All right, so welcome to the Fireside Chat with Verastem. I'm Michael Schmidt, Senior Biotech Analyst with Guggenheim. And with me today, I have Dan Paterson, President and CEO, and Jonathan Pachter, Chief Scientific Officer. Welcome. Thanks for joining us. Thanks. Great to be here. We have a few topics I'd like to discuss today, starting with your commercial launch in LGSC. Obviously, last week, you reported very strong earnings or sales in the third quarter, which suggests really good commercial momentum, in my opinion. Just remind us of what the Salesforce is currently focused on in LGSC and where you have most of the scripts seeing coming from at this point. Sure. You know, obviously, there's a lot of focus on identifying patients. Working with sites to find out where there are pockets of patients. We've done a lot of pre-work over the last couple of years on awareness. Our MSLs have been deployed for a couple of years. You know, we're finding there's good awareness. Getting appointments is easy. There's demand to come in and talk to folks. Our two big areas of focus are, as I said, identifying the patients. Once a first patient goes on at a site, getting our oncology nurse educators out to meet with the team to make sure they can optimally treat the patient. Because a big push for this launch is keeping patients on treatment once they come on. You look at a lot of oncology launches. Since a lot of these diseases, patients will stay on therapy for three to six months. There is a lot of patients who become available very quickly. What we are finding as we identify the patients, they are still on their current therapy. We have to wait till they either progress or have unacceptable side effects. It is a matter of getting them on and keeping them on. I think what we have seen in the first few quarters is kind of what we expected, it is kind of a steady ramp of patients coming in. There is not a huge bolus sitting out there untreated, and we would not have predicted that. Now the important part of keeping that momentum going is making sure in our clinical trial, we had 18 months on average of treatment duration. We want to make sure we maintain that. If we can, and it appears early that we are, that it tends to have the dynamics more like a rare disease launch where you have to find the patients and keep them on for a long time and build an annuity. Right. Maybe help us a little bit more understand, what has the distribution been so far in patients in terms of coming from large academic centers versus the community setting? Yeah, as you can imagine, because a lot of these sites were our clinical trial sites and they're most familiar with the drug, more than half is coming from the large sites. I am pleased to see a decent amount coming from the community, a decent amount coming from physicians we may not even targeted and have called on. As expected, where we expected the patients, we're seeing them too. I think part of the lift we're seeing is we're getting patients from places we wouldn't have expected early on. Nice. How do you expect that to evolve over time in terms of growth? We hope and would expect that it would continue. We had a very deliberate launch strategy, which is about half of the patients are concentrated in 100 institutions. That's where our Salesforce spends the bulk of their time because that's the bank robbers go where the bank is, if you will, or where the money is. If you look at how the market has evolved, the majority of other institutions that may not be ones that see a lot of these patients tend to be affiliated either with the large practices like a Florida Cancer Specialists, or a TOPA, or US Oncology, or somehow associated with a group purchasing organization. We were very deliberate when we set up our distribution network where we've got a couple of specialty pharmacies, which are important, and that's what we had at launch. Also, the specialty distributors over the last number of years have affiliated with or bought the GPOs and the large practices. So they're all affiliated. We can work through those organizations so that if we have a contract with them, they invite us in when they do their in-services. Instead of trying to show up in an office and get a doctor for three minutes when they're busy, we get invited to their meetings and we'll do a half hour or more presentation on the drug and get a whole ton of docs at the same time. The third leg of the stool is really the outreach we've done to patients. We've continued to do that. It seems like that is bearing fruit. We get a lot of questions, now that you've started, are you going to go after the rest of the market and hire more salespeople? We don't think we need to do that. We think we're covering the waterfront with the strategy we have. We think the resources we're putting on the launch are really right-sized. Hopefully, that'll continue. Great. When we speak with docs, the ones that we speak with are really willing to prescribe also for KRAS wild-type patients, which is obviously not on label right now. I think compared to center of care, there is the perception of benefit. What have you seen in practice so far in terms of use beyond the labeled indication? Yeah, so the majority is labeled KRAS mutant. That is what we would expect. We always modeled that our penetration would be earlier in that segment of the market. We are picking up some KRAS wild-type. Knock on wood, we've not had reimbursement issues with