I'd like to welcome everybody back to our afternoon session. My name is Andres Maldonado. I'm a Senior Biotech Analyst here at H.C. Wainwright, and happy to have you guys here. The next company that we have presenting is Verastem Oncology, and it is my pleasure to welcome Jon Pachter, the Chief Scientific Officer, and Nate Sanburn, the Chief Business Officer. Welcome, gentlemen.
Thank you.
Pleasure to have you. Always good to see you. I guess a good place to start is for investors less familiar with the Verastem Oncology story, could you give us a brief update on the pipeline overview and walk us through what the company's current strategy is for building RAS/MAPK-driven immunotherapy therapies?
Sure. Yeah. Good afternoon. It's a great opportunity to be here, and it's a very exciting time at Verastem Oncology. When I joined about 4.5 years ago from Lilly, there were opportunities within the company that I really saw were going to continue to deliver, and together with Jon as well as others, the teams have continued to do that. We're two platforms, one that's the commercial stage program, our avutametnib plus defactinib, or AVMAPKI FAKZYNJA CO-PACK, now approved in low-grade serous ovarian cancer in the KRAS-mutated population, followed by our VS-7375, which is our KRAS G12D program. Both very exciting programs. As we move forward to deliver RAS pathway inhibiting molecules for cancer, the programs have continued to go very well.
As we look through this year, we've had very good opportunities going from Q1 to Q2 on our commercial product, and we continue to work to deliver on our development of our VS-7375, with phase II programs that are open across pancreas, lung, and colorectal, and working toward what would be phase III trials, opening in pancreas, lung, and colorectal as well, by the first half of 2027. Delivering commercially in the ovarian as well as moving forward very quickly across multiple tumor types for VS-7375.
Great. Starting with a couple questions on the CO-PACK. How should we be thinking about the launch through the lens of the balance between new patient starts, duration on therapy, refills, and continuations, discontinuations, et cetera?
Sure. These are obviously the priorities for us. As we've come from launch now many months in, we've made some changes in the first quarter that have continued to deliver. You saw that in the second quarter results. We continue to work on that. Obviously, we saw some seasonality in the first quarter, which we know with this disease state is going to be a reality. As we move through this year, we continue to emphasize and deliver on what were our Q1 changes, both in people as well as tactics, and continuing to work on that commercially through the end of 2026.
Great. Maybe a quick follow-up there. The launch has seen thus far strong uptake from both gynecologic oncologists and medical oncologists. I guess, where do you still see the largest opportunity to expand that prescriber depth, especially regarding academic centers in the community setting?
Sure. As you can imagine, as we had our clinical trials in the academic setting predominantly, we've continued to penetrate the community practices. That is going well, with the ratio of academics to community being roughly 60/40 as we look forward. We continue to work on how we are engaging those community physicians, the gynecologic oncologists specifically, but also the medical oncologists. When we think about new patient starts as well as keeping patients on therapy, this is an effort of the team, and we'll continue to work to deliver on that in the near term.
I'll just add that in our phase II RAMP 201 that led to the accelerated approval, the average time of patients with KRAS-mutated LGSOC on therapy was 18 months.
Initially in the launch, we got a lot of patients that were relatively sicker, as you do in a new oncology launch, there's a real effort to be able to go to patients that are earlier and toward first recurrence, that could more replicate the kinds of benefits that we could see for patients in the phase II. That's a real effort of the company, in addition to finding new patients, getting them on earlier in their journey.
Great. Maybe to kind of round out the CO-PACK line of questioning. As investors think of the confirmatory phase III, the RAMP 301 study, I guess, where do you see that data effectively resonating with physicians the most, and where can the launch trajectory change the greatest when you garner that confirmatory trial? Maybe if you can also wrap in some of the recent updates from RAMP, I believe it was 205, and how that kind of fits in the overall ecosystem of the CO-PACK.
Sure. Let me address the RAMP 301 study. As we have said publicly, that is fully enrolled and continuing to look to read out next year. As far as the data, it is a confirmatory trial for the mutant population, and then we would read out data as it pertains to the wild type. In this population, about 30% of the LGSOC market is mutated, and 70% in KRAS, and 70% KRAS wild type. We have a number of pieces of data that we are working to analyze, some of which will be coming up at the IGCS Congress here next month, which is a very important gynecologic oncology conference, which has some of the RAMP 201 data analysis, as well as an external control analysis where we have compared What are the treatment arms from the RAMP 201 study to an external control from the GOG-0281 study?
This is a study that involved trametinib. It was a phase III trial. We are very keen on how does our therapy compare to what would be the standard of care in the LGSOC setting. Those will be important coming out at IGCS. The RAMP 301 data, as we look at next year, would look to confirm the mutation patients, as well as have the opportunity to expand that into the wild type KRAS setting.
The other thing exciting, and you alluded to this, RAMP 205 was a trial that looked at the same two agents that we got accelerated approval for in ovarian, which are avutametnib, which is a RAF/MEK inhibitor, and defactinib, which is a FAK inhibitor, with chemotherapy, with gemcitabine and Abraxane, saying in frontline metastatic pancreatic cancer. We saw a 52% response rate there, which is great. It was about a year of overall survival. So very promising. We actually started that before any RAS inhibitor was in the clinic. That was 29 patients, a meaningful number of patients. We feel that people have not thought. Well, I am sure we will talk about RAS inhibitors.
