Erasca, Inc. (NASDAQ:ERAS) Q4 2023 Earnings Call Transcript

Erasca, Inc. (NASDAQ:ERAS) Q4 2023 Earnings Call Transcript March 29, 2024

Erasca, Inc. isn’t one of the 30 most popular stocks among hedge funds at the end of the third quarter (see the details here).

Operator: 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 28, 2024. I will now turn the call over to Jonathan Lim, Chairman and CEO. Please go ahead.

Jonathan Lim: 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 for the second half of 2026 to be able to continue to execute on our pipeline.

For 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. 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 Pan-KRAS inhibitor program and 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 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 whether 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’s. 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 our 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. And 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 ORR, DCR, . You see that the combination of Napo plus training outperformed single-agent MEK inhibitor and chemotherapy.

Importantly, as per our alignment with US 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 1.5 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 benefits on this endpoint in our Phase 3 trial, Naporafenib plus dramatic dramatically 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 acne form 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, it was limited to Grade one and two events. The dose was well tolerated. The 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, the practice which Novartis did not uniformly Institute in their trials. However, we are instituting mandatory primary rash prophylaxis in both SEACRAFT-1 and two 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 Optimus and 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 slides between 0.5 and 1 milligram QD. In SEACRAFT-1, we are advancing the dose. And then SEACRAFT-2, we’re 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 napo plus training within these two trials to optimize the benefit risk profile. The clinical development plan for both SEACRAFT-1 and 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. The 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’ll look at two different doses of Naporafenib plus Trametinib, as described previously, the 400 plus 0.5 and 100 plus 1.

We’ll compare this against trametinib mono 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’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 2 if so we’ll stop Stage 1 meet with the FDA to gain their alignment around that selected dosing regimen and be able to 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 will 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 Trametinib combo 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 inhibitor. And finally, we’ll 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 napo plus versus physician’s choice of single agent MEK inhibitor for chemotherapy. The trial design randomized patients with NRAS mutant melanoma being treated in the post IO setting the Napo plus versus physician’s choice and includes dual primary endpoints of PFS and OS. Well, we only have to win on one endpoint and not both. In addition, a positive PFS endpoint is acceptable for a 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 1 and 2 trials, we believe that we have a realistic opportunity to show statistical and clinical benefit, as previously mentioned. Beyond that, 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, we’ve now 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. Well, 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.

Shannon Morris: Thank you, Jonathan, that I 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 napo plus Trametinib can be compared to multiple benchmarks. And 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 and SEACRAFT-2 may perform, while acknowledging the caveats associated with cross-trial comparison. 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 are listed on the right side of the page benchmark one is the randomized Phase 3 NEMO trial evaluating Binimetinib versus 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. Well, NEMO enrolled the majority of patients in the treatment naive or first-line setting. Given that almost half of the patients receive 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 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 multi-centre 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 2 trial progressed on the combination of BRAF plus MEK prior to enrolment and treatment with napo plus commitments.

Not only were these patients being treated in the post IO setting, they were also contemporaneously enrolled, the same trial in which the rest of the melanoma data were generated. And while their tumors have a different driver mutation, as you will see, the consistency of the data between benchmarks two and three suggest that the BRAF mutant 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 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, and this is the most rigorous trial design.

However, as noted, although the PFS results are relevant that 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. Approximately 80% of the patients in NEMO were being treated in the first-line study and had not received prior IO therapy. That’s in direct contrast to the target patient population and SEACRAFT-2, who will be second-line plus and we’ll 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, MET 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 3, SEACRAFT-2 trial. Now the Kaplan-Meier curves in this study illustrate that in a cross-study comparison, the combination of NEMO plus trametinib showed improved overall survival compared to normal 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. Now, 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 showed about 13 to 14 months of median overall survival, despite the fact that the patients enrolled in the Phase 1-2 trials were being treated in the post IO second line plus setting for us, the status really encouraging.

And that even with this higher bXenchmark from the NEMO trial Naporafenib plus Tremendous has the potential to offer OS benefits. Now, let’s move to benchmark two, which is comprised of multiple retrospective multicentre evaluations of patients with melanoma receiving cytotoxic chemotherapy or monotherapy MEK inhibitor in the post IO setting. In this set of settings studies, the median OS was about six to seven months. 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 frontline and receiving either cytotoxic chemo or MEK inhibitor monotherapy in the second-line plus setting. And 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 threw 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 makes 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’s NEMO revenue plus from that middle Phase 2 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. net 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 suggest that Napo Trametinib did not offer clinical benefit in this situation. And that the median overall survival of 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 NRAS data. We believe this benchmark could be representative of what could be observed in the SEACRAFT-2 control arm in the future. And 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 Naporafenib plus Trametinib combination was about 13 to 14 months.

