All right. Are we good to go? Great. Hey, everyone. Thanks for joining us today. I'm here with Erasca CEO Jonathan Lim and CFO/CBO David Chacko. You guys have been quite busy over this last year, and you've certainly kept us on our toes as far as data disclosure cadence. Maybe to start, maybe a very brief introduction to the company. I think most are pretty familiar with you guys at this point, but where you guys are and milestones you have coming up near term.
Yeah. Thanks, Laura. Great to be here. Thanks, everyone. Erasca is a company that's entirely focused on erasing cancer and erasing the RAS-driven cancers as well. Both of those missions are in our name, Erasca. Our pipeline consists of two main programs. ERAS-0015 is our lead program, which is a pan-RAS molecular glue. It's being explored in the AURORAS-1 phase I trial, and we have a number of exciting developments there that we can talk about today. ERAS-4001 is our pan-KRAS switch II pocket binder. This is a small molecule that hits KRAS, but it spares H and N-RAS, and that's in a phase I trial as well called BOREALIS-1. The milestones that we have upcoming for both programs are, starting with BOREALIS-1, we have a phase I update that we've guided to the second half of this year.
Given that we're in the second half, it's going to happen soon. For ERAS-0015, we have an oral plenary presentation at the Triple Meeting in Barcelona next week. There's a lot of focus and attention on that readout. Also we've guided to combination data, including panitumumab for first half of next year. I mentioned the excitement around this program. We've also guided to three pivotal trials. One is a potentially registration-enabling trial in the second-line plus non-small cell lung cancer setting. There's RAS mutant lung, and this is one that could start as early as the first half of next year for ERAS-0015 monotherapy. We also are seeking combinations of ERAS-0015 with standard of care therapies.
For instance, we're combining with pembrolizumab, and we could take a chemo-free combo into the first-line RAS mutant lung setting as early as the second half of next year. Or we could choose to combine, once we find a dose for ERAS-0015 with pembro full dose, we could layer on chemotherapy and then take that checkpoint chemo combo with ERAS-0015 for the first-line RAS mutant lung setting, and that could start in first half of 2028. That's why we broadbanded that guidance for that trial between second half of 2027 and first half of 2028.
Have you guys disclosed if you've started adding chemo on top of 0015 plus pembro yet?
We haven't, but what we have said is that we started that pembro combo in Q2 of this year. The intention would be once we identify what the right dose is for ERAS-0015, the pharmacologically active dose, or PAD, if you will, is between 16 mg of ERAS-0015 on the low end. We've seen very good activity actually in non-small cell lung cancer. I think in the April disclosure, we had something like, in the U.S., five out of six patients had a response, which was really exciting to see. So 16 mg is an active dose, but if we can dose up to 24 mg to 32 mg, then we'd feel better about just having more drug on board. Once we identify the safe, tolerated, and efficacious dose of the doublet, then the intention is to layer on carboplatin and pemetrexed.
Got it. How involved is Merck with you in this process? They're providing free drug. Are they also helping with the dose selection process, or is this something you guys are doing independently?
We have a very good collaboration with Merck. They have visibility into what we're doing, and we don't do anything without making sure that they're informed and on board with what we're doing. But we're really driving the day-to-day activities as well as the strategic direction of what we're doing with ERAS-0015 and pembro.
Got it. After you showed us data in July, the guidance was for next dataset in 2027. What inspired or led to you guys submitting for an oral presentation at Triple Meeting, the one we're going to see next week?
Yeah, it's funny. To your point, things have been moving so quickly that anytime we think we're guiding to the next milepost, we actually are able to show another dataset, and it's never intentional. At the time, our guidance is what we genuinely believe, but then things happen and we're just enrolling at such a rapid clip that it's sometimes hard to keep up with the program, but it's really fun and exciting to keep up with it. I'd say for this one, the main impetus was actually driven more by audience. The April and July datasets were primarily geared to a corporate audience and less so to the scientific audience. I think for the oral presentation for the Triple Meeting, the stakeholders that we really want to get to are the thought leaders as well as the investigator community.
