Erasca Inc Aktie

Hey, everyone. Thanks for joining the session with Erasca. My name is Alec Stranahan. I cover SMID Biotech at Bank of America. And I'm covering analyst for Erasca. And I have the pleasure of introducing and being joined by Jonathan Lim, Chairman and CEO; and David Chacko, Chief Financial Officer and CEO of Erasca. Thanks for being here, guys.

Thank you, Alec. Great to be here.

Yes. Looking forward to the conversation.

Maybe just to start, just to put the updates in context, and we'll definitely dig into those. But just at a high level, we've seen an evolution in RAS targeted therapies over the past 10 years, right? It started with unlocking the binding site for KRAS G12C. And now we've advanced to G12D and pan-RAS. You recently presented your Phase I update for double -- for ERAS-0015, which is your next-generation pan-RAS inhibitor. Response rates that were potentially best-in-class. So maybe just to start off, I guess how are you viewing the competitive setup for your RAS programs broadly? And what are sort of the upcoming readouts that get you most excited?

Yes. So you talked about the evolution of the space. I mean I think we're at a really exciting point in history in targeted therapy where you can go after a previously intractable target like RAS and actually have a pan-RAS compound make a difference there. So I think it's really exciting from the early days of G12C to pan-RAS and then seeing some of the mutant specific data coming out where we're really in a renaissance period.

So as far as our RAS targeting franchise, I mean, our name, Erasca really stands for a twin mission of erasing cancer, and eradicating RAS-driven cancer. And so with ERAS-0015, our lead molecule. For pan-RAS, it's a molecular glue that's really showing high differentiation in terms of the preclinical profile. And then we're also really excited by the data that we presented, which we'll talk more about.

And then ERAS-4001, which is a pan-KRAS compound. So I think the fact that we have both molecules with orthogonal mechanisms of action, I think that's really exciting because we can explore the full range of clinical activity as monotherapies and then also with standard of care and then with each other.

So as far as ERAS-0015, big picture, we're super excited about the data that we presented. I think on the monotherapy front. When you look at the big 3 tumor types, clear differentiation in terms of non-small cell lung cancer. So you're seeing 62% to 75% response rates within the pharmacologically active dose of 16 to 32 milligrams within non-small cell lung cancer. So depending on what subgroup you look at in the second, third line setting, in the post checkpoint platinum setting, 75% response rates really is just eye-popping. So we're really pleased and excited to see that.

And then in pancreatic cancer, we're seeing 41% response rates in the second line only setting in China. I think the data are maturing. And so we've gotten a lot of questions about that, but we're really excited that if you look at the 3 legs of the scientific stool, in terms of China lung data, U.S. lung data, China pancreatic data, those 3 legs of the stool are super strong. So we don't see any scientific reason for the U.S. pancreatic data to come in any differently from those 3.

But when we talk a little more about the opportunity in pancreatic, we think it's still a really exciting area, high unmet need. And yes, there is a comparator that is showing phenomenal data in the second-line setting, but we think there's still some ample opportunity for another player to enter into that space.

And then just to finish off on the big 3. Colorectal cancer is a very interesting area, which unfortunately has high unmet need and the fact that we're showing combinability with panitumumab with 16-milligram dose, which is the lowest end of the PAD, the fact that we're seeing early safety, tolerability and combinability there as well as activity in the form of partial response in the first efficacy evaluable patient on first scan. Well, we were really excited to see that because it means that 16 milligrams is an active dose in an otherwise very difficult to treat patient setting in the form of CRC.

So if that holds, and we can clear the DLT window at that dose and then also explore higher doses, even if it's just 16 milligrams that clears the fact that we have U.S. data of patients that are tolerating this is really promising.

Yes. Great. And like you said, Jonathan, the data that you showed for ERAS-0015, especially in the KRAS G12X non-small cell lung were among the highest observed with any molecular targeted RAS therapy. I guess what from the data set and if you want to sort of dig into the top line numbers that we saw that you presented makes you most encouraged about the profile that's emerging for ERAS-0015 and what are sort of your high conviction path, whether it's patient populations, tumor types, combinations for pivotal?

Yes. So I think the opportunity in lung is open for us in terms of RAS mutant non-small cell lung cancer. So by line of treatment, if you just look at the second, third line population that's post platinum as well as checkpoint inhibitor, that's sort of the way to think about that population is the docetaxel eligible population. So docetaxel, unfortunately, is really the standard of care there, and there's ample room for improvement. And so the fact that we're seeing 75% response rates there is really exciting.

I think the second-line setting for us is open in terms of a path for monotherapy. And so we look forward to -- at this point, we've opened up expansion cohorts at what we call the RDE. So the recommended doses for expansion are at 24 milligrams and 32 milligrams. So we've expanded that out, and we're enrolling patients with non-small cell lung cancer at both of those doses.

So once we have, call it, 20 patients in each of those expansion cohorts, then we'll package that data, have a conversation with FDA and then see what the registrational trial looks like. But we do think that a path is an open avenue for us.

And then at the same time, you probably saw the news with respect to the clinical trial collaboration and supply agreement that we signed and announced with Merck. So we're very excited to work with them to get access to pembrolizumab, which is really the standard of care right now in first-line lung.

So our plan is to combine pembro with ERAS-0015. When we filed our 10-Q, we disclosed that we're already enrolling that cohort. So that's started ahead of schedule as well. And so we'll identify the combination dose and then we'll seek a first-line indication for non-small cell lung in combination with pembro.

Okay. I guess one more question on the response profile that you're seeing and the headline numbers look really, really good. I guess in terms of cadence of updates from this dose expansion or dose escalation portion, do you expect that you'll be able to confirm the majority of these responses across both studies? And would this trigger an additional update maybe later this year? Or is it really kind of the first half of '27?

Yes. So our formal guidance is first half of next year. That's where we're committing to external update. I think in the meantime, we'll be enrolling patients. We'll basically be following the maturation of the data, both for lung as well as pancreatic in terms of the confirmation as well as when we talk about pancreatic cancer. But we have found that the minimum follow-up time as that increases, it's really important that the pancreatic responses actually deepen over time.

So I think, especially in the U.S. where you have a number of patients that are on that border of deep SD in that 28%, 29% range. There's a possibility that those could deepen over time. So that's something that will certainly follow. And then at the same time, we are enrolling these expansion cohorts with the RDE, not just in lung, but also in pancreatic. So we'll go to follow those patients.

I think the dose escalations, our priorities are exploring ERAS-0015 with standard of care. So we've talked about panitumumab for CRC. We've talked about pembrolizumab for non-small cell lung cancer. Next on deck is to be exploring chemotherapy combos for various indications, including pancreatic.

Yes. And I mean maybe we can speak to the tolerability profile, which I think blends ERAS-0015 really well to combinations. I know that there was a lot of focus after the update on the pneumonitis event. Even though this is something that we've seen with others in the class, maybe we could talk about the overall tolerability profile, how this sort of stacks up versus competing agents?

Yes. So maybe I'll speak to the overall tolerability and then David will chime in on anything I've missed. But overall tolerability, what we went into this update with a question is, is there going to be a trade-off between efficacy or safety tolerability? Or can you actually achieve a sweet spot where you could see potentially differentiated efficacy and differentiated safety and tolerability. So on the safety tolerability side, what's really interesting to us is that we're seeing numerically lower frequency and severity of rash TRAEs, GI TRAEs in the form of nausea, vomiting, diarrhea as well as stomatitis/mucositis.

And so that both end is what's really exciting. The fact that you're seeing such strong efficacy signal in non-small cell lung cancer as well as promising signal in pancreatic and then combinability with panitumumab in CRC. I think the most objective marker, for instance, with rash is the fact that we have a pan-RAS inhibitor that has shown promising safety and tolerability with an EGFR antibody, which is really critical for CRC to shut the door on that acquired resistance propensity through EGFR. So all of that bodes really well.

And then I do think kind of the drivers of why that might be happening is the higher CypA binding affinity. So the fact that when CypA is overexpressed in multiple solid tumor types, you just get this biodistribution of more drug in that tumor and local environment as opposed to in the skin and surrounding tissues. That plus maybe the lower predicted peak-to-trough ratio as driven by the longer half-life and lower clearance is another source of therapeutic window advantage.

And then finally, the fact that we're at such low doses of PAD of 16 to 32 milligrams as opposed to much higher doses, so the GI tolerability should be much better. So big picture, we're really pleased with the emerging safety and tolerability data from this update as well as ongoing. Anything to add?

Yes. No, I mean, Jonathan covered it really well. I mean I think the -- on the rash, the fact that, as Jonathan mentioned, that we are quantitatively, we're better in terms of lower frequency and severity. Qualitatively, we're hearing from our investigators that the rash here is better than what they saw with the comparator compound.

And then also on the ultimate proof in the pudding, so to speak, is the fact that you can combine as Jonathan mentioned, with anti-EGFR, which in and of itself causes [ skin ] rash. And then similarly, when you think about the GI toxicities that could be associated with this class, you want to think about combinations with chemotherapy and the fact that our rates are better, portends well in terms of our ability to combine with chemotherapies.

And so Alec, you also brought up the pneumonitis and so maybe I'll just talk about that briefly as well. This was -- in this particular patient's case, and it was obviously a very bad outcome for the patient, and we acknowledge that. But in this particular patient's case, I think it's important to understand a few things with regard to the patient. This was a patient who had been on multiple lines of prior therapy and had -- he came into the ER with a Grade 3 pneumonitis -- because his underlying lung function was already somewhat abnormal in the sense that he had lung metastasis, he had prior cryoablation of the lung because of those factors, that adds a layer of complexity in terms of the development of this pneumonitis.

And ultimately, having been a patient with cancer for as long as this particular patient was, I think he ultimately made a decision to withdraw supportive care. And so at that point, it progressed to a death, unfortunately. And we acknowledge that, and we are obviously taking that very seriously, but it feels like in this particular case, there were other mitigating circumstances that led to this particular outcome.

And the PI also communicated to our team that he felt that, had the patient not withdrawn supportive care that this would have been a different outcome.

Yes. And we've certainly seen with others that if you do implement the prophylaxis for pneumonitis, probably this patient would have survived and have been okay.

Yes. And it's also worth noting that in targeted therapy and frankly, even beyond our targeted therapy to other oncology drugs, other non-oncology drugs. Pneumonitis is a known event. CDK4/6 inhibitors have anti-PD-1s and HER2, which is very successful drug has a very high rate of pneumonitis. And so it's one of those things to your point that once you know about it, you can monitor it, monitor for it, it's something that can be much more manageable.

Okay. And I guess one more question sort of around the combinability vis-a-vis the tolerability profile. We've seen the competing compound they've had to dose down, right, to be able to thread that therapeutic window in the combo. Do you think that's something that you'll also have to do?

And I think what's interesting, let's talk about pancreatic for the time being. I think the opportunity in first line is really interesting because, as you think about what's been demonstrated there, the second-line data is really strong. And then in first line, to your point, for the combo, they have to dose down and dose modify both sides of the RAS side of the equation as well as the chemo side of the equation.

So if we explore combos with a better tolerability profile in terms of -- especially as you think about what the stacking tox could be from a GI and stomatitis perspective, if you can maintain a more full RDI or relative dose intensity on both sides of the equation, that could translate into efficacy benefit.

