I am Michael Schmidt, Senior Biotech Analyst with Guggenheim, and it is my great pleasure to welcome the next presenting company. Here with me, I have Verastem, Jonathan Pachter, CSO, and Ting Wu, Head of Development at Verastem. Is that right?
That is very good.
Yes. Obviously, the last couple of months were very active, very exciting months for Verastem. You had new data presented for VS-7375, a big capital raise as well. You announced the CEO transition. How would you describe where Verastem is today, and what should investors expect over the next year or so?
I think we are where we wanted to be exactly. I mean, first of all, avutometinib, defactinib, CO-PACK, it is a RAF/MEK inhibitor with a FAK inhibitor. It was the first novel approval we got approved in May of 2025. Now we are at the point where our sales cover the commercial force. That is really great to be break-even for that asset. Then, as you mentioned, the G12D inhibitor, VS-7375, is really exciting, looking best in class, really for any patient with a cancer driven by KRAS G12D. That is really important in pancreatic cancer, colorectal, and lung cancer, which are obviously really large market cancers. So, great point. As you say, the fundraise really lets us drive the clinical development program. We have a couple of trials that Ting will say more about that are gearing toward accelerated approval in the near term.
It is a transition. I think you mentioned Dan Paterson, who has been the CEO since 2011, felt like he has delivered it to this point. As we look toward commercializing the G12D inhibitor now in addition to the RAF/MEK and FAK inhibitor, I think Michael Bailey, the new CEO coming in January 1st, is really well-positioned to do that.
Okay, great. So maybe a couple of questions for Ting and you, Jonathan. On VS-7375, obviously you had a big data update pre-ESMO. How does that drive your development path for the program, and how do you think it is positioned in this very active space of KRAS inhibitors?
Yeah. Thanks for the question, Michael. I think the data that we have presented on October 14th really highlight that we have the potential to be best in class for G12D space, which means that that allows us to open a lot of opportunities across tumor types. Of course, obviously PDAC, CRC, and also non-small cell lung cancer, and also the recent fundraise allows us to go full steam for all these indications. We are about to fully enroll for our, I would say, PDAC and also CRC study towards the end of this year, non-small cell lung cancer to follow early next year. Then we are starting three phase III confirmatory study in the frontline setting for these indications. So exciting times.
I think it validates that we always have a great scientific story about the ON/OFF inhibition, the really good exposure proportional across dose levels, and now it is manifesting in the clinical data that is trending towards best in class. Of course, this enables a lot across indications.
Okay. Maybe just a couple follow-ups. Your partner GenFleet went with the 600 mg per day dose in their China-based studies. You obviously decided to go higher in the U.S., kind of steering in on a 900 mg per day dose. Maybe just remind us of what you've learned about the safety profile at 900 mg and how that perhaps compares to the 600 mg dose.
Yes. Basically, GenFleet did not fully explore 900 mg. I would say in general, they only dosed three patients in total at a 900 mg dose, and they decided to go for speed for 600 mg, given they have seen already favorable benefit-risk. For us, we have fully characterized 900 mg. So a few things, as John probably has already alluded to in several occasions, that we really have a good dose-proportional increase in terms of exposure across the 600 mg and 900 mg. Based on preclinical models, that 900 mg is the more optimal dose that we have hit the optimal exposure. The other thing is about the safety profile or tolerability profile is that 900 mg is identical to 600 mg.
Just a quick reminder that the main AE is GI disorders and predominantly low grade, mostly grade 1, with around 10%-15% grade 2. Other than that, it's a pretty clean safety profile. So that justifies us to go for 900 mg, given no difference in terms of tolerability compared to 600 mg.
Okay. In pancreatic cancer, which is one of the big focus areas for the field, you've reported a 41% response rate in second -line plus patients. How robust are the results at this point, and how mature was the efficacy at the recommended phase II dose?
Right. For the PDAC data, obviously, I think this is a data set that clearly shows differentiation. First, it is all the patients that we have dosed at 900 mg in a phase I study in a previously treated PDAC setting. We are not hiding any single patients. We are reporting the intent- to- treat population. Any patient dosed with 900 mg were included in that data set. Also, we are reporting all confirmed response. In terms of data robustness, I think it tells us how rigorous we are about reporting the data. We report intent-to-treat and also confirm response rate. Also, as you probably noticed , that although the sample size is not that large, but I would say it is very consistent in every setting, either in second- line or third- line beyond.
I think it is very competitive compared to what is available out there, including daraxonrasib currently as standard of care, and also the other G12D inhibitors.
