Presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player. As a reminder, this call is being recorded, and a replay will be made available on the Erasca website following the conclusion of the event. I'd now like to turn the call over to Dr. Jonathan Lim, Chairman, CEO, and Co-Founder of Erasca. Please go ahead, Jonathan. Thank you. Hello, everyone. Welcome to the Erasca R&D Update. We've made exciting progress across our pipeline, and we look forward to telling you more about this on today's call. Here with me are David Chacko, our CFO and Chief Business Officer, Shannon Morris, our Chief Medical Officer, and Robert Shoemaker, our SVP of Research. We will be making forward-looking statements during this call. Please visit our website at erasca.com to review our latest SEC filings and associated risk factors. During today's update call, we'll be discussing two main topics. First, the RAS targeting franchise, and second, a naporafenib update. We'll begin first with the RAS targeting franchise. As a reminder, ERAS-00 15 and 4001 exhibit competitive profiles that exceed our target product profile. ERAS-0015 is a pan-RAS molecular glue with best-in-class potential for patients with RAS mutant solid tumors. It has high binding affinity to cyclophilin A that, in recent Erasca-run assays, has been found to be as high as 20 times stronger than for the reference compound, namely RMC-6236. In addition to stronger CypA binding, fifteen also showed favorable ADME and PK properties relative to the reference compound, including clearance, oral bioavailability, and kinetic solubility, and preferential tumor distribution, and long residence time. We believe the totality of these favorable properties contribute to 0015's approximately 5- to 10-fold greater potency in vivo relative to the reference compound. ERAS-4001 is a pan-KRAS inhibitor with first-in-class and best-in-class potential. It is designed to spare H and N RAS and address KRAS wild-type activation. Since in-licensing these molecules in May of this year, our team has made excellent progress in advancing both programs. We successfully reproduced in-house the biological, biophysical, cellular, and in vivo data from the originator companies. We've continued characterizing the superior potency of ERAS-0015 relative to RMC-6236, and we'll share some of these data with you today. In addition, as we've previously mentioned, two critical path activities between the in-licensing and the filing of the INDs are GLP tox studies and CMC, and we're pleased to report that both are progressing well. In terms of toxicology, both compounds are performing as anticipated. The ERAS-0015 tox studies support our planned H1 2025 IND filing. As we've completed GLP phototox, GLP Ames, and the dose range finding studies in both rat and dog. We've also completed the in-life portion of the GLP tox studies for ERAS-0015. The ERAS-4001 tox studies support our planned Q1 2025 IND filing. As we've completed GLP phototox, GLP Ames, the dose range finding studies in both rat and dog, and the GLP cardiovascular telemetry study. The in-life portion of the GLP tox studies in rat and dog are nearly complete, as they are in the recovery phase. Finally, I'm pleased to report we are advancing CMC for each molecule per our plan, including the drug substance and drug product development and manufacturing. Turning to ERAS-0015, at the time of our in-licensing, data showed that ERAS-0015 had more than four-fold higher binding affinity to CypA than did RMC-6236. Since then, we've conducted additional experiments which have shown this fold difference in CypA binding affinity to be between eight- to more than twenty-fold higher, which reinforces fifteen's potential best-in-class profile. We have also conducted new studies in vitro that have shown that this higher CypA binding affinity drives higher tumor cell concentrations of ERAS-0015 versus RMC-6236 in KRAS G12D PDAC cells, with a range of 1.6-2.9-fold higher concentration in AsPC-1 tumor cells, depending on doses administered. We performed a tumor PK distribution assessment in TGI studies of ERAS-0015 versus RMC-6236 in PK-59 and PSN-1 CDX models. PK concentrations of paired tumor and blood samples were measured at 4 and 24 hours after the last dose of the TGI studies. As shown in the figure on the left, in the PK-59 CDX study, the dose-normalized ERAS-0015 across three ERAS-0015 dose levels from 0.1, 0.3, and 1 MPK. The tumor PK exposures of fifteen relative to the corresponding blood concentrations at four and 24 hours post-dose were much higher compared to the same measure of RMC-6236, which was dose-normalized for two dose levels at one and three MPK, indicating preferential tumor distribution for ERAS-0015. In addition, the decrease in the ERAS-0015 tumor concentrations from four to 24 hours post-dose was much smaller compared to that of 6236, indicating longer tumor residence time for ERAS-0015. Similar findings were also observed in the PSN-1 CDX study, as shown in the figure on the right. In the PSN-1 model, ERAS-0015 exposures were dose-normalized across 0.3 and one MPK. 6236 exposures were dose-normalized across three and 10 MPK. Taken together, these data demonstrate that ERAS-0015 had preferential tumor distribution and longer residence time relative to 6236. We believe this could be related to the higher CypA binding affinity. As you can see from the data, ERAS-0015 showed approximately eight to 10-fold higher in vivo potency compared to 6236 across multiple tumor models, irrespective of histology or specific KRAS mutation. We are pleased to see this consistency of differentiated anti-tumor activity, which, reflecting the favorable potency, ADME, and PK properties relative to the reference compound, including clearance, oral bioavailability, kinetic solubility, and preferential tumor distribution and long residence time, contribute to ERAS fifteen's potential best-in-class profile. We're pleased to report that we reproduced the in vivo activity of ERAS-0015 in what is largely considered a bellwether model for assessment of the potency of pan-KRAS and KRAS mutant-selective inhibitors, which demonstrated ERAS-0015's approximately tenfold higher potency than RMC-6236 in vivo. In parallel with ERAS-0015, we continue to characterize ERAS-4001, our pan-KRAS inhibitor that selectively inhibits KRAS, including wild type and mutant forms relative to NRAS and HRAS. We are pleased to report that in this recently conducted biochemical assay, ERAS-4001 potently inhibited KRAS in both the GTP and GDP-bound states with single-digit nanomolar IC50s. ERAS-4001's potent disruption of binding between KRAS G12D and the RAS binding domain peptide is intended to model ERAS-4001's ability to block KRAS from signaling downstream via the RAS MAPK pathway. ERAS-4001 showed the potential to inhibit KRAS mutants, whereas where KRAS spends more time in the activated GTP-bound state, such as G12D and G12V mutations. The biochemical activity of ERAS-4001 against GTP and GDP-bound states translated to promising in vivo activity, where ERAS-4001 achieved tumor stasis and regression in three sensitive KRAS G12D models and one sensitive KRAS G12V model. ERAS-4001 also showed promising activity in the pan-KRAS inhibitor-insensitive model, the KRAS G12V mutant CDX-NCI-H727, albeit at higher doses, as expected. We are also pleased to show that we reproduced the in vivo activity of ERAS-4001 in this challenging model. We will now discuss our advanced clinical-stage program, naporafenib, including SEACRAFT-1 clinical data and program next steps. As a reminder, we have been pursuing a two-pronged development approach for naporafenib to address unmet needs in patients with RAS MAPK-driven tumors. SEACRAFT-1 is the efficacy signal-seeking RAS Q61X solid tumor trial. This mutation is commonly found in melanoma, lung, thyroid, and GI malignancies. There are limited targeted therapy options available for these patients. Earlier today, at the ENA Triple Meeting, we shared preliminary phase I-B data for naporafenib plus trametinib in this SEACRAFT-1 trial, which we will review further in this call. SEACRAFT-2 is our pivotal trial in patients with NRAS-mutant melanoma. We have the potential for approval based on high unmet need, as well as having gained alignment on the regulatory path with both United States and European regulators. Compelling phase I and II data have already been generated in this indication with a combination of naporafenib plus trametinib, and we remain on track to share stage I data for the phase III trial in calendar year 2025. At the outset of the SEACRAFT-1 trial, we envisioned a range of outcomes. In one scenario, we could see activity across the board that would potentially support a tissue-agnostic path. In the other scenario, we could