Jonathan Miller: Hi guys. Thanks taking a question and congrats on the progress. I’d like to start on discontinuations from rash specifically as is in the context of this rash prophy that you’re introducing for especially and how effective, do you expect rash prophy to be in reducing actual discontinuation numbers? And and so how much more drug exposure do you think prophy will get you?
Jonathan Lim: Yes, good question. Oh, 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 maintaining relative dose intensity and so on the 400 dose seem to allow us to maintain that better than the 200 dose, but primarily a rough rash of prophylaxis. It has been shown to be quite impactful in other development of other targeted agents. And so we’re cautiously optimistic here. But Shannon, why don’t you chime in here?
Shannon Morris: I think you’ve summed it up really well, Jonathan, it’s pretty hard to predict. And I think a primary, 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 why we’re doing SEACRAFT-1 and states want to SEACRAFT-2 is to hopefully be able to evaluate that and make that dose as bad as it has the most optimal risk-benefit profile as possible.
Jonathan Miller: It makes sense. And then I guess as a follow-up, looking at the different dosing schema and the efficacy data that you’ve shown where you broken those out. If 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-1, are you expecting to see efficacy differences between those doses are you really focused on safety? And in so far as safety is a major driver for dose intensity here? What are you willing to accept in secret Part two in terms of additional over met mono when you’re going forward and dose selection?
Jonathan Lim: Yes, Jonath, 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 going to be the totality for Stage 1 of SEACRAFT-2 in the dose optimization, it’s going to be taking the totality of safety, tolerability and efficacy data from both the 400 and 100 dose and by the way, were also able to take that totality of information generated from the melanoma cohort within SEACRAFT-1, given that there’s a 90% overlap between NRAS. and Q61X. And so we can actually take that totality of information in terms of safety and efficacy, then choose the 2D or recommended Phase 2 dose, which will 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 going to be there seems to be synergy between the napo and Tram 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 really is going to be a judgment call that’s going to 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 synergies seems to be happening irrespective of dose, especially when you look at the uncooled curves for OS that Shannon mentioned, you can 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.
Jonathan Miller: Makes sense. I guess very quickly then you mentioned and obviously, there’s two dose regimens in secret two-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 going to be relatively similar from an efficacy perspective. You know, what’s the likelihood that you end up with a red with the secrets one regimen versus one of the regimens. How is that coming into to influence decision-making?
Jonathan Lim: Yes, it’s really going to be data driven. And so the dose fromSEACRAFT-1 and the 400 plus 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 ORR, DOR, PFS, DCR and even OS., it’s all been generated with those two doses. So the only new dose is the 100 plus one and rather than just reproducing the dose in this graph to design, we were able to then explore a second dose because we’re already exploring and SEACRAFT-1. So 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 that choice to go forward.
Operator: Our next question comes from the line of Michael Schmidt with Guggenheim.
Unidentified Analyst: 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 design a SEACRAFT-2? And a second question, you’ve compared the Kaplan-Meier curve with Napo with some of the control regimens. Understood. They’re all cross-trial comparisons, but it looks like it enables a couple of has a longer tail. And I was wondering, technically, is it possible to sort of like derive a hazard ratio out of these cross-trial comparisons, at least directionally? Thank you.
