So welcome to this next fireside chat with Erasca. My name is Michael Schmidt, senior biotech analyst with Guggenheim, and it's my great pleasure to welcome Jonathan Lim, CEO, and David Chacko, Chief Financial Officer. Welcome. Thanks for joining us. Thank you, Michael. Great to be here. So David, there's obviously been a lot of excitement in the market about the potential of your pipeline, specifically, ERAS-0015, your pan-RAS molecular glue, and also, ERAS-4001, your pan-KRAS inhibitor. How much potential for differentiation from other pan-RAS or pan-KRAS inhibitors do you see, and in general, before we jump into more detailed questions? Yeah. So I think at a high level, the way we look at this space is, you know, I think the RMC-6236 compound really was a breakthrough for the whole RAS, pan-RAS space, so, kudos to Revolution Medicines for being a pioneer in that space. And so as you look at the profile of 6236, I think us and other players in this ecosystem are trying to take what they've done and hopefully raise the bar for the benefit of patients. And so there's kinda two big areas to look at. One is the area of potency, and then the other is the area of PK. So I think there's some companies in this space that are really going at it from a potency perspective. So there's some companies with, you know, 10- to even 100-fold higher potency than 6236, and then there's other companies that really look at PK, and can you have higher bioavailability? Can you have longer half-life, lower clearance, so that you have a better PK profile versus 6236? And then there's us, where we're sort of looking at both parameters, and so is there a sweet spot where you can optimize potency and optimize PK to land in that, you know, what I'll call Goldilocks zone? So it's not too hot and not too cold, but it's, it's just right. And I think if the data bear this out, then, you know, it'll be- it'll be very interesting if we can hit that sweet- Right ... spot for patients. Maybe then a related question as we think about ERAS-0015 and the sort of the preclinical profile. Which of its properties are most important in driving potential clinical differentiation, in your opinion, of, of 0015? Yeah, so, you know, I gave the spoiler alert. It's really along those two dimensions, so it's potency and PK, and I think a lot of that has to do with the fact that in vivo, in animal models, we've seen sort of a 5- to 10-fold potency advantage in terms of requiring 1/10 to 1/5 of the dose of RMC-6236 to see the same degree of tumor growth inhibition or regression in most cases. So I think that's one area of differentiation, and also in vitro, in cell-based assays, we see significantly higher potency, you know, on that order of five- to 10-fold higher potency, so it all tends to be pretty consistent. On the PK side, at least from a non-clinical perspective, the profile of our molecule across multiple species looks to have higher bioavailability, oral bioavailability, as assessed by percent F, and then also, longer half-life, so longer predicted half-life, as well as lower clearance. In that PK profile, if you can have sort of a mitigation of the Cmax and just have a lower peak-to-trough ratio, then to the extent that any AEs are driven by Cmax. We don't know, just to be clear, we don't know a priori whether the on-target effects are driven by Cmax, but to the extent that they are, then there could be an advantage. I think the other thing worth noting is that there's a biodistribution advantage from the PK that we're seeing with ERAS-0015, in that the CypA that is overexpressed in multiple solid tumors, we're actually seeing a preferential distribution of our molecule into the tumor compartment versus the periphery, and if that's true, then that could also lead to a potential therapeutic window advantage. Right, that kind of semi-answers my next question, as a lot of people wonder, obviously, when you have a more potent therapy, I think the general belief is that the rash in particular is on target, dose-limiting for the Revolution Medicines drug. And so to what degree do you think you can get around that issue? Yeah. Wouldn't that just, you know... Having a 10x higher potency, wouldn't this just amplify the rash to a lower threshold, I guess? Yeah, and that's what I would worry about. I think that's a great point, Michael. If, if you're just looking at potency in a vacuum without the PK and distribution advantages, I do worry that you're slamming RAS mutations really hard, but you're also hitting wild type in healthy cells- Right ... or normal cells, right? So, if you don't have that sort of lower peak-to-trough ratio and preferential biodistribution into tumor, then I would worry about accentuating or amplifying on-target toxicity, and I think that's why, you know, there's other players in the space that probably need to look at alternate dosing regimens. With us, you know, we're really looking at daily dosing and- Right ... and continuous dosing, 'cause you really wanna keep RAS under pressure. But yeah, definitely, if potency in a vacuum, you would worry about- Right ... amplifying that. ... How well understood is this CypA overexpression in tumors? I always thought it's fairly ubiquitously expressed in the human body, but, you know, is there data suggesting it's overexpressed in certain cancers, perhaps? Or is it a general, you know, thing that you've been seeing? Yeah. So, you're right that