Steve Kelsey : Before we including in a pivotal trial. The validation is obviously — validation is a sort of a fairly hard baked word. I think we want some experience in those patients before including them as a significant part of a pivotal trial. But everything that we have learned from the preclinical models would lead us to expect the activity in G12C mutant lung cancer to be very similar to the activity in G12V and G12V-mutant lung cancer for RMC-6236. And so I don’t think we’ll validate, but we’re going to try and get some information that will help reassure us that what we’ve seen in the pre-COVID levels is also true in the clinic. With regards to numbers, again, we’re still refining the study design. We have — we obviously have to design that study we have to discuss it with the regulators.
And we’re still debating whether the G12C mutation should be in the [indiscernible], frankly. So as soon as we have finalized ourselves, I think we’ll be in a better position to explain what it is and what we’ve — and why we’ve done that. Right now, there are just a little too many moving parts to be able to be as clear as we might like to be with you, right now.
Mark Goldsmith : And if I could add to that on that last point, what Steve’s alluding to is sort of regardless of our confidence in the activity against G12C, there still are operational issues associated with having approved G2C inhibitors available and dozens of G12C inhibitors, G12C(OFF) inhibitors in clinical studies. And so there are risks associated with that cohort regardless of the performance of 6291 and so managing that is part of what we’re thinking through. And that will probably have more impact on whether G12C ends up in the core nest or on the periphery because we want to make sure to protect the entirely unserved the population that’s entirely unserved by targeted therapy today, which is the G12X without C. But we’re interested in both, and we’ll have to sort that out.
Ami Fadia : Okay. If I may just ask a quick follow-up. And maybe if you could sort of just explain the concept of the nested trial design. The way I understood it was, you would power each subset to be able to sort of — if you could just clarify.
Mark Goldsmith : Yeah. No, the way it works is the core Nest gets evaluated statistically first. So you enroll patients however they enroll. It has nothing to do with the sequence of enrollment, but then statistically, you test the core group that you predesignated as the core group. If that scores positively then that permits you to go on to evaluating a larger group that still includes the core but also now includes additional patients. And then you can keep — I mean you could do that 100 times if you want it, you can keep recycling the statistical power. But if at any point, you have to make sure you do it in the right order because if at any point, you don’t see positivity then you no longer can go on and test even larger groups because it would be futile to do so.
Ami Fadia : Got it. That’s very helpful. Thank you.
Operator: And one moment for our last question. And our last question will come from Alec Stranahan of Bank of America. Your line is open.
Alec Stranahan : Hey, guys. Thanks for taking my questions and for squeezing me in. Just a couple. At a high level, could you maybe talk about anticipated expense ramp to support the multiple mid and late stage studies you have planned for 6236 and the new candidates from the KRAS innovation engine? I guess asked another way, how do you continue to be judicious in your spending despite having almost $2 billion in cash on the balance sheet, assuming the EQRx deal closed this. And just quickly to clarify for non-small cell, is it safe to assume that 500 mg will not be pursued since you said that the pivotal monotherapy dose has been selected. And if so, is the reason just in terms of speed to start the registrational studies? Or was there something you think makes the 500 dose a non-starter? Thanks.
