Welcome to the Erasca R&D update conference call. At this time, all participants are in a listen-only mode. Following management's prepared remarks, we will hold a brief question-and-answer session. As a reminder, this webcast is being recorded today, March 28th, 2024. I will now turn the call over to Jonathan Lim, Chairman and CEO. Please go ahead. Thank you. Thank you all for joining us today, and welcome to our Erasca R&D update conference call. Here with me are David Chacko, our CFO and Chief Business Officer, and Shannon Morris, our Chief Medical Officer. We will be making forward-looking statements. Please visit our website at erasca.com to review our latest SEC filings and associated risk factors. As a reminder, our name is our mission to erase cancer. This audience is well familiar with our team and industry-leading portfolio focused on shutting down the RAS MAPK pathway. So what I'd like to highlight is that as we announced yesterday in our 10-K filing, we ended the fourth quarter with $322 million of cash, which does not include the $45 million oversubscribed equity financing with top-tier investors that we also announced yesterday. With this financing, we're pleased to be able to revise our cash runway guidance from the first half of 2026 to the second half of 2026, to be able to continue to execute on our pipeline. Erasca is a precision oncology company focused entirely on shutting down the RAS MAP kinase pathway with single-agent and combination approaches. We've assembled a deep modality-agnostic pipeline of promising assets in both early and late stages of development. This includes our lead clinical program, naporafenib, for which we plan to initiate a global phase 3 trial and our preclinical ERAS-4 pan-KRAS program, focused on developing compounds capable of targeting KRAS mutant solid tumors. In fact, these two programs will be the focus of today's R&D update. We'll provide a brief refresher on the naporafenib program, and then we'll share with you an exciting update on the overall survival data from the phase I and II trials previously conducted by Novartis of naporafenib plus trametinib that have recently matured, including how these data compare to various benchmarks. We will then provide an update on the recent progress we've made with our pan-KRAS inhibitor program and end with Q&A. Naporafenib is a potent and selective inhibitor with sub-nanomolar potency against both CRAF and BRAF, which we believe drives its efficacy, with relative ARAF sparing, which we believe helps with tolerability. On the right, you can see a clean kinome scan highlighting naporafenib's high selectivity for BRAF and CRAF. The unmet medical need is high in NRAS mutant melanoma, particularly in the second-line plus setting, where there are no approved targeted therapies. About a quarter of patients with melanoma have an NRAS mutation, which unfortunately is associated with a worse prognosis relative to wild-type melanomas. While physicians are largely satisfied with their treatment options for melanoma patients overall, and even more satisfied for BRAF mutant patients specifically, they're clearly not satisfied with their options for patients with NRAS mutations, as these options are limited after IO. Naporafenib plus trametinib showed compelling efficacy versus other comparators for the treatment of this aggressive disease. These data have resulted in fast-track designation and are the basis of our phase III trial design. Of note, meaningful benefit was observed across each of the doses tested to date, as shown in this slide. The first two columns of this table show two single-agent MEK inhibitors, binimetinib and trametinib. The middle column shows chemotherapy, which is the approved standard of care. The two columns in teal show the pooled data across the phase I and II studies for naporafenib plus trametinib at two different doses, 200 + 1 and 400 + 0.5. The takeaway from this table is that if you look across different metrics of ORR, DCR, median DOR, and median PFS, you see that the combination of napo plus trami outperformed single-agent MEK inhibitor and chemotherapy. Importantly, as per our alignment with U.S. and European health authorities, PFS can be used for the potential initial approval, and you can see here that naporafenib plus trametinib, regardless of the dose, was able to achieve approximately five months of median PFS, relative to one and a half months for chemo and about 2.8 months for single-agent MEK inhibitor. For median PFS, we're already seeing more than tripling of the approved standard of care and roughly a doubling of the single-agent MEK inhibitor, which gives us confidence that we have the potential to show both statistical and clinical benefit on this endpoint in our phase III trial. Naporafenib plus trametinib demonstrated a favorable and manageable AE profile, consistent with on-target toxicities, especially of MEK inhibition, which is known to cause rash. It's also worth noting that the severity of the dermatitis acneiform rash, which can be a more challenging form of skin tox for patients due to its appearance and distribution on visible parts of the body, such as the face, was limited to grade one and two events. The 400.5 dose was well tolerated. The 201 dose was less tolerable, especially in the absence of mandatory primary rash prophylaxis, which includes treating patients for rash even before it appears, in order to decrease the severity and/or frequency of the rash, a practice which Novartis did not uniformly institute in their trials. However, we are instituting mandatory primary rash prophylaxis in both SEACRAFT-1 and SEACRAFT-2, which we believe will improve the safety and tolerability even further, which could lead to patients staying on drug longer and