Welcome everyone to Cantor's Global Healthcare Conference on day two. My name is Eric Schmidt, and it's my pleasure to host our next fireside chat with the Verastem team. We are thrilled to have with us the company's CEO, Dan Paterson, as well as the company's, Jonathan, I don't know your title.
Chief Scientific Officer.
T he company's Chief Scientific Officer, Jonathan.
The guy for the hard questions.
T hank you. Y ou never know who's going to show up, but great to have you both here. Dan, maybe you can just give us a lay of land, high level, what's going on at Verastem these days?
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.
We're all looking forward to that data update. Should we start with G12D then? Or what would you like to do? Jonathan definitely wants to start with G12D. Okay , let's frame where you are with the program first, and then we'll talk about the upcoming data release.
Yeah.
Go ahead, Jon.
Yeah, we've treated over 200 patients now in our study. That's separate from the 300 + 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 + 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 + patients with pancreatic cancer, many of them with six months since they've started treatment, which is good. That'll be at the 900 mg, 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 + patients at 600 mg 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 mg in lung cancer. Colorectal will all be in combination with anti-EGFR, cetuximab or panitumumab, and that may be 10 patients or so.
Okay. Maybe just step back, and why is this molecule a good molecule? What's differentiated about it? How does it fit in with the rest of the G12D inhibitor field?
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 mg 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. I think by having that profile, we can certainly have much better safety than you see with pan-RAS inhibitors, but also better efficacy based on those points.
I think combinability is going to be important. Ultimately, that's the end game is combinability. We believe that's going to allow us to combine giving the full dose of our drug and potentially the full dose of the other drugs.
We've also recently completed dosing to 1,200 mg. We'll still go forward with 900 mg, but 1,200 mg, there were no DLTs, well-tolerated. That's really important to have that headroom. If we had drug-drug interactions, for example, in a combination, we'd be fine being in that exposure range, whereas other drugs that are more toxic, like the pan-RAS, can't tolerate that kind of drug-drug interaction.
You alluded to potentially being specific as an advantage, being a G12D inhibitor as opposed to pan-KRAS or even RAS multi inhibitor. What's the data to support that you wouldn't be giving up anything in terms of efficacy?
Yeah, I think that at least initially, there's often a single KRAS mutation that's driving the patient's cancer, and I think that's the thing to target. There used to be a thought that if you target it, and this came from the G12C inhibitors, if you target one variant, then other variants could come up, and that can be a resistance mechanism. Therefore, you need a pan-RAS inhibitor.
The problem is that a pan-RAS inhibitor brings rash and stomatitis and knocks out T-cell proliferation, all kinds of things that you don't want. What we and others have seen, and RevMed have reported as well, is they have a host of other resistance mechanisms that you see with pan-RAS inhibitors. So it's not really that a pan-RAS inhibitor is going to be better in terms of lack of resistance. It will just be different resistance mechanisms that the cancer throws at it.
That's kind of the science-y question. I guess the other answer to that is the efficacy we're seeing in the clinic.
Yeah, it's great. T hat is it, I think.
Are you referring down to the efficacy we have seen, or what we will see?
F or example, in June, we reported 100% response in one patient at single agent, 900 mg of pancreatic cancer. That is right there, it has been astounding. We reported a few examples that are really astounding. We also reported earlier that when you look at CA19-9, almost every patient has a really sharp reduction, which has been shown to correlate with really good outcomes.
Okay. We will get to the upcoming data presentation in just a moment, but I want to just ask one more competitive field question. Who else has a G12D, and why do you think yours is a, w ell, you have kind of addressed why you think it is the best in class r elative to the Incyte molecule in particular, what are the advantages?
Yeah. There are a couple that we follow, the ones with clinical data, and when you are in the lead, you do not want to spend a lot of time looking in the rear view mirror. It does not really help you. I think there is a G12D from RevMed, as you know, and we could talk through that. The Incyte one is interesting. In 2024 AACR, we were two posters away. We simultaneously showed that you can hit both the on and off states at the same time with similar potency, but ours is about 25-fold more potent than theirs for both the on and the off state.
I think it cross-validated that that is possible, so it has that going for it. I know that they have had issues with pneumonitis in the past, etc. We really think ours is best in class relative to any other dual on/off, and most others outside of what we have talked about are off only or on only, and that is a disadvantage.
Okay. I know you are anxious to talk about your data, so maybe just review, from a high level, what you think proof of concept that we have seen, and then we can talk about what might be constituting proof of concept in the future.