see anti-tumor activity concentrated in one or a few indications, thereby suggesting that a tissue-specific approach would be more appropriate. For reasons that we will discuss shortly, our team felt that either approach provided an exciting option for patients. We will start with the tissue-agnostic path. Recent historical precedent for other targeted therapies in oncology have shown that there is a high hurdle for pursuing a tissue-agnostic approach. If clear patient benefit can be demonstrated, it may be possible to pursue a tissue-agnostic path. Typically, you need to demonstrate efficacy across multiple tumor types, often in ten or more histologies at the time of approval. You also need to show a high response rate north of at least 30%-40%, with meaningful duration of response of over six months. The bar for a combination can be even higher because of the need to show the combination is better than the monotherapies and that the benefit is sufficient to warrant the potential additional talks of a combination. Due to the complexity of this approval path, tissue-agnostic labels are also rarely granted as an initial approval, but more often follow or occur in parallel with tissue-specific approvals. Lastly, while a tissue-agnostic label may provide for the largest number of addressable patients with a given mutation or marker, tissue-agnostic approaches can be commercially challenging. There is typically slower adoption due to modest data packages and promotional hurdles, and often there are extended timelines for reimbursement approval. Acknowledging the high hurdle for pursuing this path, the SEACRAFT-1 trial was designed as an exploratory trial to determine whether a RAS Q61X tissue-agnostic indication was feasible. Now we'll look at the data from the SEACRAFT-1 trial. With that context, I'll hand the call over to Shannon to talk through the clinical data. Shannon? Thank you, Jonathan. Now, as a reminder, this trial enrolled patients with tumors of any histology that had a RAS Q61X mutation. This waterfall slide shows a 23% response rate, including three confirmed partial responses and four unconfirmed responses, with a disease control rate of 71% in patients with melanoma, lung cancer, thyroid, and other solid tumors, excluding colorectal and pancreatic cancer. Based on what Jonathan described in the previous slide, even if all four unconfirmed responses convert to confirmed responses, these efficacy observations do not meet the typical minimum bar of 30%-40% response rates. Looking at the swimmer plot, we see that the durability of responses in non-melanoma indications is limited. While it's encouraging that several patients remain on treatment as of the data cutoff, we do not believe that this justifies moving forward in a tissue-agnostic indication. Now we turn to the ctDNA analysis of these SEACRAFT-1 patients. The left box plot shows the results of a ctDNA or circulating tumor DNA analysis of 35 SEACRAFT-1 patients, where the circulating tumor DNA was quantified at the first on-treatment sampling time point relative to baseline. In this analysis, melanoma showed the greatest decreases in ctDNA. Now, looking specifically at the population of melanoma patients in the middle box plot, ctDNA decreases correlated with imaging-based RECIST responses, as one would expect. The graph on the right further shows that on an individual patient basis, that both partial responses and stable disease correlated with ctDNA levels, falling below the limit of quantitation of the assay. Now, let's think about the other scenario, looking at a tissue-specific approach. This waterfall plot looks specifically at the NRAS mutant melanoma patients from the SEACRAFT-1 trial. In other words, these are the patients with melanoma whose RAS Q61X mutation was in the NRAS protein. This population in SEACRAFT-1 is quite similar to the population in our SEACRAFT-2 trial, given that these patients are post-immunotherapy and about 90% of patients with NRAS mutant melanoma harbor a Q61X mutation. Unlike the previous waterfall slide, which did not support a tissue-agnostic path, these data are consistent with previously shared data, with the primary difference being the improved tolerability of the combination. And this further bolsters the rationale for pursuing the tissue-specific indication of NRAS mutant melanoma in our SEACRAFT-2 trial. Here we see a 40% response rate, including three confirmed responses and one unconfirmed response. And what's of note is that the patient with that unconfirmed partial response is still on treatment, with the potential to be confirmed. The disease control rate is quite encouraging at 80%, especially in what is typically an end-of-the-line patient population. In addition, a response was observed in a patient with mucosal melanoma, which is a population that had been excluded in previous studies. This swimmer plot shows encouraging time on treatment, with 70% of patients still on treatment as of the data cutoff, including all of the confirmed and unconfirmed responders. In addition, there are several patients with stable disease who continue to stay on treatment. The combination of a clinically meaningful response rate paired with durable benefit, as shown in these waterfall and swimmer plots, is quite promising in the light of the limited treatment options available for patients with NRAS mutant melanoma. Now, let's talk about the tolerability data. Now, this includes a pooled analysis of patient data across multiple histologies in SEACRAFT-1. The combination of naporafenib and trametinib has been well tolerated in SEACRAFT-1, where we see primarily grade 1 and 2 treatment-related adverse events. If you look at the far right column of the table, we see that the frequency of high-grade treatment-related adverse events, so that would be grade greater than or equal to three, is approximately 5% or less across the various categories of events. In particular, the rate of skin toxicities has improved dramatically in SEACRAFT-1 relative to the historical phase I and II trials that were previously conducted. As you know, we have implemented primary mandatory rash prophylaxis as part of our SEACRAFT-1 and 2 protocols, and we believe that this has significantly improved the AE profile. Now, if you dig deeper into the dermatologic adverse events, you can see a side-by-side comparison of the Novartis phase I and II trials, shown in blue, relative to SEACRAFT-1, which is shown in teal. If you look specifically at the highlighted row, you see that mandatory primary rash prophylaxis has decreased the rate of grade three or higher dermatologic toxicities from about 30% in the phase I and II trials to around 12% in SEACRAFT-1. Furthermore, the rate of drug discontinuations due to adverse events, shown on the left-hand side, has also markedly decreased from about 19%-20% in the phase I and II trials to less than 10% in SEACRAFT-1. On the right-hand side, the relative dose intensity, which is a measure of how much drug a patient actually receives relative to the trial's intent, also shows a marked improvement. Looking specifically at the median relative dose intensity for naporafenib, which is the first number in the pair, you see an RDI, or relative dose intensity, of about 66%-58%, respectively, for the phase I and II trials. This means that half of the patients receive less than two-thirds of their intended dosage. In contrast, SEACRAFT-1, shown in teal, has a median RDI for naporafenib of nearly 99%, and the median RDI for trametinib of 100% means that patients received the full dose of trametinib relative to the trial's intent, versus just 59%-62% in the phase I and II trials. We're really encouraged by these data, as they suggest that mandatory primary rash prophylaxis has dramatically improved the adverse event profile, the rate of drug discontinuations due to adverse events, and the relative dose intensity for the combination of naporafenib and trametinib. And we feel that if you can improve the tolerability of the combination via mandatory primary rash prophylaxis, that this could enable patients to stay on treatment longer, with the goal of achieving treatment benefit, which seems to be the case based on this preliminary efficacy and safety data from the NRAS mutant melanoma cohort in SEACRAFT-1. With the consistent, meaningful efficacy of this combination, we have strengthened our conviction in our SEACRAFT-2 trial for patients with NRAS mutant melanoma. This table highlights in blue the efficacy observed for two single-agent MEK inhibitors, binimetinib or trametinib, as well as the approved standard of care, which is chemotherapy. That's in comparison to naporafenib plus trametinib at two different doses from the pooled phase I and II dataset, which is shown in teal. These data demonstrate