thereby could possibly increase efficacy, such as extending the PFS benefit. In addition to requiring mandatory primary prophylaxis for rash, we are also planning to conduct a dose optimization step for the napo plus trametinib combination that is expected to further enhance the benefit risk profile of the combo. This approach addresses the regulatory focus, like FDA's Project Optimist, on choosing the best dose while maximizing the probability of success for both SEACRAFT-1 and SEACRAFT-2. Based on preclinical and clinical data, the range of efficacious doses for napo in the combo with trametinib lies between 100-400 milligrams BID. For trametinib, the range of efficacious doses in the combo lies between 0.5 mg-1 mg QD. In SEACRAFT-1, we are advancing the 200 + 1 dose, and in SEACRAFT-2, we're advancing with two doses of 400 + 0.5 and 100 + 1. This is designed to allow us to efficiently test the full range of efficacious doses for the combination of napo plus trami within these two trials to optimize the benefit risk profile. The clinical development plan for both SEACRAFT-1 and SEACRAFT-2 is shown here. For the purpose of today's call, we're focusing on SEACRAFT-2 in NRAS mutant melanoma, where there is a high unmet need for patients. SEACRAFT-2 has a two-stage phase III design. Both stages have been discussed and aligned with U.S. and European health authorities. Stage one is the dose optimization portion, and stage two is for regulatory approval. In the randomized stage one portion, we'll look at two different doses of naporafenib plus trametinib, as described previously, the 400 + 0.5 and 100 + 1. We'll compare this against trametinib mono at 2 mg, which is the monotherapy dose approved for patients with BRAF mutant melanoma. The number of patients for stage one is flexible and will range between 60- 120 patients. Because this is an open label trial, we'll evaluate the data as they come in, and with as few as 20 patients per cohort, we may be able to identify a dose with an optimal benefit risk profile to move into stage two. If so, we'll stop stage one, meet with the FDA to gain their alignment around that selected dosing regimen and be able to publicly disclose the stage one data set. We also have the flexibility to enroll up to 40 patients per cohort. This stage one design has multiple advantages. First, we'll have a meaningful readout of naporafenib plus trametinib versus single agent trametinib randomized data in calendar year 2025. Second, we're comparing the napo plus trami combo against a higher bar in stage one compared to physician's choice in stage two, given that historical data show that chemotherapy is less efficacious than single agent MEK inhibitor. And finally, we'll get contribution of component information on single agent trametinib. Once we identify a dose in stage one, we plan to move forward with stage two, comparing napo plus trami versus physician's choice of single agent MEK inhibitor or chemotherapy. The trial design randomizes patients with NRAS mutant melanoma being treated in the post IO setting, the napo plus trametinib versus physician's choice, and includes dual primary endpoints of PFS and OS, where we only have to win on one endpoint and not both. In addition, a positive PFS endpoint is acceptable for potential initial approval, and in order to protect the final OS analyses, crossover is not allowed unless a statistically significant OS result is observed. If we can demonstrate a PFS benefit similar to what has already been seen across the phase I and II trials, we believe that we have a realistic opportunity to show statistical and clinical benefit, as previously mentioned. Beyond that, if we can show a benefit on OS as well, we believe that would be a significant driver of value for patients and shareholders. In that regard, the OS data from the phase I and II trials have now matured to the point where we have been able to analyze the data to see if there's a potential OS benefit as well. Before we dive into the OS data, it's helpful to understand why this is an important metric. While PFS is important, too, OS is widely accepted as the objective gold standard to measure the efficacy of a cancer therapy. Extending overall survival is an important goal in oncology, with OS being widely considered as the endpoint that is most valued for patients, physicians, regulators, and payers, and therefore, this is an endpoint that these stakeholders will ultimately be looking for. With that, I'll hand the call over to Shannon to walk us through the NAPO OS data analysis. Thank you, Jonathan. Now, to properly understand the naporafenib and trametinib overall survival data, we need to understand the benchmarks to which it should be compared. As shown in this figure, the combination of NAPO plus trametinib can be compared to multiple benchmarks. Although there is no randomized trial data for patients with NRAS mutant melanoma being treated in the post-IO setting, we believe that the benchmarks listed here allow us to triangulate how the comparator arm in SEACRAFT-2 may perform, while acknowledging the caveats associated with cross-trial comparisons. We're really excited about this analysis because we now have a mature data set for the naporafenib plus trametinib combination, and it suggests that we have the potential to demonstrate benefit for both overall survival and progression-free survival. The three benchmarks are listed on the right side of the page. Benchmark one is the randomized phase III NEMO trial, evaluating binimetinib versus dacarbazine in patients with NRAS mutant melanoma. Although this study enrolled patients with NRAS mutant melanoma, recall that our phase III SEACRAFT-2 trial targets patients who are no longer candidates for IO treatment, while NEMO