Okay.
One thing that supports that is the consistency of the data across the board. I mean, I think that we had predicted, in the preclinical models, predicted that the dual ON/OFF profile, long residence time would pay dividends as far as better efficacy, and also this dose-proportional efficacy where we can maximally hit the target. Then if you look at molecular response, like KRAS G12D variant allele frequency knockdown, we see it is extremely strong at 900 mg, and we can compare directly to data with daraxonrasib or zoldonrasib or Incyte's G12D, which they are leaving a lot of patients behind there too. It is not only even though the 22- patient dataset is really strong and consistent, and those depths of responses with two complete responses in G12D PDAC, which is, I think, a first. It is really, G12D is poor prognosis relative to other variants.
I think all of that together, the consistency really makes sense and validates that even further.
Right. Last point to add is probably the durability of disease control. We are probably the first G12D inhibitor that reports a clinically meaningful, favorable PFS. I would say not the median PFS, but we are able to report a landmark PFS at six months, which is 67%. I think this also stacks very favorable against the competition. One thing to know, a lot of these major KRAS G12D players did not report a single-agent PFS data. That also tells you the robustness of the data.
Great. No one else is obviously pursuing an accelerated approval strategy in second-line PDAC, so that's unique to Verastem, with your TARGET-D 201 study enrolling. How quickly could VS-7375 potentially reach the market in second-line PDAC, and what do you think the efficacy bar is for accelerated approval in that setting?
Well, I'll start, and John, if you want to add. First is that the TARGET-D 201 study is almost complete enrolled in the main cohort. We'll announce once we complete enroll. We believe it will be before the end of this year. Thinking about the accelerated approval precedence out there, usually you need to hit accelerated approval that you have substantial efficacy over the standard of care. There is also a component of benefit-risk , and I believe that VS-7375 could hit that mark. Thinking about what is available standard of care currently is daraxonrasib, and I think in their multidisciplinary review document, they demonstrate a lower response rate in G12D population, which is only 24%.
When you think about the accelerated approval bar with clearing the 95% confidence interval lower bound, I think once the data is consistent, we could potentially hit that target with, of course, need to pair with substantial DOR as well. So we need some time for the data to mature. We also have a pretty tolerable profile that doesn't have stomatitis and also rash. That also adds to the benefit-risk story. In terms of timing, you need that DOR to be mature. Thinking about this, we are aiming towards probably a Q2 potentially submission. Of course, we need more communication with the FDA to confirm the path to that approval.
Okay.
It could even be the end of next year that we could be. Approval could come as early as that.
Okay, sounds good.
Which would be first, likely the first G12D to get approved.
Just confirming, is that second-line plus or pure second-line?
Second- line for PDAC.
Okay. Great. You are also looking at cetuximab combination again, which is unique for Verastem. I do not think anyone else is doing that. Maybe talk to us about the rationale and-
Yeah, I think Quanta Therapeutics is doing that, but I will start preclinical and we will talk clinical as well. First of all, there was a really elegant paper from Channing Der's lab this year where they took pancreatic cancer cell lines and they knocked out with CRISPR-Cas9 each individual gene to say what best potentiates the efficacy of a RAS inhibitor in pancreatic cancer. The strongest hit was EGFR. They also looked each time they treated with various RAS inhibitors, they saw an increase in phospho-EGFR in the pancreatic cancer cell lines. We have looked preclinically at our VS-7375, the G12D inhibitor with cetuximab, and we can get regressions with that combination in pancreatic models. I think people accept for colorectal is obvious based on BREAKWATER with BRAF and based on the G12C inhibitors that anti-EGFR is the right combiner.
But I think for pancreatic cancer, it also makes very similar sense, and then the clinical observations have really-
Yeah.
Borne that out.
Thanks, John. A few clinical observations. One is that even at sub-therapeutic doses, we have seen responses. Also, for I would say higher dose level, we have seen deeper and more rapid responses in early observations. We are able to disclose some of these early observations towards like Q1 early next year, potentially in a medical conference. Of course, the TARGET-D 201 study, we are doing a randomization between monotherapy and anti-EGFR in a second-line setting. That will read out, I would say, mid-year, and we will share that data as it matures.
Okay. Just to confirm, the 1Q readout will also be second-line PDAC, is that correct?
It will be previously treated, and we probably will still disclose the phase I data, which is a 600+ mg cetuximab data, and people will be able to compare with the 600 monotherapy to understand how much that anti-EGFR is adding.
Okay. What is the purpose of the randomized second-line evaluation?