that the combination of naporafenib and trametinib is showing an improvement over the agents in blue. Now, starting first with response rate, you see a 31% and 22% response rate for naporafenib plus trametinib, versus 7% for the approved standard of care and 15% for the single-agent MEK inhibitors. The data that we shared today show a 40% response rate in NRAS mutant melanoma patients in SEACRAFT-1, which further supports the potential for this combination in SEACRAFT-2. While the patient numbers are small, we find it encouraging that the response rate is numerically higher in the SEACRAFT-1 population compared to the phase I and II trials. This could be because mandatory primary rash prophylaxis has increased the relative dose intensity for patients, such that they are receiving closer to their full intended dose of naporafenib and trametinib and are able to stay on treatment longer, thereby potentially driving better efficacy in terms of response rates and durability. Now, on the next two rows, we see the median progression-free survival and the median overall survival, which we have shared previously. These show a nice improvement relative to the agent shown in blue. The median PFS for naporafenib and trametinib is approximately five months, relative to the historical controls of approximately one point five months for chemotherapy and two point eight months for single-agent MEK inhibitors. In terms of median overall survival, as we shared earlier this year, the phase I and II trials show about 13-14 months of overall survival, relative to about seven months for the historical controls. Therefore, we believe we have the potential to win on both the SEACRAFT-2 primary endpoints, which are PFS and OS. Now, with that, I'll hand the call over to David to provide concluding remarks. David? Thanks, Shannon. In today's update, naporafenib showed a 40% response rate in patients with NRAS mutant melanoma in the SEACRAFT-1 trial and, importantly, showed an improved safety and tolerability profile relative to the historical phase I and II trials. We're encouraged that the improved response rate and improved AE profile could translate into significant patient benefit in this population. We are exploring this further in our ongoing SEACRAFT-2 pivotal trial, where investigator enthusiasm is high and site activation is ahead of schedule. In addition, we continue to be very excited about our RAS-targeting agents. The in-life portion of the GLP tox studies are tracking as anticipated, with ERAS-0015 completed and ERAS-4001 nearing completion, and we remain on track per our public guidance on these programs. We are encouraged that we have been able to reproduce the non-clinical data that were initially generated before we in-licensed the molecules, and we've generated new data that continue to support the best-in-class profiles for these molecules. We are excited about the potential for our pipeline to help patients with multiple types of RAS/MAPK-driven tumors. As SEACRAFT-2 continues to ramp up in terms of site activation and enrollment of patients with NRAS-mutant melanoma, we also have an eye toward initiating the AURORAS and BOREALIS trials for the RAS-targeting molecules next year. Our anticipated key milestones are shown here, and these remain unchanged from our previous guidance. Naporafenib is in the SEACRAFT-2 NRAS-mutant melanoma trial in combination with trametinib and is on track for its anticipated stage I randomized dose optimization data readout from the phase III trial in 2025. ERAS-0015, which is the pan-RAS molecular glue, is on track for an IND filing in the first half of next year, with phase I monotherapy data expected in 2026. ERAS-4001, the pan-KRAS inhibitor, is on track for an IND filing in Q1 2025, with phase I monotherapy data expected in 2026. We ended Q2 with $460 million in cash, and we have cash runway into the first half of 2027, consistent with our previous guidance. We'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? Great. Thank you, David. So as mentioned, we are gonna begin our Q&A session at this time. Please hold for a brief moment while we poll for questions. So our first question comes from Anupam Rama at J.P. Morgan. Please go ahead, Anupam. Hey, guys. Thanks so much for taking the question. Quick question. How do you think about the dose that you're using in SEACRAFT-1, where you're seeing responses in NRAS melanoma, relative to the doses that you're looking at in SEACRAFT-2 in the dose optimization stage? Just trying to understand the relative doses that you're studying here. Thanks so much. Yeah. Thanks, Anupam. I think we're feeling pretty good about the 200/1 based on these recent data. I think we were feeling less good about it, before, you know, without the mandatory primary skin prophylaxis. But now with the institution of that, the tolerability as well as the efficacy look quite promising. That said, we're still planning to do the Stage I dose optimization, where we're gonna be bookending the high dose of napo and low dose of napo, as well as vice versa for trami. So the two doses we're looking at are 400 milligrams BID for napo, 0.5 milligrams QD for trami, and then the other dose is 100 milligrams of napo BID plus 1 milligram QD of trami, and both of those are bookending the 200/1. So I think between the three doses that we have, we'll be able to make a decision. But both of those other two doses will be compared to two milligrams QD of trametinib, so that we'll be able to assess contribution of component. I would say that the scope of the Stage I might not be as broad as what we were thinking before, based on the fact that the 200/1 dose does look promising. Got it. Thanks so much for taking our question. Thank you. Yes, thank you for the questions, Anupam. So our next question comes from Jeff Hung at Morgan Stanley. Please go ahead, Jeff. Thanks for taking my questions. For naporafenib, in the past melanoma data, you looked at LDH. Did you see any correlation between change in tumor burden in LDH? Yeah. Thanks, Jeff. Shannon, do you wanna take that one? Sure. What I can tell you is we certainly saw responses regardless of LDH, but we haven't done a more sophisticated analysis on that, particularly given that the sample size is quite small. Okay, great. And then I know it's small numbers, but it looked like the efficacy for the other solid tumors was bimodal, with some having good tumor reduction while others were on the lower end. So just curious if there was any, you know, consistent tumor types that showed, you know, better tumor reduction. Thanks. Yeah, there wasn't really a pattern. There was sort of anecdotal evidence. So for instance, the three other responders, which all were UPR, by the way, were ovarian, bladder, and duodenal, and there wasn't really a clear signal in terms of another tissue-specific cohort beyond melanoma, and all three of those responses were short-lived, so they unfortunately don't have a chance to convert to CPRs. So, yeah, we didn't, in the other solid tumor types, we didn't really see a signal that was worth reporting. All the data that are in that waterfall you could see was represented, and all three of those non-melanoma responses were in different histologies. Okay, great. Thank you. Sure. ... Thanks for the questions, Jeff. Our next question comes from Alec Stranahan at Bank of America. Please go ahead, Alec. Hey, guys. Thanks for taking our questions as well. Just two from us. Maybe first, I think the rash prophylaxis is pretty logical. Any reason to expect that this could influence the efficacy data at all, I guess, other than maybe improving compliance to therapy? And would such a prophylactic regimen also be needed in the control arm? Just any feedback you've gotten from the FDA on that, and then I've got a follow-up. Yeah. Thanks, Alec. I'll take a first shot, and then, Shannon, feel free to chime in. But, I think, as Shannon mentioned in the prepared remarks, there does seem to be sort of a connection between the rash prophylaxis leading to a higher RDI, you know, close to 98% to 100%. So they're getting their full dose, and then that does seem to be translating into promising efficacy, both in terms of response rates as well as durability. So small patient numbers, but in the 10 patients, I think we were really pleased to see that, you know, three confirmed and one unconfirmed response is very promising, and then the fact that 70% of the patients were still on treatment as of the data cutoff. So we'll be following that pretty closely. If that leads to a meaningful durability advantage in terms of PFS and OS in the future, well, that'll be fantastic for patients. In terms of the MEK inhibitor alone, the reason why you get rash, such significant rash is from the combination of the two agents that