Benjamin Burnett: Okay. That’s great. And then I also wanted to ask, going back to that intermittent dosing conversation. Is there €“ can you frame the level of toxicity that’s tolerable? And is it likely to be different in different indications? Like could there be a scenario wherein you may have intermittent dosing for CRC or for certain tumor types but not others?
Mark Goldsmith: Not so much because of difference is the tolerability, but there could be differences in sensitivity across tumor types. And so if it’s somehow €“ I think that was really the point about not wanting to leave activity on the table. I just realized the metaphor is you want to leave it all out on the field that you don’t want to leave anything on the table to make those two metaphors. So one can imagine that there may be some benefits in some settings too if you can achieve a higher dose intensity for particular tumor types or there’s a particular combination in which that’s particularly logical to do. But I mean we’re out really of our for third metaphor to say anything like that at the moment because it should not what we’re experiencing.
And by the way, pre-clinically, as you know, the vast majority of what we showed was daily dosing, admittedly in a mouse with different pharmacokinetics, but nonetheless. We had target coverage for 24 hours a day, and we were able to do it. So this €“ what’s happening in human seems to reflect that, at least within the limits of what we can detect so far.
Benjamin Burnett: Interesting. Okay. Thank you.
Mark Goldsmith: And I think it does contrast. Maybe I’ll add one other bit of color here since we’re amongst the groups that I spent a year setting SHP2 inhibitor. It does contract significantly with the SHP2 inhibitor experience, where in humans really to get the concept overall dose intensity that we felt would be needed, it was mandatory, in our view, intermittent dosing. And pre-clinically, the anti-tumor activity even at the best optimized SHP2 inhibitor schedule and dose just didn’t €“ wasn’t in the same league as for RMC-6236. There just seems to be no question that inhibiting RAS is far different from inhibiting something upstream from the downstream.
Benjamin Burnett: I see. Okay. So it was like the guiding light here is that just €“ is it really like the PK? And are you achieving the concentration thresholds that are needed? Or is it really about efficacy?
Mark Goldsmith: I think the guiding light here is how much efficacy can we get at a tolerated dose. And so far, we’re encouraged by the efficacy signal we’re seeing so far at the tolerated doses. I mean the PK is not going to make a decision for us. It’s going to be the clinical outcomes.
Benjamin Burnett: Yes. Okay. Thanks so much. I appreciate it.
Mark Goldsmith: Thank you.
Operator: Our next question comes from Alec Stranahan with Bank of America. Your line is now open.
Alec Stranahan: Hey, guys. Thanks for taking our questions. Congrats from me as well on your initial responses. Interesting that the two PRs are G12D. Could you give us a sense of the G12X makeup for the other 10 patients in the efficacy group? Was it entirely G12D and G12C or something else?
Steve Kelsey: Well, there’s no G12C patients in this study. But right now, those patients are all being channeled into KRASG12C inhibitors, so the RMC-6291. The patients in the group overall really cover the full range of KRASG12 mutations, and the ones on the waterfall are indicated. So you can see that there are really only three types: G12V, G12D and G12A. If I’m counting correctly here, there are 1 2, 3, 4, 5, 6, 8 of the 12 are G12D mutations. So that just, I think, is completely consistent with the epidemiology of the KRAS mutations in these particular histotypes.