Oh, yes. Because, I mean, we need to establish a contribution component, especially when this is intended to have an accelerated approval intent. It also informs about the frontline design, because we also incorporate this anti-EGFR combo in the frontline. This phase II randomization will also help us for the contribution component, so we do not need to run another monotherapy in the phase III frontline. That is another benefit for this design.
But in that phase II, we are moving quickly toward 80 patients single agent and 80 patients with the cetuximab combination, and that would be potentially sufficient for accelerated approval for both.
For the combination?
For both, the combination and the mono.
Makes sense. Okay, great. Then, questions on TARGET-D 301, which is your frontline PDAC phase III study, where it's a three-arm design, so you're combining with either cetuximab or with GemNab, correct? You're not adding FOLFIRINOX, unlike some of your competitors.
Yes.
Why not?
Yes, and I think it's a choice. We didn't dose patients combined with FOLFIRINOX, and that is a choice because we believe that we are a tolerable agent, and we want to extend the patient experience and not combine with the toughest chemotherapy out there. I mean, there are RAS inhibitors out there that claims that they are very tolerable, but when you combine with the toughest chemotherapy, you're kind of losing that advantage of being tolerable. Because we are a more active drug and combined with GNP, we believe that we can convert similar efficacy or ORR to those agents who combine with FOLFIRINOX. The other point I want to make is that because for these frontline combos, patient cannot be on chemotherapy forever.
Usually, they need to stop or decrease the dose intensity around this three- to four-month mark because of either of hematologic AE or neuropathy, and what is left is the single agent. Once you have a more potent single agent, you get a better chance to win on PFS, because from that, around four months to whatever PFS you benefit, you are alone for the single agent. I think that's the other point that people sometimes get lost on these response rate, how high you can get. At the end of the day, when you are at a randomized study to read out a PFS, it's the single agent activities that matters.
I think that's a really important point, that you really need to look at the single agent activity. Some companies, if you don't have single agent activity, can obfuscate that by going to combinations very soon, but ultimately, the single agent activity is going to be the thing that carries the day. The fact that we're combinable as well gives us an advantage across the board.
Your control arm will obviously include both chemotherapy choices.
Yeah, we're allowing either.
That is correct.
What additional phase I data will you generate in frontline PDAC in the near term, if any?
Yes, I can take that one. We are currently enrolling for the frontline GNP combo, and of course, we will do the same regimen in our phase III. It is kind of keeping the momentum for our phase I study. I think that will also serve as an important evidence that this is, we want to generate, of course, exciting data to help our phase III enrollment. So we plan to disclose that frontline GNP combo data, and likely together with the cetuximab frontline data from our phase II in a future medical meeting sometime Q2 next year.
I would say across all three indications, colorectal, lung, and pancreatic, we are really setting up for success in the frontline combination. Again, with GemNab for pancreatic, we are testing that. We have already cleared 900 mg there.
Yeah.
With chemo/IO, we are testing that in the phase II. I mean, we are testing that, and similarly with modified FOLFOX6 plus EGFR, we are testing that in the phase II trial and for colorectal frontline.
Maybe then switching to colorectal also, a few moving parts here. Incyte is enrolling a third-line study with cetuximab. RevMed recently announced a frontline study with chemo and cetuximab. Remind us of your development path in colorectal and how that might fit in with the field.
Absolutely. I think our development strategy is very consistent across the three large indications. We are running these phase II single-arm previously treated studies for the intent for accelerated approval. I think the benchmarks are pretty clear for CRC, also non-small cell lung cancer, and we're doing a frontline confirmatory study for CRC will come by first half of next year. We believe that there's a very fair chance for accelerated approval in the third-line beyond setting, where the benchmark is LONSURF/bev, around 6% of ORR, 5.6 months of PFS. So if we can demonstrate a meaningful ORR plus a DOR, I think there's a fair chance that we can follow the precedence of being approved in that third- line beyond setting.
What is a good response rate, you think, for any KRAS cetuximab combination in the third -line setting, and what do you think is needed to translate into PFS or OS benefit?
Right. I think in the third -line beyond setting, like a 30% response rate will be probably the benchmark for accelerated approval. Of course, our partner GenFleet had reported 44% response rate in that population with VS-7375 plus cetuximab. We have more than 50 patients dosed in the phase II study currently. Obviously, that will come later, but we have full confidence given the consistency of data that we've seen so far, that we have a very good chance for accelerated approval or hitting that benchmark in third-line beyond setting. Now, the question about the OR translating to PFS, I think in the later line setting, something around 6.5 months, seven months will be quite meaningful, compared to the LONSURF/bev.