So that's really exciting for us is to see what the opportunity is there for first line where the unmet need is 4x the size of second line for instance.

Right. Right. Maybe a question on the EGFR activity you're seeing. This was one of the first documented patient responses with a pan-RAS in combination with an anti-EGFR in colorectal cancer. Is this combination kind of additive or potentially synergistic mechanistically from the work that you've done? And what would you want to sort of see from the study that you're enrolling there to have conviction to begin a Phase III in colorectal?

Yes. So I think history can teach us a lot. And so if you look at the label for, let's say, panitumumab, which is the combination partner that we're working with. As a monotherapy in RAS-driven CRC, the response rate is 0. So when you put pani in a setting of RAS mutant CRC, you shouldn't expect anything. But yet, when it was combined with sotorasib in the G12C CRC setting, I think that response rate went into the high 20s. I think it was 26% or something along those lines.

So that, to me, is not additive. It's quite synergistic. And then likewise, the fact that we're seeing so far, 1 for 1, 1 out of 1 response in combination with ERAS-0015 at 16 milligrams, you wouldn't expect that with pani. So I do think that, that could be a synergistic type of situation.

Now as you look at the unmet need in RAS-driven CRC, I think you can also learn from history in a BRAF space. So we were in the BRAF space with encorafenib and what was interesting from BEACON is that BRAF inhibitor plus EGFR was approved in BRAF mutant CRC with response rates 20% and the DOR was about 6 months. So that's kind of the bar right now because the unmet need, especially in third-line CRC is so high that if you can get 20% response rates or higher, then that's meaningful from a registration-enabling perspective.

So I think if we see something in that range or ideally higher than that is an area of unmet need where there's even more patients with RAS-driven CRC than there are in any of the other 2 big 3 tumor types.

Right, right, right. Just one question around the IP for ERAS-0015. Great to see the U.S. patent issue with composition of matter into 2043, I believe. Maybe you could just walk us through the distinct mechanistic basis, I guess, contemplated in the patent? And are there ways to maybe further expand the protection for assets in the pipeline?

Yes, that's right. So we did get a U.S. composition of matter patent. We announced that last October out to 2043, as you mentioned. And then with regard to the mechanistic aspect of your question, yes, this molecule has 2 distinct modifications on the chemical structure that have led to some pretty distinct advantages, both preclinically and clinically in the data that we've shown.

So preclinically, we've talked about with you before, Alec, about the enhanced binding the CypA, the better in vitro potency on the order of 4 to 5x, the better in vivo activity, the better ADME PK properties. And then clinically with the data that we've shown that -- and we've talked about here in terms of both safety and efficacy, this molecule is showing really nice activity and safety tolerability, and it's driven by those 2 key mechanistic changes from a structural standpoint.

And then in terms of your -- the latter part of your question with regard to kind of IP strategy. The short answer is, yes, there are a lot of different things we can do. We don't necessarily talk about all that publicly, as you can imagine. But there are a lot of things that you can imagine beyond just the composition of matter patent that allow us to kind of protect 0015.

Okay. And maybe one last question just around kind of the commercial outlook. The space is pretty quickly evolving. I think everyone can agree these are very large tumor types, high unmet need in PDAC, large incidents in lung. How do you see sort of your assets positioned in terms of developmental stage and sort of where the puck is going for the industry? Are you maybe leaning more on the combos? And I guess, how do you balance running the right studies that answer the right questions but also moving with a sense of urgency...

Yes. So we're a very nimble organization. We're capital efficient, but we also have some very interesting shots on goal, especially to your point, with the standard of care combos. So I think the fact that we already started the various standard of care combos for lung and CRC. That's really promising for sort of entry into multiple lines of therapy in those indications. And then I think next on deck is pancreatic cancer.

We do think that second line pancreatic cancer will be difficult. So it's really all about a combination in the first-line setting. And then it really -- there's multiple areas of opportunity. I think people are under-appreciating the opportunity in non-small cell lung as well as CRC. So I think those are still open lanes for us and then first-line pancreatic for the reasons I suggested if you can maintain RDI with combo, I think there's potential safety, tolerability and efficacy gains to be made in that area of unmet need.

Okay. Great. Maybe we can shift gears now to ERAS-4001. This is your pan-KRAS inhibitor, structurally distinct scaffold versus, I guess, approved in competing programs. I think you've argued in the past that KRAS selectivity sparing HRAS and NRAS could improve the tolerability and maybe combinability, which, for example, like anti-eGFR agents like we talked about in CRC. I guess, looking forward to the Phase I monotherapy update in the back half of this year. Can we expect a similar breadth, depth of data to the ERAS-0015 update, medical conference investor events?

Yes. I'll answer that part in a second, but just going back to the premise of the question. Yes, I mean, I think the hypothesis around pan-KRAS as a field is exactly what you said that by sparing H and NRAS that you could get a better tolerability profile, particularly when it comes to something like rash.

Now I think a key question, especially in light of the data that we just put out a couple of weeks ago with our pan-RAS program, where we did show a better rash rate and also combinability with anti-EGFR. The key question is whether with 0015, are we able to achieve some of the limitations that were perhaps surrounding the class earlier. But that said, I think with 4001 with our pan-KRAS, we are excited about that program. It's going to have a readout in the second half of this year.

You can think about that in terms of dozens of patients. It's Phase I dose escalation. So things that you would normally expect in terms of safety, tolerability, PK, initial signs of activity which will then use to be able to then initiate the mono expansion and combo dose escalation work in calendar year '27.

Okay. Are there any, I guess, clinical thresholds that you're thinking about to feel confident in initiating those expansion I guess combination cohorts?

I think we'll keep an eye, of course, on -- as we generate data as the others in the space generate data. To date, there's just been very little to point to. A couple of companies have reported some initial data. And so obviously, we're monitoring that and anybody else that has data updates to come. And that will also help inform our go-forward plan. But I think at this point, just given the relatively nascent timing or the early nature of the space right now, I think it's -- there's still a lot for us to learn as we go along.

Yes. And I guess one higher-level question, in a world where there's a pan-RAS molecular glue and KRAS inhibitor. And this is something I think about, which is what's the benefit of having a pan-RAS when you have a more specific pan-KRAS or even more specific, like G12D or G12C. How do you sort of see these coexisting? Do they have overlapping markets? Is it a combinability or like an upfront debulking and then like a maintenance kind of approach? Like how are you thinking about how this plays out?

Yes. Those are all great question. There's been a lot of debate that I've heard around exactly that same thought, right? And where do these different assets play. I think our view is that most likely they will have their kind of maybe distinct swim lanes will be data driven, of course, in terms of if we see that one asset is playing better in this swim lane and the other asset is playing better in the swim lane, that's fine.

As I alluded to, I think one of the advantages of the pan-KRAS is that by sparing H&NRAS, you can have that better tolerability profile, especially when it comes to rash. Now on the other hand, there was a paper earlier this year from [indiscernible] at all in science that talks about one of the liabilities of sparing H&RAS is that you can get bypass via PI3K. And so that can lead to resistance. And so that's where a pan-RAS that hits all 3 RAS isoforms, H,N,K might have an advantage.

Now the question there with pan-RAS is the tolerability question. But again, going back to what we mentioned with regard to our data update last month, we feel that our pan-RAS does have a good tolerability profile. So a lot of this is still evolving. The mutant selective, you brought that up as another option, and we're certainly monitoring that space as well. I think one of the key questions with the mutant selective as well is that a lot of them spare wild-type and wild-type amplification is also another potential avenue for resistance to develop.

And so you have to kind of look at all of these different puts and takes in terms of what are the pros and cons of these different approaches. I think the nice thing for us being perhaps the only company or one of only a few companies that have both a pan-RAS and a pan-KRAS is that regardless of how the field evolves, we've got a strong answer.

Yes. I'd say at this point, you guys are probably the premier experts on the MAPK pathways, just given the years of the development experience you have. Maybe last question, just on the go forward when you think about the combos. Where do you lean in on in terms of the combination partners? Obviously, you've got the supply agreement with Merck for KEYTRUDA, you've got the supply agreement with Tango for their combination study with their PRMT5. Where do you sort of see the biggest opportunity when it comes to combos at least initially?

I mean I think as we outlined, we have a lot of optionality. And so I think first order of business in terms of prioritization is what is the standard of care in the areas where we can make the most patient impact. So it's really in the big 3 and with the standard of care? And then where is the puck going to potentially go, and how can we skate there? Well, that's where working with Tango, for instance, with PRMT5 for a chemo-free solution within pancreatic and possibly lung, that's very interesting as well.

So we really want to keep our eye on the future as well as, keep our eye on what has historically worked for many years with thousands of patients of data. That's where we want to adequately combine with standard of care and then while also not taking our eye off the ball in terms of additional innovation.

Okay. And maybe just one last quick one in terms of capital allocation. How do you be good stewards of capital while driving forward the promise from the pipeline? Are there certain applications that you would partner out or tumor indications that you want to keep in-house?

I think we've shown that, for instance, in terms of -- with the PRMT5, we're really sort of letting Tango drive that, and then we're keeping our eye focused on the core indications where we can really devote our financial and human resources to pushing those forward. And then you've known us for a long time, in terms of just how we deploy capital, we're very efficient in terms of our use of capital and our cost structure is just very different from a lot of companies out there.

And we are singularly focused on the RAS targeting franchise. So we're as pure play a RAS option for investors as it gets.

Yes. Great. Well, I think with that, we're out of time, so we'll leave it there. But really want to thank Jonathan and David for the great conversation. Thanks for being at the conference. Really appreciate it. Thank you.

Thank you.

Thank you.

Greetings, and welcome to the Erasca Corporate Update Call. [Operator Instructions] As a reminder, this conference is being recorded. It is now my pleasure to introduce Jonathan Lim, CEO and Chairman. Please go ahead.

Welcome to Erasca's ERAS-0015 preliminary Phase I data update. We are excited to share these data with you and appreciate you joining us today. Here with me are David Chacko, our CFO and Chief Business Officer; Shannon Morris, our Chief Medical Officer; Robert Shoemaker, our Chief Scientific Officer; and Dawei Xuan, our SVP of Clinical Pharmacology.

Please note that we will be making forward-looking statements covered under the safe harbor provisions of the Private Securities Litigation Reform Act. We will also be making comparisons and pooling of clinical data across separate non-head-to-head studies and caution should be exercised when drawing conclusions from such data as such data may not be directly comparable. Please see the cautionary language included on the disclaimer slide of this presentation and in our latest SEC filings and the risk factors associated with our business. In addition, any statements made today represent our views only as of the date of this webcast and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligations to update these statements.

During today's update call, we'll be providing an overview of ERAS-0015, its clinical studies and the clinical pharmacokinetics and pharmacodynamics data, which will set the stage for showing ERAS-0015's potential for differentiation in the Big 3 tumor types of non-small cell lung cancer, pancreatic cancer and colorectal cancer and against a comparator.

Shannon will share a deep dive of preliminary clinical efficacy, safety and tolerability data, and then we'll wrap up with conclusions, key milestones and Q&A.