Now, as I mentioned earlier, the data you are seeing is a pooled analysis across the Phase 1 and 2 studies. And you may wonder if the pooling approaches clinically appropriate. In terms of prior therapy exposure to patients enrolled in both studies received a median of two prior lines of therapy. And as you can see from the capital 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 to 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 oXverall survival observation. Now I’d like to return to that table that 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 chemo and 2.8 months for single agent mechanisms.

Now 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 beats the NEMO benchmark by three to four months, even with the limitations of NEMO trial that likely over estimate for 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 Naporafenib 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 trials.

Given these recent updated data, we’re excited to initiate the Phase 3 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. And with that, I’ll turn the call back to Jonathan.

Jonathan Lim: Thank you, Shannon. And 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 this switch to pocket, which is a promising approach to targeting KRAS., including the most frequent mutations, G12X, 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 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, let 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 this specific mutation of interest, especially as some of these molecules potentially sparing 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 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 for Erasca internal PAN KRAS inhibitor compounds, as shown in blue, are three external compounds from revolution medicine and Loxo Lilly.

Our compounds are targeting the switch to pocket as are certain of the external compounds, although co-op editors 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 of percent 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% up. Our molecules have shown cell based nanomolar, IC50 potencies against G12D and G12V as well as good percent, which benchmarks us well against these other compounds Here, we look at comparative mouse studies of our US11930 compound versus MRTX1133.

As you can see, our compound is dosed orally, whereas the compound needed to be given intraperitoneal. 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, Oh, 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 a scaffold that we are using. In fact, mouse mortality was observed when MRTX1133 was administered at higher doses of 30 migs 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, but we also recognize that this 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 2 in RAS Q61X solid tumors and ERAS mutant melanoma, respectively. SEACRAFT-1 which achieved first patient dosing and 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 or Eric inhibitor is on track for data readout in the first half of this year in BRAF-mutant CRC. And ERAS-801 is on track for 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 3 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. And 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?

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Q&A Session

Operator: [Operator Instructions]. Our first question comes from the line of Anupam Rama with JPMorgan.

Anupam Rama: 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?

Jonathan Lim: Yes, 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 statistical and clinical benefit. And it gives you the flexibility to win on either PFS or OS. And we do have regulatory alignment from the global health authorities both in the US and Europe.

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

Michael Riad: Hi, this is Michael Riad on for Jeff on. Thank you for taking our questions on first one, how should we be thinking about the ORR rate between the 201 versus the 400.5 regimens? Is there any evidence suggests potentially broader responses at the higher tremendous. Thanks [indiscernible]

Jonathan Lim: Yes, 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 know 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?

Shannon Morris: I think you captured it. Well, Jonathan, I think the take-home message is that while in 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, it’s 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.

Michael Riad: Thank you. That’s really helpful. And if I could just a quick follow-up on 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 like inhibitor? And I’m just trying to gauge like is there a general preference towards avoiding chemo in this population?

Jonathan Lim: Yes, that’s a good question. We think that there will be regional. So this is SEACRAFT, is a global Phase 3 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 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 from our hunch is that more patients and physicians will choose the single-agent MEK, but it will be a physician’s choice.

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

Alec Stranahan: Hey, guys. Thanks. Thanks for taking our questions. Just two from me. And any additional updates you can share from 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 3, given the roughly doubling in OS and significant, but perhaps maybe smaller separation on PFS, is it right to assume you’ll likely power and PFS since this should hopefully take care of OS as well? Thanks

Jonathan Lim: Yes. Great question. So first of all, everything in terms of the clinical trial design for SEACRAFT-2, and 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 on, 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. And as a result of that, we are really well-powered with 99% powered to show a PFS benefit. And so 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?

Shannon Morris: The only thing I’d add is, you know, we’re obviously pushing 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 going to be some areas where additional overall survival data will be incredibly impactful, not only for regulatory, but for reimbursement point 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 that the beauty of having this Stage 1 is that not only will that help us understand that 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 and we always have the ability to revisit sample size if the effect sizes in Stage 1 are different than what we have projected.

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