cancer that we're exploring in our HERCULES-3 study, where we are combining there with the approved standard of care regimen of encorafenib/cetuximab. That doublet, you know, was approved with a response rate of 20%, and we're putting our ERK inhibitor on top to see if we can improve that further. So to your question about internal versus external, you know, that's a good example where we have taken, you know, our own internal compound, and combined it with what is essentially the best-in-class standard of care treatment with encorafenib/cetuximab. So most of our assets in our pipeline are meant to be used in combination. One exception to that is ERAS-801, which is our CNS-penetrant EGFR inhibitor again for GBM. That is one asset that has a potential monotherapy play.
Okay. Okay. Maybe we could just go down the list one by one for the pipeline. Starting with naporafenib, Phase 3 starting in first half of this year, but there's already a wealth of clinical data available for naporafenib before you even brought the asset in-house. I guess what drove you guys in acquiring this asset, and, you know, how does inhibiting RAF complement your current pipeline and approach?
Yeah, absolutely. So, naporafenib again is the pan-RAF inhibitor that we brought in from Novartis in December of 2022. In terms of what it was that excited us about this program, I, I'd say it's a few things. And I'll touch upon, you know, safety, efficacy. I'll touch upon its, first-in-class nature and then also its, you know, what the rest of the competitive landscape, you know, looks like as well as the complementarity with our pipeline. So on safety and tolerability, this molecule at the time that we had brought it in had already been dosed in over 500 patients to date. And so it just establishes a wealth of data around safety and tolerability, both as a monotherapy as well as in combination. So we knew that this molecule, you know, had, had a good profile in that respect.
In terms of efficacy, we're advancing it in indications where it has already shown proof-of-concept data. So for instance, in NRAS melanoma where there's a you know a very good data set across phase 1 and 2. But also in RAS Q61X solid tumors where Novartis showed data in both melanoma as well as a smaller data set in non-small cell lung where they showed about a 44% response rate in melanoma, and about 2 out of 3 patients. So small data set, but about a 67% response rate in non-small cell lung. And then what we're doing is expanding that RAS Q61 population to other tumor types where RAS Q61 is highly prevalent. So that's touches on safety, touches on efficacy. In terms of the first-in-class nature of the asset, this is also a really important aspect for especially in NRAS melanoma.
Where right now in our randomized study that we're about to initiate this quarter, we can compare ourselves against either the current standard of care in the post-IO setting, which is chemotherapy, or against single-agent MEK. If we are then able to reset the standard of care for patients and, and improve upon the benchmarks that were set by chemotherapy or single-agent MEK, that becomes then the new benchmark that others coming behind us would have to compare themselves against. And so that first-in-class nature is really important. And then the final point that I'll just mention is the complementarity of this asset with the rest of our pipeline. It is, RAF is a key node within the RAS/MAPK pathway.
Then our ability to be able to combine it with other nodes, for instance, trametinib as a MEK inhibitor, or with other assets in our pipeline, you know, that complementarity allows for a lot of synergy.
Right. That makes sense. It is kind of a central node. Obviously, there's things above and below it, that you can combine with in a logical manner, but it is, you know, a key piece of that equation, right, for combos.
Absolutely.
Great. You know, and, and it's not the only pan-RAF in development. I guess in comparison to other inhibitors out there, there, there's a few: exorafenib, tovorafenib, belvarafenib, the list goes on with, with the rafenibs. How, how do you think naporafenib compares to others, and what do you think are important factors in a successful pan-RAF inhibitor?
Sure. The profile of many of the pan-RAF inhibitors is similar in one sense, although different in other senses. It's similar in the sense that most, if not all, of the pan-RAF inhibitors have that profile that I described earlier in terms of hitting BRAF and CRAF preferentially over ARAF. So there is that similarity there amongst many of the pan-RAF inhibitors. That said, there's other, you know, distinctions amongst the pan-RAF class. So how selective is your compound? And our molecule in a kinome scan looks, you know, really good from that perspective. As I mentioned, it's already been dosed in over 500 patients to date, which just establishes that wealth of safety and tolerability data in the clinic as well.