it to date. It may be a honeymoon period, but that seems to be working well. We've got our two publications, one from the RAMP 201 study and then the original FRAME study. In the original FRAME study, actually, the response rate in wild-type was about double what we saw in RAMP. I think having those publications, being able to share them with physicians, which we can, we can't promote off-label, but we can say, here's a peer-reviewed publication, non-promotional. That helps with the education. It is a disease with very high unmet need. It just feels like we'll eventually get almost everyone. You won't ever get 100% penetration. You don't get everybody. Even our messaging from our salespeople out to the market is, if you're on something and you're doing OK, maintain on it as long as you can. This is a marathon, not a sprint. We believe, based on the data, that we're the best next choice. That's what you should try. I think that approach was really reinforced. The IGCS, which is the International Gynecological Cancer Society, just had their meeting in South Africa. We had a group down there. They had the final OS readout of the trametinib study. I think what was really good is it showed a survival advantage for using a MEK inhibitor. It allowed a crossover, and it still showed an advantage. I think the patients who got on the MEK inhibitor early did better. I think that helps reinforce the message. Get a MEK early. We believe, based on the data that we've developed, that we're the most desirable MEK. We think that'll help because there hadn't been a lot of penetration of MEK inhibitors before. Right. Right. OK, that's interesting. I know NCCN guidelines is an important lever to increase awareness among docs. Yeah, maybe talk about how you're tracking towards getting NCCN guideline inclusion. We had our submission, which we understand, or at least we were told beforehand, it would be reviewed at their annual meeting, which was in October. We've been told any updates will come out sometime after the first of the year. Just waiting on that. In the interim, just continuing what we're doing is we've got, I think, a very strong package of data if we get an initial denial to do a resubmission. That seems to be working quite well. We'll continue down that path. I know it's really early in the launch. Next year, will you be able to provide revenue guidance in LGSC? My CFO's looking at me from the back. I won't commit to providing guidance. At some point, we will. I think what we've been really using as our guide to when we give guidance on any given number is when we feel it's predictable, we have good data to support it, and we'll have good trends as opposed to things jumping all over. We're still at a point now early in the launch where it's hard to predict some of the things. A good part of our distribution and support network really only came up in the middle of the last quarter. Q4 will be the first time we've had everything up for the whole quarter. Those things I talked about before, which is the in-services they invite us to and all of that, that really has just started to ramp up. Once we get more predictability, we'll probably give some more KPIs and revenue guidance. You have been enrolling the RAMP 301 study, which is the confirmatory phase 3 trial in LGSC. There has been some discussion as it is coming out of earnings where you announced that you made a slight adjustment to the patient enrollment in the study. Perhaps just walk us through the details and rationale behind this update. Sure. I'll start. Then I'll let John jump in. Back when we planned RAMP 301, RAMP 201 was not done yet. We did not have final results. When you looked at the available comparators, there had never been a study that prospectively looked at KRAS wild-type and mutant separately. The other studies were a couple of years old. They were in an era prior to a lot of bevacizumab use. They had no prior MEK inhibitor. When you looked, they had different lines of prior therapy. We made our best guess on a sample size. We had a lot of internal debate. Should we be conservative and make the study larger? Should we go with our best guess? What we determined when we started to model it was there is an ability to do a sample size reassessment when you had 50% of the events. This was a planned interim analysis. Best-laid plans, the way the accrual curve worked for the study, it started off at a certain pace. It really accelerated. We had a lot of patients that were accrued that have not had events yet. We had less than the planned number of events when the accrual was done. We decided that if we waited three or four months to do the interim, we would lose our study sites. God forbid we had to add a few more patients, we would almost have to start putting the sites back together because they were going to move on to something else. We're blinded to what the IDBC actually saw. They recommended we add a small number of patients. They do not give us the specific reason. It could be just that there were not enough events yet. In studies like ours that have blinded central review, you can have a situation where maybe a patient in the judgment of the local physician has progressed. They take them off. They are supposed to wait till central review. If they did not, those patients get censored. You have fewer patients, therefore fewer events. This was built in as a way to kind of correct for that in a planned interim analysis. John, I do not