First, we'll begin with an overview of ERAS-0015 and the 2 clinical trials underway in the U.S. and China as well as the PK/PD profile of ERAS-0015. RAS mutations are the most common oncogenic driver mutations identified in approximately 30% of all solid tumors. Over the past decade, we've made substantial progress in addressing this previously undruggable target with recent advances in targeting KRAS G12C and RAS mutations, but we believe there are still opportunities to improve efficacy, safety and tolerability and combinability for patients. We believe ERAS-0015 has the potential to show differentiation in efficacy, safety and tolerability across multiple indications through improved PK and potency. We are thrilled to present our data and the advances we have made.

ERAS-0015 has many attributes demonstrating preclinical differentiation due to its improved binding affinity to CypA that is 8 to 21-fold higher than the comparator. This led to improved cell-based potency and greater in vivo activity with tumor regression achieved at 1/10 to 1/5 of the comparator dose in multiple mouse models. The PK properties also are differentiated with demonstrated higher oral bioavailability, lower clearance and longer half-life, which could potentially result in a lower predicted peak-to-trough ratio in the clinic and preferential tumor distribution and longer residence time resulting from ERAS-0015's higher binding affinity to the CypA that is overexpressed across multiple solid tumors.

Earlier this year, we showed promising early clinical data demonstrating translation of these preclinical properties in the clinic. Today, we are presenting substantially more clinical data to help support our assertion that the preclinical differentiation translates to the clinic. Today, we are presenting preliminary first-in-human data for ERAS-0015. However, this early data set is notable in that we will share results from 2 independent clinical trials conducted in parallel, which allows us to present a larger overall data set as well as speak to the potential generalizability of these data between the two studies.

On the left is a schematic diagram illustrating the dose escalation and dose expansion portions of the trial conducted in China by Joyo from whom we licensed ERAS-0015, which was administered orally once daily in escalating doses from 2 to 40 milligrams with the opportunity to backfill select dose escalation cohorts as well as expand select doses in a Phase Ib dose expansion portion. On the right is a schematic diagram illustrating the dose escalation portion of the trial conducted by Erasca in the U.S.

In this trial, ERAS-0015 was also administered once daily in escalating doses from 2 up to the maximum administered dose or MAD of 40 milligrams with opportunity to backfill dose escalation cohorts. The primary and secondary endpoints were similar between the 2 trials and consistent with a first-in-human trial design. Eligibility criteria were similar with one key distinction in that the China trial allowed patients with any RAS mutation solid tumor, while the U.S. trial focused on pancreatic cancer, KRAS G12X G13X lung cancer and select KRAS G12X G13X GI tumors.

As shown in these baseline characteristic summary tables, patients enrolled in the China and U.S. trials were generally similar and consistent with the population enrolled in first-in-human trials. The table on the left shows the China trial data, while the table on the right summarizes the U.S. trial data. While there are small differences in the percentage of patients with pancreatic or lung cancer that had a better ECOG status in the U.S. trial compared to the China trial, the potential effect on prognosis is counterbalanced by the difference in the number of prior lines of therapy, which suggests that the U.S. population is slightly more heavily pretreated than the China population.

This is a slide that we have shown for nearly 2 years now, ever since our investor update in May 2024, when we first laid out our thesis for in-licensing both ERAS-0015 and ERAS-4001. At that time, we laid out the 3 key attributes for an ideal RAS targeting molecule, and our thesis that better preclinical activity and PK performance could lead to a lower clinically active dose that could translate to lower risk of solubility-limited absorption leading to exposure plateau, better GI tolerability due to lower drug load and improved therapeutic window for any potential off-target toxicities, all of which we think can translate into improved clinical activity. And now let's review the clinical data that we think support our potential for differentiation in the clinic.

I'm going to begin by showing why we think ERAS-0015 has demonstrated improved PK properties in the clinic. The rest of our presentation will follow this framework of differentiated PK, differentiated efficacy and differentiated safety and tolerability with the potential benefit of improved combinability. Consistent with our predictions, ERAS-0015 has demonstrated well-behaved PK characteristics in the clinic in terms of rapid drug absorption following oral administration, dose-dependent increase in PK exposure across the entire dose range evaluated and low to moderate PK variability as shown in the PK concentration time profile figures.

The pharmacologically active doses, which I will refer to as PAD from now on, in humans were identified as 16 to 32-milligram daily based upon the observed mean steady-state average concentration at greater than or equal to 16-milligram doses, exceeding the target efficacy exposure threshold derived from an insensitive CDx model as shown in the steady-state PK profiles on the right. Based on the observed safety tolerability, preliminary efficacy and PK/PD data collected during dose escalation, we have selected 24 and 32-milligram daily as the recommended doses for expansion, which I will refer to as RDEs from now on for further evaluation in accordance with FDA Project Optimus.

We also compared the PK data between China and U.S. trials. As you can see from the PK figures, the single-dose PK profiles between the 2 trials are largely comparable, which provides reassurance that there are no obvious differences in the PK between Chinese patients and U.S. patients in a cross-trial comparison. ERAS-0015's dose exposure relationship translated into robust PD activity as measured by the reduction in KRAS mutant allele fraction in ctDNA. At PAD, there was a statistically significant greater reduction in KRAS mutant allele fraction compared to lower dose levels. Notably, all 14 patients treated at PAD achieved at least a 75% reduction in KRAS mutant allele fraction with 5 patients achieving complete clearance. This biomarker response data further supports the PAD determined from human PK and translational pharmacology data.

Now I'm going to discuss ERAS-0015's potential differentiation in the Big 3 tumor types and against the comparator. The reason why we refer to metastatic colorectal cancer, lung cancer and pancreatic cancer as the Big 3 is because of the large number of patients affected by KRAS mutations in the U.S. and globally in these 3 tumor types relative to the long tail of other solid tumor types where the unmet need is significant, but not quite as prevalent. Unfortunately, there are approximately 74,000 patients with KRAS-mutated colorectal cancer and over 50,000 patients with either KRAS-mutated lung cancer or pancreatic cancer in the U.S. every year, representing a significant unmet medical need for new therapies.

Learning from the storied history of targeted therapy development in oncology over the past few decades, including the experience of predecessor pan-RAS and mutant-selective KRAS targeting molecules, we know that the Big 3 tumor types have varying levels of sensitivity to targeted inhibition. We predict that KRAS-mutated lung cancer would have the highest sensitivity to pan-RAS inhibition, manifesting as faster, deeper responses to ERAS-0015 monotherapy administered at the PAD of 16 to 32 milligrams. We predict that EGFR-mediated primary and adaptive resistance would be a key issue in KRAS-mutated colorectal cancer, therefore, requiring a combination approach with anti-EGFR antibodies to achieve meaningful clinical benefit.

Finally, we predict that KRAS-mutated pancreatic cancer sensitivity would lie somewhere between the other two tumor types. We know from the comparator that up to 50% of patients with KRAS-mutated pancreatic cancer exhibited delayed RECIST responses that weren't observed until after 14 weeks or more of treatment. We hypothesized that the higher doses of 24 and 32 milligrams may be able to overcome the relative insensitivity of pancreatic cancer to monotherapy pan-RAS inhibition and induce RECIST responses more quickly.

I'm now going to share with you our preliminary Phase I clinical data for ERAS-0015 that further underscores the relative sensitivity in the clinic of the Big 3 tumor types to pan-RAS inhibition. In order to provide you with the most applicable comparison, our data disclosure today will include data cuts based on non-head-to-head studies that we believe are similar to those used for the comparator, though our future data disclosures might not follow this methodology. And the comparator data have been generated since that time, which may differ from what we are presenting today. Beginning with second-line plus KRAS G12X lung cancer, we are pleased to report our data showing robust efficacy. At 8 milligrams or above, a total of 39 patients were treated in the U.S. and China, and we observed a response rate of 62%. Shown in the middle column, 37 of the 39 patients were treated at the 16 to 32-milligram PAD, and the response rate was also 62% with remarkable consistency of responses between the 2 regions.

Next, I'll call your attention to the teal box, which shows the results of a subgroup analysis. These data represent patients with KRAS G12X lung cancer who were post checkpoint and platinum therapy being treated with ERAS-0015 in the second or third-line setting and who were docetaxel-naive. The purpose here was to understand the clinical activity of ERAS-0015 in a patient population who would traditionally receive docetaxel. In this 16-patient subgroup, ERAS-0015 at the PAD demonstrated an impressive 75% response rate with consistency of responses observed between the 2 regions. Finally, while the maturing data set for U.S. patients treated at 24 to 32 milligrams is still early with 1 response and 2 patients still on therapy with stable disease, the response rates observed in the patients in the China trial suggest that increased ERAS-0015 dose correlates with higher response rates. On a global basis, the response rates were 64% at the RDEs, which is in line with or better than many of the top targeted therapy drugs in lung cancer.

To provide additional perspective of how we believe ERAS-0015 fits within the RAS targeting landscape. On the left, you can see examples of first-in-class drugs within the KRAS targeting space, including the KRAS G12C inhibitors and the comparator, all of which achieved response rates in the high 30% and low 40% range. On the right, you can see examples of what we believe are potentially best-in-class RAS targeting molecules with differentiated preclinical properties such as potency in the case of Divarasib and potency and PK in the case of ERAS-0015.

With the potentially best-in-class molecules, response rates increased to the high 50s for Diva, as you can see in the blue box in the upper right and to low 60s to mid-70s percentages for ERAS-0015 in the dark blue and teal boxes in the lower right. The comparator data in this example in the gray box in the lower left are from ELCC 2025. The 40 patients in the denominator are a subgroup of the 73 patients treated in the 120 to 220 milligrams range, where the subgroup is defined as those patients who received the first dose of the comparator at least 14 weeks prior to DCO to allow 2 potential scans. Harbor RAS G12X mutations are second- or third-line post-immunotherapy and platinum chemotherapy and have not received docetaxel previously.

In contrast, looking now at the dark blue box on the right, you see that in all comers, ERAS-0015's response rate was 62% at the 16 to 32-milligram PAD who had received their first dose of ERAS-0015 at least 8 weeks prior to DCO in the U.S. or had at least 1 post-dose tumor assessment in China, which compared favorably to the 38% response rate for the comparator. Furthermore, the teal box shows a similar population of 16 patients who were second or third line post immunotherapy and platinum chemotherapy, and docetaxel-naive with a response rate of 75% that is nearly double what was observed with the comparator. Perhaps most strikingly, the lower bound of the 95% confidence interval for both response rates excludes the 38% value observed with the comparator, which indicates that the clinical activity observed with ERAS-0015 is significantly better than that reported for the comparator. If this observation holds in later phase studies, ERAS-0015 could be among the very best molecularly targeted therapies in oncogenic mutation-driven lung cancer.

Moving on to pancreatic cancer. It has been previously reported by the comparator that among patients with a response, half of the patients experienced their first response after 14 weeks of treatment, which we believe explains why their data cuts and reported response rates from ESMO 2023, the ENA Triple Meeting 2024 to their corporate update in June 2025 have evolved over time. This table shows the impact of dose, longer minimum follow-up and line of treatment on response rates and explains why the initial response rate in patients with second-line plus KRAS G12X pancreatic cancer at ESMO 2023 was 19.6% at doses greater than or equal to 80 milligrams using an efficacy evaluable population, including only those patients whose first dose of the comparator was taken at 8 weeks prior to DCO and then evolved to 29% in a more homogeneous efficacy evaluable patient population defined as second line only and starting the comparator at doses of 160 to 300 milligrams, at least 14 weeks prior to the DCO. It is this second-line population that was ultimately assessed in RASolute-302, where one of the key eligibility criteria was restriction of the number of prior lines of therapy to one in the metastatic setting.