Because I'd say that the investigators that stay abreast of all the corporate developments in biotech land are very familiar with our data, but then those that are really sort of knee-deep in the day-to-day clinical work in their centers may not be familiar with our data. This really is intended to be a coming out party, so to speak, to the scientific community to make sure that we're on everyone's radar, so that they're very familiar with our lung and our pancreatic data. I will say that because we've been enrolling very quickly, I'd say that this would be a materially expanded update relative to what we've shown in April and even July.
Can you elaborate a little bit more on that point? Should we expect maybe double number of patients, enrichment for earlier line, especially in PDAC, second-line patients?
Yeah.
Any context you can give us?
Yes. What we have said is that it will be a larger dataset. I think for efficacy evaluable patients in both pancreatic and lung, I think your double is a reasonable estimate. It will be at least that, so it will be at least double the patients. Especially we have been putting our thumb on the scale with respect to what we call the RDE. So within that PAD of 16 mg-32 mg, 24 mg and 32 mg are the recommended doses for expansion, and we have been expanding those levels. You will see a lot more patients at those doses because we want to be able to, both for Project Optimus as well as for our own drug development internal decision-making purposes, pick a dose that is very rational to go forward with.
For instance, in lung cancer, which tends to be a more sensitive tumor type, you can see pretty good activity across a dose range. I think in a pretty relatively insensitive tumor type like pancreatic, that is where dose might matter a little more and getting especially exposure. With our molecule, historically we have shown that there is very good dose proportional increases in exposure as you go up in dose. So we do not have the exposure plateau that has been observed with other molecules in the class. I think with pancreatic, it will be important especially for us to see what do we observe at 32 mg versus 24 mg versus 16 mg, et cetera. To answer the second part of your question, in terms of the composition of patients, we have not really been focused on earlier lines of treatment.
It is really just enrolling patients and letting the chips fall where they will. In the July dataset for panc, for instance, three-quarters of those patients were actually third line plus. They are heavily pre-treated. I would say with this updated dataset, we have both followed those patients over time, so you will be able to see did the patients who had unconfirmed responses at the time, did they confirm? Are they still on treatment or are they falling off treatment? You will get a sense of durability. With the new patients, what is happening with them? I would say, unless we enrolled a whole bunch of patients with second line only, you are still going to see probably a heavily pre-treated population.
Got it. We have been hearing investors setting bars somewhere around greater than 40% for PDAC, 60% + for lung cancer. What is your degree of comfort hearing those bars going into this update?
Yeah, if you go back to actually our April update, we had put together a scorecard where we felt that if we, from an efficacy standpoint, can just first principles, if you look at targeted therapy, what is a meaningful delta in terms of response rates? Ultimately, you want that to translate into durability. So when you have an early dataset, if you do not have PFS, much less OS, or OS much less PFS, is your response rate meaningfully different? From KOLs, we understood that in both panc and lung cancer, if you are 10 percentage points or more higher than what has been reported for comparators, that that is a meaningful delta.
If you take pancreatic cancer, for instance, depending on line of treatment, if you look at RASolute 302, about 82% of the patients were treated with second line, in second line, and then 18% were first line. If you adjust for those first-line patients and pull those out, that response rate bogey for second line only is about 29%. If you have a four handle in terms of response rate, then you are meaningfully different, right? That is going to be more than 10 percentage points better, just by definition, if you have a four handle. That is all comers without caveats. If you can hit that, we think that would be meaningful. I think in non-small cell lung, what we have seen in the past is response rates in the 60s, and I think that is why that six handle is in people's minds.
