This morning we've got Dan and Jonathan from Verastem. Thank you so much for joining us this morning. As we jump right into it, obviously the bulk of our questions are going to be on AVMAPKI pathway and on KRAS, but I'll give you just a minute or two to introduce yourselves and the company and talk to us about what you want to talk about. Sure, sure. Dan Paterson, President and CEO. You know, we're developing small molecules that target the RAS pathway. I think we're in a unique position here in that we actually have a drug that launched, so it's actually two drugs that launched together: avutometinib in low-grade serous ovarian cancer, which is a rare, underserved population of ovarian cancer patients, and then have been attracting a lot of attention with our G12D inhibitor, which, you know, John can describe, you know, why we think it's potentially best in class. We're going to have to move very quickly in the clinic with that while managing the launch, and you know, that's been the interesting dynamic, but we think 2026 will be a really important year for us. I'm John Pachter, I'm Chief Scientific Officer. John and I have both been there about 14+ years, kind of from the beginning, so this is our baby, but this is really the heyday of, I mean, everything's coming to fruition all at once is really exciting. We've really tried to build a cohesive platform around targeting RAS-dependent cancers, and that's really paid off in terms of investigator relationships and the ability of our drugs to work together, but it's enabled us to move the G12D inhibitor really quickly now too, so exciting to talk to you about it. Excellent. Let's start with the launch. What are our expectations coming into 2026 here? How are you having conversations with investors about it? I mean, obviously the launch evolving in 2025 was very interesting, but what have been the, what were the sticking points in 2025? How do you expect the market to evolve? Yeah, I think it was really two things. One was what is the ultimate market size? You know, I think there's still questions around that. You know, I think every quarter where we perform well, I think we're putting that to bed a little bit. That was really a big issue. The, you know, the whole dynamics around the launch, you know, is there going to be a big bolus of patients? Are there patients sitting out there? We've said all along, and I think what we really are seeing is, you know, this is a disease where they need pretty much constant therapy, so there's not a bunch of watching and waiting sitting out there. You know, what we're seeing is what we predicted, which is when a patient comes off their current therapy, either due to disease progression or intolerability, that's when we want them to switch to our drug. We believe they should be the first switch. We're working on really getting that messaging out there, but it really is kind of a, there's a lot of patients we're tracking and they're doing okay on their current therapy. They will come off eventually. They will eventually come off, and, you know, this is a disease where it's a marathon, not a sprint, and they should stay on their current therapy as long as they possibly can, and then we hope we're their first choice after that, and that's the dynamic I think we're seeing, and, you know, hope to continue that. In 2026, you know, I think we've got some work to do. I think, you know, we're not going to give guidance, but consensus is all over the map and trying to tighten that range a little bit, you know, and work through that, but, you know, it really is continuing to deliver quarter by quarter as we make great progress on the G12D asset. How does that market break down? When we think about consensus being all over the map, and we think about the launch dynamics being all over the map from the street perspective, how does that market break down among key categories? You know, obviously we talk about academic versus community, but there are multiple lines of therapy. As you say, it is a marathon, not a sprint. What are the key subgroups here that we should be tracking? Yeah, I mean, so it's a very interesting market. Women can have this disease for quite a long time. You know, they live with it on average 10 years. The KRAS mutant, interestingly, and it's different from other cancers, actually do better, and so they live for on average 12 years, where the KRAS wild type, it's roughly seven. You know, the way it breaks out, roughly half the patients are at about 100 institutions in the country, and so that's the main target of our core sales force, calling on doctors one-on-one. A good portion of the rest of the market, which is out in the community, are affiliated with very large practices that have GPO contracts, and we contract with the GPOs. Our closed distribution network is the distributors that are associated with those GPOs, and as part of our contracting with the GPOs, we get invited in when they have meetings. Instead of trying to reach every single doc in those networks, we'll call on the prominent ones, and it really is the GynOnc that I think drive a lot of this market, even though you'll see a lot of medical oncologists prescribing things that tends to be the infusional therapies because they have infusion chairs and the GynOnc may not. Right now we're seeing the majority of prescribing is driven by the GynOnc. I'd say our mix of community and academic is probably slightly skewed towards academic right now, which you would expect in the early time of a launch because the KOLs are there, they have more experience with the drug, they're on the trial, and really just now we're starting to see the impact of getting those distributor and GPO contracts in place, and hoping to see that lift continue. We've been surprised at how well the launch has gone. You know, hopefully it will continue. We had to scramble quite a bit at the beginning because we're approved almost two months ahead of our PDUFA date, which, you know, as you're trying to balance spending and when you have things ready, you know, you always identify the things with a long timeline that you can't impact and you make sure they're done early, and then there are other things you can scramble around, and there was a bit of that, but now we've got everything in place and looking forward to delivering, you know, quarter by quarter as we continue to make progress on the G12D program. Fabulous. One more question on the launch. You submitted for NCCN