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 Q&A session. As a reminder, this webcast is being recorded today, March 28, 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. 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 continue to execute on our pipeline. As a precision oncology company focused entirely on shutting down the RAS/MAPK 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. I will provide a brief refresher on the Napo program and then we'll share with you an exciting update on the overall survival data from the Phase 1 and 2 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 the Pan-KRAS inhibitor program and move to the 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 could see a clean KINOMEscan highlighting Naporafenib's high selectivity for BRAF and CRAF. The unmet medical need is high 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 melanoma. While physicians are largely satisfied with their treatment options for melanoma patients overall and even more satisfied for BRAF-mutant patients specifically, they are clearly not satisfied with 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 3 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 1 and 2 studies for Naporafenib plus Trametinib at two different doses. The takeaway from this table is that if you look across different metrics of Objective Response Rate, Disease Control Rate, you see that the combination of Naporafenib plus Trametinib outperformed both single-agent MEK inhibitors and chemotherapy. Importantly, in alignment with US and European health authorities, Progression-Free Survival can be used for potential initial approval. You can see here that Naporafenib plus Trametinib, regardless of the dose, was able to achieve approximately five months of median PFS relative to 1.5 months for chemotherapy and about 2.8 months for single-agent MEK inhibitors. For median PFS, we’re already seeing more than tripling of the approved standard of care and roughly doubling of the single-agent MEK inhibitor, which gives us confidence that we have the potential to show both statistical and clinical benefits on this endpoint in our Phase 3 trial. Naporafenib plus Trametinib dramatically demonstrated a favorable and manageable adverse event 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 toxicity 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 dose was well tolerated. This was less tolerable, especially in the absence of mandatory primary rash prophylaxis, which includes treating patients for a 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 safety and tolerability even further, potentially leading to patients staying on the drug longer, thereby possibly increasing 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 Naporafenib plus Trametinib combination that is expected to further enhance the benefit-risk profile of the combination. This approach addresses regulatory focuses like the FDA’s Project Optimus in 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 Naporafenib in combination with Trametinib lies between 100 - 400 milligrams BID. For Trametinib, the range of efficacious doses in the combination slides between 0.5 and 1 milligram QD. In SEACRAFT-1, we are advancing with one dose, while in SEACRAFT-2, we are advancing with two doses of 400 plus 0.5 and 100 plus 1. This is designed to allow us to efficiently test the full range of efficacious doses for the combination of Naporafenib plus Trametinib within these two trials, optimizing 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 3 design. Both stages have been discussed and aligned with US and European health authorities. Stage 1 is the dose optimization portion and Stage 2 is for regulatory approval. In the randomized Stage 1 portion, we will look at two different doses of Naporafenib plus Trametinib, as described previously: the 400 plus 0.5 and 100 plus 1. We will compare this against Trametinib monotherapy at 2 milligrams, which is the monotherapy dose approved for patients with BRAF mutant melanoma. The number of patients for Stage 1 is flexible and will range between 60 to 120 patients because this is an open-label trial. We will 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 2. If so, we will stop Stage 1, meet with the FDA to gain their alignment around that selected dosing regimen, and publicly disclose the Stage 1 dataset. We also have the flexibility to enroll up to 40 patients per cohort. This Stage 1 design has multiple advantages. First, we will have a meaningful readout of Naporafenib plus Trametinib versus single-agent trametinib randomized data in the calendar year 2025. Second, we're comparing the Naporafenib plus Trametinib combination against a higher bar in Stage 1 compared to physician’s choice in Stage 2, given that historical data show that chemotherapy is less efficacious than single-agent MEK inhibitors. Finally, we will get contribution of component information on single-agent trametinib. Once we identify a dose in Stage 1, we plan to move forward with Stage 2, comparing Naporafenib plus Trametinib versus physician’s choice of single-agent MEK inhibitors or chemotherapy. The trial design randomizes patients with NRAS mutant melanoma being treated in the post-IO setting comparing Naporafenib plus Trametinib versus physician’s choice and includes dual primary endpoints of PFS and OS. We only have to win on one endpoint and not both. Additionally, a positive PFS endpoint is acceptable for a potential initial approval; 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 1 and 2 trials, we believe we have a realistic opportunity to show both 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 1 and 2 trials has matured to the point where we have been able to analyze the data to see if there is 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 gold standard to measure the efficacy of a cancer therapy. Extending overall survival is an important goal in oncology, with OS being widely considered by patients, physicians, regulators, and payers as the endpoint that is most valued. 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 Naporafenib OS data analysis.