are targeting MAP kinase. And so, when you just have either MEK alone or the pan- RAF agent alone, you don't get the frequency and severity of rash that warrant the primary skin prophylaxis, but I'll see if I misstated anything there, Shannon. No, nothing to add. Just you've stated it correctly. Trametinib's frequency and severity, while certainly, you know, clinically significant, is not high enough to warrant mandatory primary prophylaxis. Okay, that, that's helpful. And then just quickly, and apologies if you've mentioned this, but just the one unconfirmed PR in the NRAS melanoma cohort. Sounds like this responder could potentially be confirmed on the next scan. Is that sort of the right way to be thinking about it? Yeah. It's a timing situation. So, that patient hadn't had their confirmatory scan as at the time of the data cutoff. But that patient remains on treatment, so it is possible that that patient could convert to a CPR. Okay. Appreciate the color. Thank you so much. Thank you. Yes, thanks for the questions, Alec. Our next question comes from Michael Schmidt at Guggenheim. Please go ahead, Michael. Hey, good morning. It's Yigang for Michael. Thanks for taking our questions. I guess two quick ones from us. The first one, how should we think of the component contribution of the two agents to the safety profile, particularly to the rash, AE, and, you know, how does the adoption of prophylaxis allow you to choose the dose in the H2 study? Are you going to be able to use a higher dose of napo or trami? And then the second question, how should we think of the performance of maybe chemotherapy in the patient population, or melanoma patient population enrolled in the study, given the patient base characteristics? Thank you. Yeah, thanks for the question. So in terms of the rash, it's as I mentioned in response to Alec's question, which is that either agent alone, whether MEK or pan RAF, you do get some rash, but you don't get the frequency and severity that you get when you combine the two agents. And so, for instance, in the Novartis-run Novartis-sponsored phase I and phase II, the frequency of grade three or higher TRAEs that were derm or skin-related were in sort of the 36% range. Whereas with the mandatory skin prophylaxis, that came down substantially to about 10% or 11%. So there was a meaningful reduction from that, and mechanistically, if you are blocking MAP kinase with at two nodes, then you're exacerbating an on-target what is known to be an on-target AE. So hopefully that answers your question there. In terms of the performance of chemotherapy, right now, that is the standard of care, is chemotherapy. Single-agent MEK actually is not approved, but it is on the NCCN guidelines. But with chemotherapy, the response or the PFS is only about one and a half months. With single-agent MEK, it's about two point eight months, and in the phase I, phase II setting with napo and trami, we saw five and a half months. Now, with the mandatory rash prophylaxis and the enhanced RDI, if that can be pushed beyond five and a half months, there's a potential upside there, which would be really great for patients. We do think these data are promising from SEACRAFT-1, that show that with the 200+1 dose and the mandatory rash prophylaxis that there could be some potential upside, but we'll have to track that, and it'll be data-driven. Did that address your questions? Yep, that's super helpful. Thank you. Thank you. Great. Thanks for the questions, Michael. Our next question comes from Kevin Strang at Goldman Sachs. Please go ahead, Kevin. Hi, this is Kevin on for Chris. Thanks for taking our questions. Wanted to switch gears and talk about the RAS molecules and development. So, for ERAS-0015, you talked about the preclinical efficacy comparisons. I wanted to ask about the potential safety profile, given how far you are along here, you know, getting to the clinic. Based on what you've seen so far, what you know about the molecule, what are your expectations as you enter the clinic next year? Yeah. Thanks, Kevin, for the question. I'd say with ERAS-0015, you know, there, there's hasn't been any surprises in the GLP talks, and so no surprise is good, in general for talks and, and similarly for ERAS-4001. I'd say the predicted, clinical, safety and tolerability issues, or TRAEs, will likely be, skin-related, just based on the comparator compound, where rash by far seems to be the predominant, TRAE. And so that is likely an on-mechanism type effect. There's also GI components to the, tolerability issue, and, in that case, you know, if we have, let's say, one tenth or one eighth of the, of the potency, then there's a possibility that there's potential, upside there in terms of GI tolerability. But I think the predicted toxicity profile is gonna be in that sort of, you know, skin and GI category. Great. Thank you. And then just a quick follow-up in terms of, you know, competition here. We saw some clinical data this week, and then, you know, I wanted to ask more about the potential preclinical competition as well. You've mentioned in the past sort of the difficulty in designing these molecules and the IP involved. How are you thinking about potential competitors in development here? Yeah, I'd say in the pan RAS molecular glue, you know, clearly RevMed is plowing ahead with really, you know, very promising data for patients, especially in PDAC. So we're really excited about that molecule for patients. And then I would say that in that category, we're in second, 'cause, you know, we're on track for an IND in the first half of next year. And then I think there's some Chinese companies that are in the mix, but further behind. But it's really a shortlist in that category. I'd say in the pan KRAS category, there's a number of other players, both big pharma and small biotech, both domestically as well as international. So I think that's more of a crowded space. We are in the vanguard, so we'll be in that first wave in terms of KRAS selective, but H and N sparing. And in that case, you know, hopefully there is a therapeutic window, especially when you wanna combine it with other agents that can be rash-inducing. We think that 4001 could be very interesting for that. But we like the fact that we have two agents with orthogonal mechanisms of action that could be combined with standard of care as well as with each other. Great. Thanks for taking our questions. Sure. Thanks for the questions, Kevin. Our next question comes from Graig Suvannavejh at Mizuho. Please go ahead, Greg. Okay, good morning. Thanks for taking my questions, and thank you for the updates as well. I was just curious, with respect to SEACRAFT-1, I believe the trial design overall was to enroll a total of 100 patients. I might have missed this if you commented before, but where are you in that, and is the plan to, if you are further enrolling patients, just to focus on the melanoma cell population? Yeah. Greg, thanks for the question. So, yeah, the original plan was to enroll 100 patients, and, and the goal of, the Q4 update was actually to have an interim read of, less than 100 patients. We actually blew away, from an enrollment perspective, our original goal, and so we actually have enrolled 82 patients. We have stopped enrollment because the 82 patients that, that we've seen in terms of the data don't justify moving forward with a tissue-agnostic label, as we mentioned in our, prepared remarks. What, what was presented at the ENA triple meeting was the 52 patients, excluding the 30 patients with CRC and PDAC, that are, basically, none of them had, actual responses. The best response with was SD. And so the totality of data from all the other tumor types, as well as melanoma, was reported at the ENA triple meeting and also in this investor call. That's really the sum total of all the patients, is the 82 patients. And from an efficacy standpoint, the 30 patients with CRC and PDAC did not have any responses, as would be expected with those tumor types. Okay, thank you for that. Sure. ... Great. Thanks for the questions, Greg. I'll now turn it back over to Jonathan for closing remarks. Okay. Really appreciate everyone joining this call. We are very excited about the progress that we've made on both the RAS targeting franchise as well as naporafenib. I think the development path forward has really crystallized for naporafenib and trametinib to be focused on the NRAS-mutant melanoma opportunity, which the probability of success for that indication has gone up pretty significantly based on the data that we've reported today. So very excited to share that with all of you, and we look forward to keeping you posted as we keep pushing forward on our pipeline for the benefit of patients everywhere. Thank you, everyone. Take care. Good morning, and welcome