Further restriction of the target patient population to only those patients dosed at 300 milligrams resulted in an ORR of 35% at a later disclosure. Applying this methodology to our data set, you can see that ERAS-0015's response rates increased significantly with longer minimum follow-up and earlier line of treatment, yielding impressive 40% to 50% response rates in the PAD, RDE and 32-milligram only dose ranges in an efficacy evaluable population defined as having received ERAS-0015 in the second-line setting at least 14 weeks prior to the DCO. Notably, the response rates observed for ERAS-0015 in the second-line setting, which is the same population evaluated in RASolute-302 compared favorably to the response rates achieved with the comparator.

The preliminary data in pancreatic cancer, consistent with what we saw with the preliminary lung cancer data, suggests that differentiated preclinical characteristics such as potency and PK could potentially drive improved clinical activity. In this subgroup of second-line only patients, ERAS-0015's 40% response rate in a sample size of 20 patients treated at a similar dose range is more than 10 percentage points higher than what was observed with the comparator administered in a comparable dose range, which is encouraging to see.

Now switching to colorectal cancer, achieving meaningful clinical activity with the RAS/MAP kinase pathway inhibitor monotherapy has been challenging due to adaptive pathway reactivation, primarily driven by EGFR-mediated upstream signaling. This is why EGFR inhibition is a key strategy to enhance the activity of RAS/MAPK pathway inhibitors in colorectal cancer. However, anti-EGFR antibody monotherapy has demonstrated limited clinical activity in RAS mutant colorectal cancer, as you can see with the low monotherapy response rates. This is because RAS mutations activate the RAS/MAPK pathway downstream of EGFR, reducing tumor dependence on upstream EGFR signaling. Consistent with this biology, RAS mutations are excluded in the FDA labels for the approved anti-EGFR antibodies, cetuximab and panitumumab in colorectal cancer.

However, the combination of an anti-EGFR antibody with a KRAS G12C inhibitor showed a markedly improved response rate to 26%. Likewise, we hypothesized that combining an anti-EGFR antibody with ERAS-0015 would be a rational combination. I'm pleased to disclose that we started enrolling our first combination dose escalation cohort of ERAS-0015 with panitumumab ahead of schedule earlier this year in the first quarter. Three patients have enrolled in a cohort evaluating 16 milligrams of ERAS-0015 in combination with the approved dose of panitumumab. Two have completed the DLT evaluation period and no DLTs have been observed as of March 31 data cutoff. Based on the absence of DLTs, paired with anecdotal feedback from the investigators indicating that the AEs are consistent with the known profile of panitumumab, we feel these data provide the best evidence of rash tolerability with our compound. We are excited to report that in the first efficacy evaluable patients initial scan, a partial response was observed, which is really incredible to see. Given that panitumumab is not expected to have any activity in KRAS-mutated colorectal cancer, we feel these data provide the first indication that the KRAS G12C inhibitor plus anti-EGFR antibody experience where they did see activity with the combination may generalize the ERAS-0015 plus anti-EGFR antibody in terms of potentially demonstrating synergistic efficacy.

This is the case study of the ongoing response in a 77-year-old male patient with Stage IV KRAS G12D colorectal cancer treated with 16 milligrams of ERAS-0015 daily in combo with standard of care doses of panitumumab. The patient was heavily treated with 3 prior lines of therapy before receiving the ERAS-0015 plus panitumumab combo. At the first restaging CT scan, the tumor shrank by 34% and the patient continues on treatment. His TRAEs include low-grade rash, paronychia, pruritus and mucositis. On the right, you can see the lesion in the liver shrinking from baseline to cycle 3, which is great to see representing to our knowledge, the first documented patient to show response to a pan-RAS molecular glue with anti-EGFR combination.

We look forward to assessing the safety, tolerability and efficacy of this combination in other patients in the future. ERAS-0015 safety and tolerability results are promising as well. We are showing data from the U.S. trial only because of the similarities in reporting TRAEs versus China, where the approach to reporting TRAEs is significantly different and difficult to generalize to the U.S. population. We also are taking a more conservative approach by showing safety in patients with pancreatic and lung cancer on the left-hand side, treated at the 16 to 32-milligram PAD, which does not include patients treated at lower doses as well as safety in the 8 milligrams and above dose range on the right-hand side. The frequency and severity of rash, GI and stomatitis are quite promising for ERAS-0015 as evidenced by the low frequency of grade 3 and above TRAEs and the low frequency of dose interruptions and reductions as well as discontinuations.

By minimizing dose modifications and discontinuations, adequate drug exposure can be maintained and clinical benefit maximized. We are also showing early signs of combinability of ERAS-0015 with panitumumab and a response demonstrated in the first patient on first assessment, as mentioned earlier. The fact that ERAS-0015 has been able to combine with an anti-EGFR antibody, a drug class known for skin toxicity without DLTs observed in the 2 patients who have completed the DLT window, provides the best clinical evidence of the more favorable rash profile of ERAS-0015. We feel that this speaks to the potential for differentiation of ERAS-0015.

For context, this slide shows the safety and tolerability data of the comparator from their public disclosures. Dose interruptions of the comparator were not disclosed in the ESMO 2023 data set, but they were subsequently disclosed in later investor decks for lung and pancreatic cancer in 2024 and 2025. These data further highlight the substantially reduced dose modification and discontinuation rate of ERAS-0015 versus the comparator with just 12% to 17% interruptions versus 34% to 43%, 7% dose reductions versus 14% to 30% and 0% dose discontinuation, matching the comparators rate in second-line plus pancreatic cancer.

We included a scorecard in our corporate deck a few weeks ago that lays out the potential scenarios for our view of differentiation of ERAS-0015 compared to the comparator. As you'll recall, showing differentiated efficacy in one or more efficacy attributes or differentiated safety in 2 or more safety and tolerability attributes would be a differentiated scenario. Showing compelling performance data in both efficacy and safety would be a paradigm-shifting scenario in our view. We have populated the scorecard with ERAS-0015's preliminary Phase I data and are pleased to report that the early clinical data suggests the potential for the paradigm-shifting scenario. I realize this is probably the most detailed data chart you've ever seen from a public biotech company, but we wanted to lay out all the key efficacy, safety and tolerability data to allow you to contextualize our belief in ERAS-0015's differentiation.

From an efficacy standpoint, I'll point you to the top row in the efficacy section. Recall that the most relevant data for pancreatic cancer is the clinical activity in second line as that population is most representative of the RASolute-302 patient population. Although the data are still immature, we achieved 40% to 50% response rates achieved in the PAD, RDE and 32-milligram doses, where the comparator achieved 29% to 35% response rates in its prior study.

In the second row of the efficacy section, you'll find the lung cancer data showing the 62% to 64% response rates at PAD and RDE, and the 75% response rate in the post-immunotherapy platinum docetaxel-naive second, third-line setting. These are significantly higher than what the comparator achieved in its study as evidenced by the lower bound of the 95% confidence interval, excluding 38% and are competitive with what's been observed with the most successful targeted lung cancer drugs in their studies. We've talked about the safety and tolerability advantages, and they're summarized here for your convenience as well.

To summarize, we're thrilled to report that ERAS-0015's early clinical data suggests potential for achieving the paradigm-shifting scenario based on performance in both efficacy attributes, 11 to 15 percentage point response rate increases in second-line KRAS G12X pancreatic cancer and 24 to 37 percentage point response rate increases in second-line plus KRAS G12X lung cancer and second, third-line subgroup. This is in the context of also showing differentiation in all 5 safety and tolerability attributes, including demonstrating promising early combinability with anti-EGFR therapy. We think these early data and the improvements in efficacy and safety data suggests ERAS-0015's potential to be an exciting new option for delivering benefit to patients and addressing the huge unmet need in RAS-mutated solid tumors.

With that, I'll hand the call over to Shannon to go through the clinical efficacy, safety and tolerability for ERAS-0015 in further detail. Shannon?

Thank you, Jonathan. As Jonathan indicated at the start of the call, my goal is to provide a deeper dive into the ERAS-0015 clinical efficacy and safety data with a specific focus on those patients with lung cancer and pancreatic cancer. As a reminder, our overarching hypothesis has been that the preclinical differentiation would translate into improved efficacy and safety in the clinic. We feel that the data being shared today indicate that our hypothesis may be coming to fruition.

Let's start with the efficacy data in patients with KRAS G12X lung cancer from the China trial. In the upper left, you see a table summarizing the objective response rates and disease control rates by dose. In the lower left, you can see the waterfall plot, which shows the maximum change from baseline in target lesions. Because no patients with KRAS G12X lung cancer treated with 32 milligrams ERAS-0015 are included in the efficacy evaluable population, which is the data set being shown in this slide today, the data summarized here focuses on the doses of 16 and 24 milligrams. As shown in the table, the response rate was 63% in the efficacy evaluable population. Given the heavily pretreated nature of these patients, we performed an additional subgroup analysis, focusing on those patients who received both immune checkpoint inhibitor and platinum-based therapies were being treated on our trial in the second or third-line setting and have not received docetaxel. While the data are still maturing, the response rate of 73% is impressive and supports evaluation of ERAS-0015 in earlier clinical settings.

This next figure provides a visual representation of the time on treatment for each individual patient in the population defined as any patient who received 1 dose of ERAS-0015. All patients with unconfirmed and confirmed partial responses were continuing on treatment as of the data cutoff date. This is an important point since the response rates we are reporting include both confirmed and unconfirmed responses. Given that our data are still maturing, the unconfirmed responses have the potential to be confirmed. This observation, paired with the fact that many additional patients with stable disease remain on treatment speak to the strong safety and tolerability data of ERAS-0015 as well as its potential to provide durable clinical benefit to patients.

Transitioning from the data generated in China, I now want to share the U.S. data generated for patients with KRAS G12X lung cancer in the efficacy evaluable population. Although the U.S. data set is less mature, the response rate of 60% observed in the 16 to 32-milligram dose range speaks to the generalizability of the China data to a U.S. population. Additional evidence for the consistency of the data between the China and U.S. trials is provided by the response rate of 71% in that same subgroup population I mentioned for the data from China. That's patients who had received both immune checkpoint inhibitor and platinum-based therapies were being treated on the trial in the second or third-line setting and had not received docetaxel. Note that this subgroup analysis includes 7 patients treated at greater than or equal to the 8-milligram dose of ERAS-0015 versus the 5 patients treated at the 16 to 32 pharmacologically active dose range that you saw on the earlier slide that Jonathan presented.