know. Yeah, the initial trial was 270 patients. They had the option of they could have called it futile, which they didn't. They could have said, need to enroll another 100, which they didn't. The idea of just upsizing it by 29 patients, which is probably about 20 KRAS wild-type and 10 KRAS mutant, and that's split between the two arms, it's really quite incremental. It just tells you that we're very close and in the sweet spot for success. We saw it as a very positive signal. Right. Maybe just confirming, but it sounds like the analysis was done earlier than anticipated and based on fairly immature data. Is that right? Yeah, more immature than planned. Again, this is where when you project these things out, you project the number of events you'll have based on how quickly patients come on, how long they're likely to be on before an event. There is a whole bunch of factors that could have led to it. I think the fact that it's a small number of patients and it's both the KRAS mutant and wild-type, we view it as very positive. We'll wrap that up pretty quickly in the first quarter. An optimist might say it's a minor adjustment, which suggests you're really close to the target. Exactly. OK. Yeah, based on that, I guess, what is your current projection in terms of timing of the top line data readout on the study? We're projecting we'll finish the final accrual in Q1 of this year. We should have the PFS readout probably second half of 2027. Gotcha. Any updated view or confidence even that this study succeeds on both the mutant and the wild-type KRAS population? Yeah, I would say the fact that because they could have easily said only add patients to the mutant. That gives us confidence. I think that both are in the ballpark. We just have to play it out. Makes sense. I think in the past, you've talked about a $4 billion TAM in LGSC across both wild-type and mutant patients. Any updated views on the size of the opportunity now that you are in the market? I don't think we've seen anything that would change our view of the market. We've never given projected peak sales. I think the analysts are running where from $200 million-$300 million up to $600 million plus. I don't think we're seeing anything that changes that. I think the fact that both the 201 study and the 301 study accrued faster than we expected tells us there are definitely patients out there. Our Japanese bridging study accrued very quickly. We are confident there are patients out there. We think a lot of times when you have a disease where there is no specific treatment, there's not a lot of effort to identify those patients. Just to remind folks, there is no ICD-10 for LGSC. The coding lumps them in with ovarian cancer. It literally is what's on the PATH report that would distinguish them. If you did not have a different treatment for them, you probably would not pay a lot of attention to that. We think the awareness of the disease is going up. There may be more out there than we thought. OK. OK, so we'll keep our eyes on that. Maybe shifting gears over to VS-7375, one of your key pipeline drugs, your KRAS G12D inhibitor, which you in-licensed from GenFleet, a company in Asia, who presented several updates recently at ESMO and perhaps even subsequent to that. Just remind us of how you think the phase I data has evolved this year and how it stacks up in a category. Sure, John. Yeah, great. Yeah. There have been a number of presentations that were along the KRAS G12D. First of all, it's an on-off dual inhibitor, which we think is really best in class. RevMed agents only hit the on state. There are others, like Quanta, that just presented at the triple meeting that only hit the off state and do not show much single agent activity. We think from preclinical modeling, it's really best in class. Along, at the recommended phase II dose in China, GenFleet reported the 69% response rate. That's in lung cancer, obviously. In second plus line pancreatic cancer, they gave an update at ASMO. More recently, Dan and I were in Shanghai a couple of weeks ago. There was a joint investor event between RevMed and GenFleet. I should say, just for this audience, GenFleet has. Verostem. GenFleet. What did I say? You said RevMed. Wow. That would be an interesting investor event, actually. Oh, that's interesting. GenFleet has China rights. Verastem has ex-China rights. They're moving very quickly in China and generating a lot of data. At ASMO, they reported on just the pancreatic cohort. In the investor event that we just did, they did a subsequent analysis of just the second line versus third line plus RevMed. I got the name right there. Typically, reports only second line because they don't work as well in third line plus. What GenFleet showed is that in second line, it's a 58% response rate in pancreatic cancer at the recommended phase II dose, so really best in class, really kind of playing out what we saw preclinically. That's very exciting. It opens up a lot of doors. I think when you think of accelerated approval paths, the RevMed agents, for example, their G12D had about a 30% response rate in second line pancreatic. And their PanRAS had a 29%-35% response rate. We're sitting at 58% response rate and 69% in lung. As I said, that opens up potentially accelerated approval paths. I think it's likely to be even more active in front line. Even single agent in front line would probably outdo chemo but maybe a viable path as well. So we're very excited about all that. A