Erasca, Inc. Common Stock Morgan Stanley 24th Annual Global Healthcare Conference

Yeah, I think taking a step back, we're really excited about ERAS-0015. This is a potential best-in-class pan-RAS molecular glue. It's one that is in phase I dose escalation study called AURORAS-1. Going into that program, pre-clinical activity looks really interesting because this is a molecule that's been optimized on both potency as well as PK. From a potency perspective, the binding affinity is about 10 to 20 times higher to cyclophilin A than the predecessor compound, and that translates into about a 5 to 10x potency advantage, and then also much stronger PK characteristics in terms of longer half-life, shorter clearance, and then much higher absorption within the local tumor environment because of CYPA overexpression.

Going into the clinic, we weren't sure if we would need to make trade-offs between higher efficacy or stronger safety and tolerability, or in that unique case, whether we could actually see both. I think from the early clinical data in the phase I setting with AURORAS-1, we've presented data twice this year at our April R&D day and then a July update. What's interesting is that you're seeing very promising single-agent efficacy within the second line plus pancreatic cancer setting. To your point, at pharmacologically active dose ranges, which is between 16 to 32 milligrams, we're seeing response rates in the 40%-57% range, which really is very compelling. If that persists within that range, that truly is best in class for that indication.

As a company, we'll talk about this later, but we're really focused on first-line pancreatic cancer, where the unmet need is about, unfortunately, four times the size of what it is in the second-line pancreatic cancer space. Within non-small cell lung cancer that's RAS driven, about a third of all patients with RAS lung have a G12X mutation or a mostly KRAS mutation of some sort. What we've seen there is response rates in the 62%-75% range, which really is extraordinary for a targeted therapy. That really puts it in a select group of molecules where you have some of the best targeted therapies that are seeing response rates that high, and that's at that pharmacologically active dose of 16 to 32.

When you limit the data set to just second, third line only, post checkpoint and post platinum, that's where we see response rates in the mid-70s. That's on the efficacy side where I think one of the reasons we're seeing that higher efficacy is that the PK and exposure is dose proportional. When you move up from 16 to 24 to 32 milligrams, you're seeing very good dose proportional increases in exposure, which then is really grabbing that additional efficacy. But you'd worry if that's coming at a cost of safety and tolerability, and we're just not seeing that. We're actually seeing very reasonable frequency and severity of rash, very low grade, mostly grade 1, some grade 2, and then very minimal GI in terms of diarrhea and vomiting, very low vomiting and nausea, if at all. Then in terms of stomatitis, those rates are quite low.

I think what's interesting is a measure of how well-tolerated a drug is what's called the relative dose intensity, and our median RDI stays at 100% through that dose range. We think we're in that sweet spot of having both encouraging safety tolerability as well as encouraging efficacy.

Yeah. The key combinations that we are looking at, all of that data that I just mentioned in lung and pancreatic is monotherapy data. As we think about combinations, we sort of have a hierarchy of priorities. The top priority is really what does this molecule do with standard of care therapy within certainly the big three tumor types of lung, pancreatic, and colon are key areas of focus for us. With lung, a key priority is to see what does this do with pembrolizumab, and then what does it do with pembro plus chemotherapy if you need that, for instance, especially for patients with low PD-L1 expression. Then whether a chemo-free or a chemo-containing regimen is needed, that is going to be a data-driven decision.

I think when it comes to pancreatic cancer, you certainly want to be able to explore both chemo-containing as well as chemo-free regimens. In that regard, we are already starting to explore combinations with gemcitabine and Abraxane, because that really is a standard of care in that frontline setting. We also have disclosed a partnership with Tango Therapeutics for combination with vopimetostat, which is a PRMT5 inhibitor. The public guidance from Tango Therapeutics is initiating a dose escalation of the combo of ERAS-0015 with vopimetostat in the second half of this year. Finally, with CRC, you really need to have an answer for EGFR activation, which can be a mechanism of resistance, especially when you put RAS MAP kinase under pressure with a pan-RAS inhibitor.

In that regard, we are excited to have disclosed in July the successful completion of the lowest dose of 16 milligrams, where that passed the DLT window, and so we were able to dose up to 24. So 16 is a viable go-forward dose with panitumumab full strength, and that is something that at the time of the disclosure, we were expanding. In the first half of next year, we are going to be disclosing various monotherapy and combination arms. At minimum, I think panitumumab is something that because we started that first this year in the first quarter, we are calling that out as part of the first half 2027 disclosure.

Yeah. We're confident based on the early clinical data that we have a meaningful therapeutic window because we are seeing meaningful efficacy differentiation, but not at a cost, as I mentioned. In fact, as we in July showed the data of safety and tolerability by dose, we were worried that if you see a certain rash rate at 16 and 24 milligrams, do you suddenly see a spike at 32 milligrams? We didn't see that. We actually saw numerically lower frequency and severity of rash at 32 milligrams. Now, that could come up over time, but it's really in that same ballpark. So I think the therapeutic window seems very reasonable from 16 to 32.