All right, great. Thanks. Welcome to this next fireside chat with Verastem. With me today, I have Dan Paterson, CEO, and Jonathan Pachter, Chief Scientific Officer. Welcome. Thanks for joining us. Great to be here. And so again, my name is Michael Schmidt, Biotech Analyst with Guggenheim, and we'll jump right into Q&A. So Dan, Verastem had a very productive, busy 2024, which set up a few key value inflection points in the coming months, most notably the upcoming potential U.S. approval of avutometinib and defactinib. And so just to kick off the discussions, could you just provide a quick overview of where the company stands in terms of the pipeline right now and sort of near term? Sure, sure. No, 2024 was a good year for us, but I think 2025 is going to be a transformative year. So we have our NDA under review for avutometinib and defactinib in low-grade serous ovarian cancer. We announced December 31st the NDA was accepted with priority review. And so that's ongoing. We have almost daily interactions with the agency, and so that's proceeding to put to bed any concerns over what's going on in the administration. They are actively reviewing the drug, and we do hear from them every day. So that is ongoing. The other big things coming up for us, in addition to the launch, we will have additional readouts in our frontline metastatic pancreatic cancer study that's combining avutometinib, defactinib with Gem/Abraxane. We reported early data at ASCO last year where we had an 80%+ response rate, and we'll have a meaningful update on that this quarter. We gave a quick update on our combination with sotorasib. The exciting thing there is we did add defactinib in, and it's now a triplet, which was always the plan. And first, we reported the first three patients that were treated with that triplet combination in the first scan to have had at least a 20% tumor shrinkage. So we're excited to update on that kind of mid-year. And then really exciting is our G12D inhibitor that we licensed from GenFleet. We announced JPMorgan Week that we exercised the option early on that. And the reason we did that is our three criteria were, first and foremost, we wanted to see acceptable human PK because bioavailability has been a challenge orally for these drugs. And we are seeing blood levels, even with protein binding, well within what we think we would need based on preclinical data to see efficacy. We've also seen accompanying efficacy in both lung cancer and pancreatic cancer. We've seen multiple responses already. And then the last piece was really safety, and dose escalation has gone through six treatment levels with no dose-limiting toxicities. So between the launch, the label expansion, and then the G12D program, we think 2025 is going to be a really transformative year for us. Yeah, for sure. A lot of moving parts. So maybe just going through that in a little bit more detail, sort of starting or going back to your RAMP 201 study in LGSOC, again, where the FDA decision is coming up this summer. And so as we think about the commercial opportunity there, maybe remind us on how the data, the clinical profile in the results, really provides the treatment options for these patients and how does it compare to standard of care. Yeah, so low-grade serous ovarian cancer, unlike high-grade, is very resistant to chemotherapy. And so standard of care is actually right now the same as high-grade, although there's been very little studying of these things in LGSOC. There's been two big studies that were done. Based on those studies, standard of care, you'd expect anywhere from 6%- 13% response rate. And we're seeing across the whole population a response rate above 30%, and in the KRAS mutant, 40%. And so we think much better efficacy profile. Safety, we've had about a 10% dropout rate due to AEs. Standard of care, much higher than that. And I think importantly, even though these aren't regulatory endpoints and really won't factor into the accelerated approval, but we think will factor into adoption, is 82% of patients, regardless of KRAS status, had some level of tumor shrinkage. And when you talk to the key opinion leaders, you know this is a tumor that can get bulky in the gut, and any level of tumor shrinkage is good because what they fight off is not having to have secondary surgeries or to have blockages based on the tumor growing. So the vast majority of patients having tumor shrinkage is a big deal. And then the other thing that's really important to them, and again, not a regulatory endpoint at this point, but so-called clinical benefit rate, which is the percentage of patients that have CR/PR or stable disease of at least six months. Across the whole population, it's 60%. And even with the wild type, which has a lower response rate, it was 50% and 70% in the KRAS mutant. Those are things that really matter to physicians when they're trying to decide what treatment to use. So we're very excited. The feedback we've gotten from the KOLs is very positive. We've been engaged with the patient groups for a number of years. This is the kind of market where we think a company of our size can get our arms around the market quite easily. Then you look at the relative pricing of newer drugs for smaller indications more recently. Pricing is relatively high. Then because patients, the mutant in particular, stay on therapy for almost two years, it's much more like a rare disease model where you develop an annuity over time versus patients cycling on and off therapy every three months- six months. We think it's likely to have a modest initial uptake, but when they build over time, it should build quite an annuity and a pretty big market opportunity. Right. And so you recently talked about some additional data analysis and disclosures on the LGSOC data, including, yeah, again, some more analysis of the FRAME and RAMP 201 study. Anything investors should expect there as it pertains to some of those? Yeah, so the publication for FRAME will be coming out, and we haven't given updated data on that in a little while because that was an investigator-sponsored study, and they wanted to get into a good journal, so that