But if you just look at KRAS G12X, at some of the best targeted therapies in the space, divarasib, for instance, as a G12C inhibitor, is very potent. They demonstrated 56%-59% confirmed response rates. That is in G12C, which tends to be more sensitive to targeted therapy than, say, G12D and non-G12C mutations. So, if ERAS-0015 is able to achieve something that meets or exceeds the threshold of that benchmark, we will be feeling really good going into next year with two pivotal trials with that potentially registration-enabling monotherapy second-line plus study, and then the phase III in first-line lung. So, that is kind of the benchmark for pancreatic and lung. Then, I want to talk about safety and tolerability. What we have reported previously in April and July is safety and tolerability that is very promising.
First of all, 100% median RDI, so relative dose intensity is 100%, meaning that it does not matter where in the PAD, whether you are at 16 mg to 32 mg or even just 32 mg alone, patients are receiving the intended dose without a ton of discontinuations or dose modifications. We reported numerically lower frequency and severity of TRAEs in terms of rash, GI, stomatitis. You might say, "Okay, that is numerically lower, but how do I interpret that?" I think the ultimate objective way to measure that is when patients receive that, are they having to down-dose or interrupt those doses? If you look at what has been reported, daraxonrasib is a great pioneer drug, and we really were thrilled when they got approval, and we are thrilled by the recent disclosure in terms of how rapidly it has been adopted in pancreatic cancer.
We are really rooting for patients to get that. We also think that there is room for improvement, especially when it comes to the fact that in the New England Journal paper, the interruptions and reductions were 56% and 36%, respectively. We think there is room for improvement there. If we can more than half those rates, I think that would be meaningful, and that would be sort of the ultimate metric of tolerability and safety. Finally, when you look at combinability, I think the fact that ERAS-0015 at an active dose of 16 mg was able to be dosed with full-dose panitumumab, it has been the first pan-RAS agent to be able to clear an active dose of anti-EGFR without any DLTs. All that is something that I think people should look at very closely when we report our safety and tolerability data next week.
On the safety front, in the RAS inhibitor space, there has been a lot of talk now about GI tox maybe not being super on target and maybe more so related to drug load or the amount of drug you are delivering. Especially in the G12Ds, we have seen that IV-infused drug alleviates almost all the GI tox. You guys seem to strongly believe that it is not just the lower dose that is driving improved AEs. You referenced the CRC combo trial, so it seems like you are implying skin must be differentiated to some degree. Why do you think this is? If it is not the lower dose, do you think it is the greater potency?
Yeah. I think the lower dose for GI tox definitely helps. I think we are seeing drug load does matter when it comes to the nausea, vomiting, diarrhea. Then, I think by having one-tenth of the dose of the comparator, we address a lot of that. There is on-target GI tox from MAP kinase inhibition. We have seen it from other inhibitors elsewhere in the pathway. I think that to some degree, that is on target, and to some degree, it is related to dose load or drug load. The other way to look at it is, this molecule, ERAS-0015, was designed to be optimized on both potency and PK.
I think by being engineered to have an eight to 21-fold higher binding affinity to cyclophilin A or CypA, as a result of that higher affinity, we see a 5x to 10x higher potency, both in vitro and in vivo. That is why you are getting the one-tenth of the dose is able to achieve a similar anti-tumor effect in animals, and then that seems to be translated in the clinic. On top of that, it has been optimized for PK, so it has got a lower clearance, longer half-life, and just a very nice dose proportional behavior. The PK is very well-behaved. What you see in vivo models is that CypA is overexpressed in many solid tumors. I think what is happening is when ERAS-0015 is administered, we see better biodistribution in these animal models, where it is almost going preferentially to the tumor.
because of that CypA overexpression, and I think as a result of the higher binding affinity, we are seeing that in terms of a therapeutic window.
Yeah
which in the clinic is very meaningful.
We have also been getting a lot of questions on, specifically in PDAC, which is incredibly RAS addicted, the importance of hitting H and N-RAS. You guys are kind of working on two sides of the experiment with the pan-RAS and the pan-KRAS. Do you guys have any thoughts of how important it is to hit broadly, when it comes to maybe ORR or durability, and maybe how that varies across different types of indications?