it is endogenously expressed, and it is a, CypA is a chaperone protein. There are other—there's CypB, there's other, Cyp types of proteins, but it's pretty ubiquitous in the body. But there are data, both published as well as internal, that suggest that it's overexpressed across multiple solid tumor types, including, as you would imagine, the big three tumor types of lung, pancreatic, and colon. Yeah. Okay. Then, maybe shifting to your ongoing phase 1 clinical study, the AURORAS-1 study, and just, you know, I think you've provided some updates recently, some anecdotal information from this study. Just remind us of, you know, the key takeaways from this study so far. Yeah, so I mentioned the preclinical one-tenth to one-fifth of the dose of ERAS-0015 to achieve the comparable tumor growth regression achieved by RMC-6236. So what we saw was multiple responses, confirmed and unconfirmed partial responses in patients at 8 milligrams, which is one-tenth of the dose at which first responses were seen with RMC-6236. So that's kind of thesis-reinforcing in terms of that 10-to-1 ratio, and so we were really pleased that it wasn't just sort of a one-response accidental type thing, but it does seem to be a pattern where there were three responses at the time of the January data cutoff. The second point worth noting is from a safety and tolerability perspective. I think if we had seen any outsized impact of having a higher potent, more highly potent molecule hitting, the RAS target, if we saw something out of the ordinary on the safety and tolerability side, we would have had to say something about it. But the fact that, this looks generally, safe and well-tolerated in terms of no DLTs observed as of the data cutoff, predominantly low-grade, AEs and, a generally safe and tolerated, profile. So that was really gratifying to see, and it's also thesis-reinforcing. And then finally, we have started dosing 40 milligrams, but prior to dosing 40, we had seen, dose proportional PK, which also is thesis-reinforcing. So, no signs of that exposure plateau that's seen with the comparator compound, but you know, we're really excited about the totality of what we're seeing so far. Yeah. On the tolerability side, have you commented on how many patients have been treated in total so far in this study? And how high did you go in dose? It sounds like maybe up to 40 in the days, yeah. Yeah, we're dosing 40 now. We haven't said... So basically, we will be reporting data on dozens of patients, and so that'll be from a safety, PK, and efficacy perspective, and that's in the first half of this year. Right. We're on track for that guidance. Right. But, maybe extrapolating, if you're starting 40 now, it sounds like, the data that you've seen so far is from patients dosed less than 40- That's right. -correct? Okay. Yeah. Yeah, and obviously, great to see activity at low doses. What have you talked about in terms of patient histology? Have you seen any differences, or is it too early to look at response rates necessarily by histology? Yeah, we'll be commenting on that in the first half readout. What we have disclosed is that one of the three responders was a 72-year-old man with advanced stage non-small cell lung cancer that was driven by G12V, and he had multiple prior treatments, including chemo and checkpoint inhibitors, and basically progressed on all of those, and after the first cycle, had an unconfirmed partial response- Okay ... which was subsequently confirmed. He was on supplemental oxygen, and after a week of just 8 mg daily dosing of ERAS-0015, came off oxygen and went back to work. So these are the kinds of stories that really get you motivated. It's, it's really what we're all about as a company, to erase cancer, and so we're really excited about that. I think the other point worth noting is that when you look at the... And David will talk about the Pan-KRAS molecule that we have, which we're also excited about. But if you look at Pan-RAS and Pan-KRAS, especially Pan-KRAS, there seems to be a different bar between G12V and G12D. So G12D seems to be more sensitive to Pan-KRAS inhibitors- Mm ... than G12V. And if you look preclinically, the Bellwether model to test the potency of different pan-KRAS inhibitors, so not the molecular glue, but pan-KRAS, is the H727 G12V non-small cell lung cancer model, and it took 300 milligrams BID, twice daily, of our ERAS-4001 molecule to see tumor growth regression. With ERAS-0015, it just took 1 milligram daily to see pretty profound regression. So I think the fact that we're seeing a confirmed partial response in a patient with G12V non-small cell lung cancer... That also seems to be, you know, we're seeing good translation from the preclinical prediction- Right. and what we're seeing in the clinic. Right. In terms of the inhibitory activity across different KRAS mutations, I know you have a table in the deck, but yeah, remind me how the ERAS-0015 compares to daraxonrasib, and yeah, maybe just leave it at that. So in a panel of dozens of different, predominantly G12X mutations, but also G13X, and then also, KRAS wild type, we were seeing significantly increased potency across the board. There was equipotency against PK59, but then when you actually test that, in vivo models, we still saw a, an advantage in terms of, lower dose required. Right. I guess my question is, does it have a different preference towards certain KRAS mutations relative to