to the Erasca Virtual R&D Update. At this time, all attendees are in a listen-only mode. A question and answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player. As a reminder, this call is being recorded, and a replay will be made available on the Erasca website following the conclusion of the event. I'd now like to turn the call over to Dr. Jonathan Lim, Chairman, CEO, and Co-Founder of Erasca. Please go ahead, Jonathan. Thank you. Hello, everyone. Welcome to the Erasca R&D Update. We've made exciting progress across our pipeline, and we look forward to telling you more about this on today's call. Here with me are David Chacko, our CFO and Chief Business Officer, Shannon Morris, our Chief Medical Officer, and Robert Shoemaker, our SVP of Research. We will be making forward-looking statements during this call. Please visit our website at erasca.com to review our latest SEC filings and associated risk factors. During today's update call, we'll be discussing two main topics. First, the RAS targeting franchise, and second, a naporafenib update. We'll begin first with the RAS targeting franchise. As a reminder, ERAS-0015 and four thousand and one exhibit competitive profiles that exceed our target product profile. ERAS-0015 is a pan-RAS molecular glue with best-in-class potential for patients with RAS mutant solid tumors. It has high binding affinity to cyclophilin A, that in recent Erasca-run assays, has been found to be as high as twenty times stronger than for the reference compound, namely RMC-6236. In addition to stronger CypA binding, fifteen also showed favorable ADME and PK properties relative to the reference compound, including clearance, oral bioavailability, and kinetic solubility, and preferential tumor distribution, and long residence time. We believe the totality of these favorable properties contribute to fifteen's approximately five- to tenfold greater potency in vivo relative to the reference compound. ERAS-4001 is a pan-KRAS inhibitor with first-in-class and best-in-class potential. It is designed to spare HRAS and NRAS and address KRAS wild-type activation. Since in-licensing these molecules in May of this year, our team has made excellent progress in advancing both programs. We successfully reproduced in-house the biological, biophysical, cellular, and in vivo data from the originator companies. We've continued characterizing the superior potency of ERAS-0015 relative to RMC-6236, and we'll share some of these data with you today. In addition, as we've previously mentioned, two critical path activities between the in-licensing and the filing of the INDs are GLP tox studies and CMC, and we're pleased to report that both are progressing well. In terms of toxicology, both compounds are performing as anticipated. The ERAS-0015 tox studies support our planned H1 2025 IND filing. As we've completed GLP phototox, GLP Ames, and the dose range finding studies in both rat and dog. We've also completed the in-life portion of the GLP tox studies for ERAS-0015. The ERAS-4001 tox studies support our planned Q1 2025 IND filing. As we've completed GLP phototox, GLP Ames, the dose range finding studies in both rat and dog, and the GLP cardiovascular telemetry study. The in-life portion of the GLP tox studies in rat and dog are nearly complete, as they are in the recovery phase. Finally, I'm pleased to report we are advancing CMC for each molecule per our plan, including the drug substance and drug product development and manufacturing. Turning to ERAS-0015, at the time of our in-licensing, data showed that ERAS-0015 had more than four-fold higher binding affinity to CypA than did RMC-6236. Since then, we've conducted additional experiments which have shown this fold difference in CypA binding affinity to be between eight to more than 20-fold higher, which reinforces ERAS-0015's potential best-in-class profile. We have also conducted new studies in vitro that have shown that this higher CypA binding affinity drives higher tumor cell concentrations of ERAS-0015 versus RMC-6236 in KRAS G12D PDAC cells, with a range of 1.6- to 2.9-fold higher concentration in AsPC-1 tumor cells, depending on doses administered. We performed a tumor PK distribution assessment in TGI studies of ERAS-0015 versus RMC-6236 in PK-59 and PSN-1 CDX models. PK concentrations of paired tumor and blood samples were measured at four and 24 hours after the last dose of the TGI studies. As shown in the figure on the left, in the PK-59 CDX study, the dose-normalized ERAS-0015 across three ERAS-0015 dose levels from 0.1, 0.3, and 1 MPK. The tumor PK exposures of ERAS-0015 relative to the corresponding blood concentrations at 4 and 24 hours post-dose were much higher compared to the same measure of RMC-6236, which was dose-normalized for two dose levels at 1 and 3 MPK, indicating preferential tumor distribution for ERAS-0015. In addition, the decrease in the ERAS-0015 tumor concentrations from 4 to 24 hours post-dose was much smaller compared to that of RMC-6236, indicating longer tumor residence time for ERAS-0015. Similar findings were also observed in the PSN-1 CDX study, as shown in the figure on the right. In the PSN-1 model, ERAS-0015 exposures were dose-normalized across 0.3 and 1 MPK. 6236 exposures were dose-normalized across three and 10 MPK. Taken together, these data demonstrate that ERAS-0015 had preferential tumor distribution and longer residence time relative to 6236. We believe this could be related to the higher CypA binding affinity. As you can see from the data, ERAS-0015 showed approximately eight- to 10-fold higher in vivo potency compared to 6236 across multiple tumor models, irrespective of histology or specific KRAS mutation. We are pleased to see this consistency of differentiated anti-tumor activity, which, reflecting the favorable potency, ADME, and PK properties relative to the reference compound, including clearance, oral bioavailability, kinetic solubility, and preferential tumor distribution and long residence time, contribute to ERAS-0015's potential best-in-class profile. We're pleased to report that we reproduced the in vivo activity of ERAS-0015 in what is largely considered a bellwether model for assessment of the potency of pan-KRAS and KRAS mutant-selective inhibitors, which demonstrated ERAS-0015's approximately tenfold higher potency than RMC-6236 in vivo. In parallel with ERAS-0015, we continue to characterize ERAS-4001, our pan-KRAS inhibitor that selectively inhibits KRAS, including wild-type and mutant forms, relative to NRAS and HRAS. We are pleased to report that in this recently conducted biochemical assay, ERAS-4001 potently inhibited KRAS in both the GTP- and GDP-bound states with single-digit nanomolar IC50s. ERAS-4001's potent disruption of binding between KRAS G12D and the RAS binding domain peptide is intended to model ERAS-4001's ability to block KRAS from signaling downstream via the RAS MAPK pathway. 4001 showed the potential to inhibit KRAS mutants, whereas where KRAS spends more time in the activated GTP-bound state, such as G12D and G12V mutations. The biochemical activity of 4001 against GTP and GDP-bound states translated to promising in vivo activity, where ERAS-4001 achieved tumor stasis and regression in three sensitive KRAS G12D models and one sensitive KRAS G12V model. 4001 also showed promising activity in the pan-KRAS inhibitor-insensitive model, the KRAS G12V mutant CDX-NCI-H727, albeit at higher doses, as expected. We are also pleased to show that we reproduced the in vivo activity of 4001 in this challenging model. We will now discuss our advanced clinical stage program, naporafenib, including SEACRAFT-1 clinical data and program next steps. As a reminder, we have been pursuing a two-pronged development approach for naporafenib to address unmet needs in patients with RAS/MAPK-driven tumors. SEACRAFT-1 is the efficacy signal-seeking RAS Q61X solid tumor trial. This mutation is commonly found in melanoma, lung, thyroid, and GI malignancies. There are limited targeted therapy options available for these patients. Earlier today, at the ENA triple meeting, we shared preliminary phase I-B data for napo plus trami in this SEACRAFT-1 trial, which we will review further in this call. SEACRAFT-2 is our pivotal trial in patients with NRAS-mutant melanoma. We have the potential for approval based on high unmet need, as well as having gained alignment on the regulatory path with both U.S. and European regulators. Compelling phase I and II data have already been generated in this indication with a combination of naporafenib plus trametinib, and we remain on track to share stage I data for the phase III trial in calendar year 2025. At the outset of the SEACRAFT-1 trial, we envisioned a range of outcomes. In one scenario, we could see activity across the board