Yeah.
For most of this conversation. I think that people may not have thought enough about after a patient, for example, with pancreatic cancer, if their cancer progresses on a RAS inhibitor, where do you go?
When you look at the different mutations that seem to drive that, they all still feed into the MAP kinase pathway. For the most part, it is RAS amplification. It can be RAF mutations in the case of daraxonrasib.
Yeah.
It can be upstream receptor tyrosine kinases. So avutametnib, defactinib with chemo makes great sense there. A lot of our investigators from that trial, which was frontline initially.
Sure.
Will now be looking at how does that do after a patient progresses on a RAS inhibitor with pancreatic cancer. So that is another exciting place where the RAS /MAPK franchise can go.
Great. No, that is a perfect segue to the next section I want to talk about. Obviously, we are in a so-called RAS revolution, and there is an incredible amount of noise from the development of multiple programs. Here, I think, is a perfect time to discuss the development of VS-7375 and the key points of its differentiation ahead of all that news flow to make the case of why having a KRAS on and off inhibitor is probably the next phase of innovation and growth here.
Yeah. There are four things I would highlight. I think first is dual on/off. I can come back and go deeper.
Sure.
But hitting both the on and the off state is really important, and hitting it potently and equipotently. So ours is about 15 picomolar for both, which is probably best in class. We also have a very long residence time or slow off rate relative to that, which is important for maximizing efficacy. Our drug is extremely selective for KRAS G12D. To our knowledge, KRAS G12D doesn't mediate any normal function in the body. So you don't get rash or stomatitis or other things that you see with- Recent proof of this with a pan-RAS inhibitor like daraxonrasib. Also, pan-RAS inhibitors knock out T-cell proliferation to some degree, which is on target for them, but not for our agent.
Yeah.
The fourth point that I think is underappreciated is the importance of dose-dependent exposure in the patients. If we look at a lot of the RAS inhibitors, they max out as you go higher for pharmacokinetic reasons. You can't quite get to full inhibition.
In the case of the pan-RAS inhibitors, they may be more limited by their toxicity, and you can't go all the way up. We're very excited that our agent can dose dependently give higher exposure, 900 mg, our go forward regimen really seems to deliver the necessary amount of drug for every patient across diseases, and I think that'll really translate when we show data in October, and we see what we think is best-in-class efficacy with our G12D inhibitor.
Perfect. With that said, you are advancing VS-7375 in both pancreatic non-small cell lung cancer and colorectal cancer. How should investors view your prioritization of those settings? I guess at the end of the day, which tumor types could most clearly establish the proof of concept here?
Yeah. There are different things that the different tumor types can show. Certainly, there are unmet needs in all of them. Even lung, which you'd say is the least prevalent. 5% of lung is more than 4% for ALK, for example, and that's a huge market. They're all meaningful markets. I think taking them in turn, I think pancreatic cancer, in many ways, is a proving ground. We've seen that the on-only inhibitors typically give you about 30% response rate in pancreatic cancers like zoldonrasib, daraxonrasib, for example. I think other G12Ds are just 35%, 37%.
I think it's really second line and third line pancreatic is a good opportunity, we think, to show that ours is best in class given the attributes that I just described.
But it's about 40% of patients with pancreatic cancer, their cancer is driven by a G12D mutation. We've heard from pancreatic cancer investigators that they would much rather treat with a G12D selective agent that's safer upfront rather than something that's hitting a lot of things other than what you need to hit for that patient. Colorectal is really the white space. There's really nothing out there. We do know that RAS inhibitors typically give you about 10% response rate in colorectal as a single agent, and it's really about combining with an anti-EGFR like cetuximab. I think that's what we'll be showing in October, that combination, and the fact that our agent is very select and doesn't have rash or stomatitis. We are really enabled with good tolerability to combine with an EGFR inhibitor, whereas pan-RAS, that's much more of a challenge, for example.
Finally, in lung, a couple of ways to win, really. I think better response, better safety relative to the pan-RAS inhibitors. But the other thing that's really interesting is we've been told by lung cancer investigators that if we're effective against brain cancer metastases, ours would be the drug of choice for G12D lung cancer. So that we have a cohort in our phase II of 25 patients with asymptomatic lung mets— I mean, brain mets from lung cancer that is designed to answer exactly that question.
Got it.
Really multiple chances to show the best-in-class potential.
Great. Maybe going a little deeper, obviously the strategy of combining VS-7375 with EGFR inhibition, maybe starting with pancreatic cancer. I guess, tell us how important that combination is in that setting and how you are able to leverage that? Is it just because the safety is on board or is there underlying mechanistic rationale that really gets you guys excited there?
Yeah. There is actually beautiful mechanistic rationale. Channing Der's lab had a paper in February where they used CRISPR to knock out each gene in the genome one at a time in pancreatic cancer cells and ask what would best potentiate the efficacy of a RAS inhibitor. They found that one of the very best hits was EGFR.