If you look at the rest of the field in terms of the number of patients that those other molecules that you've mentioned, you know, have been dosed in, I think that gives us a nice advantage there as well. You know, just to comment specifically on some of the molecules that you've mentioned, you know, I would say that, tovorafenib to start with them, you know, they've positioned themselves primarily as in pediatric indications, versus the indications that we're going after are broader and include the adult populations. With regard to the other pan-RAFs that are playing maybe in similar spaces, I would say the next closest behind us was the Roche/Genentech compound, belvarafenib. Per their most recent disclosure, they have actually chosen to deprioritize that program. And then the next closest behind that was probably Kinnate molecule, exorafenib.
Exorafenib, around this time last year at AACR, had disclosed clinical data for their program, which showed, you know, it showed, I would say, reasonable levels of activity, but maybe not enough for it to have generated a much more excitement. Ultimately, Kinnate ended up doing a transaction with Pierre Fabre for the pan-RAF inhibitor, and that asset is now with Pierre Fabre. And so we're keeping an eye on the space, but I think especially with the deprioritization of belvarafenib, it just gives us a little bit more of an advantage in this space in terms of potentially being first-in-class.
Yeah. Maybe just on that belvarafenib deprioritization, anything to be read through to naporafenib, or was that kind of just a business decision that Roche made?
Yeah. Hard to say exactly what was going on inside the company, but, you know, from our standpoint, I think it is specific to the molecule. Belvarafenib's kinome scan, for instance, does not look as clean as our kinome scan. I think, you know, we also have the advantage of combining with trametinib, which is a best-in-class MEK inhibitor. It is, you know, one of the most widely approved MEK inhibitors with approvals in 80+ countries. And so I think that, there's multiple factors, I think, that worked in our favor with that naporafenib-trametinib combo, that, you know, probably played into decision-making.
Okay. That's helpful. Maybe looking at the next updates, there's an upcoming SEACRAFT-1 update that I believe has been guided to maybe the middle of this year. Could you help frame what we should expect in the update? You know, what does good look like in your view and whether you think certain tumor types could be enriched?
Sure. So SEACRAFT-1 is our study of naporafenib plus trametinib in RAS Q61X solid tumors. We have guided to that readout being between Q2 and Q4 of this year. That study initiated in Q3 of last year. Enrollment is moving along well. We got a bolus of patients towards the end of last year, early this year, that were predominantly within certain tumor types like CRC. And so now we're continuing enrollment and trying to enroll other tumor types where Q61 is highly prevalent. So just as a reminder, you know, Q61 mutations are highly prevalent in about a half a dozen tumor types, including melanoma and lung, which Novartis generated some data in, but also head and neck, thyroid, CRC, and pancreatic.
And so, we are enrolling those tumor types again where Q61 is highly prevalent to be able to see if we can pursue a tissue-agnostic label in the RAS Q61X setting. The data update later this year, you can think about it in terms of, you know, double-digit number of patients. In an ideal world, we want to make sure that we have an ample number of patients across different tumor types. We are looking to see if we can continue to enroll across those different tumor types now.
Okay. And what would be sort of the next step, once that data is in hand? Have you, you know, started putting together what a pivotal study could look like, for those patients?
Yeah. So SEACRAFT-1 is currently, has optionality for us to pursue either a tissue-agnostic path or a tissue-specific path. So once we see the data later this year, we'll have, we'll be able to make an informed decision about whether we're seeing activity across a variety of different tumor types, which then allows us to potentially pursue that tissue-agnostic path versus, you know, activity in just a smaller handful and we pursue a tissue-specific path. In the case of a tissue-agnostic path, you know, because there isn't really a good comparator, that study is actually a single-arm study at that point that we could then, you know, based on, call it, 100 patients' worth of data, potentially approach the FDA around a potential accelerated approval.