that would potentially support a tissue-agnostic path. In the other scenario, we could see anti-tumor activity concentrated in one or a few indications, thereby suggesting that a tissue-specific approach would be more appropriate. For reasons that we will discuss shortly, our team felt that either approach provided an exciting option for patients. We will start with the tissue-agnostic path. Recent historical precedent for other targeted therapies in oncology have shown that there is a high hurdle for pursuing a tissue-agnostic approach. If clear patient benefit can be demonstrated, it may be possible to pursue a tissue-agnostic path. Typically, you need to demonstrate efficacy across multiple tumor types, often in ten or more histologies at the time of approval. You also need to show a high response rate north of at least 30%-40%, with meaningful duration of response of over six months. The bar for a combination can be even higher because of the need to show the combination is better than the monotherapies and that the benefit is sufficient to warrant the potential additional talks of a combination. Due to the complexity of this approval path, tissue-agnostic labels are also rarely granted as an initial approval, but more often follow or occur in parallel with tissue-specific approvals. Lastly, while a tissue-agnostic label may provide for the largest number of addressable patients with a given mutation or marker, tissue-agnostic approaches can be commercially challenging. There is typically slower adoption due to modest data packages and promotional hurdles, and often there are extended timelines for reimbursement approval. Acknowledging the high hurdle for pursuing this path, the SEACRAFT-1 trial was designed as an exploratory trial to determine whether a RAS Q61X tissue-agnostic indication was feasible. Now we'll look at the data from the SEACRAFT-1 trial. With that context, I'll hand the call over to Shannon to talk through the clinical data. Shannon? Thank you, Jonathan. Now, as a reminder, this trial enrolled patients with tumors of any histology that had a RAS Q61X mutation. This waterfall slide shows a 23% response rate, including three confirmed partial responses and four unconfirmed responses, with a disease control rate of 71% in patients with melanoma, lung cancer, thyroid, and other solid tumors, excluding colorectal and pancreatic cancer. Based on what Jonathan described in the previous slide, even if all four unconfirmed responses convert to confirmed responses, these efficacy observations do not meet the typical minimum bar of 30%-40% response rates. Looking at the swimmer plot, we see that the durability of responses in non-melanoma indications is limited. While it's encouraging that several patients remain on treatment as of the data cutoff, we do not believe that this justifies moving forward in a tissue-agnostic indication. Now we turn to the ctDNA analysis of these SEACRAFT-1 patients. The left box plot shows the results of a ctDNA or circulating tumor DNA analysis of 35 SEACRAFT-1 patients, where the circulating tumor DNA was quantified at the first on-treatment sampling time point relative to baseline. In this analysis, melanoma showed the greatest decreases in ctDNA. Now, looking specifically at the population of melanoma patients in the middle box plot, ctDNA decreases correlated with imaging-based RECIST responses, as one would expect. The graph on the right further shows that on an individual patient basis, that both partial responses and stable disease correlated with ctDNA levels, falling below the limit of quantitation of the assay. Now, let's think about the other scenario, looking at a tissue-specific approach. This waterfall plot looks specifically at the NRAS mutant melanoma patients from the SEACRAFT-1 trial. In other words, these are the patients with melanoma whose RAS Q61X mutation was in the NRAS protein. This population in SEACRAFT-1 is quite similar to the population in our SEACRAFT-2 trial, given that these patients are post-immunotherapy and about 90% of patients with NRAS mutant melanoma harbor a Q61X mutation. Unlike the previous waterfall slide, which did not support a tissue-agnostic path, these data are consistent with previously shared data, with the primary difference being the improved tolerability of the combination. And this further bolsters the rationale for pursuing the tissue-specific indication of NRAS mutant melanoma in our SEACRAFT-2 trial. Here we see a 40% response rate, including three confirmed responses and one unconfirmed response. And what's of note is that the patient with that unconfirmed partial response is still on treatment, with the potential to be confirmed. The disease control rate is quite encouraging at 80%, especially in what is typically an end-of-the-line patient population. In addition, a response was observed in a patient with mucosal melanoma, which is a population that had been excluded in previous studies. This swimmer plot shows encouraging time on treatment, with 70% of patients still on treatment as of the data cutoff, including all of the confirmed and unconfirmed responders. In addition, there are several patients with stable disease who continued to stay on treatment. The combination of a clinically meaningful response rate paired with durable benefit, as shown in these waterfall and swimmer plots, is quite promising in the light of the limited treatment options available for patients with NRAS-mutant melanoma. Now, let's talk about the tolerability data. Now, this includes a pooled analysis of patient data across multiple histologies in SEACRAFT-1. The combination of naporafenib and trametinib has been well-tolerated in SEACRAFT-1, where we see primarily Grade One and Two treatment-related adverse events. If you look at the far right column of the table, we see that the frequency of high-grade treatment-related adverse events, so that would be grade greater than or equal to three, is approximately 5% or less across the various categories of events. In particular, the rate of skin toxicities has improved dramatically in SEACRAFT-1, relative to the historical phase I and II trials that were previously conducted. As you know, we have implemented primary mandatory rash prophylaxis as part of our SEACRAFT-1 and 2 protocols, and we believe that this has significantly improved the AE profile. Now, if you dig deeper into the dermatologic adverse events, you can. Here you can see a side-by-side comparison of the Novartis phase I and II trials, shown in blue, relative to SEACRAFT-1, which is shown in teal. If you look specifically at the highlighted row, you see that mandatory primary rash prophylaxis has decreased the rate of grade three or higher dermatologic toxicities from about 30% in the phase I and II trials to around 12% in SEACRAFT-1. Furthermore, the rate of drug discontinuations due to adverse events, shown on the left-hand side, has also markedly decreased from about 19%-20% in the phase I and II trials to less than 10% in SEACRAFT-1. On the right-hand side, the relative dose intensity, which is a measure of how much drug a patient actually receives relative to the trial's intent, also shows a marked improvement. Looking specifically at the median relative dose intensity for naporafenib, which is the first number in the pair, you see an RDI, or relative dose intensity, of about 66% to 58%, respectively, for the phase I and II trials. This means that half of the patients receive less than two-thirds of their intended dosage. In contrast, SEACRAFT-1, shown in teal, has a median RDI for naporafenib of nearly 99%, and the median RDI for trametinib of 100% means that patients received the full dose of trametinib relative to the trial's intent, versus just 59% to 62% in the phase I and II trials. We're really encouraged by these data, as they suggest that mandatory primary rash prophylaxis has dramatically improved the adverse event profile, the rate of drug discontinuations due to adverse events, and the relative dose intensity for the combination of naporafenib and trametinib. We feel that if you can improve the tolerability of the combination via mandatory primary rash prophylaxis, that this could enable patients to stay on treatment longer, with the goal of achieving treatment benefit, which seems to be the case based on this preliminary efficacy and safety data from the NRAS-mutant melanoma cohort in SEACRAFT-1. With the consistent, meaningful efficacy of this combination, we have strengthened our conviction in our SEACRAFT-2 trial for patients with NRAS-mutant melanoma. This table highlights in blue the efficacy observed for two single-agent MEK inhibitors, binimetinib or trametinib, as well as the approved standard of care, which is chemotherapy. That's in comparison to naporafenib plus trametinib