Alec Stranahan: Got it. That’s helpful. And just a follow-up, thinking through the balance of safety, efficacy, you said your goal is to maximize responses. But would this be through the lens of keeping this forward as a monotherapy? Or would you take a hit on efficacy at a lower dose if safety is good with an eye towards combinations, since I know you’ve shown in the past some preclinical data combining 6236 with anti-PD-1.
Steve Kelsey: Yes. That’s a great question. But I don’t think we’re there yet. I just don’t think that we know enough about the tolerability profile or what’s going to be dose limiting to know whether €“ either to know at what level of toxicity we would be prepared to tolerate as a single agent or in due in combination with anything. So it’s really too early. It’s a very reasonable question, but it’s just one which we don’t have an answer to right now. Because as you know, toxicity is not all created equal. I mean some toxicities are very well managed and easily tolerated, and some are absolutely horrible and unpleasant and are going to be clearly less limiting. We’re just going to have to keep dose escalating and following these patients and see what happens.
With a view to maximizing the dose for response, that’s not actually the primary €“ it’s not the primary driver here. The main driver is durability. We’re looking for durability because there are only two approvable endpoints that are going to make people prescribe this drug. One of them is progression-free survival and the other is overall survival. A response rate per se without either of those two things is not particularly helpful for patients. And so we’re really looking not just consumer shrinkage but the durability of that.
Mark Goldsmith: And if I could just add just one small point. On the combinations, we’ve shown data that 6236 can combine with, for example, 6291. Effectively, it goes lower than just that we typically use for monotherapy studies in the mouse. So we have a lot of flexibility in the combination realm. And so determining the recommended Phase II dose for monotherapy doesn’t necessarily dictate the limits of what we do in combinations where we may lower the dose impact that ensure the combination study we will start with a lower dose.
Alec Stranahan: Okay. That makes sense. And just on the duration versus ORR point, it sounds like the mid-year update, the median follow-up is just not going to be long enough to get to that duration question, and it’s going to be more about just the gross responses, correct?
Mark Goldsmith: I can’t answer that because we don’t really know. But again, all 12 of these patients are still on study. And in pancreatic second-line cancer, one doesn’t have to wait 18 months to find out whether or not you’ve got a drug that’s active compared to standard of care. So I think one has to really talk about individual indications in order to know what the reference, the benchmark is for that particular indication.
Alec Stranahan: Okay. One last quick one, if I may. Just on the differences between 6236 and 9805 as it relates to the binding to G12D, whether it’s covalent inhibition or another aspect that you think could result in different clinical profiles beyond just the therapeutic window that was mentioned before.
Mark Goldsmith: Right. Well, it has the differentiated feature that is selective for G12D it forms a covalent plus selective bond with the G12V of RAS and hence, it’s basically irreversible. RMC-6236 is non-covalent and so €“ and it’s reversible. So it’s binding, will go up and down with wherever the plasma levels are, whether it’s intracellular concentrations are at that minute in time. But the trade-off is you capture activity against a wider range of RAS proteins that might be part of the overall oncogene addiction for RAS tumor cell. So there are trade-offs between those. And I think it’s just really yet to be determined which of those is more favorable. Obviously, overlaid on top of that is tolerability, how much dose can you give, et cetera.