Okay. Very, very interesting. Great. And I guess, you know, we, we talked about other RAF inhibitors, but, I think this is worth putting a finer point on. You mentioned before that NAPRA-TRAM is likely the first in the, in the field. Maybe walk us through how this is an advantage both in terms of, logistics around your pivotal program, but also, you know, creating a moat, for, for additional competition.
Yeah. So again, with the combo of NAPRA plus TRAMI, and I'll, I'll talk about the NRAS melanoma example in particular here. The, the combination of NAPRA plus TRAMI has shown a median PFS in the phase 1 and 2 study of approximately 5 months, and that's regardless of the dose levels that you look at. By comparison, the standard of care is chemotherapy, which has a PFS of only 1.5 months. Single-agent MEK inhibitors are used in this population off-label. The PFS there is about 2.8 months, and so you're seeing already that across the phase 1 and 2, we're seeing a PFS that's anywhere from 2-3x those comparators.
You know, and then we showed data earlier this year, where the OS data, the overall survival data, had reached a level of maturity that we were able to analyze that data from the phase 1 and 2 studies, which showed a median OS of about 13-14 months relative to what we consider to be the most relevant historical controls coming in at about 6-7 months. And so on both of the primary endpoints for our pivotal study, PFS and OS, we're showing a nice benefit versus, you know, the what we think the comparator arm will do in the SEACRAFT-2 study.
So again, what where first-in-class really matters is that where we can compare ourselves on both a PFS perspective and an OS perspective against these bars that have been set by chemotherapy and by single-agent MEK, which we think that we can beat those bars in our phase 3 study, that then allows us to raise the bar for anybody coming behind us. You know, let's say that we are able to reproduce or maybe even beat some of the numbers that we've shown in phase 1 and 2, so call it, you know, 5 months or more of PFS, 13-14 months or more of OS, that then becomes the new bar that anybody coming behind us would have to try to beat.
And especially, you know, given Roche's decision to deprioritize belvarafenib, exorafenib now being in the hands of Pierre Fabre, you know, it creates that opportunity for us to really try to, you know, become the first approved in that indication and, and create that moat that you're talking about.
Yeah. Very, very good. Definitely looking forward to the updates for NAPRA and, you know, the pivotal study starts over the course of the year. Maybe we could switch gears to 801, since this one will be coming into focus with data, I think later this year. Dose escalation has been completed. MTD has been reached with a dose expansion planned. I think that was the latest update. Maybe walk us through how this asset, you know, was designed and how it's performing so far in the clinic.
Yeah. The molecule itself came from the labs of Michael Jung and some of his collaborators at UCLA. For the audience, Michael Jung was the inventor behind enzalutamide and apalutamide. He then turned his attention to what would become ERAS 801. And what he was trying to do was to design a molecule that was purpose-fit for GBM, specifically in terms of two aspects. Number one, he wanted to have very high CNS penetration because approved EGFR inhibitors, even like osimertinib, have good CNS penetration to treat secondary brain tumors, meaning metastases, for instance, from lung cancer, but not enough CNS penetration to treat primary brain tumors like GBM. So that's point number one, high CNS penetration.
Point number two is to have activity against V3, which is a key oncogenic mutation in GBM, but also against wild type because there is oncogenic signaling that involves the heterodimer of V3 plus wild type. And so if you spare wild type, that is a potential liability where you can still get oncogenic signaling. So those were the two main parameters that that team at UCLA was trying to optimize for, and they used that to then create ERAS-801. Now, with regard to how it's done in the clinic, you know, GBM is a very tough disease, high unmet need, and therapies are obviously needed, you know, here. ERAS-801 has moved along well in the clinic. We announced at the end of last year, shortly after Thanksgiving, that we had completed the dose escalation. As you mentioned, we had gone through multiple cohorts, roughly 33 patients.
We had identified an MTD dose of 240 milligrams as well as an MTD minus one dose, and that we would be moving into the dose expansion. That study is enrolling well, and that we will be announcing data later this year. The other thing that we mentioned, as part of that update, is that the, you know, the PK, the safety, tolerability, other sort of factors looked good in line with what we were expecting as well as, you know, kind of the consistent with the mechanism.