at two different doses from the pooled phase I and II dataset, which is shown in teal. These data demonstrate that the combination of naporafenib and trametinib is showing an improvement over the agents in blue. Now, starting first with response rate, you see a 31% and 22% response rate for naporafenib plus trametinib, versus 7% for the approved standard of care and 15% for the single-agent MEK inhibitors. The data that we shared today show a 40% response rate in NRAS-mutant melanoma patients in SEACRAFT-1, which further supports the potential for this combination in SEACRAFT-2. While the patient numbers are small, we find it encouraging that the response rate is numerically higher in the SEACRAFT-1 population compared to the phase I and II trials. This could be because mandatory primary rash prophylaxis has increased the relative dose intensity for patients, such that they are receiving closer to their full intended dose of naporafenib and trametinib and are able to stay on treatment longer, thereby potentially driving better efficacy in terms of response rates and durability. Now, on the next two rows, we see the median progression-free survival and the median overall survival, which we have shared previously. And these show a nice improvement relative to the agent shown in blue. The median PFS for naporafenib and trametinib is approximately five months, relative to the historical controls of approximately 1.5 months for chemotherapy and 2.8 months for single-agent MEK inhibitors. And in terms of median overall survival, as we shared earlier this year, the phase I and II trials show about 13-14 months of overall survival, relative to about 7 months for the historical controls... Therefore, we believe we have the potential to win on both the SEACRAFT-2 primary endpoints, which are PFS and OS. Now, with that, I'll hand the call over to David to provide concluding remarks. David? Thanks, Shannon. In today's update, naporafenib showed a 40% response rate in patients with NRAS-mutant melanoma in the SEACRAFT-1 trial, and importantly, showed an improved safety and tolerability profile relative to the historical phase I and II trials. We're encouraged that the improved response rate and improved AE profile could translate into significant patient benefit in this population. We are exploring this further in our ongoing SEACRAFT-2 pivotal trial, where investigator enthusiasm is high and site activation is ahead of schedule. In addition, we continue to be very excited about our RAS targeting agents. The in-life portion of the GLP tox studies are tracking as anticipated, with ERAS-0015 completed and ERAS-4001 nearing completion, and we remain on track per our public guidance on these programs. We are encouraged that we have been able to reproduce the non-clinical data that were initially generated before we in-licensed the molecules, and we've generated new data that continue to support the best-in-class profiles for these molecules. We are excited about the potential for our pipeline to help patients with multiple types of RAS/MAPK-driven tumors. As SEACRAFT-2 continues to ramp up in terms of site activation and enrollment of patients with NRAS-mutant melanoma, we also have an eye toward initiating the AURORAS and BOREALIS trials for the RAS-targeting molecules next year. Our anticipated key milestones are shown here, and these remain unchanged from our previous guidance. Naporafenib is in the SEACRAFT-2 NRAS-mutant melanoma trial in combination with trametinib and is on track for its anticipated Stage I randomized dose optimization data readout from the phase III trial in 2025. ERAS-0015, which is the pan-RAS molecular glue, is on track for an IND filing in the first half of next year, with phase I monotherapy data expected in 2026. ERAS-4001, the pan-KRAS inhibitor, is on track for an IND filing in Q1 2025, with phase I monotherapy data expected in 2026. We ended Q2 with $460 million in cash, and we have cash runway into the first half of 2027, consistent with our previous guidance. We'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? Great. Thank you, David. So, as mentioned, we are gonna begin our Q&A session at this time. Please hold for a brief moment while we poll for questions. So our first question comes from Anupam Rama at J.P. Morgan. Please go ahead, Anupam. Hey, guys. Thanks so much for taking the question. Quick question, how do you think about the dose that you're using in SEACRAFT-1, where you're seeing responses in NRAS melanoma, relative to the doses that you're looking at in SEACRAFT-2 for in the dose optimization stage? Just trying to understand the relative doses that you're studying here. Thanks so much. Yeah. Thanks, Anupam. I think we're feeling pretty good about the 201 based on these recent data. I think we were feeling less good about it before, you know, without the mandatory primary skin prophylaxis. But now, with the institution of that, the tolerability, as well as the efficacy, look quite promising. That said, we're still planning to do the Stage 1 dose optimization, where we're gonna be bookending the high dose of napo and low dose of napo, as well as vice versa for trami. So the two doses we're looking at are 400 milligrams BID for napo, 0.5 milligrams QD for trami, and then the other dose is 100 milligrams of napo BID plus 1 milligram QD of trami. And both of those are bookending the 201. So I think between the three doses that we have, we'll be able to make a decision. But both of those other two doses will be compared to two milligrams QD of trametinib, so that we'll be able to assess contribution of component. I would say that the scope of the Stage I might not be as broad as what we were thinking before, based on the fact that the 201 dose does look promising. Got it. Thanks so much for taking our question. Thank you. Yes, thank you for the question, Anupam. So our next question comes from Jeff Hung at Morgan Stanley. Please go ahead, Jeff. Thanks for taking my questions. For naporafenib, in the past melanoma data, you looked at LDH. Did you see any correlation between change in tumor burden and LDH? Yeah. Thanks, Jeff. Shannon, do you wanna take that one? Sure. What I can tell you is we certainly saw responses regardless of LDH, but we haven't done a more sophisticated analysis on that, particularly given that the sample size is quite small. Okay, great. And then I know it's small numbers, but it looked like the efficacy for the other solid tumors was bimodal, with some having good tumor reduction, while others were on the lower end. So just curious if there was any, you know, consistent tumor types that showed, you know, better tumor reduction? Thanks. Yeah. It wasn't really a pattern. There was sort of anecdotal evidence. So for instance, the three other responders, which all were UPR, by the way, was ovarian, bladder, and duodenal. And there wasn't really a clear signal in terms of another tissue-specific cohort beyond melanoma, and all three of those responses were short-lived. So they unfortunately don't have a chance to convert to CPRs. So, yeah, we didn't in the other solid tumor types, we didn't really see a signal that was worth reporting. All the data that are in that waterfall you could see was represented and it, all three of those non-melanoma responses were in different histologies. Okay, great. Thank you. Sure. Thanks for the questions, Jeff. Our next question comes from Alec Stranahan at Bank of America. Please go ahead, Alec. Hey, guys. Thanks for taking our questions as well. Just two from us. Maybe first, I think the rash prophylaxis is pretty logical. Any reason to expect that this could influence the efficacy data at all, I guess, other than maybe improving compliance to therapy? And would such a prophylactic regimen also be needed in the control arm? Just any feedback you've gotten from the FDA on that, and then I've got a follow-up. Yeah. Thanks, Alec. I'll take a first shot, and then, Shannon, feel free to chime in, but I think, as Shannon mentioned in the prepared remarks, there does seem to be sort of a connection between the rash prophylaxis leading to a higher RDI, you know, close to 98%-100%. So they're getting their full dose, and then that does seem to be translating into promising efficacy, both in terms of response rates as well as durability, so small patient numbers, but in the 10 patients, I think we're really pleased to see that, you know, three confirmed and one unconfirmed response is very promising, and then the fact that 70% of the patients were still on treatment as of the data cutoff, so we'll be following that pretty closely. If that leads to a meaningful durability advantage in terms of PFS and OS in the future, well, that'll be fantastic for patients. In terms of the MEK inhibitor alone, the reason why