Yeah. I think that for Accelerated Approval, which is the goal of our phase IIs, that now we have three phase IIs ongoing in lung, colorectal, and pancreatic, the three main cancers where G12D is most prevalent. I think in general for Accelerated Approval, probably 30% response rate is a minimum, and you want to see at least six months durability, just for the FDA in general. But relative to the space, I think for lung, for example, there is a G12D inhibitor that was 52% response rate. But they had to take out the patients with prior docetaxel when they reported those data. Our drug does not care about whether there has been prior docetaxel. It is going to look good regardless. In pancreatic, it is a pretty low floor set by some of the divarasib as well as zoldonrasib are about 30%, I think.
Zoldonrasib, it was 2024, has not been updated since, and most of those were unconfirmed at the time. So I think we would certainly hope to be well over 30%. And then in colorectal, I think all RAS inhibitors, and we have seen this with sotorasib and divarasib, are going to be 9% or 10% as single agent, but really the promise is anti-EGFR combination cetuximab or panitumumab. We would like to see 30% there. And the other point that Dan made is ours is a very combinable drug. Obviously, with the amount of rash that you see with the pan-RAS inhibitors, it is much more difficult or impossible to combine with anti-EGFR, which is really critical for colorectal.
Maybe we'll just dive a little bit deeper into pancreatic because I know there's a lot of focus there. You referenced the benchmark of zoldonrasib, or you could've said daraxonrasib also, I guess.
About 30%-ish.
30% in the second line setting. That's where we're going to see your data, of course, in the second line monotherapy setting.
That is right.
So let's be clear. What gives you confidence that a 30 +, slightly higher, but I do not know how. Where is the confidence coming from that a 40% or 50% response rate could satisfy a-
I will. Relative to the second line comment, our drug should work in third line. I think other drugs, you lose a lot of efficacy when you go to third line and beyond. We do not think that we will see that either. I think ours will be strong across lines of therapy.
Others are going into first-line strategies with either zoldonrasib or with the Incyte G12D.
Right. We'll be meeting with the FDA this year about our phase III designs for lung, colorectal, and pancreatic. Then in the first half of next year, we'll be starting phase IIIs in each of those, and those will all be in front line. Those will be the confirmatory studies if we get Accelerated Approval or if we don't, those will be the first approvals.
How do you think about the third-line market in a future era where there are frontline therapies?
I think that ultimately the frontline therapy will be variant selective. We are hearing from every investigator, that's where you go. Ultimately, our G12D, we think will be the best G12D inhibitor and really, frankly, the best agent at all to use for a patient with KRAS G12D-driven cancer.
Yeah, I think in a world where frontline is dominated by either a G12D specific or even a pan-RAS, when you look at its second and third line in PDAC, I think the best potential candidate there would be our avutometinib- defactinib combination with gemcitabine and Abraxane, where we've put out frontline data that was a 52% response rate, with survival somewhat similar to what we saw with the RevMed drug. We don't think that's necessarily going to be competitive in the frontline, but given the mechanism, given the fact it's downstream from RAS, we're starting some work now to show that's the preferred regimen after a RAS inhibitor.
Okay. If the FDA required a randomized controlled study in the latter line pancreatic setting, I assume that isn't of interest to you in that case, you might as well just do that in the frontline setting.
Yeah, frontline-
No, absolutely. I don't think it is going to be required in that setting. Obviously, with the RAS inhibitors being new, there is not really data on what the efficacy is after that, and I think the bar will be relatively low, and will probably be the same generic 30% response rate with some durability.
Okay. With the update in PDAC in October 14th, you mentioned, are we going to get a sense of the regulatory strategy beyond the data?
Yeah. AA as well as frontline design.
Yeah. What we have said is both for CRC, Lung, and PDAC, we have got the phase II, the single arm studies going on right now. We have talked to the agency about Accelerated Approval. Obviously, you do not get anything definitively from the agency till you have data. It is always a review issue. In the meetings we are having and will be having, it is really a discussion of anything we need to tweak on those studies, confirming the design of the phase III studies, and then also a discussion, a Breakthrough Therapy designation. Those things are all kind of in the mix as we have those interactions.
Can you provide us an update on how the phase II expansion cohorts are going? Maybe we should come back to lung and colorectal, but just in general.
Well, all three are opened.
Yeah.
We are not seeing any issues with accrual whatsoever. People have always raised the issue now that there is an approved drug, are you going to be able to accrue to the study? We have gone back to all of our investigators and we hear pretty uniformly that a G12D specific agent would be the one to use first, and then potentially use a pan-RAS afterwards, or the regimen I talked about before with avutometinib, defactinib, gemcitabine, and Abraxane.
Okay. Let us go a little bit deeper in lung cancer then. Jonathan, this is where you noted that your dose expanding at 600 mg, and now you will be going to 900 mg, I think is that?