Wow.
That if you inhibit that, you unlock the potential of various RAS inhibitors in the context of pancreatic cancer. They also saw in pancreatic cell lines, whenever they treated with any of the RAS inhibitors relevant to the mutation in that cell line, they saw an increase in phospho-EGFR across the board.
Wow.
These really make sense together. We have preclinical data specifically with VS-7375 and cetuximab, where we see good regressions in pancreatic cancer. Everyone has assumed that EGFR is what you need to do for colorectal, but we found for pancreatic, it makes a lot of sense.
Mm-hmm. As well.
We also showed in June a case study. We find that pancreatic cancer often takes a while to get to a deep response.
What we find clinically is when we combine with anti-EGFR, we can get a response often on the first scan. It really accelerates the depth of response of the patients with pancreatic cancer.
That's very helpful. I guess in the context of the upcoming data, I believe in October, how comfortable are you with proposing the potential for read-through between the pancreatic EGFR RAS inhibitor combination to that colorectal combination? Mechanistically, is there enough overlap, or is this a true just exploratory kind of study, see how far you guys can go? Help us understand the prioritization there.
We really wanted to show real data. We've been disciplined about not leaking out five or seven patients here and there. We were really waiting for denominators of 20 patients where we can talk about intent to treat rather than evaluable. We can talk about confirmed responses or at least confirmed plus can confirm.
I think there needs to be more discipline in the space. For pancreatic, we'll have 20+ patients for lung, 20+ patients at one dose.
Colorectal, we'll be looking directly at the colorectal data that we show within anti-EGFR. I think we're not trying to necessarily borrow from this to give rationale for that. We're trying to show data in each.
And is there overlap in terms of clinical study design as the programs progress that one can learn from the other? Or are these truly unique tissue types that might need a little bit more refinement?
I think pancreatic is especially challenging because of the stromal density. I think that lung cancer, you often get a response on the first scan, and that's probably the easiest for a single agent. I think where our PK advantage is, I mentioned the dose dependence really can show its colors might be in pancreatic where you need enough drug to penetrate the tumor.
There can be some differences, but if you show that you have the best-in-class G12D inhibitor.
Yeah.
Or RAS inhibitor in one setting, that should translate to another setting.
That makes sense. Then maybe just through the lens of dosing. Obviously, you said the 900 mg dose is important, but you can dose up to 1,200 mg.
That's right.
How should we be thinking about that moving forward in terms of what doors does that open for you beyond the studies that you're already starting in terms of some of the latter combinations that you have in mind?
Great question. I think that 900 mg is our dose. We are very happy with the exposure, the coverage of target, what we are seeing, but we did recently go up to 1,200 mg. We see more exposure, and that is well-tolerated. That is going to be important for a couple of reasons. One is for Project Optimus, we can show that we can go here, but we have chosen this lower dose because it is sufficient, and that really satisfies generally that kind of thinking. The other point is if we have drug-drug interactions, sometimes they can increase the exposure of our drug. We know we have a lot of headroom, whereas there are other drugs that if they were to have a drug-drug interaction, they are already maxed out as far as tolerability. Having that headroom is really another advantage.
Before we end, I should mention that in addition to the three phase IIs in lung, colorectal, and pancreatic that are ongoing now, we are also in the first half of next year, we are setting up three phase IIIs that will be all frontline, and those will be the confirmatory studies. It is a very complete program.
Great. I will leave the question for both of you. Over the next 12-18 months, outside of the data coming in October, what should be our expectations for the performance of the CO-PACK, where the CO-PACK is going next? For you, Jon, where some of the most underappreciated signals in the RAS space that you guys are most excited about for yourselves and throughout the kind of landscape there?
Maybe I will address the CO-PACK, and Jon, I will hand it to you for VS-7375. As we think about the CO-PACK, we talked about the plans, and we are executing all those plans. We talked about them early. We continue to deliver into the third quarter on the launch. I think in addition to what you have seen in low-grade serous ovarian cancer over the course of the next six months, as you said, we want to continue to work on the data that would be in the pancreas space, too. For CO-PACK, it is the launch of KRAS mutant LGSOC.
It's also continuing to deliver on the RAMP 301 study and reading that out to analysis, as well as understanding in pancreas cancer how the CO-PACK can work in combination with gemcitabine and Abraxane and how we see that developing as the market moves forward to have the RAS revolution, as you said, moving into first line as we would expect, what will it look like for avutametnib defactinib after that. That's a key part.
As far as the future of the RAS space, I think that RAS inhibitors now for deadly cancer like pancreatic are delivering a one-year survival.
I think that's great relative to where we were, but we really have a long way to go, and so I'm very personally excited about some of the combinations we're combining with our FAK inhibitor in the clinic now. We're going to be combining with the RAS because pan-RAS, we're going to be combining with the PRMT5. These are all approaches that could potentially give you longer duration of benefit and longer survival, and I think that's really where the field needs to go.
Great. I think that's all the time we have today. But on behalf of myself and the entire family at H.C. Wainwright, congrats on all the progress you guys have made, and we look forward to future updates.
Thanks very much.
Thank you.