Similar to the data from the China trial, all patients with unconfirmed responses remain on treatment, such that the responses still have the potential to be confirmed in the future. These data also show that ERAS-0015 administered at doses as low as 8 milligrams induced responses in patients with lung cancer. This case study provides one example of a response we are seeing in patients with lung cancer and the meaningful impact ERAS-0015 can have on an individual patient's quality of life. This patient was a 70-year-old gentleman with metastatic G12D lung cancer who had received both immune checkpoint inhibitor therapy and platinum-based therapy. He started treatment with ERAS-0015 8 milligrams once daily and had a 37% decrease in his target lesions at the first imaging assessment consistent with an unconfirmed partial response. This partial response was subsequently confirmed at the next imaging assessment and the patient remains on treatment as of the data cutoff date.

To the left, you see CT images at baseline and from the first tumor assessment. The red circles indicate the areas of improved aeration, that's the darker parts in both his left and right lungs, and this resulted in the patient being able to come off oxygen within 1 week of starting therapy. In parallel with his disease response, the patient had minimal toxicity from the treatment with only a Grade 1 treatment-related rash being reported as of the data cutoff date.

Now that I've shared our lung cancer data, I would like to share our KRAS G12X pancreatic cancer data using the same format. This slide summarizes the response rate and shows a waterfall plot for the efficacy evaluable patients enrolled in the China trial. For those patients treated in the second-line plus setting at a dose range of 16 to 32 milligrams, the response rate was 36%. In a subgroup analysis focusing on a more homogeneous second-line only patient population, the response rate was numerically higher at 41%. This figure summarizing the time on treatment for all patients with KRAS G12X pancreatic cancer illustrates that even those patients without distinct RECIST responses can have meaningful clinical benefit manifesting as prolonged stabilization of disease.

Of note, all patients with unconfirmed partial responses remain on treatment as of the data cutoff. As mentioned earlier, this is an important point since the response rates we are reporting include both confirmed and unconfirmed responses. And we want to make sure we accurately describe the clinical activity of ERAS-0015 given that the data are still maturing. Overall, while the U.S. data is still immature, when it is combined with the China data, the totality of data indicates that pancreatic cancer is less sensitive to RAS inhibition by ERAS-0015 compared to lung cancer as evidenced by the difference in response rates between the 2 tumor types. Despite the lower response rate, ERAS-0015 does induce stabilization of disease in pancreatic cancer within the dose range of 16 to 32 milligrams as demonstrated by the number of patients still on treatment on the waterfall that have deep decreases in target lesions very close to the minus 30% line.

We also see high disease control rates observed in efficacy evaluable population. And since almost all the patients who had tumor shrinkage without overt RECIST responses are still on treatment, there is potential for those patients to ultimately have RECIST responses as follow-up matures. And finally, the data summarized in the table on the right shows that ERAS-0015 was associated with numerically higher response rates with longer minimum follow-up and earlier line of therapy. In keeping with our theme, the figure summarizing time on treatment for the U.S. patients with KRAS G12X pancreatic cancer shows that all patients in the efficacy evaluable population with either confirmed or unconfirmed responses and even many of those with stable disease remain on treatment.

As Jonathan mentioned earlier, we're seeing tumor shrinkage in pancreatic cancer as early as the first tumor assessment, but achieving a RECIST response often takes additional time and multiple assessments. Importantly, as we've shown, ERAS-0015 needs to be in the pharmacologically active dose range of 16 to 32 milligrams to drive meaningful tumor shrinkage as measured by response rates and disease control rates. The case study in this slide provides another example supporting that point. The patient was a 75-year-old gentleman with metastatic G12D pancreatic cancer who received prior standard therapies as listed on the table. He enrolled in the U.S. trial and started receiving 8 milligrams daily ERAS-0015. Unfortunately, at the first assessment, the patient was found to have progressive disease per RECIST based on a new lesion, and an increase in target lesions. He continued treatment beyond progression and escalated his dose to 16 milligrams, which is in the lower end of the pharmacologically active dose range.

Encouragingly, for our patient, subsequent scans revealed the disappearance of the new lesion and a decrease in the target lesions up to minus 33% at the last imaging assessment. While the official RECIST outcome remains progressive disease, this case highlights the importance of dosing within the pharmacologically active dose range and suggest the potential benefit for patients being treated beyond progression. While we think the preliminary clinical efficacy data we have presented speaks to the potential for differentiation of ERAS-0015, efficacy is only one side of the equation.

To ensure our patients have the best outcomes possible, the efficacy must be delivered in the setting of a safe and tolerable drug, which leads us to the safety and tolerability portion of our presentation. This slide summarizes the most frequent treatment-related adverse events observed in the U.S. trial at 16, 24 and 32 milligrams. Events occurring in greater than or equal to 10% of patients include only 4 terms: rash, diarrhea, stomatitis and nausea, all of which are consistent with what's been observed in this class. For your awareness, I want to note a related Grade 3 pneumonitis case that progressed to Grade 5 after the patient decided to discontinue aggressive supportive care. The patient was a 66-year-old male with heavily pretreated metastatic pancreatic cancer who received 24 milligrams of ERAS-0015. The patient presented to the emergency room with Grade 3 pneumonitis, immediately discontinued ERAS-0015 and was treated aggressively with high-dose steroids and infliximab. During the course of this treatment, the patient elected to withdraw supportive care and ultimately passed away.

As we look across the broader data set, treatment-related adverse events are infrequently resulting in significant dose modifications or discontinuations of drug. This ability to maintain patients on therapy at their intended dose is encouraging as it suggests that patients are able to stay on the prescribed dose of ERAS-0015, which we predict will contribute to clinically meaningful efficacy. Sometimes it can be difficult to have a true appreciation for the safety and tolerability of a drug unless you really talk to the patients receiving it or the physicians administering it. To provide a more nuanced view of the safety and tolerability of ERAS-0015, this slide highlights a variety of comments made by the physicians taking care of the patients with cancer receiving ERAS-0015. I'm not going to read each and every quote, but I think it's fair to say that these physicians feel that the ERAS-0015 version of the rash, which is the most common event seen with this class of molecules, has differentiated itself on this front.

And with that, I'll hand the call back to Jonathan.

Thank you, Shannon. We are rapidly advancing ERAS-0015, which we believe is a potential best-in-class pan-RAS molecular glue, that has shown early clinical differentiation. We've been able to move the program forward quickly, which underscores the significant unmet need and high investigator patient enthusiasm. We completed dose escalation in less than 1 year, including identifying 2 monotherapy RDEs. We're excited about the clinical profile of ERAS-0015, which showed strong and differentiated efficacy, safety and PK data, along with early signs of combinability with anti-EGFR therapy. It's also worth mentioning that all patients who had an unconfirmed PRs are pending and have the opportunity to confirm with subsequent scans. We believe that this profile, therefore, positions ERAS-0015 to potentially be the preferred RAS targeting agent with meaningfully improved outcomes for patients. Finally, we are grateful to the patients, their families and the investigators and study teams. Our anticipated milestones are shown here. In addition to reporting the Phase I monotherapy data today, we're pleased to have initiated the mono expansions and combo dose escalation ahead of schedule, and we're narrowing the guidance to H1 of 2027 for select mono expansion and combo dose escalation data.

In summary, these are exciting times for Erasca to be developing ERAS-0015 and ERAS-4001 for the benefit of patients globally. ERAS-0015 is one of the most promising drugs I've ever had the privilege of working on in my career. We have the team to be able to execute on these programs, which we believe significantly advance our mission of erasing cancer and specifically eradicating RAS-driven cancers. Based on these promising preliminary Phase I results for ERAS-0015, we believe we've taken an important step forward in this direction.

I'd like to thank you for taking the time to join us today. With that, we'll conclude our formal remarks, and I'll turn the call back to the operator for Q&A. Operator?

[Operator Instructions] Our first question is from Anupam Rama with JPMorgan.

Congrats on the data. Just a quick one on the patient death and the treatment-related pneumonitis. Just remind us, did you see any additional events of this AE and how we put this AE into context? And then a second question on when you think about the totality of data here and sort of unlocking combination potential, you talked about panitumumab. How do you think about that -- with this data in hand, how do you think about that unlocking of combination potential and guiding your development strategy?

Yes. Thanks, Anupam. So on the pneumonitis, we haven't seen any other grade 4 or grade 5 TRAEs -- and pneumonitis is a rare drug-related toxicity that is seen in many oncology drugs. So for instance, both approved KRAS G12C inhibitors have warnings and precautions for pneumonitis in their labels. And then also the comparator has also reported pneumonitis at a level of 1 out of 50 patients for monotherapy. And in this case, the withdrawal of supportive care is really why this progressed from Grade 3 to Grade 5.

In terms of your other question, yes, the combinability with panitumumab is very promising. And so that's really an objective marker of the tolerability from a rash perspective. We also think that the overall lower frequency and severity of rash, GI and stomatitis TRAEs bodes well for combining this with other standard of care agents like chemotherapy and checkpoint inhibitors, for instance.

Our next question is from Maury Raycroft with Jefferies.

Congrats on the data update. A lot of data in here. Maybe to start off, wondering if -- so you're guiding to having more data first half of next year. Between now and then, could you provide some sort of incremental update along the way and comment on how you're seeing responses and durability maturing? And then maybe as a follow-up to Anupam's question earlier, if you could just talk more about next steps for development plan and how you're thinking about prioritizing different paths in non-small cell lung cancer or PDAC and whether you pursue second-line PDAC.

Great. Thanks. So yes, I'll take on that second one first. So in terms of development plans, based on the compelling data that we've seen really across all 3 of the Big 3, and it's maturing to be fair. But we're going to move forward aggressively on all 3 fronts. In terms of lung, there's a clear signal there. In terms of pancreatic, there also is a signal. I think our -- a lot of our focus will be in the first-line setting with combinations, especially based on the promising safety and tolerability data, we think that combinability with chemo could be a promising path forward. And then with colorectal cancer, just the fact that we have early signs of combinability with an EGFR inhibitor, all of that is very exciting to see. So we're going to leave no stone unturned in terms of looking at the Big 3. And in terms of future data updates, our data will mature, and we'll be looking at other opportunities to provide updates. But right now, we're committing to the first half of next year.

Our next question is from Jonathan Miller with Evercore ISI.

I'll just echo the last comment, a really detailed presentation. I would love to ask again about combos in PDAC in particular. Do you think your safety profile is supportive of a FOLFIRINOX combo in first line? And how rapidly do you think you could advance a FOLFIRINOX combo or any combo -- chemo combo in first-line PDAC into a later-stage trial? And then just to clarify your earlier question about the Grade 5 event. I think we are familiar with pneumonitis as a rare, but serious side effects in general here. But you -- your medical team, the patient's medical team's official opinion is that this was a moderate-grade pneumonitis event that only progressed to life-threatening status because of the withdrawal of supportive care and that -- we should expect that pneumonitis in general won't be more severe than with other drugs in this category?

Yes, that's right, Jon. It was a very rare event that happened in one patient that was that Grade 3. And the investigator told us directly that he thought that if the patient had continued supportive care, then it might have been a different outcome. So yes, it's very unfortunate for the patient, but that was the feedback. In terms of combinations with pancreatic cancer, FOLFIRINOX is a possibility. We also think that Gem/Abraxane is a good combination to look at. So we'll be exploring whether a modified Gem/Abraxane or nonmodified Gem/Abraxane is the way to go. So the way to look at it is there's sort of a path that's already been established and shown to be tolerated, but we can explore various combos based on the safety and tolerability data that we've seen.

