Verastem, Inc. 12th Annual Cantor Fitzgerald Global Healthcare Conference

The guy for the hard questions.

Sure. We're kind of a tale of two cities. We've got the commercial product right now of avutometinib and defactinib in low-grade serous ovarian cancer. That launch has been going quite well, really pushing to keep the growth going there. Then, what I would call a potential blockbuster in our G12D inhibitor, obviously, with the pan-RAS getting approved by Revolution Medicines, that's great proof of concept on targeting the RAS pathway. So, great for patients, great for all of us that are playing in this space. I do believe they've left some upside both on the efficacy and the safety side, and we're really focused on that. We're going to have a pretty significant data update in October.

Yeah. Go ahead, John. Yeah, we've treated over 200 patients now in our study.

That's separate from the 300 plus patients that have been treated in China by our partner GenFleet. So really, at this point, I think in early days, eyes were on the GenFleet data. At this point, we'll have significant data. That's where people should look. We'll be reporting out of the phase I, on October 14th. We wanted to wait until we had 20 plus patients at a given dose as opposed to dripping data out. We're finally here. We've been waiting for this moment. We'll have 20 plus patients with pancreatic cancer, many of them with six months since they've started treatment, which is good. That'll be at the 900. 900 milligrams will importantly be the go forward regimen probably for all indications and across combinations because it's very well tolerated.

For lung cancer, also 20 plus patients at 600 milligrams because the FDA, there's a different division, and in our phase II, they wanted to wait for that, which is now ongoing, and that's at 900 in lung cancer. Colorectal will all be in combination with anti-EGFR, cetuximab or panitumumab, and that may be 10 patients or so.

Yeah, great. One of my favorite questions. It's importantly a dual on/off inhibitor, so it hits both the on GTP state and also the off GDP state. There are other molecules that only hit the off state, and from what I've seen, they have no clinical efficacy essentially when they're targeting G12D as a single agent. There are other molecules that only target the on state, and we feel like that's a problem, that if you want to target it wherever it lives, and that's what our molecule does really potently. Secondly, there's a very long residence time when it binds. Some agents that we've looked at only last for an hour once they bind. Ours lasts 18-24 hours once it's binding, so it's really holding the target. Ours is extremely selective for G12D. KRAS G12D mutation is not meeting any normal function.

Therefore, that's great tolerability. To the degree that you're hitting wild type, obviously, you get rash and stomatitis and all kinds of unpleasant things that really aren't necessary. I think one thing that people underappreciate is the importance of dose-dependent pharmacokinetics in the patients. If you look at many of the RAS inhibitors, they can't really go to full inhibition of target for one of two reasons. Either their pharmacokinetics plateau out and they can't keep going up, or in the case of the pan-RAS inhibitors, they may be too toxic to go all the way up to maximally inhibit the target. I think one of the things that 900 allows us to do is get really all patients up into the right dose range, and I think that's going to be really important ultimately.