guidance already. How do you think about the potential changes in guidance, I should say, impacting uptake in the market and the overall size there? Yeah, I mean, I don't think it impacts the size. You know, we've been told we should see an update in the guidelines sometime after the first of the year. I think it probably impacts launch trajectory more than anything else. You know, the majority of patients we get now are the mutant. We are getting some wild type. We're also getting some that were just totally off-label. You know, I think that will die down over time. You know, we are still getting good reimbursement. Patients are getting on drug relatively quickly. It's getting paid for. We're not giving away much free drug. Our patient copay assistance program is very active. You know, we felt very strongly and, you know, frankly, I think one of the best parts of IRA is the out-of-pocket cap for Medicare patients because we could never directly help them, and that's great. On the commercial patients, you know, we've got, you know, pretty high income limits to do copay assistance to make sure there's little to no burden based on the copay, and as a relatively rare disease, you know, we're not doing to insurance companies what Wegovy is doing. You know, that's their big concern these days, and so it's really just making sure that we can get the drug available to patients and they get on. Importantly, given the long length of therapy that we saw in the clinical trial, it is translating that into real-world use, and we have oncology nurse educators that when we get a first patient from a given practice, we get them in there to educate the whole staff on how to optimally treat the patients, what to look for, and, you know, they have been really busy, and so that is a good sign. Okay. Let's talk a little bit about RAMP 301 then, I guess. Added more patients on IDMC recommendation. You talked about the enrollment being complete next quarter. When do you be comfortable giving guidance onto the readout timing? Just real quickly, when we designed the trial, our 201 trial wasn't done. There weren't other clinical trials that had been done that prospectively broke out mutant and wild type, and so, you know, we had comparators that we had to do our best guess, and we could have sized the trial quite a bit more, or the alternative we were given by the statisticians was when we have roughly half the events, we would do a planned interim analysis and see if we were in a zone of promise, which means we're doing pretty well, and then we could either keep the trial the same or add up to 100 patients. We were advised to add 29 patients, which tells us we're doing quite well. They had us add patients to both wild type and mutant, so we think that bodes well. What we've guided on interim, or really initial results from the study, which would be the PFS, which is the primary endpoint, probably second half of 2027. We don't really see that changing from where we are. Where since it's event-driven, as we get closer, we'll probably be able to give tighter guidance, but obviously anxious to get that data out there. Yeah, makes sense. How are you thinking about the performance of investigators' choice as a comp arm these days? Anything to bear in mind as we think about those different geographies? You know, we specified five investigator choice ones that we agreed with the FDA and our steering committee that were properly appropriate. You know, in prior studies that were done, the trametinib study, for example, there were a couple of standard of care therapies that had 0% response rate that just aren't included in the bucket anymore. It's going to be hard to compare across the trials because we've got, again, the prospective breaking out of wild type and mutant, which wasn't done in prior trials, and then slight differences in the comparators, but, you know, we are feeling pretty good about the study after the interim analysis and, you know, looking forward for the ultimate result. Great. Maybe let's pivot to KRAS, and John, we'll get you in here. How do we view the current competitive landscape? I mean, obviously KRAS as a space has been very interesting to people for quite a while. There are multiple other approaches, multiple mechanisms of action. We're all trying to comp, you know, what's your current take? Yeah, there are pan and there are variant selective. You can be, there's a RAS multi from RevMed, which hits RAS regardless of the RAS type, and then you start to hit normal cells, so you get more RAS. You probably knock out T cell proliferation, which is RAS dependent. There are reasons to prefer variant selective. There are the pan KRAS that only are KRAS selective. Interestingly, although they've been in clinical trials that go for a long time, we haven't seen anyone present, so I think there's something not working there. I'm not sure exactly what. There are folks that still promise they're going to give us data next year. Okay, we'll see. Then the G12D, which is where we are. The breakdown is also, do you hit the on-state, the off-state? Both. Do you hit both? I think Quanta at the triple meeting has an off-selective. From what I could tell, they didn't have any single agent activity. G12D tends to like to be in the on-state, so hitting the off-state only is even less effective than it was for G12C. RevMed has done a nice job of educating the world that hitting the on-state is better than hitting just the off-state, but with their RAS multi daraxonras ib, it's also been shown that it converts the on-state to the off-state, which sounds like good news, but basically it's converting to a state that that molecule, which is not covalent, cannot bind. What's really exciting about ours is it's with low picomolar, so very high affinity, it's binding both the on and the off-state of G12D similarly, so that there's no place that the KRAS can hide. As you look at preclinical and clinical data, that really seems to be the magic. We see in the preclinical data when we compare it to RevMed, which we see as our main competitor at this point. Also getting most of the attention, I think, in the space. Yeah, that's right. I think that what we see is if we use the maximum dose that they use preclinically, we see better durability in G12D models preclinically and also better regression. As you turn to the clinical data, in lung, it was shown, so generally I should say, is running really quickly in China with the molecule, and we're