enrolled the majority of patients in the treatment-naive or first-line setting. Given that almost half of the patients in NEMO received survival prolonging immune checkpoint inhibitors after discontinuation of the study treatments, we believe the NEMO data overestimates the overall survival benefit of both binimetinib and dacarbazine. For the SEACRAFT-2 target population, where the IO therapy will be received prior to enrollment on this trial. What's particularly encouraging is that even with this higher bar in NEMO, the data from naporafenib plus trametinib trials suggests that the combination may exceed this benchmark. Now, benchmarks two and three are those that we believe are most similar to the SEACRAFT-2 patient population, because they measure survival for patients with melanoma being treated in the post-IO setting. Benchmark two is comprised of multiple retrospective, multicenter evaluations of patients with melanoma receiving either cytotoxic chemotherapy or MEK inhibitor monotherapy in the post-IO setting. Benchmark three is the BRAF mutant melanoma patients from the Novartis phase II trial, who progressed on the combination of BRAF plus MEK prior to enrollment and treatment with naporafenib plus trametinib. Not only were these patients being treated in a post-IO setting, they were also contemporaneously enrolled to the same trial in which the NRAS mutant melanoma data were generated. While their tumors have a different driver mutation, as you will see, the consistency of the data between benchmarks II and III suggests that the BRAF mutant and NRAS mutant patients are behaving similarly when treated with therapies that don't offer survival benefit. Now, let's walk through each of these in order. First, we have the NEMO benchmark, which showed a median overall survival of about 10-11 months, which was similar between the two arms. To understand the relevance of this benchmark, there are some important points to consider. First, it's a randomized phase III trial with a large sample size, and this is the most rigorous trial design. However, as noted, although the PFS results are relevant, since PFS directly measures the effect of study treatment in isolation, the patient population enrolled in NEMO is not directly generalizable to the SEACRAFT-2 population for overall survival, and that's due to the availability of immune checkpoint inhibitor therapy following progression. Now, approximately 80% of the patients in NEMO were being treated in the first line setting and had not received prior IO therapy. That's in direct contrast to the target patient population of SEACRAFT-2, who will be second-line plus and will have received prior IO therapy. In addition, approximately 45% of patients who progressed in NEMO were reported to have received IO post-trial. We believe that both factors likely contribute to an overestimation of the overall survival for what either monotherapy MEK inhibitor or cytotoxic chemotherapy can achieve in SEACRAFT-2. Nonetheless, as I mentioned before, if we're able to demonstrate a benefit, even against this higher bar, we believe that it really bodes well for our phase III SEACRAFT-2 trial. Now, the Kaplan-Meier curves in this study illustrate that in a cross-study comparison, the combination of NAPO plus trametinib showed improved overall survival compared to NEMO, despite the potential overestimation of this endpoint. As shown in the top figure in the NEMO trial, patients treated with vemurafenib and dacarbazine experienced a median overall survival of approximately 10-11 months. Now, in contrast, looking at the bottom of the slide, a pooled analysis of data from the phase I and II trials evaluating naporafenib plus trametinib showed about 13-14 months of median overall survival, despite the fact that the patients enrolled in the phase I, II trials were being treated in the post-IO second-line plus setting. For us, this data is really encouraging in that even with this higher benchmark from the NEMO trial, naporafenib plus trametinib has the potential to offer OS benefit. Now let's move to benchmark two, which is comprised of multiple retrospective, multicenter evaluations of patients with melanoma receiving cytotoxic chemotherapy or monotherapy MEK inhibitor in the post-IO setting. In this set of studies, the median OS was about six to seven months. Now, as mentioned previously, we believe that this patient population is likely to be similar to the SEACRAFT-2 comparator arm population, both in terms of having received IO in the front line and receiving either cytotoxic chemo or MEK inhibitor monotherapy in the second-line plus setting. Since neither cytotoxic chemotherapy nor MEK inhibitor monotherapy have been shown to have an OS benefit in this clinical situation, the OS for these patients likely represents the natural history of their underlying melanoma. The one important caveat to these data is that these are retrospective analyses, which are less rigorous than a prospective randomized trial. That said, in the absence of any prospective analyses that we could identify, and given the remarkable consistency of these data and the observations for benchmark three, we feel that it's a reasonable benchmark. The four studies contributing to this benchmark are shown here. You can see that the progression-free survival is in the two to three-month range, consistent with other literature. For overall survival, if you throw out the 4.4 months value, which could be an outlier, you're seeing about six to seven months of median overall survival consistently. Even though these data are from retrospective analyses, the consistency of the data for both chemo and single-agent MEK gives us reasonable confidence in how SEACRAFT-2 comparator arm might perform. Now, let's finally look at