In the phase II?
Yeah, i n the phase II.
That's right.
Set the benchmarks for the October update.
Yeah, ultimately, there's a benchmark out there of 50%. And again, as I said, that was specifically not including prior docetaxel. For ours, we think that won't matter whether there's prior docetaxel, but that 50% range is the right benchmark.
Why do you think docetaxel mattered in that study?
They chose to not report any of the patients that have had prior docetaxel, which usually-
Yeah.
Yeah. No, I do not know that it mattered. I think for ours, it does not, it should not.
Okay. But usually when data is not given, it is-
It is because it is not as good.
Okay, fair enough. Did you say 20 patients again, with the 600 mg?
In lung, yes.
Yeah. Okay. The response rate that you need to hit for an Accelerated Approval here you think is what?
North of 30%, but for a competitive environment, more like 50%. I think there are a couple ways to win in lung that we've heard from the investigators. One is that the triplex inhibitors don't cross the blood-brain barrier, is what we've heard from many. So if we were to be effective in reducing brain mets for lung cancer, ours would be the drug of choice. Or else, if our efficacy response rate durability is better, that's obviously the other.
Yeah. A secondary consideration is always going to be tolerability.
Right.
What does a confirmatory study in lung look like?
The frontline study is very simple. It's single agent, I'm sorry. It's our agent combined with chemo, with pembrolizumab, compared to chemo pembrolizumab alone in frontline.
Yeah, which is slightly different from the approach in PDAC. In PDAC, we're going to be obviously comparing to standard of care. We'll be combining with standard of care, but we also believe we have the ability to have a combination with cetuximab, which would be a chemo-free regimen, which we think would be really attractive. And we're seeing some really exciting data combining with cetuximab in PANC, as well as CRC.
Now that RAS inhibitors are giving more efficacy than chemo, it's time to think about getting rid of all the toxicity that chemo brings.
Yeah. Okay, and on the CRC front, 10 patients each, did you say? In the two cohorts, about?
About 10 patients.
Yeah. The monotherapy benchmark is quite low, around 10%.
Yeah, I think I should be more on the EGFR combination, cetuximab combination.
Yeah. In that case, since the standard therapy is so low, it is really going to be the generic rule around what do you need for Accelerated Approval, which is probably north of 30%.
With combination or with the mono?
With combination.
With the combination.
Yeah. I think you can look at G12D, you can look at G12C. Single agent, I think the bar has been set at 8% or 9%. That's not something I think anyone would take forward.
You guys are a smallish company.
We are.
Got a lot going on with this one molecule, a lot of different places it could go, both on accelerated and confirmatory basis, a lot of different tumor types. Strategically, what are you going to do?
That's a great question. Stepping back a little bit, we did the Oberland deal that we announced when we did earnings, and that was really to give us enough cash to take a little pressure off having to decide today what we're going to do. So, whether it's raising money through the equity markets at hopefully a higher stock price and over time, partnerships either on the A&D side, where maybe there's a way to pull some of that revenue forward to fund the program, or the right kind of a deal on the G12D inhibitor. We don't want to give away upside, but I do believe this is an area where the pie actually gets bigger with a large partner. This is a huge opportunity. It's not just cash, it's execution.
So having a large partner by our side with a deal structured the same way where we protect upside but have a way to fund these trials in a non-dilutive way, I think would be very attractive. We're having those discussions, and it's always a trade-off of the earlier you can bring in a partner, the more you can take advantage of their expertise, but you don't want to give away upside, and so that's a judgment call, and we're having those conversations with our board all the time.
I assume potential partners can have access to the data in real time?
Yes.
In terms of potential collaborations or partnerships, and the combinability that you referenced earlier, there are some other novel mechanisms out there that I'm sure you'd want to access. I think you've alluded to potentially a partnership or a collaboration in the RAS inhibitor space. How should we think about that?
Yeah, everyone asks should you combine with a pan-RAS? We had made the strategic decision, we didn't want our own pan-RAS. But we've talked about working with Erasca, which we think is potentially best in class to combine with their drug, and we're trying to find the best way to combine without bringing all the toxicity of a pan-RAS forward and be able to do that. We have said we're very interested and have some really compelling pre-clinical data on our PRMT5 combination and really making sure that we choose the right partner there. Some have some DDI issues when they combine with RAS inhibitors, and we're trying to find a way to have the simplest path forward there, but that is a very high priority for us.
You think we'll see a collaboration on either the Erasca front or a PRMT5 player this year?
I would think so.
Yeah. Okay.
We've got about six minutes left, so I think we ought to do the CO-PACK its justice.
Okay.