A lot of these KOLs give a feedback that response rates still matter, because although these patients are having PFS, most of these agents are not ideal with a lot of side effects, and response rate still matters in some patients in this setting. I think the last question around, okay, the recent failure of KRYSTAL-10, how does it affect? I think this is a different setting because they are not able to combine with chemotherapy. They did it in a second line versus chemotherapy. I don't think that's a great analog, I would say. For us, we're aiming for frontline combined with chemo add-on. I think that will give us a really good chance, considering the BREAKWATER present that will confer a meaningful survival benefit in the frontline setting.
In the third-line colorectal setting, really the best response rate of what's left there is about 6% response rate.
Monotherapy.
With fruquintinib. Right. So, 30% is a vast improvement relative to that.
Yeah. Lung cancer trailing a little bit behind the other two opportunities. Just remind us of your registration path now in lung cancer.
Yeah, it's quite similar. We are running this TARGET-D 202 study, enrolling for previously treated non-small cell lung cancer. Patients who receive at least one line of standard of care, including a platinum-based chemotherapy and an immune checkpoint inhibitor, can be eligible for this study. I think one of the distinctions from the other study is that for our study, we don't restrict prior taxane status, and we will allow prior taxane exposure in this study. That is quite different from the other, I would say, G12D inhibitors or KRAS inhibitors have done in the past. The benchmark here is also very clear that the standard of care is docetaxel or docetaxel plus ramucirumab, with a response rate ranging from 13%-23%. What we have demonstrated in our October disclosure, that 600 mg already, I think, will be able to clear the accelerated approval path, the bar.
We are testing 900 mg as a go-forward dose. If the dose response we have seen in other indications holds, we will be able to demonstrate something really substantial and even better than what has been shown in the KRAS G12 space, around best around 50%. I think we will be able to exceed that. Coupled with a frontline combination with standard of care in the frontline setting starting first half next year, will be our development path.
Okay. The other thing that we've heard that's important in lung cancer is that brain mets are a real problem, and the tri-complex inhibitors, which are very large molecules, we've heard don't really cross the blood-brain barrier. So, we have a cohort in our phase II in lung of 25 patients with asymptomatic brain mets, and we're looking at reduction of those brain mets. I think that'll be really important, isn't it?
Okay.
We've been told that everybody would use this as the preferred agent if we can affect brain mets.
There's been a lot of interest in industry, looking at novel combinations that are chemotherapy-free, be it with PRMT5 inhibitors. We saw a PARP1 inhibitor combination concept recently, then pan-RAS perhaps as well. What is Verastem planning in that regard?
Yeah, I mean, pre-clinically, really let me actually back up for a sec. I think that it's really sad to me in this day and age of RAS inhibitor success that we can just deliver a median of 12 months overall survival for patients with pancreatic cancer. I think that's just a call to action. I think any combination that can get you three years, five years would be wonderful. In preclinical models, when we look at PRMT5, a combination that's really striking. I mean, we can either get very long complete responses or very long, very deep responses when we combine in various. I think if you have pancreatic cancer, that's really bad news. But then I think ultimately if you hear that you have G12D and MTAP deletion, that would be good news.
That really suggests that you could ultimately get a really safe oral regimen frontline that should give you a long-term response. We're close to announcing who that partner will be. There are a few variables in the PRMT5 space that we've looked at carefully, and we think that we'll move forward quickly with that. That'll be mainly in PDAC that we do that combination. As far as pan-RAS, I think combining zoldonrasib and daraxonrasib are similar agents. They're both tri-complex inhibitors. I think they share a lot of the same resistance mechanisms. I think taking a more orthogonal combination, like our ON/OFF dual that's a switch II binder together with a pan-RAS is really intriguing, and the preclinical data have been amazing. Again, kind of tracing the X-axis, you just can knock out tumor growth and get deep regression. We've partnered with Erasca for that, with their pan-RAS.
We're both currently doing preclinical characterizations, although we communicate a lot about that. I think one of the things I'm really interested in is can we lower the dose enough of the pan-RAS so that we don't bring in the rash and stomatitis, but we still benefit from that synergy that the preclinical models predict.
Okay.
I think PARP, we've thought about that as well. It's interesting.
Got you. All right. Unfortunately, we're up on time, so we will talk about CO-PACK next time, but—
Okay. Look forward to it.
Appreciate the time and welcome—
Thanks very much.
The KRAS G12D program. Thank you so much.
Great.
Thank you.
Thank you.