the data for benchmark three which is focused on BRAF mutant melanoma patients enrolled within Novartis' naporafenib plus trametinib phase II trial. Here, the median OS was about six to seven months, consistent with benchmark two. To interpret these data, it's important to note that this patient population had prior IO, as well as progression on a BRAF/MEK combination prior to enrollment, followed by treatment with napo plus trametinib. We believe the fact that no responses were observed and that the median progression-free survival was short, at only 1.8 months, suggests that naporafenib and trametinib did not offer clinical benefit in this situation, and that the median overall survival, about six to seven months, is likely representative of the natural history of the underlying disease. Again, very similar to benchmark two. The one caveat to this benchmark is that these patients had disease with a different driver mutation. However, the prognostic impact of that mutation compared to NRAS in this very specific clinical setting is unclear. Therefore, because of the consistency of these data with benchmark two, paired with the fact that these data were generated in the same trial as the NRAS data, we believe this benchmark could be representative of what could be observed in the SEACRAFT-2 control arm in the future. In looking at the Kaplan-Meier curves, you see that there's a steep drop-off in survival for the BRAF mutant patients, with a median OS of roughly six to seven months, while the median overall survival for the napo plus trametinib combination was about 13-14 months. Now, as I mentioned earlier, the data you are seeing is a pooled analysis across the phase I and II studies, and you may wonder if the pooling approach is clinically appropriate. In terms of prior therapy exposure, the patients enrolled in both studies received a median of two prior lines of therapy. As you can see from the Kaplan-Meier curves in this figure, where we are showing the curves for each dose in each study, there's remarkable consistency across the studies and across doses, with a median overall survival of about 13-15 months. It's the reproducibility of these results across studies and doses, as compared to the three benchmarks, that increases our confidence in the median overall survival observations. Now, I'd like to return to that table that we previously looked at, where we quantified the potential PFS benefit for the napo plus trametinib combination, which was about five months across doses, relative to 1.5 months for chemo and 2.8 months for single-agent MEK inhibitors. Now, when we overlay the overall survival data on this table, you can see that the median overall survival of 13-14 months for napo plus trametinib beats the NEMO benchmark by three to four months, even with the limitations of the NEMO trial that likely overestimate the overall survival. And that value definitely beats benchmarks two and three, which we believe are most similar to the SEACRAFT-2 comparator arm. In conclusion, while comparison of clinical trial data across separate trials may be confounded due to differences in trial protocols, conditions, and patient populations. The combo of napo plus trametinib has shown the potential for a benefit in both PFS and OS, which are the two primary endpoints for the SEACRAFT-2 pivotal trial. Given these recent updated data, we're excited to initiate the phase three trial in the first half of this year, with the goal of bringing a meaningful new treatment option to patients in this area of high unmet need. With that, I'll turn the call back to Jonathan. Thank you, Shannon. Next, we would like to discuss our pan-KRAS inhibitor program, where we are exploring both internal and external opportunities to develop a potent and orally bioavailable inhibitor. We are targeting the switch II pocket, which is a promising approach to targeting KRAS, including the most frequent mutations, G12X and G13X. Pan-KRAS inhibitors can provide deep and durable inhibition, while also minimizing the risk associated with targeting HRAS and NRAS, thereby potentially leading to improved tolerability and/or combinability relative to a pan-RAS approach. In addition, pan-KRAS inhibitor drugs have the potential to address a broad patient population, where mutant selective KRAS drugs are unavailable, and patient populations where both mutant and wild type forms of KRAS can contribute to oncogenic signaling and resistance to other RAS MAPK inhibitors. The epidemiology of KRAS tumors is shown here. Approximately 230,000 patients are diagnosed annually in the United States with solid tumors harboring KRAS mutations. As expected, most of the patients are found in colorectal, non-small cell lung cancer, and pancreatic cancer. There's a long but sizable tail of other tumor types as well, as shown on this graphic, where you can see tens of thousands of patients. This landscape analysis highlights some of the key players in the pan-RAS, pan-KRAS, and mutant selective spaces, and is not intended to be exhaustive. In terms of pan-RAS, encouraging preliminary clinical data have emerged, but these are still early. In addition, tolerability and combinability may be challenging. Moving to the pan-KRAS space, we believe there's an opportunity for a greater therapeutic window by specifically targeting KRAS as compared to the pan-RAS inhibitors, with a more straightforward mechanism of action. However, because these approaches are still early, the translation to clinical efficacy is still unknown, because there are no clinical data available as of today. In terms of mutant selective options, there is the potential for greater potency of these molecules against a specific mutation of interest, especially as some of these molecules potentially