Thank you, Jonathan. To properly understand the need for 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 Naporafenib 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 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 dataset 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 listed on the right side of the page are benchmark one, which is the randomized Phase 3 NEMO trial evaluating Binimetinib in patients with NRAS mutant melanoma. Although this study enrolled patients with NRAS mutant melanoma, recall that our Phase 3 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 treatment, we believe the NEMO data overestimate 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 in this trial. What's particularly encouraging is that even with this higher bar in NEMO, the data from the Naporafenib plus Trametinib trials suggests that the combination may exceed this benchmark. 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 comprises multiple retrospective multicenter evaluations of patients with melanoma receiving either cytotoxic chemotherapy or MEK inhibitor monotherapy in the post-IO setting. Benchmark three consists of BRAF mutant melanoma patients from Novartis’ Phase 2 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 the post-IO setting, they were also contemporaneously enrolled in the same trial in which the rest of the melanoma data were generated. While their tumors have a different driver mutation, as you will see, the consistency of the data between benchmarks two and three suggests that BRAF mutant and NRAS mutant patients are behaving similarly when treated with therapies that don't offer a survival benefit. Let's walk through each of these in order. First, the NEMO benchmark showed a median overall survival of about 10 to 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 3 trial with a large sample size, which makes this the most rigorous trial design. However, as noted, while 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 due to the availability of immune checkpoint inhibitor therapy following progression. Approximately 80% of the patients in NEMO were being treated in the first-line study and had not received prior IO therapy. This contrasts directly with the target patient population in SEACRAFT-2, who will have received prior IO therapy. Additionally, 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, if we demonstrate a benefit against this higher bar, we believe it bodes well for our Phase 3 SEACRAFT-2 trial. The Kaplan-Meier curves in this study illustrate that in a cross-study comparison, the combination of Naporafenib 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 Binimetinib and dacarbazine experienced a median overall survival of approximately 10 to 11 months. In contrast, looking at the bottom of the slide, a pooled analysis of data from the Phase 1 and 2 trials evaluating the Naporafenib plus Trametinib combination showed about 13 to 14 months of median overall survival, despite the fact that patients enrolled in the Phase 1 and 2 trials were being treated in the post-IO second-line plus setting. For us, this is really encouraging, and even with this higher benchmark from the NEMO trial, Naporafenib plus Trametinib has the potential to offer OS benefits. Now, let’s move to benchmark two, which comprises multiple retrospective multicenter evaluations of patients with melanoma receiving cytotoxic chemotherapy or MEK inhibitor monotherapy in the post-IO setting. In these studies, the median overall survival was about six to seven months. As previously mentioned, we believe this patient population is likely to be similar to the SEACRAFT-2 comparator arm population, both in terms of having received IO in the frontline and receiving either cytotoxic chemotherapy or MEK inhibitor monotherapy in the second-line plus setting, with neither cytotoxic chemotherapy nor MEK inhibitor monotherapy shown to have an OS benefit. The OS for these patients likely represents the natural history of their underlying melanoma. One important caveat to these data is that they are retrospective analyses, which are less rigorous than a prospective randomized trial. However, in the absence of any prospective analyses that we could identify, and given the remarkable consistency of these data and observations for Benchmark three, we feel that it's a reasonable benchmark. The studies contributing to this benchmark are shown here, illustrating that progression-free survival is in the two to three month range, consistent with other literature. For overall survival, if you exclude 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 chemotherapy and a single-agent MEK inhibitor gives us reasonable confidence in how the SEACRAFT-2 comparator arm might perform. Finally, let's examine the data for Benchmark three, which focuses on BRAF mutant melanoma patients enrolled in Novartis's NEMO trial receiving Naporafenib plus Trametinib. 