Okay. Maybe help contextualize the dose escalation data, which should be the first readout, with the dose expansion data as another upcoming readout. What sort of weighting should be placed in terms of importance, or are they both additive towards to the profile of 801?
I would say that they're both additive to the profile. I, I would clarify that, you know, what we've guided to is that we would have a readout in 2024, which actually gives us flexibility to either do one broader update across dose escalation plus dose expansion, or to do, you know, two separate ones. So we may actually end up doing it as just one bigger update. The other thing that I'll point out is with regard to the, this, this applies to any sort of study in, in oncology. You want to make sure that you're at a biologically relevant dose as well as in a biologically relevant patient population. So obviously in a dose escalation study, certain doses are going to be lower than your biologically relevant dose.
That is just one consideration that you need to take into account whenever you look at any sort of dose escalation study.
Okay. Okay. Great. Maybe moving on to, to ERAS-007. This is your ERK inhibitor. You'll be giving an oral presentation for HERCULES-1 in combination with encorafenib and cetuximab and BRAF-mutant CRC at ASCO.
Mm-hmm.
In a couple of weeks, you've guided to an update in the first half. Does this, I guess, fulfill that? And what should we be looking for in the data?
Yes. It does fulfill that corporate commitment. In terms of the data, so just as a reminder, at ASCO last year, we showed data for this combination in our Hercules-3 study of 007 plus encorafenib cetuximab. The combination of encorafenib cetuximab, that doublet is the approved standard of care in BRAF colorectal cancer, which was approved with a response rate of 20%, and a duration of response of about 6 months. So our plan by adding ERAS-007 to that doublet to create a triplet was to see if we can improve upon that 20% in 6 months. What we showed at ASCO last year, and it was a small dataset, but in 6 patients who were treated at the 100 milligram, BID QW dose, which was the maximum administered dose, out of those 6 patients, we saw 3 responses.
So a 50% response rate. Again, albeit it is a small denominator of patients, but it compared favorably versus that historical benchmark of 20%. And so the update that we're going to be providing at ASCO later this quarter is really around longer-term follow-up of those patients that we had shared at last year's ASCO, but additional patients that have since been enrolled in the study. And so, you know, you can imagine that this will be double-digit number of patients who are treated with that triplet of 007 plus encorafenib and cetuximab. And it will be focused specifically on patients who are encorafenib cetuximab naive.
Okay. Okay. That was going to be my next question because I remember at the prior ASCO update, you sort of cut the data, depending on prior exposure to EC.
Yeah.
And so it sounds like naive is sort of the setting that you're pursuing.
So yeah, you know, I think one of the things that we had talked about at ASCO last year was the fact that, you know, the concept of preventing resistance versus reversing resistance, that preventing resistance just generally is an easier thing to try to accomplish, if easy is even the right word in oncology. So we want to, because we saw that promising signal at ASCO last year in the EGFR-naive patient population, you know, that's where we wanted to focus our efforts going forward.
Okay. Any other data we should be looking out for at ASCO? I think you might have a few posters as well.
We do. So we have two other posters at ASCO. One is on our ERAS-601 program, which is a SHP2 inhibitor in combination with cetuximab in chordoma. Last year, shortly after Thanksgiving, in that same announcement around ERAS-801, which we already talked about, we also announced that we were deprioritizing our FLAGSHIP-1 study of ERAS-601. But that said, that trial, we want to have a readout for that trial, for patients, for the investigators. So we will be sharing data on that combination of ERAS-601, our SHP2 inhibitor, in combination with cetuximab. So that will be at ASCO. Then the other poster that we have is a trials in progress poster to describe our SEACRAFT-1 study. Again, that's the combination of NAPO plus trametinib in RAS Q61X solid tumors.
Okay. Okay. That makes sense. And, you know, I guess given the biologic rationale of hitting multiple nodes in the MAP kinase pathway, you know, SHP2 is one example of that. Would you ever reconsider restarting combo studies, with either, you know, 007 or NAPO, if the monotherapy data is looking compelling?