spare KRAS wild type. However, oral bioavailability and stability have proven challenging for G12D inhibitors. Mutant selective inhibitors, such as G12D inhibitors, may also be susceptible to resistance mediated by KRAS wild type activation, and this could be addressed by a pan-KRAS inhibitor that hits both KRAS wild type as well as mutations. Here, we highlight a few of our internal compounds that are showing promising in vitro potency and in vivo PK. Shown in teal are four Erasca internal pan-KRAS inhibitor compounds, and shown in blue are three external compounds from Mirati, Revolution Medicines, and Loxo@Lilly. Our compounds are targeting the switch II pocket, as are certain of the external compounds, although co-op competitors also use a molecular glue approach to target this protein. The key metric to look at for oral bioavailability is the%F, shown in the second to bottom row. Our target of%F is for our molecules to be at 10% or higher, which you can see that we've achieved with all of our molecules. MRTX1133 is the flagship bearer for highly potent molecules against KRAS G12D, but its oral bioavailability is only at 0.2% F. Our molecules have shown cell-based nanomolar IC50 potencies against G12D and G12V, as well as good%F, which benchmarks us well against these other compounds. Here we look at comparative mouse studies of our ERAS-11930 compound versus MRTX1133. As you can see, our compound is dosed orally, whereas the Mirati compound needed to be given intraperitoneally. You can see that 1133, which is shown with the red curve, shows a good tumor response. With an oral dose of our molecule, 930, we're getting a similarly good tumor response. Looking at the body weight change on the right, our molecule is also better tolerated, which we think has to do with the scaffold that we are using. In fact, mouse mortality was observed when MRTX1133 was administered at higher doses of 30 mg/kg. Hence, there seems to be a tolerability cliff for this compound. We're encouraged by the progress that we are making with our internal compounds, and we like this program, but we also recognize that the space is rapidly evolving and could close quickly... hence, we are looking at both internal as well as external opportunities to accelerate our advancement into the clinic. I'll conclude with a reminder of our upcoming milestones. Naporafenib is being tested in both SEACRAFT-1 and SEACRAFT-2 in RAS Q61X solid tumors and NRAS mutant melanoma, respectively. SEACRAFT-1, which achieved first patient dosing in Q3 of last year, is on track for a data readout between Q2 and Q4 of this year. SEACRAFT-2 is on track to initiate the pivotal study in the first half, with a randomized readout from stage one of the pivotal study in 2025. ERAS-007, our ERK inhibitor, is on track for a data readout in the first half of this year in BRAF mutant CRC, and ERAS-801 is on track for a data readout in 2024 in GBM. In summary, we continue to make strong progress across our pipeline, including our range of early and late-stage programs. Given the phase III start planned for H1 of this year, we're particularly excited about the NAPO OS data that we shared with you today, as it shows the potential for us to win on both primary endpoints of PFS and OS. In the context of the importance of the target, we're also encouraged by the progress we're making on pan KRAS inhibitors and our potential to move into that exciting space. With that, we'll conclude our formal remarks, and I'll turn the call back to the operator for Q&A. Operator? Thank you. We will now be conducting a question-and-answer session. If you would like to ask a question, please press star one on your telephone keypad. The confirmation tone will indicate your line is in the question queue. You may press star two if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment, please, while we poll for your questions. Our first questions come from the line of Malcolm Kuno with JP Morgan. Please proceed with your questions. Hi, in SEACRAFT-2, on the dual primary endpoint of PFS and OS, is there a hierarchy here or, and do you have regulatory sign-off on this? Yeah, thanks for the question. In terms of dual primary, there's not really a hierarchy, but, in terms of, winning on, on either or both, from a, a statistical and clinical benefit, it, it gives you the flexibility to win on either PFS or, or OS. And, we do have regulatory alignment from, the global health authorities, both in the U.S. and, Europe. Great. Thank you. Thanks for the question. Thank you. Our next questions come from the line of Jeffrey Hung with Morgan Stanley. Please proceed with your questions. Hi, this is Michael Riad on for Jeff Hung. Thank you for taking our questions. First one, how should we be thinking about the ORR rate between the 201 versus the 400.5 regimen? Is there any evidence to suggest potentially broader responses at the higher tremelimumab dose? Thanks, and we have a follow-up. Yeah, good question. Maybe I'll take a first cut, and then Shannon, feel free to chime in. In terms of the ORR, first of all, it's small patient numbers, and it's important to note that this is a very aggressive disease in the second line plus setting post-IO. And so there is some variability there, but really the most important metric is progression-free survival. And so if you look at actually the DCR, which includes both ORR as well as stable disease, both of which get captured in PFS, you can see that they're relatively similar DCR rates. And so we do think that with PFS, that's going to be the main driver. But Shannon, do you want to comment further on that? I think you captured it well, Jonathan. I think the take-home message is that while, you know, objective response rate can be a quick and dirty screen to