Ellie Merle: Just a high-level strategy one. How are you thinking about which indication you would next start a pivotal study in? And how are you thinking about prioritization around moving into another tumor type relative to moving into a combination by a frontline lung? Thanks.
Dr. Mark Goldsmith: Hi. Thanks for joining us and thanks for the question. Yes, very straightforward. Our top priority is going to be to move into first line indications in the disease areas that we’ve identified, pancreatic cancer and lung cancer, because we have the most traction there, we have the most data there, we’re moving forward into second line. And so, it is our immediate priority behind those first two pivotal trials in second line is to get this compound into first line settings. And there’s a lot of opportunity across first line settings for pancreatic and lung. That’s not necessarily just one trial for each. There are a lot of subsets of early stage disease. So, there’s quite a lot to do there. Behind that would be other indications going beyond or other tumor types going beyond lung and pancreatic cancer.
And as you saw from the AACR, we certainly have evidence of activity in multiple tumor types and multiple genotypes beyond the core that we had studied previously. So, we feel like there’s a great opportunity, but we definitely prioritize these in the way that you alluded to and that I described.
Operator: Our next question comes from Ami Fadia with Needham and Company. Please go ahead.
Poorna Kannan: Hi. This is Poorna on for Ami. Thank you for taking our question. So my first question is, at AACR, you presented patient cases, where two patients had dose reductions. So just wondering, based on the mechanism action and preclinical profile, do you anticipate the safety profile for 6236 to be different based on the mutational profile? And the second question is that given the competitive space in non-small cell lung cancer, what would you need to see in terms of clinical profile from the triple therapy to move forward with development?
Dr. Mark Goldsmith: Okay. Well, on the first question, maybe I could just sort of put that in context and then if Dr. Lin wants to add anything, if he can. We did show a couple of cases with dose reductions. I don’t think one should take those as representative of the percentage of patients across hundreds of patients receiving compound. Those cases were picked to illustrate certain mechanistic points about the activity of the compound against different genotypes and tumor types, which they did very successfully, including showing examples of complete responses. They weren’t particularly picked to show a safety or tolerability profile that really comes from a much larger kind of aggregate data set. And if anything, we might have leaned towards showing more examples of tolerability or side effects just to illustrate that the compound does carry some side effects.
I mean, that’s for sure. I’m not sure of any drug that doesn’t. And even though the profile for the compound has been quite attractive and people have seen that and commented on it, that doesn’t mean that there are no side effects associated with it. And so, we want to be just very clear, especially when we’re picking out a few examples of particularly interesting responses to make sure that people are seeing that there can be side effects that cause for dose reductions. And the last point I’d make, maybe this might transition over into Wei Lin space, but even in those cases where there were dose reductions, the doses were still quite substantial and their responses were persistent that they were sustained. And so those dose reductions really didn’t seem to have much impact.
So, Wei, is there anything you’d like to add to that?
Dr. Wei Lin: I think you answered completely now. Fully agree.
Dr. Mark Goldsmith: It’s trained me well.
Poorna Kannan: So, I guess for the second question, just wanted to understand what would you need to see from the clinical profile of the triple therapy, 6291, 6236, with pembro to move forward with clinical development?
Dr. Mark Goldsmith: Yes. Well, I think there are two different parts. What does 6291 plus 6236 look like? And I think an earlier question asked what would give us confidence about the activity, and that’s really comes from those two targeted agents, so that’s a separate question. And then for safety, we’d have to be confident that we could combine those three agents together to be able to move forward into a registrational study. Don’t think it’s likely that the triplet, we would have a great deal of efficacy data that would drive it specifically, but again maybe Wei wants to comment on that.
Dr. Wei Lin: Yes, I agree. I think we’re initially want to establish the combinability of each of the component a doublet and then the status safety of all three. I think if each of the doublet component within the triplet is combinable, then we feel pretty confident that triplet will be combinable. I think on the efficacy side, without putting any numbers, I think you can appreciate what the benchmark is really the CMO alone typically give a 30% to 40% response rate, in combination with pembro about 50% response rate. So far, I think the current data we presented each of our monotherapy whether it be 6291 or 6236, it’s about 40% in non-small cell lung cancer, right. So if we’re able to combine the two, we’re optimistic that we’ll have an agent that will be superior to chemo alone, then combined pembro should actually produce a fairly promising triplet that could improve on standard care.
Dr. Mark Goldsmith: And I should just clarify, the person who’s just speaking is Dr. Wei Lin, our Chief Medical Officer, who we didn’t introduce earlier, but he’s joined us, so you get the benefit of his input.
Operator: Our next question comes from Alec Stranahan with Bank of America. Please go ahead.
Alec Stranahan: Just two for me. Maybe first on your RAS(ON) inhibitor doublets. I thought it’s interesting that you’re combining G12C or G12D specific inhibition with your multi-RAS as they will likely have some target overlap. I guess maybe could you talk about your thought process here? Is this primarily driven by thoughts around mechanisms of resistance or maybe something else like optimizing the therapeutic window?
Dr. Mark Goldsmith: Dr. Kelsey is chomping at the big to answer that question.
Dr. Steve Kelsey: There’s one empiric reason, I think, predominantly and one mechanistic reason why we wanted to put those two combinations together. The original concept biologically goes back to the observations that were made by multiple researchers looking at mechanisms by which tumors escape from mutant-selective RAS inhibitors, particularly the G12C(OFF) inhibitors. And demonstrating that there are really two major mechanisms, both of which involve up regulation or circumnavigation of the mutant RAS so that signaling through the RAS pathway can continue. And we felt very strongly that if that is the main mechanism by which tumors are escaping from our mutant-selective RAS(ON) inhibitors, then a really good solution to that potentially would be our RAS multiinhibitor because it does a number of things.