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 treatment as well as progression on a BRAF plus MEK combination prior to enrollment, followed by treatment with Naporafenib plus Trametinib. We believe that the absence of observed responses and the short median PFS of only 1.8 months suggest that Naporafenib plus Trametinib did not offer a clinical benefit in this situation, and the median OS of about six to seven months likely reflects the natural history of the underlying disease. Again, very similar to benchmark two, with the caveat that these patients had a different driver mutation. However, the prognostic impact of that mutation compared to NRAS in this context is unclear. Therefore, due to the consistency of these data with benchmark two, paired with the fact that these data were generated in the same trial as NRAS data, we believe this benchmark could be representative of what could be observed in the SEACRAFT-2 control arm in the future. Looking at the Kaplan-Meier curves, you see a steep drop-off in survival for the BRAF mutant patients with a median OS of roughly six to seven months, while the median OS for the Naporafenib plus Trametinib combination was about 13 to 14 months. The data you are seeing is a pooled analysis across the Phase 1 and 2 studies. You may wonder if the pooling approaches is clinically appropriate. In terms of prior therapy exposure for patients enrolled in both studies, the patients received a median of two prior lines of therapy. As you can see from the Kaplan-Meier curves in this figure, where we show the curves for each dose in each study, there's remarkable consistency across the studies and dosing with a median overall survival of about 13 to 15 months. The reproducibility of these results across studies and doses compared to the three benchmarks increases our confidence in the median overall survival observation. I'd like to return to that table we previously looked at, where we quantified the potential PFS benefit for the Naporafenib plus Trametinib combination, which was about five months across doses relative to 1.5 months for chemotherapy and 2.8 months for single-agent MEK inhibitors. When we overlay the overall survival data on this table, you can see that the median overall survival of 13 to 14 months from Naporafenib plus Trametinib exceeds the NEMO benchmark by three to four months, even with the limitations of the NEMO trial that likely overestimated overall survival. That value definitely exceeds 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 combination of Naporafenib plus Trametinib has shown the potential benefit in both PFS and OS, which are the two primary endpoints for the SEACRAFT-2 pivotal trials. Given these recent updated data, we're excited to initiate the Phase 3 trial in the first half of this year, aiming to bring 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. Now I'd 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 2 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, potentially leading to improved tolerability 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. Moving to the PAN KRAS space, we believe there's an opportunity for a greater therapeutic window by specifically targeting KRAS 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 as there are no clinical data available as of today. In terms of mutant-selective options, there is potential for greater potency of these molecules against this 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. This could potentially be addressed by a PAN KRAS inhibitor that hits both KRAS wild-type and mutations. Here, we highlight a few of our internal compounds that are showing promising in vitro potency and in vivo pharmacokinetics. Shown in teal are our internal PAN KRAS inhibitor compounds; shown in blue are three external compounds from Revolution Medicine and Loxo Lilly. Our compounds are targeting the switch 2 pocket, as do certain external compounds; however, coactivators also use a molecular glue approach to target this protein. The key metric to look at for oral bioavailability is the percent, as shown in the second-to-bottom row. Our target for our molecules is 10% or higher, which you can see 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%. Our molecules have shown cell-based nanomolar IC50 potencies against G12D and G12V, as well as good percent oral bioavailability, which benchmarks us well against these other compounds. Here, we look at comparative mouse studies of our US11930 compound versus MRTX1133. You can see that our compound is dosed orally, whereas MRTX1133 needed to be administered intraperitoneally. Our compound is also better tolerated with less body weight change, which we think is due to the scaffold we are using. In fact, mouse mortality was observed when MRTX1133 was administered at higher doses of 30 mg per kilogram, since there seems to be a tolerability cliff for this compound. We are encouraged by the progress that we're making with our internal compounds, and we like this program. However, we also recognize that this space is rapidly evolving and could close quickly. Hence, we are looking at both internal and 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 ERAS mutant melanoma, respectively. SEACRAFT-1, which achieved first patient dosing in Q3 of last year, is on track for 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 1 of the pivotal study in 2025. ERAS-007, our ERK inhibitor, is on track for data readout in the first half of this year in BRAF-mutant colorectal cancer, while ERAS-801 is on track for data readout in 2024 in glioblastoma. In summary, we continue to make strong progress across our pipeline, including our range of early and late-stage programs. Given the Phase 3 start planned for the first half of this year, we're particularly excited about the Naporafenib OS data that we shared today, as it shows our potential to win on both primary endpoints of PFS and OS. Additionally, we are 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 turn the call back to the operator for Q&A.