look for activity, I think what's most important to patients and to the regulators is progression-free survival and overall survival. And I think in those settings, we definitely have a lot of consistency of data to suggest that, we are definitely in the clinically relevant dose range here. Thank you. That's really helpful. And if I could, just a quick follow-up. In the post-IO setting, can you provide any added color on what's driving the decision to go for chemo in this setting versus a single agent MEK inhibitor? And I'm just trying to gauge, like, is there a general preference towards avoiding chemo in this population? Yeah, that's a good question. We think that there will be regional preferences in terms of practice patterns. So this is SEACRAFT-2, a global phase III trial, so we anticipate that there will be regional preferences in terms of practice patterns. So for instance, in the United States, the preference will more likely be a single-agent MEK inhibitor for both physicians and patients. And then in certain European countries where the standard of care is firmly ensconced in chemo, that chemo would be provided. But our hunch is that more patients and physicians will choose the single-agent MEK, but it will be a physician's choice. Thank you very much. I appreciate the call. Sure. Thank you. Our next question has come from the line of Alec Stranahan with Bank of America. Please proceed with your questions. Hey, guys. Thanks, thanks for taking our questions. Just two from me. Sure. Any additional updates you can share from your recent FDA or Novartis interactions around the NAPO pivotal program? Sounds like feedback has been fairly positive on both fronts. And then as a follow-up, any thoughts around powering needed in the randomized phase III, given the roughly doubling in OS and significant, but perhaps maybe smaller separation on PFS? Is it right to assume you'll likely power on PFS, since this should hopefully take care of OS as well? Thanks. Yeah, great question. So first of all, everything, in terms of the clinical trial design for SEACRAFT 2, that all represented, full regulatory alignment from last year. So the second half of last year was a key area of focus for us to gain regulatory alignment on, SEACRAFT 2 in terms of the clinical design, and that two-stage design, and comparator, et cetera, with both FDA as well as European regulators. And so, both they as well as Novartis, have been very supportive of our efforts. And then in terms of power, high level, and Shannon can chime in as well, we've really powered the second stage of SEACRAFT 2 to largely around to achieve 80% power for OS benefit. As a result of that, we are really well powered with 99% power to show a PFS benefit. And so it, it's really, I think with the 350 patients, 175 in each arm on a one-to-one randomization basis, the study is well powered. But, Shannon, did I miss anything there? The only thing I'd add is, you know, we're obviously poising this for a global approach to regulatory approval, and while we certainly have the ability to have conversations based on progression-free survival, we know there are certainly gonna be some areas where additional overall survival data will be incredibly impactful, not only for regulatory, but for reimbursement points of view. So that's one of the reasons we've really focused on making sure we have the ability to detect a difference in overall survival. The only second point I would make is the beauty of having the stage one is that not only will that help us understand the dose and pick the most optimal dose, but it also will give us an evaluation of the potential effect size versus trametinib, which is expected to be the most efficacious comparator. We always have the ability to revisit sample size if the effect sizes in stage one are different than what we have projected. Great, that makes sense. Thanks, and congrats on the progress. Thanks, Alex. Thanks. Thank you. Our next questions come from the line of Jonathan Miller with Evercore ISI. Please proceed with your questions. Hi, guys. Thanks for taking the question, and congrats on the progress. I'd like to start on discontinuations from rash specifically, and I ask this in the context of this rash prophy that you're introducing for SE2 especially. You know, how effective do you expect rash prophy to be in reducing actual discontinuation numbers? And so how much more drug exposure do you think prophy will get you? Yeah, good question. I'll take a first cut and then Shannon will chime in here. I think it's really also not just about discontinuation, but also sort of the maintaining relative dose intensity. And so, the 400 dose seemed to allow us to maintain that better than the 200 dose. But primary rash prophylaxis has been shown to be quite impactful in development of other targeted agents, and so we're cautiously optimistic here. But, Shannon, why don't you chime in here? I think you've summed it up really well, Jonathan. It's pretty hard to predict, I think a priority, you know, from a quantitative approach, how effective the rash prophylaxis will be in this setting. Certainly, we know from the EGFR rash that it can have a major impact, and that's the whole reason, right, why we're doing SEACRAFT-1 and stage one of SEACRAFT-2, is to hopefully be able to evaluate that and make that dose as that as has the most optimal risk-benefit profile as possible. Yeah, it makes sense. Then I guess as a follow-up, looking at the different dosing schema and the efficacy data that you've shown, where you've broken those out, it. And you mentioned this yourself a couple of times, it doesn't look like there's really obvious efficacy differences in those curves across the different dosing regimens. So I'd love to get a sense for your