you get rash, such significant rash is from the combination of the two agents that are targeting MAP kinase. And so, when you just have either MEK alone or the pan-RAF agent alone, you don't get the frequency and severity of rash that warrant the primary skin prophylaxis. But I'll see if I misstated anything there, Shannon. No, nothing to add. Just you've stated it correctly. Trametinib's frequency and severity, while certainly, you know, clinically significant, is not high enough to warrant mandatory primary prophylaxis. Okay, that's helpful. Then just quickly, and apologies if you've mentioned this, but just the one unconfirmed PR in the NRAS melanoma cohort. Sounds like this responder could potentially be confirmed on the next scan. Is that sort of the right way to be thinking about it? Yeah. It's a timing situation. So, that patient hadn't had their confirmatory scan as of the time of the data cutoff, but that patient remains on treatment, so it is possible that that patient could convert to a CPR. Okay. Appreciate the color. Thank you so much. Thank you. Yes, thanks for the questions, Alec. Our next question comes from Michael Schmidt at Guggenheim. Please go ahead, Michael. Hey, good morning. It's Yigang for Michael. Thanks for taking our questions. I guess two quick ones from us. The first one, how should we think of the component contribution of the two agents to the safety profile, particularly to the rash, AE, and, you know, how do the adoption of prophylaxis allows you to choose the dose in the S2 study? Are you going to be able to use a higher dose of napo or tramet? And then the second question, how should we think of the performance of maybe chemotherapy in the patient population, or melanoma patient population enrolled in the study, given the patient base characteristics? Thank you. Yeah, thanks for the question. So in terms of the rash, it's as I mentioned in response to Alec's question, which is that either agent alone, whether MEK or pan RAF, you do get some rash, but you don't get the frequency and severity that you get when you combine the two agents. And so, for instance, in the Novartis-run, Novartis-sponsored phase I and phase II, the frequency of grade three or higher TRAEs that were derm or skin-related were in sort of the 36% range. Whereas with the mandatory skin prophylaxis, that came down substantially to about 10 or 11%. So there was a meaningful reduction from that. And mechanistically, if you are blocking MAP kinase with at two nodes, then you're exacerbating an on-target, what is known to be an on-target AE. So hopefully that answers your question there. In terms of the performance of chemotherapy, right now, that is the standard of care, is chemotherapy. Single-agent MEK actually is not approved, but it is on the NCCN guidelines. But with single-agent chemotherapy, the response or the PFS is only about 1.5 months. With single-agent MEK, it's about 2.8 months, and in the phase I, phase II setting with naporafenib and trametinib, we saw 5.5 months. Now, with the mandatory rash prophylaxis and the enhanced RDI, if that can be pushed beyond 5.5 months, there's a potential upside there, which would be really great for patients. So we do think these data are promising from SEACRAFT-1 that show that with the 200+1 dose and the mandatory rash prophylaxis, that there could be some potential upside. But we'll have to track that, and it'll be data-driven. Did that address your questions? Yep, that's super helpful. Thank you. Thank you. Great, thanks for the questions, Michael. Our next question comes from Kevin Strang at Goldman Sachs. Please go ahead, Kevin. Hi, this is Kevin on for Chris. Thanks for taking our questions. I wanted to switch gears and talk about the RAS molecules in development, so for ERAS-0015, you talked about the preclinical efficacy comparisons. I wanted to ask about the potential safety profile, given how far you are along here, you know, getting to the clinic. Based on what you've seen so far, what you know about the molecule, what are your expectations as you enter the clinic next year? Yeah, thanks, Kevin, for the question. I'd say with ERAS-0015, you know, there hasn't been any surprises in the GLP talks, and so no surprise is good in general for talks and similarly for ERAS-4001. I'd say the predicted clinical safety and tolerability issues, or TRAEs, will likely be skin-related just based on the comparator compound, where rash by far seems to be the predominant TRAE. And so that is likely an on-mechanism type effect. There's also GI components to the tolerability issue, and in that case, you know, if we have, let's say, one tenth or one eighth of the pill burden, there's a possibility that there's potential upside there in terms of GI tolerability. But I think the predicted toxicity profile is gonna be in that sort of, you know, skin and GI category. Great. Thank you. And then just a quick follow-up in terms of, you know, competition here. We saw some clinical data this week, and then, you know, I wanted to ask more about the potential preclinical competition as well. You've mentioned in the past sort of the difficulty in designing these molecules and the IP involved. How are you thinking about potential competitors in development here? Yeah, I'd say in the pan RAS molecular glue, you know, clearly RevMed is plowing ahead with really, you know, very promising data for patients, especially in PDAC. So we're really excited about that molecule for patients. And then I would say that in that category, we're in second, 'cause, you know, we're on track for an IND in the first half of next year. And then I think there's some Chinese companies that are in the mix, but further behind. But it's really a short list in that category. I'd say in the pan KRAS category, there's a number of other players, both big pharma and small biotech, both domestically as well as international. So I think that's more of a crowded space. We are in the vanguard, so we'll be in that first wave in terms of KRAS selective, but H and N sparing. In that case, you know, hopefully there is a therapeutic window, especially when you wanna combine it with other agents that can be rash-inducing. We think that four thousand and one could be very interesting for that. But we like the fact that we have two agents with orthogonal mechanisms of action that could be combined with standard of care as well as with each other. Great, thanks for taking our questions. Sure. Thanks for the questions, Kevin. Our next question comes from Graig Suvannavejh at Mizuho. Please go ahead, Greg. Okay, good morning. Thanks for taking my questions, and thank you for the updates as well. I was just curious with respect to SEACRAFT-1. I believe the trial design overall was to enroll a total of 100 patients. I might have missed this if you commented before, but where are you in that? And is the plan to, if you are further enrolling patients, just to focus on the melanoma subpopulation? Yeah, Graig, thanks for the question. So, yeah, the original plan was to enroll 100 patients, and, and the goal of, the Q4 update was actually to have an interim read of, less than 100 patients. We actually blew away, from an enrollment perspective, our original goal, and so we actually have enrolled 82 patients. We have stopped enrollment because the 82 patients that we've seen in terms of the data don't justify moving forward with a tissue-agnostic label, as we mentioned in our, prepared remarks. What, what was presented at the ENA triple meeting was the 52 patients, excluding the 30 patients with CRC and PDAC, that are, basically, none of them had, actual responses. The best response was SD. And so the totality of data from all the other tumor types, as well as melanoma, was reported at the ENA triple meeting and also in this investor call. That's really the sum total of all the patients, is the 82 patients. And from an efficacy standpoint, the 30 patients with CRC and PDAC did not have any responses, as would be expected with those tumor types. Okay. Thank you for that. Sure. Great, thanks for the questions, Greg. I'll now turn it back over to Jonathan for closing remarks. Okay. Well, really appreciate everyone joining this call. We are very excited about the progress that we've made on both the RAS targeting franchise as well as naporafenib. I think the development path forward has really crystallized for naporafenib and trametinib to be focused on the NRAS-mutant melanoma opportunity, which the probability of success for that indication has gone up pretty significantly based on the data that we've reported today. And so very excited to share that with all of you, and we look forward to keeping you posted as we keep pushing forward on our pipeline for the benefit of patients everywhere. Thank you, everyone. Take care.