really learning from that. That's really benefiting us as we design our whole registration plan. What they reported to the world in lung was a 69% response rate at the recommended phase II dose, which really is best in class mapping with the preclinical data, the dual on-off. Recently it was shown that in second line pancreatic, they're seeing a 58% response rate at the recommended phase II dose, specifically looking at the second line pancreatic patients. That 58% response rate you could compare to 30% for the G12D from RevMed or 29%-35% in the second line for the RAS mutant. Again, really best in class, really exciting. Although it bears mentioning in the GenFleet data, they do have tolerability concerns, especially around GI, which maybe don't mirror RevMed's tolerability concerns exactly, but they don't feel unrelated either. How do we think about that? Yeah, let's dissect that. Right. First of all, let's separate out RevMed's G12D from their pan RAS. Their pan RAS, because it hits RAS broadly, stomatitis, rash, GI toxicity, I've heard it's not easy to give. For example, in frontline pancreatic, they had 10% of their patients discontinuing for adverse events. They also give like a gram and a half of this stuff. It's a lot of. They're giving a lot of drug. Gently has reported, I think it's been 3%-4% of patients that have to discontinue for tolerability. One of the differences is that GenFleet, when they ran the trial, patients are fasted. Patients, they didn't allow prophylaxis in the phase I especially. In our trial, we're feeding patients and we're giving the first two cycles prophylactic antiemetics mandatory. These are just common practices in the U.S. for RAS inhibitors, and we've seen that we didn't see any nausea, vomiting, diarrhea greater than grade one. Those measures have really worked out nicely. The other thing that's really fascinating in China, investigators typically don't like to make a call between treatment emergent and treatment related adverse events, so they show them as pretty much identical, whereas people absolutely make that call in the West, and you'll see RevMed, for example, would never talk about the treatment emergent AEs. They talk about the lower number, which is treatment related. There are a lot of apples and oranges. There are reasons why they tell us never to compare between trials, and we all do it anyway. All right, makes sense. While we, yeah, so we talked a little bit about the Chinese data. While we're on the topic, you know, maybe can we talk about the path forward in these different geographies and what we should be expecting when from you versus the collaborator? They're continuing to move quickly. They've started a phase III trial in China. They've started combinations as well. In our study, we're getting through the recommended phase II dose single agent. I would guess it's not going to be too dissimilar from the 600 mg choice that GenFleet had made. We've started our cetuximab combination, which will be our approach to second line colorectal. That should move quickly. Again, we haven't seen [rash] as a single agent. The cetuximab combo is very important. That should be really important for everyone. It is really white space for us. That's right. Similarly, we're looking at chemo combinations or chemo- IO for lung too. It is really important to get into frontline lung, to pancreatic, as quickly as we can. You know, somebody could get approval in second line. If we get approval in frontline, their trial becomes new. I mean, it does not matter anymore because now do they work after another RAS inhibitor? Yeah, absolutely. Frontline is important here. The other thing that we've seen from a lot of folks in the KRAS space, I mean, established players, is that a driver of resistance is KRAS amplification. One thing I ask everybody, and this is especially a challenge for folks who are already at the top of their ability to dose like RevMed, how do you think about mechanisms of resistance for an inhibitor versus the pan- RAS glues versus a degrader versus any of these other mechanisms? How do we think about that? It's a really fascinating question, and it's emerging all the time. I think the first thing to say is that cancer is never going to say, "I'm not going to develop a resistance mechanism to that drug." At first, you know, you heard RevMed saying, "Well, we're going to hit RAS broadly," and if you look at the G12Cs, it's other RASes that are driving the resistance. You just get a different resistance mechanism. You're going to have with the tri-complex inhibitors, you could get a RAS mutation, you could get a cyclophilin mutation. Those will be just different mutations. You're right, the amplification is fascinating as a resistance mechanism. It tends to be the mutant form that's getting amplified. I think if there's any place, I think that the RAS degraders have not been that interesting as single agents because they tend to be IV, but maybe there's a place for them in the case of the RAS amplification, but that's really yet to be seen. I think so far we're starting to look at resistant cells to the RevMed drugs and does our drug work in that setting, you know, but in preclinical models, we look better as far as the efficacy. As we think about data from your trials coming in the upcoming year, I guess, obviously we're hoping to see recapitulation of some of GenFleet's efficacy data, at least with a better tolerability. Right, improvement of safety, that's right. Do we have additional benchmarks for the cetuximab combos or for whether in PDEC or in colorectal for the chemo combos? How are you setting expectations for the combo settings? I mean, I think that if you look at single agent RAS inhibitor, it's, I think daraxonras ib was a 9%, like 2 out of 22 or something like that. I think really colorectal, there's a huge need there. We know cetuximab itself is not, it doesn't work for KRAS mutant colorectal. It's, you know, if you're in the 30% range, it really worked well for the G12Cs to combine with an EGFR. We expect that with a more active agent than those G12Cs had been, we expect it to be impressive. Excellent. Any last thoughts in our last couple of seconds? No, we're looking forward to 2026. As I said, we've got to keep the momentum on the launch going. We've really got a lot of work cut out in front of us with the G12D and really have to accelerate that development program. It is going to be a busy year for us. We look forward to seeing more.