manuscript should be coming out, and then we do have a medical meeting coming up in the next quarter where we'll be breaking out more subgroups looking at things by line of therapy and different types of therapy, so giving a little more depth to the data we presented in Dublin late last year. Okay, great. And then so the initial approval presumably will be in the KRAS mutant LGSOC. Our expectation is it's likely to be a KRAS mutant for the first indication. The way accelerated approval works, it depends very heavily on two things. One is response rate, and the other is cross-trial comparisons, which by their nature are dicey. Arguably, the 17% response rate that we saw is at the low end where the agency has granted accelerated approval, so we're not expecting it. And then the other challenge is there's never been a prospectively designed study that broke out wild type. And so when you've got an ad hoc retrospective look at wild type and the number is numerically on the lower end, it's a lot to expect to get an accelerated approval for that subset. Having said that, we do believe, based on the totality of the data and the feedback we've gotten from KOLs, we believe our chances of getting on the NCCN guidelines regardless of KRAS status are quite high, and there are other drugs on the NCCN guidelines that are not nearly as favorable profile, and so we believe that's the important thing for both reimbursement and adoption. Right. And then obviously the confirmatory phase III study, the RAMP 301 study is now ongoing. And obviously that's in the all-comers setting. Perhaps talk just about how enrollment has been going so far and also your confidence in the positive outcomes in all-comers. Yeah, no, great question. So obviously in discussions with our steering committee, which is ENGOT and GOG, so the big gynecology groups, they were very excited to have both wild type and mutant included. The FDA agreed. The studies grew quite well, actually probably better than we expected and well within what we think we need based on our discussions with the agency to not slow down accelerated approval at all. The confidence in the outcome, even for wild type, really has to do with that disease control rate or clinical benefit rate I mentioned. The clinical benefit rate is, again, CR/PR plus stable disease of at least six months. And that's a decent proxy for PFS, which is the primary endpoint for the study. And that was much closer to mutant in the 201 data than response rate was. And so we feel reasonably confident, I'd say very confident, that we'll have a positive outcome for both in that study. Right. And then as we think ahead to the post-approval timeline, suppose June 30th and the commercial launch, perhaps just discuss what you have been doing to prepare commercially for the launch in the U.S. and, yeah, how investors should think about perhaps any analogs as it pertains to the launch trajectory. Sure. Yeah, we've been preparing for launch for well over a year right now, as one has to do because there are precedents for drugs with breakthrough therapy designation and priority review being approved before the PDUFA date. We're targeting before that because we want to be able to launch into the channel the week we get approval. We've been working with patients for over two years now. We have an unbranded patient website called Let's Talk About LGSOC, which is really meant to educate the community on the differences between LGSOC and other ovarian cancer. Because of the way that site works, patients are able to opt in, and we've had over 2,500 patients opt into the website that we can communicate directly with. We've also been working really closely with the HCP community to educate on the differences in the disease, and awareness around the disease and our drug regimen has gone way up based on those efforts. And so that's underway. We announced at JPM Week a strategic partnership with IQVIA. The reason we put that in place is you look at a small biotech that's launching a drug, and you have the collective wisdom of the people you've hired, and it's not hundreds of people. And you look at an IQVIA, and they've literally participated in hundreds of launches. With the pharmaceutical market evolving the way it has over the last few years, access challenges, the growing role of digital, we felt the ability to tap into that knowledge base and then, importantly, tap into their infrastructure because they've got world-class data infrastructure that will allow us to understand what's going on in the market and react quickly. We've thought that was really important to have that kind of heft behind us. So we're prepared for the launch. The way we think of the market is really in three segments. About half of the patients are seen at large centers. So 100 centers cover half the patients. That'll be the primary role of both our sales force and then obviously the MSLs who've been out in the field for two years now will help drive that. The other half of the patients are at smaller community centers. The majority of them belong to the large practices that are affiliated with the group purchasing organizations, the GPOs. The GPOs are associated with or owned by the distributors. Those will be our limited distribution network. And the way you get to those is not one-on-one detailing because they don't want their doctors to see sales reps, but they actually have monthly in-services where they invite their partners, which we would be one in, to educate the physician groups. And then they're very guideline-driven, and the guidelines are actually embedded in their electronic medical records. And so we're doing all that now to really prep for that. And then the third leg of the stool is really the patients and being able to reach out to them. Right. How quickly do you think this could be included in NCCN treatment guidelines? We would expect to be included, I would say, within a month or so. When we launched duvelisib, our prior drug, one of the things that went well was getting on NCCN guidelines in about a week. And when a new drug gets approved, they tend to have a proactive meeting. You don't have to wait