Our next question is from Laura Prendergast with Stifel.

Is there any specific indication line of therapy that you guys have most conviction in right now as far as pursuing? And then if you could just comment on the adverse event prophylaxis or management versus molecular glue comparator that you've been using here?

Yes. So I'll let Shannon answer that one. Do you want to talk about that, Shannon?

Yes. So in terms of prophylaxis, we do not have mandatory primary prophylaxis for any of our adverse events. So that means that the patients are not starting prophylactic antibiotics or topical steroid creams or anything like the rash, nothing for anti-emesis. Obviously, we do stress very aggressive management if an adverse event does appear. We think that's really important to getting the best risk benefit profile for the drug. Back to you, Jon.

And in terms of your -- yes, thank you, Shannon. And then in terms of your line of therapy question, we think with lung, everything is on the table, second line plus as well as first-line in pancreatic. Our focus will be on first line, but based on the emerging data, second line is not off the table. So we'll be assessing all our options for that. And then colorectal cancer is very interesting, especially the promising combinability with panitumumab. So that's an open lane for us.

Our next question is from Michael Schmidt with Guggenheim.

Is it correct to assume that the 40-milligram QD dose was just not yet evaluable? And do you have plans of going higher perhaps? I'm not sure if you will. And then a bigger picture question. I mean, obviously, you've broken out the data between the study in China and the U.S. study. But obviously, still, it's a fairly high contribution in terms of Chinese patients to the data set. And I'm just wondering if you could confirm that the study was done at a single hospital in China or perhaps at more than one center? And what your confidence level is that the data is representative of a potential global study in the future?

Yes. Thank you, Michael. Shannon, do you want to comment on the 40-milligram dose as well as the multicenter nature of the China trial?

Sure. So while we did not see dose-limiting toxicities as defined by the protocol of 40 milligrams, we did see toxicities that we as well as the treating investigators did not feel would support continued dose escalation or continued evaluation at that dose, particularly since we had already had quite good activity observed at -- in that pharmacologically active dose range of 16 to 32 milligrams. So we felt there was no need to push the dose higher.

In terms of the China study, that is a study that was done in multiple sites. And in terms of generalizability, I think what I think about there is tumor response is a fairly objective quantifiable response or quantifiable endpoint, much less sensitive to subjective -- that's much less subjective and I'd say, gives us much more confidence that what we're seeing in China will generalize to the United States and to continued development. Time will tell, obviously, but we do have confidence in that data because of those -- because it is so objective and quantifiable.

Yes. And the other thing to add is the eligibility criteria for key prognostic and predictive factors are similar between the two studies. The baseline characteristics between the two trials are similar as we showed on Slide 8. The PK profiles between the two populations are similar. And then efficacy between the two regions is generalizable because the standard of care treatment options are similar. And as Shannon mentioned, the measures of efficacy are quantitative and objective. So changes in tumor size over time as measured by imaging. This was not done in one site. This was done in multiple Phase I sites in China.

Our next question is from Sean Laaman with Morgan Stanley.

Thanks for the very detailed presentation, most appreciated. I've got a couple of questions on the combo. So how much dose -- I think you just might have answered it for the 40-milligram comments, but how much dose flexibility do you believe you have with ERAS-0015 when moving into combo regimens, particularly with EGFR inhibition? And thinking forward with the data and the combo cohorts, what safety or PK markers will you prioritize before expanding combos more broadly?

Yes. Thank you, Sean. So the dose for the combos, we're exploring within the PAD. So the pharmacologically active dose of 16 to 32 milligrams is a good area to explore further because it's active, as I mentioned in the PK section of the presentation. So the fact that 16 milligrams, the lower end of the PAD looks to be combinable with panitumumab, that's promising. If that clears, it's possible that we could go up to 24 milligrams and see if that is tolerated. And if not, the fact that we're seeing a response, albeit in one patient so far, that's very promising. So the fact that it's good validation that even the 16-milligram dose in the lower end of the PAD is an active dose where we're seeing activity that you wouldn't otherwise expect with panitumumab monotherapy. And then in terms of just the full range of safety and PK, we will be evaluating safety, PK and efficacy for the combos. Anything to add, Shannon?

Nothing from me.

Our next question is from Kelsey Goodwin with Piper Sandler.

Congrats on the update. Two from me. For the first one, for the U.S. PDAC data using the 8-week follow-up versus your competitor using 14 weeks, I guess, in the China data set for you guys, was the 8- to 14-week time frame meaningful in patients converting? Obviously, there are a lot of stable disease patients for you guys in the U.S. data set. And then second, maybe building on the 40-milligram cohort, just given the cleaner safety you saw at less than 40 milligrams, why do you think you couldn't push to 40 milligrams and beyond?

Thank you, Kelsey. So yes, there basically -- in PDAC, as I mentioned, dose seems to be a driver in pancreatic as does minimum follow-up, so the 8 versus 14-week and then also line of treatment, second line versus third line plus. And there was an effect of that in both China as well as the U.S. In China, the enrollment over there had about a 4-month head start, and there was much faster enrollment at the higher doses in China versus the U.S. because there are somewhat looser guardrails in terms of the number of patients that you can enroll at each dose. And so there is a more mature data set in China. That said that 14 versus 8-week prior to DCO did have an impact on the China data as it did in the U.S.

In terms of 40 milligrams, I'll answer that and then invite my colleagues to chime in. But we are seeing very good activity at the PAD of 16 to 32 milligrams. And it does -- we weren't sure if we would identify a dose range that could achieve that sweet spot of seeing promising efficacy, coupled with promising safety and tolerability. And in that PAD, we're seeing both. So at 40, that's where you start to see an increase, for instance, in two of the patients, there was a grade 3 rash, as you could see in the safety table. And so that's where, as Shannon mentioned, we didn't think that the risk benefit of pushing the 40-milligram dose further warranted further exploration of that dose. But Shannon, do you want to chime in?

I think you've described it accurately. When we're sitting here thinking about this from a physician's point of view, right, we're always thinking efficacy in the setting of safety and tolerability. And based on the criteria for the pharmacologically active dose, the exposures of patients are predicted and are shown to be as high as they need to be to get that tumor shrinkage. And so it really comes down to optimizing risk benefit. And it was -- again, with conversations with ourselves as well as the treating investigators, the ultimate conclusion was that pushing the dose higher would not lead to better risk benefit.

Our next question is from Joseph Catanzaro with Mizuho.

Maybe two quick ones for me. So there's some precedent in the RAS molecular glue space that lung patients maybe need a lower dose than PDAC patients to maintain treatment persistence. How do you see that playing out with ERAS-0015, so essentially potential dose in lung versus PDAC? And then I guess related, you showed the G12C case study. Wondering if you think there is potentially a similar path for ERAS-0015 in lung that mirrors the KRAScendo trial. So essentially head-to-head with the RAS molecular glue class. So I appreciate there's no approvals here just yet.

Yes, Joseph, thank you for the question. I mean I think in the case of G12C, that was done. In the case of pan-RAS, that may not be required because it does seem to still be potentially open lane. I think in terms of the dose in lung and PDAC, we're not convinced that there needs to be a different dose between those, but we're certainly open to exploring that, whether it does seem that pancreatic might need a higher dose, but I think more data and maturity of data will tell. I'll just see if Shannon has anything to add on either of those.

No, I think you're exactly right. I mean I think we feel very comfortable that 24 to 32 milligrams certainly looks like the doses we're going to take into expansion. And so I think only time will tell in terms of as that data mature, as we see how the response is, see what the durability is, I think committing to anything at this point would be premature.

Our next question is from Alec Stranahan with Bank of America.

Two from me. First, just on the confirmed versus unconfirmed. I guess, what are your expectations around timing and ability to confirm the remaining patients, particularly in the China study where many of the responses were observed. And then just on connecting the dots to survival that we'll see in future updates. I guess curious based on the literature or what we've seen for competitors, what a 10 to 15% point improvement in ORR and PDAC could mean in terms of PFS or OS? Or is there maybe another metric such as, I guess, disease control rate, time on therapy, et cetera, that you think could also help inform this?

Yes. Thanks, Alec. Well, first of all, I mean, great question. It's worth noting that there's still multiple ongoing responses. So I think the fact that 23 out of 24 responding patients in lung cancer remain on treatment, including all responders treated at 24 to 32 milligrams. And in pancreatic, 20 out of 23 responding patients remain on treatment, including all responders treated at the 24 to 32 milligram RDE. It's also worth noting that any patient that had what we called a UPR or unconfirmed PR was actually a pending partial response. So the reason they had a UPR is because they hadn't yet had their confirmatory scan.

So to your point, I think we'll know a lot more in the second half of this year regarding the maturing of those UPRs or pending PRs. I think in terms of the sort of 10 to 15 percentage points of differentiation and how that maps to durability metrics like PFS, DOR and OS. Shannon, you should comment further. But in general, in targeted therapy, when you have higher response rates for certain drugs, that does tend to correlate with longer durability as well. But maybe, Shannon, you can comment further.

No, I think I completely agree. I think the mechanism of action definitely has an impact, right? So the immune checkpoints are going to have a different situation than a targeted therapy. But I would say in general, higher response rates do tend to give more durable or ultimately lead to improved PFS and OS. Nothing is over 100% correlation, but we certainly are excited about where we're at. And as the data matures, we hope it continues to mature the way we've seen it to date.

Thank you. There are no further questions at this time. I'd like to hand the floor back over to Jonathan Lim for any closing comments.

I'd like to thank everyone for joining us on this call. Really appreciate the attendance and the questions, and we're really excited about what we're doing over here at Erasca in terms of seeking to eradicate RAS-driven cancer. And we think that with ERAS-0015, this really helps us take an important step forward. So we look forward to talking to all of you soon. Take care, everyone.

This concludes today's conference. You may disconnect your lines at this time. Thank you for your participation.

All right. Let's go ahead and get started. Welcome, everyone, to the 44th Annual JPMorgan Healthcare Conference. My name is Anupam Rama. I am one of the SMID-cap biotech analysts here at JPMorgan. I'm joined by my squad, [ Rati Pinhe ], Priyanka Grover and Joyce Zhou.

Our next presenting company is Araska. And presenting on behalf of the company, we have CEO, Jonathan Lim.

Thank you, Anupam. Good afternoon, everyone. It's great to see all of you here. 2026 is off to a very exciting start, and I look forward to telling you more about what's in store for Araska. Before I do so, I will be making forward-looking statements. So I encourage you to visit our website at erasca.com to find our latest SEC filings.

At Araska, our name is basically aligned around our mission to erase cancer and also to eradicate RAS-driven cancer. So it's a portmanteau with a double meaning. I started this company with Kevan Shokat, luminary from UCSF, who's really the father of G12C RAS targeting. And he and I cofounded this company in 2018 around a disruptive idea to target RAS. We've since then assembled a world-class scientific advisory board of leading pioneers. We're entirely focused on the RAS/MAP kinase pathway. We have a team with deep expertise in planning and execution of global development, and I'm very excited to share some recent data that we have for our lead pan-RAS program.