Yeah, you want to talk about the allele-specific piece?
Yeah, absolutely. It is a great question, Laura. In terms of the response rates that Jonathan was mentioning earlier, I think it is also really important to look at the mutational level as well. We just saw from the FDA documents that were released that the comparator compound had a 24% response rate in G12D pancreatic cancer. If you look at the allele-specific molecules that have released their data, they seem to be range-bound between the 30%-40% range, if you look at D-specifics like zoldonrasib or Incyte's molecule or Verastem's molecule, including their most recent data update. Investors that have looked at our data disclosure have noted that it was a small N, but they saw that depending on dose, we were at about a 50% or higher response rate in G12D pancreatic cancer. The question becomes, why is that?
One hypothesis is actually what you are getting at, Laura, this idea that it is not only important to hit the mutation, but also to hit wild type, because there is the propensity for oncogenic signaling to go through the wild type protein because of wild type amplification. A pan-RAS not only hits the mutation, but it also hits all three isoforms of RAS wild type. A mutant selective, on the other hand, would only hit the mutation without hitting the three isoforms of wild type. The pan-KRAS would hit the mutation, and it would hit KRAS wild type, but it would not necessarily hit H and N-RAS wild type. That is the spectrum that you are looking at with mutant selective hitting the least and pan-RAS hitting the most, and that being a potential differentiator in terms of stopping that oncogenic signaling.
We have heard some investors question, now that we are seeing the G12D inhibitors also move into frontline, in a disease like pancreatic cancer where patients' disease progresses very quickly, could a situation emerge where a doctor would just prefer to give a pan-RAS inhibitor because you can give it to any patient, you do not have to wait for the genotype to come back of the patient?
Yeah, no, that's a really critical point, Laura. I do worry that any delay in treatment, if waiting for the genotype test to come through, any delay could be detrimental. We do think that maybe in a later line, the allele-specific approach makes a lot of sense. But, if you have a pan-RAS that is showing promising efficacy as well as safety tolerability, and you can just have that be a go-to treatment of choice in the frontline setting, we think, of course, it's self-serving for me to say this, but-
Yeah
we fundamentally believe that for all the reasons David mentioned, scientifically, it should translate into higher response as well as durability, because you're addressing both the primary and acquired resistance mechanisms, if our scientific hypothesis, which is based on a lot of evidence in the literature, and then preliminary clinical data as reported. We do think that that would be an advantage, both from a timing perspective and then also from a scientific perspective.
Yeah. As you think about designing a phase III for frontline PDAC, is this something that could benefit enrollment, given the broad RAS label where you don't need to detect a RAS mutation? Could we think about enrollment in your trial in the same manner where you don't need to test before enrolling, or will there still be this need to detect the RAS mutation or know what the status is before enrollment?
Yeah, no, I mean, if the pace of enrollment in the second line plus setting is a sign of what's to come, we're not too worried about enrollment. We just think, for a few reasons. One is, unfortunately, the unmet need is super high, in spite of the fact that in first line, there is no technically fully approved molecule in the first line setting. That's wide open for enrollment. The unmet need is super high, and then I'd say that the excitement around our molecule amongst investigators as well as patients is very high. I think that gives us confidence that going into the phase III trial that we're starting next year, that enrollment should be fine.
Now we've seen Verastem and Tango have the FDA sign off on using ORR as a co-primary endpoint. Is this something that you guys think will likely apply to your phase III as well, after alignment with FDA?
Yeah, because we think that daraxonrasib has changed the paradigm in pancreatic cancer in second line. I think FDA seems to have acknowledged the fact that patients will have access to a RAS inhibitor, to RAS(ON) once they progress on some of these investigational regimens. I think it's, as in any paradigm shift, as has happened in lung and breast and other tumor types, FDA has shown a willingness to accept other endpoints that are not OS, so whether it's PFS, ORR, et cetera.