daraxonrasib, or is it across the board? No, it's - similar? Yeah, it's pretty similar. Okay. And so as we think about... Yeah, maybe talk a bit about the upcoming data disclosure in the first half. I think you got it. Mm-hmm. I think you said you talked about dozens of patients. How much information will you be able to share? And is it in terms of efficacy, will it be an ORR focus for the most part, or will you have visibility on PFS already as well? Yeah. So I think, to be fair, you know, by the time of the disclosure, we'll still have been in the clinic less than a year. So the fact that we're even guiding to a first-half update, just speaks volumes in terms of, unfortunately, the unmet need, but also how quickly we're enrolling, and the fact that, investigator and patient enthusiasm is very high. So I think the fact that we were able to give the, sort of, you know, clinical data update that we were able to at the beginning of the year at the, JPM conference, and then the fact that we can guide to a first-half update is great. So, you really need time for appropriate follow-up for durability. So to really get a fair read of PFS, you probably need to wait a little bit. I mean, we will have a sense of how many patients are on trial, how many patients fell off, so how many are still on study drug—and that can be a proxy, but that'll be an evolving metric. What we can say is what we think the response rate is in sort of an apples-to-apples population relative to the comparators- Right and what that might look like. Right. And so many of those trials in this space tend to enroll more PDAC patients, perhaps than lung cancer patients. Is that something that you're seeing as well, or any comments on the histology distribution in the study? Yeah. So, it'll be enriched for the big three tumor types. We are seeing non-big three patients as well in this study 'cause it's all comers. So, basically, organically, you would expect that pattern of distribution. We're not seeing sort of a spike of one tumor type versus the others. There seems to be a reasonable distribution. So, you know, if we have sort of a certain number of slots, they're not all getting filled with one tumor type- Right For instance. Okay. But we also aren't sort of, you know, guiding investigators towards one or the other. We do have the possibility for backfilling, and so that's where we can sort of put our thumb on the scale. But you know, in terms of just the core dose escalation, it's really whatever types of patients are available. Sure. Okay. And then, yeah, I think you got it to initiation of dose expansion cohorts in the second half. So talk a bit about your plans there. What are your plans for dose expansions as a monotherapy, and then also, how do you think about potential combinations? Yeah. So, I think, you know, for monotherapy, the usual suspects would be, you know, pancreatic and lung. I think we'll probably want to get a good handle at meaningful doses of what this can do in, you know, outside of those two histologies. But you know, monotherapy is really predominantly those two histologies. And then for combo, we're looking at different standard of care agents, as well as potential investigational agents that could combine, most focused on the big three, but also there could be opportunities outside of the big three. Right. And then we get this asked a lot, the treatment landscape could obviously change fairly soon, especially in pancreatic cancer, perhaps in lung too. But, yeah, how does that, you know, factor into your longer term development strategy, and what are your thoughts on path to market? I know it's still early, but I'm sure you have thoughts on that. Yeah. I think if we don't have a differentiated compound, then we'd be predominantly looking at areas outside of second-line pancreatic. I think if we have a differentiated compound, then, you know, it, it's wide open. So in either case, unfortunately, the unmet need is just so significant across the board that there is more than enough need and appetite for a new Pan RAS molecule. And then I think with Pan KRAS coming behind, the fact that we have both orthogonal shots on goal and the ability to potentially combine them as well, I think leads to some very interesting- Yeah - upside opportunities. As we think about differentiation, so, you know, perhaps at RPTD and expansion cohorts, what type of activity in phase Ib expansion would, you know, give you confidence in meaningful differentiation from daraxonrasib? ... Yeah, I mean, I think if you can have 10 points or higher of absolute difference in ORR, that could translate pretty well. Hopefully, that translates into a durability advantage- Mm -as well, in either or both of pancreatic and lung. And so- Okay ... I think that seems like a reasonable bar. Right. And if you can hit that, that would be really great. Makes sense. Okay, great. Then maybe in the last few minutes, a few questions on 4001, your pan-KRAS inhibitor. So that's been a category where I think the field's been moving more slowly. There's been some early data from other companies available early this year, but generally some other companies had setbacks. And so, yeah, maybe talk about your approach to pan-KRAS inhibitor in general, and then, you know, early comments on the phase I study, perhaps. Sure. Yeah, so ERAS-4001 is our pan-KRAS inhibitor. It's a Switch II Pocket binder. So to Jonathan's last point about, you