This is ERAS-0015, which is a pan-RAS molecular glue with best-in-class potential for various RAS solid tumors. And we also have ERAS-4001, a pan-KRAS program with first-in-class potential for KRAS solid tumors. So this is really our 1-2 punch for addressing RAS-driven tumors, and we're nearly entirely focused on those 2 programs. We're well capitalized with $362 million in cash reported in our Q3 earnings and cash runway into second half of '28.

I mentioned that Kayvon is a pioneer in the industry. We also have Mike Barney as our Chair of R&D, and we're really surrounding these individuals with amazing luminaries across the R&D spectrum in academia.

This is our pipeline. So I mentioned the bulk of our activities and focus are on ERAS15 and 4001. We also have a program called ERAS-12. There's a bispecific antibody against EGFR that's in the discovery stage. So I'll focus this presentation on our RAS molecules. We've been in this space for quite a while, and I'll say that the ideal RAS targeting molecules integrate 3 key attributes. So you want to have strong preclinical activity. You want to have strong PK performance in the form of oral bioavailability and clearance. And then you also want to have a strong proprietary space.

At the center of that Venn diagram is the ideal RAS targeting molecule, and we think we have 2 ideal RAS targeting molecules. Now on the preclinical and PK front, you ideally would want to have a lower clinically active dose that could translate into lower risk of solubility, limited absorption and the exposure plateau that's been observed with the most advanced pan-RAS molecular glue in development. You also could potentially have some upside in the form of better GI tolerability because of lower drug load and the effect on local tissues in the GI tract and then ideally an improved therapeutic window.

So ERAS-0015 and 4001 exhibit very good profiles that exceed our target product profile along those 3 dimensions. So starting with ERAS-0015. This is a highly potent molecule with sub-nanomolar to 13.8 nanomolar IC50 across multiple RAS mutations. In vivo, we've been able to observe very strong tumor regression at doses as low as 0.3 milligrams per kilogram up to about 5 mpk. The oral bioavailability as measured by F percent or the free fraction across multiple species is very high, and the IP is strong with exclusivity expected until 2043 and beyond with patent term adjustment.

We're pleased to announce U.S. patent covering composition of matter that was issued in the fourth quarter of last year. ERAS-4001 is also a very potent molecule with sub-nanomolar to single-digit nanomolar IC50. It does take slightly higher doses to see tumor regression, so between 30 to 300 mpk twice daily. This too has good oral bioavailability, which has been difficult for the class of pan-KRAS molecules. And this also coincidentally has strong IP exclusivity out to 2043 and beyond.

The thesis behind a pan-KRAS molecule is potentially wider therapeutic window because you are H and NRAS wild-type sparing. So by hitting KRAS really hard and sparing H and NRAS, you could potentially have better tolerability. Now the question is with ERAS-0015, if we have a pan-RAS molecular glue that also has potentially a wide therapeutic window, then can you achieve with a pan-RAS molecular glue what you're trying to achieve with a pan-KRAS molecule. That thesis also is something that we're testing. And we think ultimately, if you could take these compounds and combine them, well, that would be a source of differentiation as well.

So I'm going to start with a deep dive on ERAS-0015. This is the potential best-in-class pan-RAS molecular glue, and I'll also update you on the clinical update that we shared earlier this week. So ERAS-0015's potential differentiation really stems from the high binding affinity to cyclophilin A or CypA. And so this works by a similar molecular glue mechanism where this has about 8 to 21-fold higher binding affinity to CypA versus RMC-6236. And as a result of that, you just get many more of these bipartite moieties.

So if you have 0015 with CypA, that bipartite moiety, we call it a Pacman molecule goes hunting for RAS to form a tripartite or ternary complex that then takes RAS out of circulation. And so by having the higher binding affinity, you just have a lot more -- this is a nod to all of you who grew up in the '80s, but pan-RAS Pacman molecules that just take RAS out of circulation. Now what does that mean? Well, it results in better potency across multiple cell lines. You can see various degrees of full potency versus 6236 against different mutations of interest across the spectrum of KRAS and other drivers.

And you could see sparing of RTK-altered cell lines. And importantly, in vivo, we're seeing ERAS-0015 demonstrating comparable antitumor activity to RMC-6236 at just 1/10 of the dose. And so I'm going to show you on this slide, a sensitive KRAS G12D pancreatic model, where you could see it's called PK59. 6236 was able to achieve very good tumor regression with 3 mpk. And what's really impressive is that ERAS-0015 was able to achieve the same degree of tumor regression with 0.3 mpk or 1/10 of the dose. So that just gives you a sense of how potent both of these molecules are, but 6236 in this comparison requires 10x the dose.

On this insensitive model, KRAS G12V non-small cell lung cancer, this is a model called NCI-H727. In the industry, amongst academia, especially, this is widely viewed as a bellwether model of sorts because it's where you have -- it's very difficult to see tumor regression with pan-KRAS molecules in this type of model, but you could see that 6236 was able to achieve good tumor regression with 10 mpk. And also impressively, ERAS-0015 was able to achieve that with just 1 mpk. So again, the 1/10 of the dose in an insensitive model.

So we have a lot of other models that we've shared. They are in the public domain, so I encourage you to view our prior presentation. So we won't walk you through the half dozen or so other models. But importantly, from a PK perspective, the kinetics of ERAS-0015 also look very promising. So if you look at the tumor distribution and residence time, 15 does look like it has preferential tumor distribution and longer residence time. So if you focus on the graphs on the left, this is the same PK59 model, that sensitive PDAC model that I just mentioned a couple of slides prior.

So if you look at the light blue bars for ERAS-0015 versus RMC-6236, you could see that the levels of both drugs go down pretty substantially from 4 to 24 hours. But if you look at the medium to dark blue bars, you could see that 6236 diminishes or decreases over that 24-hour period, but ERAS-0015 levels are sustainably high.

And so what that tells us is that -- well, the reason for that is that there is a CypA that's overexpressed in multiple solid tumor types. And because of the higher binding affinity of ERAS-0015 to CypA, it's just lingering in the tumor and surrounding tissues a little longer. And so that tumor distribution and residence time, if that translates -- well, certainly, the PK kinetics look preferential in that case. But if that translates into a safety or efficacy advantage, then that will be really cool to see. And then that's not just one model, but it's also seen in another model called PSN1 on the right.

From a PK perspective, ERAS-0015 showed promising PK across multiple small and large animal species. So I'll draw your attention to the boxed areas. Clearance-wise, ERAS-0015 had lower clearance across the board relative to 6236, longer half-life and a higher oral bioavailability as expressed by F percent.

So I'm now going to switch gears to talk about AURORAS-1. This is the name of the first-in-human clinical trial that started dosing last year. The key eligibility criteria are patients with advanced RAS mutations that -- where RAS is a driver in different solid tumors. They received prior therapy and had no previous treatment with a RAS inhibitor. So ERAS-0015 was given as a single agent, and it was oral once-daily dosing or QD dosing.

So the goals of this single-agent monotherapy trial is to show signs of clinical efficacy, ideally to show well-behaved PK characteristics, reasonable safety and tolerability and to also inform combination therapy where, as you know, combination therapies really are standard of care, especially for the big 3 tumor types of colon cancer, pancreatic cancer and non-small cell lung cancer. So AURORAS-1 was designed to evaluate the potential for single-agent differentiation and also whether ERAS-0015 can be a potential best-in-class RAS-targeting molecule for combo development across multiple solid tumors.

Now I would say that the pace of enrollment, we were hoping that AURORAS-1 would enroll briskly, and we were pleasantly surprised by the pace of enrollment that has advanced even faster than we anticipated, which unfortunately underscores the significant unmet need. There's still a lot of work to be done, but it does highlight that there's been very high investigator and patient enthusiasm.

So just to summarize the preclinical differentiation, the thesis is really around the in vivo activity, so seeing comparable efficacy at 1/10 to 1/5 of the 6236 dose in multiple mouse models and then the PK properties in terms of higher BA, lower clearance and longer half-life and the preferential PK kinetics around the tumor distribution. And all of those stem from the cellular potency as well as the CypA binding affinity.

Now we were very pleased to see that with early clinical data, the preclinical thesis does seem to be reinforced by what we're seeing with the efficacy, safety, tolerability and PK data seen to date. So we have seen ongoing confirmed and unconfirmed responses in multiple patients with differing tumor types and differing RAS mutations with ongoing responses in the form of 2 confirmed and 1 unconfirmed partial response in patients also with different tumor types and different RAS mutations at a low dose of 8 milligrams QD and additional ongoing responses in multiple patients at greater than 8 milligrams QD.

So I will say in terms of the CPRs versus UPRs, the reason why some responses are unconfirmed versus confirmed is that those patients have not been on study long enough to have confirmatory scans. So it's not a function of them falling off of treatment. In fact, I will say that all responding patients as of the data cutoff were still on treatment. And so that's a promising sign.

I can also say that we have been cleared since this press release. We have been cleared to start the 40-milligram dose cohort. So that just puts in a perspective that at a low dose of 8, there's still a lot of headroom when it comes to safety, PK, tolerability and efficacy. So we're very pleased with that. The safety and tolerability profile has been favorable with no dose-limiting toxicity and predominantly low-grade AEs observed at all doses evaluated and then well-behaved linear PK seen across all doses evaluated. In fact, there's been no evidence of the exposure plateau that was seen with the other molecule.

So I know that Anupam is going to ask me about all the different doses that were evaluated in this trial. We will disclose all of that in the first half of this year. So top line safety, tolerability, PK and initial efficacy data for dozens of patients are planned for this first half. But in the meantime, based on the early signs of activity as well as safety and tolerability and PK, we think 15 has the potential to become a preferred RAS targeting backbone for combinations.

So this is a case study. One of the confirmed PRs was in a 70-year-old heavily pretreated patient with KRAS G12V non-small cell lung cancer treated at 8 milligrams daily. And so you could see multiple lines of treatment, both with chemotherapy as well as checkpoint inhibitors. At the first restaging CT scan at cycle 3, this patient had UPR, and that was confirmed with the first confirmatory scan at cycle 5, and that was at 8 milligrams, after which the patient was dose escalated to 16. That patient continues on treatment as of the data cutoff.

You're looking at CT scans where the patients -- pretend the patient's feet are coming out towards you. So the left lung is on the right and the right lung is on is on the left, but everything in white means that the lung has either collapsed or is full of fluid. And so you could see in green that there's almost complete white out. There's basically complete white out of the right lung and the left lung has heavily collapsed as well.

After cycle 3, you could see significant expansion and aeration of both lungs. And the patient, in fact, clinically was able to come off supplemental oxygen after just the first week of 8 milligrams of treatment. So patient is currently asymptomatic from disease and from treatment, and this is really why we're doing what we're doing, and it was just really exciting to see this patient doing this well.

So switching gears to ERAS-4001. This is the potential first-in-class pan-KRAS molecule. This has very high affinities and long residence times to KRAS G12D, G12V and even G12C. It does hit KRAS wild type, which is important because there is a propensity for KRAS wild-type driven amplifications to be potential oncogenic drivers in different solid tumors. It is H and NRAS wild-type sparing, which leads to the potential wide therapeutic window. So this is both a GTP and GDP-bound KRAS inhibitor. So it has single-digit nanomolar IC50 against both the GDP and the GTP states.