Our first question comes from Anupam Rama with JPMorgan.

In SEACRAFT-2 on the dual primary endpoint of PFS and OS. Is there a hierarchy here? Or do you have regulatory sign-off on this?

Yes, thanks for the question. In terms of dual primary endpoints, there's not really a hierarchy between them, but winning on either or both from a statistical and clinical benefit gives you the flexibility to win on either PFS or OS. We do have regulatory alignment from global health authorities both in the US and Europe.

Our next question comes from the line of Jeffrey Hung with Morgan Stanley.

Hi, this is Michael Riad on for Jeff. Thank you for taking our questions. First one, how should we be thinking about the ORR rate between the 201 versus the 400.5 regimens? Is there any evidence suggesting potentially broader responses at the higher dosage?

Yes, good question. I'll take a first cut, and then Shannon can feel free to chime in. First of all, it's small patient numbers, and it's important to note this is a very aggressive disease in the second-line plus setting post-IO, so there is some variability there. But the most important metric is progression-free survival. If you look at the Disease Control Rate, which includes both ORR and stable disease, you can see that they are relatively similar DCR rates. We do think that with PFS as the main driver, that will be the focus. Shannon, do you want to comment further on that?

I think you captured it well, Jonathan. The take-home message is while the objective response rate can be a quick and dirty screen to look for activity, what's most important to patients and regulators is progression-free survival and overall survival. In those settings, we definitely have a lot of consistency of data to suggest that we are in the clinically relevant dose range here.

Thank you. That's really helpful. If I could just do a quick follow-up on the post-IO setting. Can you provide any added color on what's driving the decision to go for chemotherapy in this setting versus a single agent like an inhibitor? I'm trying to gauge if there is a general preference towards avoiding chemo in this population.

Yes, that's a good question. We think there will be regional factors. SEACRAFT is a global Phase 3 trial, so we anticipate regional preferences in practice patterns. For example, in the United States, the preference will be more for single-agent MEK inhibitors for both physicians and patients. In certain European countries where the standard of care is firmly entrenched in chemotherapy, that's what would be provided. However, our hunch is that more patients and physicians will choose the single-agent MEK, but it will be a physician’s choice.

Our next question comes from the line of Alec Stranahan with Bank of America.

Hey, guys. Thanks for taking my questions. Just two from me. Any additional updates you can share from your recent FDA or Novartis interactions around the Naporafenib pivotal program? It sounds like feedback has been fairly positive on both fronts. As a follow-up, any thoughts around powering needed in the randomized Phase 3, given the roughly doubling in OS and significant, but perhaps somewhat smaller separation on PFS? Is it right to assume you'll likely power for PFS since this should hopefully take care of OS as well?

Yes, great question. First of all, everything in terms of the clinical trial design for SEACRAFT-2 represents full regulatory alignment from last year. The second half of last year was a key focus area for us to gain regulatory alignment on SEACRAFT-2 in terms of the clinical design, comparator, etc. Both the FDA and European regulators, as well as Novartis, have been very supportive of our efforts. Regarding powering, we have powered the Second stage of SEACRAFT-2 primarily to achieve 80% power for OS benefit, which also leads to being well-powered at 99% for PFS benefit. So we believe with 350 patients, 175 in each arm on a one-to-one randomization basis, the study is well-powered. Shannon, did I miss anything there?

The only thing I'd add is that we're pushing for global regulatory approval. While we certainly can have conversations based on progression-free survival, we know there will be some areas where additional overall survival data will be impactful, not only for regulatory purposes but also from a reimbursement point of view. That’s one of the reasons we've focused on ensuring we can detect a difference in overall survival. The beauty of having this Stage 1 is that it will help us understand that dose and assess the most optimal dose. We also have the ability to revisit sample size if the effect sizes in Stage 1 differ from what we projected.

Our next question comes from the line of Jonathan Miller with Evercore ISI.

Hi guys. Thanks for taking my question and congrats on the progress. I'd like to start on discontinuations from rash specifically in the context of the rash prophylaxis that you're introducing. How effective do you expect rash prophylaxis to be in reducing actual discontinuation numbers? How much more drug exposure do you think prophylaxis will get you?

Yes, good question. I'll take a first cut, and then Shannon can chime in here. It's not just about discontinuation; maintaining relative dose intensity is also important. The 400 dose seems to allow us to maintain that better than the 200 dose... again, rash prophylaxis has proven to be impactful in other developments for targeted agents. We're cautiously optimistic here. Shannon, do you want to add anything?

You've summed it up well, Jonathan. It's difficult to predict from a quantitative approach how effective the rash prophylaxis will be. Certainly, from previous data, we know it can significantly impact outcomes. The rationale behind SEACRAFT-1 and Stage 1 in SEACRAFT-2 is to evaluate that and make the dosing as optimal as possible.

It makes sense. Looking at the different dosing schema and the efficacy data you've shown where you’ve broken those out, it doesn't appear there's really obvious efficacy differences across the doses. In SEACRAFT-1, are you expecting to see efficacy differences between those doses, or are you primarily focused on safety? If safety is a major driver for dose intensity here, what are you willing to accept in SEACRAFT-2 in terms of additional over-met toxicity when you proceed with dose selection?

Yes, that's a really astute observation. In terms of decision-making for SEACRAFT-1 and SEACRAFT-2’s dose optimization, it's essentially a totality analysis of safety, tolerability, and efficacy across both the 400 and 100 doses. We can leverage the information from the melanoma cohort within SEACRAFT-1 due to a 90% overlap between NRAS and Q61X mutants. Ultimately, the totality of information in terms of safety and efficacy will allow us to choose the recommended Phase 2 dose to discuss with the FDA. It does seem there is synergy between Naporafenib and Trametinib, and thus there isn't much discrimination regarding PFS and OS between the two doses tested to date.