Do you want to give us an update on commercially the progress you've made? I know last quarter was an uptick.
Yes. We made a number of significant changes after Q1. We are seeing some pretty good tailwinds both in getting new patients. We are seeing an interesting uptick, not that it is part of our commercial plan, but an interesting uptick in PDAC patients, as well as continuing to penetrate the low-grade serous ovarian cancer market. Obviously, the focus of our sales force is the label, which is KRAS mutant, and that is progressing well. We are starting to see patients that stay on longer. That was an issue early on in the launch where I think, and it happens in any launch, you get the sicker patients that would not have gone on the clinical trial. They are trying it, and we are starting to see patients that stay on longer.
Both new patients coming on and then making progress on keeping patients on, and those were areas where you had specific initiatives we designed, and that seems to be working well. We're feeling really good about the year. We're feeling good about the quarter as well. There was a little seasonality in the summer. This isn't acute leukemia, so patients go on vacation for a week or two. They may not start their regimen till they get back. We are seeing really good momentum there.
Okay. How do you size up the low-grade serous ovarian cancer marketplace? What's your latest on the TAM?
Yeah. We've not put out numbers ourselves, and I think it depends quite a bit on when we get wild type in the label where we can actively promote it. When we look at the estimates from the different analysts, they range from anywhere from $200 million up to, there's one up at $800 million. It's probably somewhere in the middle there. We're very focused on making sure we can get the data from RAMP 301 completed. It's an event-driven study, so the accrual finished last year, and once we've got the events and can get in front of the agency, really to make the case to expand the label, then we can actively promote there.
You think we'll see data next year?
I think we will, yes. It's going to depend on the events coming in, what we've guided up until now. It's somewhere around the middle of the year, we should hit that benchmark. The nice thing with AI and all those things, you can actually get all the tables all ready to go. You just dump the data in, so it really helps with the cycle there.
Dan, you noted a recent uptick in PDAC usage. I had thought we'd seen a downtick earlier in the year, as reimbursement was maybe a factor. What's the latest?
We are seeing more PDAC patients. I think it's primarily driven by the data that we had from RAMP 205, where we did have a 52% response rate, survival looking somewhat similar to Revolution Medicines. Obviously, it's not something we promote. We're not getting reimbursement for 100% of those patients, nor do we expect to. But we are working with folks with our data packet and through our specialty pharmacy to make sure if, in fact, we can get reimbursement, we get reimbursement.
The availability of divarasib of late, is it too early to say if that's having an impact in that way?
I think it's probably too early. Obviously, it's available. We've heard as patients switch from the EAP to commercial, there's been some disruptions. I don't know that we've seen the full effect of that yet. Again, our market is low-grade serous ovarian cancer. It just happens to be a by-product with a lot of focus, I think, on the PDAC market. It's good for all of us that there is the focus on there. I think it really sets up a really nice opportunity when we have our data in PDAC to really highlight that and show the differences.
The data are impressive, as you said, in the PDAC subpopulation. What, if anything, can you do to take advantage of that?
Well, I think everyone is now stepping back and saying it's not the same drugs, chemo combinations we've used for 20 years. They are having conversations with their physicians, and the physicians are quite aware there's something new. I think it just opens the aperture of them being aware of new things coming up, where maybe they weren't paying attention before.
But in terms of developmental program or anything like that.
I think for us, the next thing we need to do, and we're doing the preclinical work right now, and it'll probably be an IST because we are cognizant of the cost of doing these trials, which have gone up quite a bit in the last four or five years. We need to develop some clinical data to show our avutometinib defactinib regimen with gemcitabine is effective after a RAS inhibitor, and I think that's a critical thing for us to do to set that up to be the preferred regimen after what will dominate frontline therapy again, e ither a G12D specific or a pan-RAS. You're going to need something after that, and we want to position that drug to be the preferred.
A very important opportunity.
It is actually.
There's surprisingly little focus on that in the space.
Yeah.
What comes next?
I would fund that trial.
No. Look, we firmly believe for the 40% of PDAC patients that have a G12D mutation, we're starting to hear this from all the KOLs, that the specific agent is probably the preferred one. The burden's on us to show efficacy.
We do believe, obviously, tolerability is going to be a big deal. These aren't lab results. The rash you get from a pan-RAS is not a PARP inhibitor-type rash. It's a severe rash, and people will put up with it when that's the only option. If there's another option, the physicians are very clear they want to try the specific first. Once you come off of that, I think it's really on us to show that our other regimen may be preferable to then using a pan-RAS.
It's a great summary of the field, thank you. Great way to end our talk.
Very good.
Dan, Jonathan, appreciate it.
Thanks.
Thank you.
Always a pleasure.