And then we're seeing potent and selective inhibition of cells across G12X and G13D as well as wild-type cell lines, which is nice to see. In vivo, you could see a pancreatic model where at doses of 100 mpk BID, you get good tumor regression. And that's also seen across other tumor types and basically in vivo models at doses as low as 30 mpk BID.

And in terms of that bellwether model, I mentioned to you that pan-KRAS inhibitors have a more difficult time to see tumor regression in the H727 model. It was really nice to see regression in this model with 4001, but it was at a dose of 300 mpk. And in terms of the PK, ERAS-4001 shows promising PK across multiple species, including mouse, rat and dog. And I think of note, if you look at the bioavailability, it's really quite high across multiple species.

So we have a number of key milestones this year and next. ERAS-0015 for AURORAS-1. I mentioned that in the first half of this year, we'll have a Phase I monotherapy data set. And then in the second half of this year, we plan to initiate monotherapy expansion cohorts as well as to initiate combination dose escalation cohorts with readouts from those activities in 2027. And then for ERAS-4001, we're enrolling the BOREALIS-1 Trial. We mentioned in our press release that this trial is enrolling as anticipated, and we are guiding to Phase I monotherapy data in the second half of this year and to initiate monotherapy expansion cohorts as well as combination dose escalation cohorts in 2027.

So I just want to end by summarizing that we have an experienced team with a track record of serial success, world-class SAB, promising pipeline that targets large underserved markets, really focused entirely on RAS/MAPK and then clinical advancement of an industry-leading RAS targeting franchise. I think the fact that we sort of straddle both worlds of pan-RAS as well as pan-KRAS makes us very unique in the industry with multiple potential near- and long-term value drivers and a strong capital base to be able to go after that.

So thank you very much, and I think we will morph into the Q&A.

Thank you, Jonathan. I'll ask the first couple of questions, but I'll open it up to the audience. So feel free to raise your hand when I prompt you. I got to ask, man, what do you think about all these headlines that we've been seeing in the space related to you and your competitor?

I mean I'll say that we respect Revolution Medicine as a pioneer in the space. And maybe I'll just echo what my colleagues said, which is as a company policy, we don't comment on rumors. But I think it just speaks to the excitement around this space and just the fact that there's scarcity value for programs that can really move the needle in such a high unmet need.

Questions from the audience on this point?

Really, that's the only question.

So actually, now digging into 15 -- ERAS-0015. You said in the first half -- I think you said we'll get safety, PK and maybe some efficacy. So maybe you could walk us through 2 things, dozens of patients, how much follow-up, the types of tumors you're going to be focused on. And then ultimately, like when you do -- when we do think about the early revolution data? Like what are you looking for in that data on the key metrics?

Yes. So we'll definitely have efficacy data. So it's not maybe, it's definitely. And we'll have safety, PK and efficacy. I think what we look for on the safety tolerability front is for this class of compounds and really, we just have N of 1 right now in terms of what's publicly available now N of 2 with our molecule.

But I think you want to see good safety and tolerability, and we'll probably pay particular attention to sort of the rash as well as the GI AE profile. So I think that's going to be a key areas of focus. I think the fact that we haven't seen DLTs and the fact that we've seen predominantly low-grade AEs across the board, that's promising. And the fact that we're able to open a 40-milligram dose cohort, if you just take this 1/10 framework to the natural conclusion, that would be the equivalent of 400 milligrams of 6236, just in terms of sort of that potency PK argument from in vivo.

And so I think we're hopefully going to enter uncharted territory. Now from a PK standpoint, the fact that we were able to say that we have linear PK observed at all doses evaluated, and this is not including the 40 because 40 is now open. So the fact that we're not seeing the exposure plateau also is entering uncharted territory for the pan-RAS molecular glue class. I'd say the fact that we saw first clinical responses, and it wasn't just one response, which might have been a fluke, but the fact that there were multiple responses across multiple tumor types and multiple RAS drivers, I think the fact that we saw that with 8 milligrams, which is a really low dose. I mean I haven't worked on a drug that where single-digit milligrams has seen clinical responses like that.

The first clinical response with 6236 was seen with 80 milligrams. And so we were pleasantly surprised that at 1/10 of the dose, we were able to see first clinical response. So I would say that if you just look at the recommended dose across panc and lung for 6236, that range is 200 to 300 milligrams. So at doses above 8, once we get into biologically relevant doses, I think we certainly can look at what the response rate looks like in the different tumor types. To answer your question, it will be predominantly the big 3 tumor types.

Technically, it's all [ comers ]. So you may see some patients that fall outside the big 3, but it's really concentrated on the big 3. Durability is tough because it really depends on which dose levels. Of course, the earlier dose levels, you'll just have more follow-up for the -- if we're opening 40 now, I'm not going to give you a year of follow-up on 40 milligrams, but the doses in between will have various lengths of time of follow-up. And we'll just report the data what they are. So -- and then you'll work your magic and interpret it.

Is there an ORR threshold you're looking for?

Nothing numerical because I don't think -- I think when we open up the expansion cohorts, then that's probably a more fair look at it. Now we do have in our protocol, the ability to backfill cohorts, but still you just never know what you get during the dose escalation phase. So I mean, I'm sure everyone will look at the numbers, but there's not sort of a threshold in our heads as to what we're expecting or guiding to. I think people -- it will be apples and oranges, and it really is the totality of the safety, tolerability, PK and efficacy that we'll be looking at.

Questions from the audience?

So tell me if I'm getting too literal with the math, right? But if the RevMed dose is 200 to 300, and you're going with this 10x potency, you said you're starting a 40-milligram expansion cohort. So with that, do you think that's like a testing ground like a thesis tester for kind of like higher doses relative to what they saw? And when would we have a decent enough mature data set for 40?

Yes, that's a good question. So first of all, just one clarification. It's not an expansion cohort. It's actually an escalation cohort. So 40 milligrams is part of the ordinary course dose escalation, which follows a modified Fibonacci. And so I would say that, yes, I mean, if you believe the 1/10 framework, then 20 to 30 would be sort of the imputed dose that would be equivalent to 200 to 300. If you believe the 1/5 then it's more 40. So maybe reality lies somewhere in those bookends. I'd say if we're just starting 40 now, then it probably wouldn't be fair to evaluate durability in the first half. But later this year, that might be something that's more meaningful.

Additional questions from the audience?

Then I guess maybe a similar-ish question for ERAS-4001. Kind of what are you thinking about size and scope of the update in the second half of the year? And kind of in your mind, what's an encouraging update?

Yes. So 4001, what we're guiding to there is that we'll have that data in the second half of this year. That will be similar in terms of what Jonathan described in terms of dozens of patients. We're going to be looking there at the safety PK as well as initial signs of activity. This is a very interesting class in the sense that for a while, there actually hadn't been much in the way of clinical data disclosures. Obviously, that's no longer the case, but we will have our data update in the second half of this year.

Congrats on the progress. I'm just wondering if you could share some thoughts on how you envision the commercial space evolving. I know it's early days, but if you have a market leader that's going after specific mutations and then you're coming on as the follow-on, I'm just curious how you're looking at that and how that's, in some ways, coming back to your development strategy and how you're looking to take things forward?

Yes. Thank you for the question. I'd say in a world where, let's say, that ERAS-0015 just turns out to be a me-too compound in terms of no real clear differentiation, but it's just sort of second in class, still a pretty good place to be because you have such a massive unmet need. I'd say maybe certain lines of treatment within pancreatic would be a tough nut to crack, but everything outside of that is still pretty wide open for a second-in-class molecule.

I mean if you just look at history of the checkpoint inhibitor space and other areas where there's certainly room for more than one molecule, if not half a dozen to a dozen. And so with this, if we're comfortably in second and in that first wave, and that's a good place to be. Now in a world where we show best-in-class or me better potential, then that everything is sort of wide open for us. And that's -- that would be a really exciting place to be. And it will be great for patients, of course.

Questions?

Thanks, Jonathan, for sharing. So it seems like the 6236 is going to have early approves next year. So is there a chance that FDA would require a head-to-head comparison for your molecule with the revolution...

It's possible in the U.S., yes, for second-line pancreatic, I wouldn't rule that out. But I'd say that if you wanted to enroll a trial outside the U.S. and seek sort of alternative strategy, that's a possibility. Now in a world where you have true differentiation, then a head-to-head wouldn't be as daunting as if it was just a me-too molecule.

Very nice encouraging early data for your pan-RAS. My question is around -- you have 2 portfolios, right? One is pan-RAS and pan-KRAS. And pan-RAS, you show relative good safety and tolerability at least in early clinical data. So where do you see how you position these 2 assets if the RAS turn out to be also tolerable?

Right. Yes. I think there's sort of swim lanes for each, and it really depends on what the data show for both molecules. I think if you believe the thesis around H and NRAS wild-type sparing, then it's great to have a pan-KRAS molecule to do that. Now if our pan-RAS molecule is able to be very well tolerated, then is there a world where you just kind of double down on that? Possibly, but it's still nice to have a pan-KRAS molecule.

I think we're going to continue to be data-driven. And so we won't know until we see what 4001 is capable of. And really, that timing difference is because ERAS-0015, AURORAS-1 started before BOREALIS-1 and enrollment has exceeded our expectations for that trial, whereas BOREALIS-1 has been performing. It's been enrolling like any typical Phase I trial has. It just hasn't been enrolling as quickly as AURORAS-1. And so that's really the timing delta.

Any final questions from the audience? I have one. Go ahead.

Great progress. Just on 4001, it's maxed out at 300 mg per kilogram. What do you think is happening pharmacologically there? And can you say a little bit about what combinations you think RAS inhibitor will look most effective with?

Yes. So in terms of combinations, I mean, it depends ultimately going back to the previous question, what kind of combinations are we thinking about for the pan-RAS versus the pan-KRAS. And so you would think, for instance, about combining with standard of care agents by the tumor type. You can also think about potentially investigational agents as another wave of combinations for us to consider.

So we're considering all of that, and we'll be data-driven in terms of how exactly we want to pursue that based on what we're seeing from the initial data that we generate as well as other data that are generated externally. Can you repeat the first part of your question? I don't think I followed that part.

[indiscernible] you used 300 milligrams per kilogram in the animal model, whereas you're using 8 milligrams or starting 8 milligrams in man. So can you just sort of talk about what you think is happening pharmacologically with that drug?

Yes. Okay. So I believe the one you're referring to is in the 8727 model, that's the one that Jonathan mentioned, is typically an insensitive model, particularly to pan-KRAS molecules. And so the fact that, that molecule was actually even able to show regression, albeit at a high dose, but the fact that it was able to show regression is actually really encouraging for that molecule. So I think it just speaks to more of that model being a very tough model for a pan-KRAS.

And just broadly speaking, how do you -- for both molecules, how do you think about unlocking sort of the combination potential because that's where you're going to ultimately go, right?

Yes. I mean I think if you need a wider therapeutic window for combinability then a pan-KRAS molecule for certain indications might be the way to go. And then for certain cases, especially pancreatic and lung where pan-RAS has been able to demonstrate combinability with both chemo as well as checkpoint inhibitors. So that could be the swim lane for pan-RAS.

Thank you, David and Jonathan.

Thank you.

Thank you.