Very quickly, you mentioned there are two dose regimens in SEACRAFT-1, but also introduced a different regimen from SEACRAFT-1. There are now three different dose regimens. What’s the likelihood that one of the SEACRAFT-1 regimens ends up being selected versus one of the SEACRAFT-2 regimens? How does this influence decision-making?

It's going to be data-driven. The doses from SEACRAFT-1 and the 400 plus 0.5 from SEACRAFT-2 have generated historical data regarding ORR, DOR, PFS, and DCR, while exploring a second dose with the 100 plus 1 in SEACRAFT-2 allows us to capture the totality of information from the three doses. Thus, moving forward will be based on the data-driven analysis we perform next year, focusing on safety, tolerability, and efficacy and developing a comprehensive recommendation.

Our next question comes from the line of Michael Schmidt with Guggenheim.

Hi, good morning. This is on for Michael. Thanks for taking our questions. First question, how does the OS data compare to your internal expectations when you designed SEACRAFT-2? And do you think it's possible to derive a hazard ratio from some of these cross-trial comparisons directionally?

Yes, I won't comment specifically on hazard ratios. What I will say is that our biometrics and broader Naporafenib team assumed a worst-case scenario. All of our power assumptions were based on the control arm performing in line with what was historically seen with NEMO. These factors mentioned earlier could overshoot the natural history of the disease. If the control arm performs in line with benchmarks two and three, we are excited by the possibility of showing both statistical and clinical benefits. If the control arm performs more aligned with benchmarks reflecting a lower range for OS, it can yield stronger data.

Our next question comes from the line of Chris Shibutani with Goldman Sachs.

Great. Thank you. Several questions regarding the study designs have been described, but just to clarify, SEACRAFT-1 involves potential tissue diagnostics. We have 1b data coming for the combination around Q2 to Q4. What are the gating factors driving that time span? What kind of tumor types distribution might you be able to help us with? Also, regarding the financing announced, David, could you clarify how you feel this bolsters your runway to support your programs?

Yes, thanks, Chris. There are no real gating factors beyond operational efficiency and patient enrollment. Since FPD in Q3 of last year, we've activated multiple sites. Enrollment is brisk and reflects solid tumor types that align with epidemiology. Common tumors where RAS Q61X manifests include colorectal and pancreatic cancers, and we are enrolling patients regardless of tumor type. Following patients also ensures we have meaningful follow-up offered for this data in Q2 to Q4, which guarantees a meaningful update.

Yes, Chris, we completed a $45 million oversubscribed private placement with high-quality investors. This financing secured our runway out to the second half of 2026, compared to the previous guidance of the first half of 2026.

Our next question comes from the line of Graig Suvannavejh with Mizuho.

Yes, good morning. Thank you for taking my questions and for the presentation today. I have two questions: first, given your Naporafenib OS data, were there any patient characteristics across the dose cohorts that may have influenced the OS results? Could you potentially see different OS results? And then follow up with the second question after.

Sure. We did evaluate baseline characteristics that are prognostic for melanoma, such as LDH and stage prior lines. We examined these characteristics across doses and found it difficult to identify a specific subset driving results due to the small sample sizes. The aggregate data supports that these results are reflective of the overall population.

Thank you. My second question is about OS read-throughs for Naporafenib. Based on what you might see from OS in your NRAS melanoma patients, are there any read-throughs to KRAS Q61X mutated solid tumors or any other populations?

Yes. As noted earlier, the 90% overlap between NRAS and Q61X provides direct read-throughs for melanoma cohorts within SEACRAFT-1. In terms of OS implications on other solid tumors like non-small cell lung cancer or colorectal cancer, these will depend on context and type-specific behaviours. If there's synergy, it will be great, but we can only assess this through a data-driven analysis.

Our next question comes from the line of Andres Maldonado with HC Wainwright.

Hi guys. Congrats on the progress, and thanks for including me here. I'd like a follow-up on the last question. How should we consider the synergistic contribution to OS between Naporafenib and Trametinib? Is it driven more by inhibiting BRAF and CRAF or their unique ability to destabilize RAS complexes, since it could have implications for tissue types reliant on RAS Q61.

Yes, thanks. It's tough to determine individual contributions right now. The upcoming Stage 1 will give us insights comparing trametinib single agent at that 2-milligram dose versus the two different combos. There is certainly synergy, which indicates that it might not matter much, as long as you're seeing the combination working effectively.

Thank you. We have reached the end of our Q&A session. That concludes today's teleconference. We appreciate your participation. You may disconnect your lines at this time and enjoy the rest of your day.