know, orthogonal mechanisms between 0015 being a CypA binder and 4001 being a Switch Two Pocket binder, we like having that. The molecule itself has very good properties in terms of its in vitro potency, the in vivo activity, the PK profile, all of those look good. We filed and cleared an IND on this program back in Q2 of last year. So the trial, which we call BOREALIS-1, is advancing now. We've guided to data in the second half of this year from that study, similar to what Jonathan described with 0015. This will be also dozens of patients so that we can tell, you know, a fulsome story about this program, focused on safety, PK, initial signs of activity. And what we've guided to beyond that is that in calendar year 2027, we'll be able to initiate the monotherapy dose expansions as well as the combination dose escalation work. Right. And any comments on how the molecule perhaps compares preclinically to other pan-KRAS inhibitors as far as there's data available for those...? Yeah, so, unlike ERAS-0015, where the structure of the comparator compound RMC-6236 is known, and so we were able to do head-to-head comparisons that Jonathan described in terms of the preclinical differentiation, we were able to do that there. There's just very limited availability of structures in the pan-KRAS space, and so it makes those sorts of comparisons more difficult. Now, we do have certain properties of our molecule that we like. I alluded to some of them earlier in my previous response. You know, this molecule also has activity against both the GDP and GTP state of the molecule. Single-digit nanomolar potency against both, albeit more potency against the GDP state. And, you know, Jonathan mentioned about the potential for combinations of these two assets. That is also a potential advantage of having a pan-RAS that has, you know, dual mechanism of blocking effector protein binding downstream, but also GTP hydrolysis with the pan-RAS. And that GTP hydrolysis can then push the RAS protein into the GDP state, where 4001, as a pan-KRAS that has more potency against the GDP state, could come in and mop up that GDP state of the protein. As we think about the phase I study, I guess what is the ideal clinical profile or target profile of 4001 relative to 0015? Yeah, I mean, I would say that we are fortunate amongst the players in this space in the sense that we've got both assets. So, you know, we, I guess, regardless of how the field evolves, we've got an answer. At this conference last year, you all hosted a nice panel with David Hong and with Ryan Corcoran, talking exactly about sort of where do each assets fit pan-RAS versus pan-KRAS. For us, regardless of how it goes, I mean, we, we like both assets. Jonathan described, you know, how well the 0015 program is progressing. We're also very excited about 4001, and regardless of how it goes, you know, we've got an answer. Right. And is the hypothesis still that perhaps with pan-KRAS, you can get more efficacy out of it with a better therapeutic window, essentially by hitting less off-target RAS molecules? Is that right? Yeah, that is the hypothesis. And if you look at some of the data that you were alluding to, Michael, earlier, that came out earlier this year with another pan-KRAS molecule, they actually did show that by sparing H and N RAS, they actually showed less rash. And so that is a potential advantage of the pan-KRAS class. Now, to some of the comments that Jonathan was mentioning earlier, if we are able, with our double zero one five compound, to have sort of a Goldilocks approach, where we can hit all three RAS isoforms, there was actually a paper, earlier this year in Science, that talked about sparing H and N RAS can actually lead to bypass via PI3K, and so there's actually some advantage of hitting all three isoforms. So if ERAS-0015 can allow you to hit all three isoforms, but not have as bad of a rash profile, perhaps, you know, maybe there's a Goldilocks there. Now, ERAS-4001, with its sparing of H and N, could also allow you to have some of those advantages of sparing, you know, the toxicities associated with H and N. Right. And, is there a time, perhaps next year, where you approach a decision to advance either one of the therapies, or is there an opportunity to advance both, perhaps in different areas? Yeah, for sure. I mean, we're gonna be data-driven. We always have been as a company, and so we'll see as the data, as we generate the data, both ourselves, as well as the field as a whole, generates data, and we learn more about what a pan-RAS can do and what a pan-KRAS can do, you know, we'll look to see if it makes sense that they each have their own swim lane or one asset, you know, kind of is the one ring to rule them all, so to speak, using the Lord of the Rings analogy. So there, we will be data-driven once we have, you know, more of a data set to look at there. Right. It sounds like you mentioned earlier, but is there a combination? Is there, is there opportunity to combine the two, or does it not make sense, from a scientific perspective? No, I think there's rationale. I mean, there's rationale to combine either of these agents with standard of care agents or with investigational agents, including with each other. Okay, great. Well, thank you. I think our time is up, but that was very interesting. So thank you for your time, Jonathan and David. Yeah. I appreciate it. Thank you, Michael. Thank you, Michael.