couple of questions in the investment community. One is on the tolerability profile, which I know there was some discussion of some of the GIAs that are a little bit higher perhaps than expected based on the selectivity. Maybe talk a bit about your own phase I study in the U.S. What are you doing to perhaps reduce some of those side effects and how that's been going? Yeah, it's a great question. Right, in the GenFleet trial in China, they only have fasted patients. They didn't allow prophylaxis in their phase I. In the phase II, they're allowing prophylactic antiemetics but not mandating them. It's hard to see a direct correlation on safety profile. In the trial that we've now started in the U.S., which we're now expanding to Europe as well, we cleared the 400 mg and 600 mg cohorts, which are both we know are active doses. We didn't see any nausea, vomiting, or diarrhea that was greater than grade 1. The difference is that we have fed patients that we're starting with. Also, we're using a prophylactic antiemetic. Those measures seem to be really helping. The other thing on the side talking about adverse events, at ASMO, GenFleet presented a slide. They showed treatment emergent adverse events and treatment related. What's really striking there is that they're almost identical between treatment emergent and treatment related. Typically, in China, they tend to report everything they see as treatment related without really making a distinction. Whereas in the U.S. and Europe, when you look at data from others, they almost never share their treatment emergent AEs. They only show the treatment related, which looks better. I think, again, it's an apples to oranges comparison. Certainly, in our trial, we have very experienced investigators, the David Hongs and the Melissa Johnson, who will make really good determinations about what's treatment related. I think the AE profile is looking promising. Also, I think in the RevMed, sorry, yeah, in the RevMed, Darix and Raseb, about 10% of patients with single agent Darix and Raseb had to discontinue for adverse events. In GenFleet's trial, it's been 3% or 4%. I think the tolerability has been fine as far as allowing for the efficacy. Yeah, I mean, we think our objective in the U.S. is to show equivalent efficacy to what was seen in China in better tolerability. And we think if we can do that, that bears out the preclinical profile. Yeah. Is there any reason why or how confident are you that the efficacy aspect of the data, the efficacy, translates to the U.S. study? We know that prior therapies are pretty similar now. That is one variable to think about. GenFleet also showed what the co-mutations were. I'd gotten questions before, maybe keep one in STK11. These things are different in China. They are showing that those are pretty prevalent in China as well. Looking at those variables, it seems to be similar. Now it is just a show-me story to see what we see in the U.S. I think by mid-year of next year, we would like to get out with some data from our trial. OK. I know some of the investigators were enthusiastic about it. Just remind us of how you're enrolling patients in the study in terms of the doses that are being selected and how that's been going. Yeah, so it's initially the single agent dose escalation. Again, we cleared 400 mg and 600 mg. We're looking at one higher dose before we finalize the recommended phase II dose in the U.S. It could end up being very similar or identical to what they've chosen in China. That might open the door to combined data and maybe get to breakthrough therapy designation faster, for example, by drawing on data from both China and the U.S. Once we cleared the 600 mg cohort, we also opened several combination cohorts. We're combining with Cetuximab. As a single agent, we haven't seen rash. That should be quite promising for colorectal cancer, combining with chemo pembrolizumab to get into front line lung, and combining with gemcitabine paclitaxel to get into front line pancreatic. These are key combinations. Preclinically, we're modeling combination with our FAK inhibitor and our RAS/MEK inhibitor. These look promising as well. We might think about moving those forward at some point. I want to make sure we don't gloss over that point. I mean, we submitted Chinese clinical data in with our IND, which allowed us to start at the 400 mg dose, which was an active dose. That probably cut six to nine months off the phase I program. We're going to continue to try and maximally leverage data out of China to the extent it's consistent with what we see in the U.S. We think we can do that. I have been really impressed with how quickly GenFleet has been able to accrue to these studies. They've just moved incredibly fast. What is GenFleet doing around combinations? Is there any data that they may be generating that you could leverage in the U.S.? They've started combinations. Actually, I think they started their phase III in pancreas as well. Again, they're going very fast. We stay very close to them. We have calls every week. We were over there on a planning session a couple of weeks ago and really trying to maximally leverage the data that comes out of there as appropriate. To the degree that we take different paths, then we'll learn from each other. That's also really fruitful. OK, great. Thank you. Unfortunately, we have to wrap up. Really appreciate it. OK, pleasure. Really appreciate it. Thanks. Great to be here. Thanks. be here. Thanks.