Yeah. While we, I mean, just to comment on some of the, you know, programs that we had deprioritized, like 601, for instance, our SHP2 inhibitor, what we deprioritized was the flagship 601 study, the clinical study, but then, we are continuing to explore 601, preclinically to see, you know, where else it could play. Because I think SHP2 is still, you know, an important target. It hasn't panned out the way the field has hoped in terms of, it as a target clinically, but it may just require finding the right spot for it. And so, you know, I think if there is preclinical rationale for various combinations, that is something that we are, you know, continuing to explore preclinically, and then, you know, we can always make decisions based on that data.
At least you have an internal asset to add into a, you know, a doublet or a triplet or a quadruplet down the road if that's where the field goes.
Yeah. Yeah. That's right.
Okay. And one question on the pipeline, I guess, you know, you talked about the reprioritization or deprioritization of a few studies. How are you balancing bringing new assets to the clinic, and with maybe the highest potential ROI with preserving capital as you support your later stage studies, especially with the NAPO phase 3s getting off the ground?
Yeah. Great question and probably the, you know, top question for every single biotech, especially right now. Yeah, that's exactly right. It's a, it's a balance to make sure that we are, adequately resourcing, you know, for instance, naporafenib is our lead program. And so, you know, we are, you know, all systems go in terms of continuing to advance naporafenib, in the SEACRAFT-1 and 2 studies, but also thinking about the other programs that are in our pipeline, both clinical stage as well as preclinical stage, to make sure that, you know, there is the appropriate balance. You know, certainly, I think naporafenib is a really exciting asset, you know, in terms of its first-in-class potential.
It's been, you know, de-risked just given how much data has been generated for it, the fact that it's shown proof of concept in melanoma as well as preliminary proof of concept in non-small cell lung. But, you know, so we're pushing that forward as quickly as possible, but also looking at the rest of our pipeline in terms of their potential as well.
Okay. You know, we talked about naporafenib, ERAS-801, ERAS-007. Those are sort of the main three that I get asked on. Is there anything else maybe earlier in the pipeline that you know could be coming into the fold over the next 12-18 months that gets you guys excited?
Yeah, absolutely. So, in March of this year, we announced a financing that was largely based upon our NAPO median OS data that I already had commented on as part of this fireside. In that same announcement, we also talked about the efforts that we were making around our RAS targeting efforts. You know, RAS targeting is a super, you know, important effort just given the unmet need there, the number of patients. And so this has certainly been a prime focus for us. And in that March update call that we hosted, you know, we mentioned that we're making good progress around our internal program, but that we're also looking at external opportunities that might allow us to accelerate our entry in this space. And so again, high unmet need and something that, you know, we are very much focused on.
Certainly stay tuned for more on that.
Okay. Great. And maybe, you know, in the last minute or so that we have, just to wrap everything back up, we've talked about a few different programs with data on the horizon. Maybe you could just lay out the cadence of data updates, you know, for the rest of this year and into next.
Yeah. So starting first with naporafenib, again, the pan-RAF inhibitor that's in our SEACRAFT-1 and SEACRAFT-2 studies. SEACRAFT-1 is on track for a data readout between Q2 and Q4 of this year. SEACRAFT-2, which is the NRAS melanoma pivotal study, is on track to initiate that pivotal phase 3 study this quarter, and then we'll have data from our stage one portion of that phase 3 study that will be randomized data against trametinib monotherapy. We'll have that data in calendar year 2025. ERAS-007, which is our ERK inhibitor in BRAF CRC, is on track to have data this quarter, in fact, at ASCO. And then ERAS-801, which is our CNS-penetrant EGFR inhibitor, is on track for data this calendar year.
Okay. That was pretty impressive, all those catalysts in 40 seconds. I can tell you've run that through that a few times, but, unfortunately, we'll have to leave it there for now. But David, thanks for the discussion and for participating in the conference.
Absolutely. Thank you.
All right. Thanks a lot.