for their regular schedule. We've already started the process. A key part of that process is having a peer-reviewed publication, which has already been submitted. So we're well on the way for getting all that done. Okay, great. And then I think in the past you've discussed a $4 billion total market opportunity for this. Perhaps can you just break it down a little bit more and how you think about perhaps the incidence-driven opportunity versus a prevalence market that you think there is? Yeah, I mean, when we think of the market, there's really four segments. It's taken a while to educate the market around this because typically when you think of a cancer indication, you look at the incidence because it's kind of one and done. You get a chance to get someone, and then you kind of move on. Lung cancer is a good example of that. The difference with LGSOC is these patients go through, on average, 10 years of cycling through therapy. You have the newly relapsed, and our label is likely to be after one or more prior therapies. That would be a key part of the market. That's probably $1.5 billion just in its own, and that market refreshes every year. A segment of that, probably 30%, is mutant, and about 70% is wild type. Then you've got what we call the prevalent population. So these are the pool of patients that may have been through one or, actually, in our study, up to 11 prior therapies, but there's this pool of patients out there. They're not well served right now. And they tend to have more mutant than wild type because the mutant patients live on average 12 years and wild type seven. So that pool gets enriched over time. And that's the segment that, the way we've modeled it, that big pool we should be able to penetrate over three to five years. And then the incident group refreshes every year. Gotcha. Okay, cool. And then how should folks think about the ex-U.S. opportunity? Obviously it's a big world. We've probably made the most progress in Japan. We're doing a small bridging study that should be able to give us conditional approval relatively quickly. That study is occurring quite well. We will then roll those sites into our 301 confirmatory study, but we think we can get conditional approval off that study. Europe, there's a question on whether we'll be able to get approval based on RAMP 201, or oftentimes they like to see randomized studies and survival. We've started those discussions. Part of what we're doing is a lot of the groundwork we had to do in the U.S., which is first educating that it's not ovarian cancer, that it's a very different disease, work on getting orphan drug status. And then we'll have the formal discussions around, do we need the 301 study or can we get an approval on 201? Okay. And then China, we're having discussions, but and again, when we've done this before, we did a relatively small bridging study to be able, but we're not as advanced as we are in Japan right now. Okay, great, so then maybe switching gears to discussing some of the other opportunities, and so maybe first in PDAC, you mentioned some early data last year. Just remind us just to step back where you see opportunity for your combination, perhaps relative to other emerging therapies, and then what additional data we should see this year? Sure, John, you want to? Sure, so yeah, as Dan mentioned in the first cohort, what we reported initially was an 83% response rate in previously untreated metastatic pancreatic cancer, so five out of six patients responding. What we're currently doing in that trial is optimizing essentially the chemotherapy to get the best risk-benefit, and that's something that we'll be giving an update in the first quarter, and by the middle of the year, we expect it, we'll announce the recommended phase II dose, which cohort is moving forward into an expansion phase, and ultimately, the registration path would then be to compare to standard of care chemotherapy alone, such as Gem/Abraxane. Yeah, and for context, Gem/Abraxane is a single agent and frontline is anywhere from 23%-36% response rate. And so if we can stay north of 45%-50%, we think it's quite an interesting signal. Right. And, will we get any visibility on duration or PFS this year? Yeah, so we'll likely have PFS. We won't have OS. But as you may know, even though we track response rate as an early indicator in pancreatic, if you talk to any of the physicians that treat it, it's really PFS and OS. And unfortunately, those are short endpoints in that disease. And so you can measure them, but we will have some level of durability as well. Gotcha. Okay. And then just maybe stepping back, how do you see this position relative to other emerging therapies? There are pan-RAS inhibitors that are being worked on and perhaps other things. I think in frontline pancreatic, we're well ahead. I think the pan-RAS are looking to combine with chemotherapy. They haven't released any data yet to my knowledge. I think they're really early in that regard. I think the really strong response rate really compares favorably to, for example, RevMed's. In second line, they're about a 30% response rate. So the 83% response rate we've seen is quite different from that, obviously, but we'll see how that progresses. Right. All All right, so looking forward to seeing more then here soon and then in the middle of this year. And then, yeah, you mentioned the combination with sotorasib. Just remind us where you are with those activities. Yeah, so we've always been very interested in our FAK inhibitor, defactinib. And when we initially talked to Amgen and when we set up the joint steering committee, we decided to start with a doublet of sotorasib with our RAF/MEK inhibitor, avutometinib. Now that we've seen that firmly that that's well tolerated, we've now added the FAK inhibitor, which has always been our intention. In the first three patients, we just reported recently that the tolerability was very good, even though it's a triplet. And also, these are patients that have been previously treated with a KRAS G12C inhibitor and progressed. And two of the three patients had at least a 20% reduction on their first scan, and we continue to