And 6291 is the very best KRAS G12C inhibitor out there that we will want to combine it with RAS Companion inhibitors; so that’s our default path. I think we assume that’s the main path. But if it does stand out in monotherapy in ways that reflect what we’ve seen preclinically, significantly, that could open up a monotherapy path to approval but it’s just not our primary assumption around this.
Michael Schmidt: Yes. Okay, that makes sense. And then on 6236, perhaps more near term, once you have reached to recommend Phase II dose in the Phase I portion of the study, how do you think about pursuing specific tumor histologies or specific mutations in Phase Ib study in dose expansion cohorts down the road?
Mark Goldsmith: Yes. Well, I’m going to turn it over to Steve. He said we’re open-minded. So maybe you can put some matters around how open-minded we are.
Steve Kelsey: I think it’s pretty straightforward in RMC-6236. I think as you already said, the preclinical data shows that the activity definitely favors the G12 mutant tumors. And so there are essentially 3 histotypes there. You’ve got non-small cell lung cancer, pancreatic cancer and colorectal cancer. And we are planning to develop RMC-6236 really in 3 different ways. The first is as a single agent. We will test it as a single agent and we will see whether the single-agent activity in any of those cysteines is sufficient for half 2 registration. The second thing we’ll do is we’ll do combinations starting with things that don’t have overlapping toxicity. So the most obvious candidate there will be checkpoint inhibitors. And the third plant that is to use RMC-6236 as of companion inhibitors for mutant selective RAS inhibitors and the first one in the first half there will be RMC-6291.
So, I think you can expect a fairly broad program for RMC-6236 once a recommended Phase II dosing schedule has been established. And the actual breadth and the focus will really depend on the degree switches as active as a single agent.
Mark Goldsmith: Michael, we were also asking, though, if we see a signal in both, let’s say, G12C and G12D how would we go to prioritize one versus the other? Is that what you’re asking about also?
Michael Schmidt: Yes, just generally. There will be overlap with less selective inhibitors there will be overlap in tumor authority as well. I’m just wondering how you prefer one with the other.
Mark Goldsmith: Sure. Well, those are different axes and we’ll have to look at those as Steve said. But with regard to mutations, I think one of the benefits of doing the back-build strategy that we have loaded up for this is that we will collect additional information than just the information we need to go escalate. We will also be able to enroll additional patients at the previous dose level and keep doing that as long as we wish to up the dose escalation scale. And that allows us to sample more patients which means more genotypes and more histotypes but it’s not going to give us a grade of 10 by 100. It’s still going to be relatively small numbers. And we’ll be very excited if we see signals across multiple isotypes and genotypes that maybe we’ll have to decide what to prioritize or maybe not. We’ll just have to see what information emerges there.
Operator: Our next question comes from Chris Shibutani with Goldman Sachs.
