Mark Goldsmith: Yes. Well, we fully expect the therapeutic index to be wider with the new selective inhibitors or by definition, if they’re €“ if it’s not wider, if they’re having wild-type RAS effects, then they’re not mutant selective. So there will be a wider therapeutic index. I think as we talked about before, I mean, ultimately, the issue isn’t therapeutic index. It’s how high can you dose and what’s the absolute impact at that dose level. But it will all converge around 1.0, as you have talked about before, because that’s the point of MTD dosing. But I think just to go back to the big picture, we’re obviously quite encouraged by a significant level of anti-tumor activity that we’ve seen at as Steve described a very well-tolerated dose range.
And although this is below the 25 mgs per kg that we used as our standard dosing in mice, it’s not below dose levels that we know should have anti-tumor activity. So it’s actually quite consistent with our collection of preclinical data. So we’re quite encouraged about it. But I think the mutant-selective inhibitors, one would expect to be €“ have much more flexibility around dosing. And we think of RMC-6236 as sort of the highest-risk molecule from that perspective. And today’s information, in our view, substantially lowers our calculation around that risk profile.
Michael Schmidt: Yes. Great. And then could you €“ when I was looking at the waterfall chart on Slide 12, could you just comment on response kinetics? Did they all €“ did you see these responses early at the first scan? Did they happen later? Did they deepen over time? How should we think about that?
Mark Goldsmith: Yes. Well, there is a row across the bottom that says most recent scan, and that was designed to give you the information of what the bar represents. And you’ll see that it varies. Some of them are cycle three, day one, which would be the first post-treatment scan, and others are at cycle five day one. I think the case that Steve described is pretty informative there where from the first scan, which would have been cycle three, day one, it was an aggregate 17% tumor lung reduction by RECIST criteria. Although the scan looked a little more impressive than that, that’s what it was. But by cycle five day one, it’s pretty clear that the tumor is nearly obliterated across all three of those lesions. And so that score is RECIST in the 70% range, just probably in terms of tumor content is far more than a 70% reduction.
That’s what we have. That’s what we’re seeing so far. As we get to higher doses, possibly, it will take fewer cycles to see that. Who knows? But it might also just be the kinetics of the tumors. That’s the sort of thing we need more information on to be able to give a more precise answer.
Michael Schmidt: Right. And just in terms of the study conduct going forward, do you plan to enrich for certain tumor types, perhaps lung cancer and PDAC? Or are you still continuing with the all-comers approach at this point?
Mark Goldsmith: Well, I think as we’ve described it publicly and I think we’ll stay with this is that the backfill patients really give us the greatest opportunity to put finger on a scale, if you will. And clearly, we’re showing some information that we think is exciting and the investigators think is exciting. So I would imagine you’ll see more of some of these patients in the backfills. There’s always this tension, and I know you and I have also talked about this before. There’s a tension between wanting to sample across tumor types and genotypes because that’s important information too versus wanting to get a deeper data set in a smaller number of tumor types of genotypes. I think in a sense, it’s sort of playing out that way we could get immunology with predicted. So we end up with a larger data set with G12D and a pancreatic cancer, not surprisingly. But we’ll continue enrolling patients across these potentially with some enrichment by the investigators.