follow those patients. I think it could be pretty soon that cohort is essentially the recommended phase II dose that's going forward in LGSOC with full dose sotorasib. It could be quite quick to substantiate that as a recommended phase II dose and then get into expansion cohorts in lung. I think the importance of this is really, well, so the expansion cohorts would be both G12C naive and pretreated. But the other thing that the preclinical data are really spectacular for how the FAK inhibitor helps. We know that it helps in LGSOC with the avutometinib. The agency has accepted that contribution. There was a presentation at ASCO by another company, which had a doublet of a G12C inhibitor and a FAK inhibitor, and they saw a 90% response rate in previously untreated lung cancer, which was astounding, and there was a tremendous reaction at ASCO. So we're very excited to see the contribution of the FAK inhibitor. But if that really hits, as we expect it would, that's not just sotorasib. That would resonate across all G12C inhibitors, but even more importantly, for our G12D program, for the KRAS inhibitors in general, our FAK inhibitor, which we think is best in class and would likely be approved by the middle of next year in its first indication, we think could really combine with a lot of things really important. Yeah, we think this is potentially the year of FAK. I mean, John and I both bear the scars of our 12 years with the FAK inhibitor. It's tough developing a drug with no single agent efficacy because general dogma is you just kill it. And we had such strong preclinical data, we wanted to see it through. And I think the RAMP 201 study was the first time we showed in the clinic that it really added benefit. And now, assuming the preclinical data we saw with sotorasib and avutometinib holds up, we should see that in that study as well. And in pancreatic cancer, we had applied to PanCAN, the Pancreatic Cancer Action Network, for their Therapeutic Accelerator Award. And we were the single recipient that year of that. That was the first time they had that. And so they gave us $3.8 million to run that trial. So really nice that that's not on our dime, but even more importantly, gave us access to their network of excellent investigators. And many of those are also going to be investigators on our U.S. KRAS G12D trial. Right. And so there are obviously other second generation G12C inhibitors now available that are better than sotorasib. Is that part of your plan to perhaps expand activities there with other G12C or other RAS inhibitors? As I said, it's really a proof of concept study. If the FAK inhibitor is clearly helping as we expect, it would certainly make sense for all G12C and more broadly among the KRAS inhibitors. So yes. Okay, great, and then maybe just the last couple of minutes, let's just talk about your D inhibitor real quick from GenFleet. Maybe first, yeah, how did you, I guess, what are the characteristics of the molecule that made you license it in the first place? Yeah, well, let me start by saying GenFleet, we scoured the earth for a good partner to, we're really trying to consolidate our approaches around RAS-driven cancer types. And GenFleet actually had generated the G12C inhibitor, which last year they just announced it was the first to be approved in China. So they've really demonstrated what they can do. It's really an excellent collaboration for us based on their discovery capabilities, but also the economics of it. So we've chosen three targets around RAS-driven cancers, the G12D being the most advanced. The agent that we're advancing hits the on and the off state, which is really important. RevMed only hits the on state. Others like Lilly and Quanta only hit the off state. We think it's really important to hit both states so that the KRAS G12D has nowhere to hide. The oral availability that we've seen clinically is excellent, as Dan mentioned. We're getting to exposures that correspond to where we've seen very deep regressions across all preclinical models. And I think, so I really think it has great potential to be best in class. Right, and then you mentioned, or you started talking more about the initial phase I study that was done in China, right, so remind us again, what was done there and then what the path to the U.S. is. Perfect. So So at the time, we released some information shortly ago. And at the time, there had been 26 patient doses with single agent in that study. They had gone through six expansion cohorts, I mean, dose escalation cohorts and seen no dose limiting toxicities, which was excellent. Again, good oral availability and, as Dan mentioned, clear partial responses in both lung cancer patients and pancreatic cancer patients. Our intent is to start where they left off and go from there. We're not going to redo the escalation in the U.S. We're going to leverage that data as much as we can. We've already chosen the sites in the U.S., which are really the best of the KRAS experts in the United States. And so that's, so we're going to redo a phase I-ish type study. So we said that we'll submit the IND this quarter, and we would open it by the middle of the year in the U.S. Then ultimately, how do you think about path to market? Is this sort of a monotherapy play in PDAC and lung or are there other opportunities? I mean, I think in pancreatic, there's room to beat RevMed if we're north of 30%, which given what we know preclinically, we're optimistic about that. And then in something like colorectal, we know that the pan-RAS from RevMed has a 9% response rate in colorectal. It's plagued by 90% of patients having rash, whereas we expect we'll have a much better time combining with an anti-EGFR like cetuximab. So that should be a great opportunity too. Right. So the next, and then I think you presented China phase I data formally. Yeah, I think at a medical meeting this year, yes, in the mid-year roughly. Okay. So we'll look forward for that mid-year conference. And with that, I think it's time to wrap up. So a lot going on. Lots of catalysts in 2025. Appreciate it. Well, thanks for your time. All right. Thank you. Thank you to all of you.