expectations in SEACRAFT part one. Are you expecting to see efficacy differences between those doses, or are you really focused on safety? And insofar as safety is a major driver for dose intensity here, what are you willing to accept in SEACRAFT part one in terms of additional toxicity over MEK mono when you're going forward in dose selection? Yeah, John, I think that's a really astute observation because that's where I personally, that's what I personally believe as well, is that ultimately. Well, first of all, to answer your question on the decision-making criteria, it's really gonna be the totality for stage one of SEACRAFT-2, it's in the dose optimization. It's gonna be taking the totality of safety, tolerability, and efficacy data from both the 400 and 100 dose. And by the way, we're also able to take the totality of information generated from the melanoma cohort within SEACRAFT-1, given that there's a 90% overlap between NRAS and Q61X. We can actually take the totality of information in terms of safety and efficacy to then choose the RP2D or recommended phase II dose, which we'll talk to FDA about before proceeding with, and then that's the data that we'll disclose in 2025. But to answer the first part of your question, it is gonna be— there seems to be synergy between the napo and trami combo, and there's not a lot of discrimination when you look at the PFS and OS between the two doses that have been tested to date. So it, you know, it really is gonna be a judgment call that's gonna be largely based on what available safety and efficacy data that we have next year in terms of moving forward. And ultimately, my belief is that it may not matter, that the synergy seems to be happening irrespective of dose, especially when you look at the unpooled curves for OS that Shannon mentioned. You could pick one of those and do pretty well. So then I think safety becomes, safety and tolerability becomes a little more important in that choice. Makes sense. I guess, very quickly then, you mentioned, obviously there's two dose regimens in SEACRAFT-2 part one, but you also mentioned bringing in melanoma cohort from SEACRAFT-1, which is a different dose regimen entirely, right? So now there's three different dose regimens, which seem like they're gonna be relatively similar from an efficacy perspective. You know, what's the likelihood that you end up with the SEACRAFT-1 regimen versus one of the two SEACRAFT-2 regimens? How is that coming in to influence decision making? Yeah, it's really gonna be data driven. And so, you know, the 200 + 1 dose from SEACRAFT-1 and the 400 + 0.5 dose from SEACRAFT-2, those are the two doses that, historically, if you look at all the data tables that we've shown for OR, DOR, PFS, DCR, and even OS, it's all been generated with those two doses. So the only new dose is the 100 + 1. And rather than just reproducing the 200 + 1 dose in the SEACRAFT-2 design, we were able to then explore a second dose because we're already exploring 200 + 1 in SEACRAFT-1. We'll just take the totality of data from those three different doses, and then, next year, we'll be looking at the safety, tolerability, and efficacy data to make the choice to go forward. Great. Thanks so much. Thank you. Thank you. Our next question has come from the line of Michael Schmidt with Guggenheim. Please proceed with your questions. Hi, good morning. It's Yigang for Michael. Thanks for taking our questions. First question, how does the OS data compare to your internal expectations when you design SEACRAFT-2? And And a second question, you've compared the Kaplan-Meier curve of napo with some of the control regimens. Understood they're all cross-trial comparisons, but it looks like napo's Kaplan-Meier curve has a longer tail. I was just wondering, technically, is it possible to sort of, like, derive a hazard ratio out of these cross-trial comparisons, at least directionally? Thank you. Yeah, thanks. So we don't comment specifically on hazard ratios, but what I will say is that the biometrics and clin dev and broader naporafenib team at Erasca basically assumed worst case. We really all of our power assumptions and calculations were predicated on the control arm performing on par with what was historically seen with NEMO. And you can see, you know, for various reasons that Shannon mentioned during our formal remarks, that could be an overestimate of what the quote-unquote natural history of disease could be. So, you know, if, if the control arm performs more in line with benchmarks two and two, which is probably a more relevant benchmark, given that those are post-IO settings versus the NEMO trial, which was pre-IO, or 80% of the patients received either chemo or MEK inhibition before receiving IO. But that said, all of our power calculations were predicated on the control arm performing in line with NEMO. So that's why we're even more excited about the possibility to show both statistical and clinical benefit if the control arm performs more in line with benchmarks two and three, which is that roughly seven-month OS range versus the 10-11. Does that answer your question? Yep, that's very helpful. Thank you. Thank you. Thank you. Our next question has come from the line of Chris Shibutani with Goldman Sachs. Please proceed with your questions. Great. Thank you. Several of the questions relating to the study designs have been described, but just remind us, for SEACRAFT-1, amongst the potential for tissue agnostic, we have 1B data coming for the combination at any time from Q2 to Q4. What are the gating factors for that time span? What kind of denominator, what kind of tumor types distribution might you be able to help us with in terms of expecting? And then, so obviously that overnight you did the financing. David, if you