Can you speak to where you are with the chemo combo for PDAC right now?
Yeah, we started that earlier this year, and so we're making good progress on chemo combo. Yeah, so that's something that we think if you can pair ERAS-0015 with chemo with less dose reduction on both the pan-RAS side of the equation as well as the chemo side of the equation, that should translate into more durable benefit in that first-line pancreatic setting.
Are you guys enrolling frontline patients there yet?
We haven't said.
Okay.
The goal of that dose escalation, just to be clear, is less to do with seeing what it does in frontline patients and more to identify really safety and tolerability. We're not limiting it to just first line.
Makes sense. Will this be part of your combo update in the first half of 2027?
We haven't said. The combo update in the first half of next year will include panitumumab, so we have specifically called that out. I'd say, based on our work with pembro as well as chemo, that could be part of the mix, but we haven't specifically guided to that.
Got it. Promising durability. Could there be an accelerated approval path for your pan-RAS?
I think if you just look at historically what's happened in targeted therapy, I think targeted therapies that do have response rates that are clinically meaningful have been able to pursue that path. That's certainly something that we're looking at. We would, of course, need FDA to sign off on that before we pursue that.
Makes sense. As far as lung, for frontline, you were starting to see at least RevMed saying that the G12C inhibitors have started this precedent of segmenting by mutation, and them focusing on selective inhibitors there. Do you guys still have strong conviction that there's a lot of room for a pan-RAS broad approach there, and maybe even if that could be perhaps more digestible to maybe a community setting doc, to have one option to apply to all their RAS patients?
We do, for the same reason we talked about in pancreatic. We think in lung, it is a similar dynamic. To be fair, it is a much more fragmented market opportunity, but it is one where the experiment just hasn't been done in terms of a single molecule that can broadly address all RAS mutations. We do think if we have a tolerable regimen with pembro and if we can layer on chemo, then that could be a very unique value proposition for patients as well as physicians to just have one go-to regimen, sort of like KEYNOTE-189. If there were that analog in the RAS space, that could be paradigm-changing as well.
With the last minute we have here, I know we didn't talk too much about the pan-KRAS data set upcoming, but if you could just provide quick expectations for assuming any day now, what we could expect there as far as patient numbers. Will it be an efficacy update too, or more so safety PK? Anything you can provide.
What we've said on ERAS-4001, our pan-KRAS inhibitor, as Jonathan mentioned earlier, is that we'll have a data update in the second half of this year. It is a phase I dose escalation study, and so it would be what you expect from a phase I dose escalation in terms of safety, PK, initial signs of activity. And we've guided to it being about dozens of patients. This is an all-comer study, so as long as a patient has a KRAS mutation, then they're eligible for it.
Got it. And I've heard you guys, maybe I'm just more focused on the pan-RAS, but I've heard you guys numerous times mention the potential for a combination between the pan-RAS and the pan-KRAS. Is there any other combination for the pan-KRAS that you guys are heavily considering moving forward with near term?
The main focus is really the combo with ERAS-0015. We just see it as a really interesting companion molecule that can complement, if not synergize with the pan-RAS. Pan-RAS works by two main mechanisms. One is steric clash, the other is increased hydrolysis from GTP to GDP state RAS, and then ERAS-4001 as a GDP-preferring molecule really exerts that one-two punch. We have a scientific poster next week showing in vitro and in vivo synergy of that combo. We do think that the scientific underpinnings for that combo are strong.
Would PDAC be the initial focus or broadly across the big three for RAS?
Probably more CRC would be a focus for that because we think PDAC, we're very comfortable with ERAS-0015 and sort of going after PDAC with both chemo as well as chemo-free combos.
Great. Well, we're out of time. Time flies when you're talking about RAS.
Thanks, Laura.
But really nice to see you guys, and thanks everyone for coming out today.
Yeah. Thank you.
See you in Barcelona.