could just give some clarity in terms of where you feel that gives you confidence of the runway in terms of supporting your programs. Thank you. Yeah, thanks, Chris. I'll answer your first question, and then David will answer your second one. So, there are no real gating factors other than really just enrolling the patients. Well, operationally, since FPD in Q3 of last year, we've really been ramping up the number of sites that have been activated and enrolling. So we're almost running at full tilt at this point. And so enrollment has been brisk. You would imagine that there's going to be a range of different solid tumor types that sort of reflect the epidemiology. So there's sort of the most common tumor types where RAS Q61X shows up is the GI cancers, like colorectal cancer. There's some pancreatic. You also want to look for non-small cell lung cancer, thyroid, and you know, potentially head and neck and other solid tumor types. And so it's really all comers. There's no constraints. It's really whichever patients show up with a RAS Q61X mutation, irrespective of the solid tumor type, we're enrolling them. And then it's really a matter of following them up so that there's a meaningful length of follow-up of those patients, so that when we present the data, you know, there's something meaningful to say. And so that's really going to dictate the timing within the Q2 to Q4. I would say in terms of the scope, it's going to be dozens of patients, so it'll be a meaningful update. And Chris, on your second question with regard to the private placement that we announced as well. Yes, we did do a $45 million oversubscribed private placement with high quality investors, and with that, we were able to push our runway out from H1 of 2026, which was our previous guidance, to H2 of 2026. Great. Thank you for that. Thank you. Thank you. Our next question has come from the line of Graig Suvannavejh with Mizuho. Please proceed with your questions. Yeah, good morning. Thank you for taking my questions, and thanks for the presentation today. I had two. I'll ask my first, and then I'll follow up with the second. So, with your Napo OS data, in the context of small patient numbers, were there any patient characteristics across those cohorts that may have driven, you know, the OS results, or could you potentially see different OS results? I'll ask that first. Thanks. Sure. Shannon, you want to take that one? Sure. So we did look for, w e did an evaluation of baseline characteristics, you know, things that are prognostic for melanoma, like LDH, stage, prior lines, ECOG, those sorts of things. And we looked among doses across trials, and I can say again, really small sample sizes. So I think it's pretty difficult to identify a specific subset that is driving those results. And, actually, I would say that the fact that you've got two different doses across two studies, you have four different observations here. The fact that all of them were quite similar to one another, I think, really argues that there isn't a specific subset driving this, that this is sort of reflective of the overall population. So back to you, Jonathan. Thank you. Thank you. And then my second question is just trying to get a sense of OS read-throughs for Napo, and I guess the question is, based on what you might see from OS on in your NRAS melanoma patients, are there any read-throughs to RAS Q61X mutated solid tumors or any other read-throughs that for other patient populations? Thanks. Yeah. So to my earlier point, where there's that 90% overlap between NRAS and Q61X, I would say that there is a read-through for the melanoma cohort within SEACRAFT-1, that has RAS Q61X mutations, because all of those patients will have NRAS. And so that, that is, you know, an almost direct read-through. And then in terms of OS implications on other cohorts, solid tumors, like non-small cell lung, CRC, I think those are going to be context dependent and more dependent on the histology. If there is a read-through, that'll be great, but scientifically, it's tough to say whether there is or isn't. So that'll, that'll be a data-driven type of analysis. Helpful. Thank you again for taking my questions. Sure. Thank you. Our next question has come from the line of Andres Maldonado with H.C. Wainwright. Please proceed with your questions. Hi, guys. Congrats on the progress, and thanks for sneaking me in here. So maybe a follow-up to the last question. You know, how should we be thinking about the synergistic contribution to OS between Napo and trametinib in the context of the efficacy being driven more by BRAF and CRAF being hit by Napo, or is it being driven more by trametinib's unique ability to break RAF MEK complexes? And obviously, that has implications to the tissue types in RAS Q61, where maybe, you know, melanoma is far more heavily reliant on, you know, breaking the RAF MEK complex. Is there any broad thoughts there on how we should balance the synergistic contribution between the two arms? Yeah, thanks. I, I think at this point it's probably really difficult to tell the individual contributions, which is why we think stage one will give us some info in terms of, trametinib single agent, at that 2 mg dose versus, two different combos. So there, there definitely a synergy. It's probably, roughly, you know, similar contributions, but I guess, you know, that's the benefit of synergy, is that the 1 + 1 = 3, right? So I, I think in some ways it, it almost doesn't matter, as long as you're seeing synergy. Great. Thank you very much. Sure. Thank you. We have reached the end of our question and answer session, and with that, that does conclude today's teleconference. We appreciate your participation. You may disconnect your lines at this time. Enjoy the rest of your day.