Hello, everyone. Welcome to our Fireside Chat with Immuneering. My name is Li Watsek, a biotech analyst here at Cantor, and with me today is CEO Ben. Thanks for joining me. Maybe to kick us off, I would turn it over to you, Ben, to give us maybe a quick overview.
Sure. Well, thanks, Li, for having me today. Thanks to the whole Cantor team, and thanks to everyone joining us. I co-founded this company 18 years ago, and the idea was really to engineer overall survival, f igure out how to help cancer patients live longer. When you just come in as an engineer and you look at the data, the data shows that there's really two ways to keep cancer patients alive longer. You can attack the tumor, and you can protect the patient. But 99% of all the work in the field to date is focused on attacking the tumor.
We said, "What if you could do both? What if you could attack the tumor while protecting the patient? Could you help patients live longer and have better quality of life?" When I say protect the patient, I mean minimizing the side effects so patients can have better performance status, so they can be more likely to go on to second-line treatments and so y ou can combine better. I mean helping patients maintain their weight, their body mass, their strength, their stamina. I mean not driving the genetics of the tumor to be more aggressive. Right? All those things are about protecting the patient. We said if we can do that, protect the patient while attacking the tumor, we can help patients live longer and also help them live better, have better quality of life.
I think the technology that we developed really enabled us to pursue that strategy.
Mm-hmm. Maybe introduce us atebimetinib, which I think is a good molecule to validate this concept of Deep Cyclic Inhibition.
Absolutely. Yeah. So atebimetinib is our furthest along program.
It is a Deep Cyclic Inhibitor of MEK and the MAPK pathway. The MAPK pathway is the most common pathway in cancer. Within that pathway, MEK is a great target. It is downstream of RAS, it is downstream of RAF, and it is really hard for the tumor to get around an effective MEK inhibitor. It is kind of like you are targeting the narrow point of the funnel, or you are trying to blockade the Panama Canal as opposed to the Caribbean Sea. So it is a really strategic target. In fact, it is a validated target, both clinically and commercially. First-generation MEK inhibitors have been shown to extend overall survival in BRAF mutant cancers in combination with RAF inhibitors. They have demonstrated themselves commercially as well. In 2025, there was $3.7 billion in revenue driven by MEK inhibitors, either alone or in combination with RAF inhibitors.
It is a target that is validated both clinically and commercially, and yet it has really only lived up to a fraction of its full potential. There are two main reasons why. Number one, the first-generation MEK inhibitors have all been really toxic, really poorly tolerated, and they have been limited mainly to BRAF mutant disease. When we designed atebimetinib, we focused on overcoming those two limitations.
It is novel composition of matter. We created it in-house. Brett Hall, our Chief Scientific Officer, is the lead inventor on the composition of matter patent, which was granted in the U.S. last summer. We designed it to work more broadly, to work not just in BRAF mutant disease, but also in RAS mutant disease, which is about 3x as many patients as BRAF mutant disease. We did that by changing how it sits in the pocket so that it blocks RAF-mediated phosphorylation of MEK. That was the first thing we did, and then we said we need to give this much better tolerability in order for it to be combined, in order to protect patients, as I talked about earlier. In order to do that, we developed a new technology called Deep Cyclic Inhibition.
The idea of Deep Cyclic Inhibition is really to decouple side effects from activity. I think in oncology, too often we sort of view side effects as a necessary thing, right?
Yeah.
An indication that the drug is working, because often they're on-target toxicities. Right? This is one of the ways that cancer is most insidious. Right? It uses the same growth pathways that healthy signals need.
Right.
We all have the MAPK pathway for a reason other than for cancer to hijack it. If you just shut it off 24 hours a day, you're going to hurt a lot of the healthy cells in the skin, in the gut, in the mouth, that are dividing. Whereas the tumor cells use the same pathway, they just use it continuously. They need it all the time, not intermittently like the healthy cells. The idea of Deep Cyclic Inhibition is, can we block the pathway completely for several hours a day and then let go?
Give the pathway back. We're depriving the cancer cells of the continuous signaling they need to rapidly grow and divide, but we're giving the healthy cells back the signaling that they need to function.
That is the concept, and the idea of that is to decouple the side effects from the activity. I think really all the clinical data we have shown to date suggests that we have done that successfully. I think the tolerability that we have demonstrated, both in monotherapy and in combination, is really quite favorable relative to anything that is out there for this pathway, whether it is a prior MEK inhibitor or a RAS inhibitor.
Mm-hmm. Ben, I think that is a great point. You talked about the differentiation between atebimetinib from perhaps other MEK inhibitors in this space. We know in PDAC, in particular, MEK inhibitors prior generation has not had great success.
That is right.
You guys think you are going to be different, and you have shown some pretty nice data. You guys also share some ctDNA data at AACR, which I saw was pretty interesting. Can you talk a little bit about that, and then how that supports your differentiation from the other MEK inhibitors just to support that statement?
Yeah, absolutely. You're right, the first-generation MEK inhibitors did not work in pancreatic cancer.
Yeah.
Pancreatic cancer is primarily RAS driven. First-generation MEK inhibitors did not work in RAS-driven cancers because of the RAF-mediated phosphorylation of MEK that I mentioned earlier. For us, it's completely logical that the prior MEK inhibitors did not work in pancreatic cancer, and it's completely logical that ours is working in pancreatic cancer because we designed it to overcome the specific issue that prevented prior MEK inhibitors from working in RAS mutant disease. That to us is all according to plan, right?
That's how we designed it. We're not surprised to see that it's working so well in pancreatic cancer. Now, you mentioned the circulating tumor DNA data, and this is something we shared at AACR earlier in the year. What's exciting about this is circulating tumor DNA, and particularly acquired alteration data, what this is telling you is how a tumor is getting around a drug, right? If you look at RAS inhibitors, for instance, the tumor frequently gets around the RAS inhibitors by acquiring alterations on the same pathway. If you look at a mutation-specific RAS inhibitor, like a G12C inhibitor, the tumor will acquire alterations in KRAS G12D or G12V. It will basically change lanes to get around the tumor. If you look at pan-RAS approaches, you frequently see KRAS amplifications.
The tumor will just make more copies to get around it. What we reported at AACR is we see very few acquired alterations in the MAPK pathway. What this is telling us, again, is we are blocking the Panama Canal, right?
We are blocking a narrow point in the pathway where it is hard for the tumor to get around it.
What we saw instead were acquired alterations in other pathways unrelated to the MAPK pathway.
I think one of the reasons that is so important comes back to protecting the patient, because a tumor with amplified RAS is a very aggressive tumor. If you look at how RAS inhibitors are changing the genetics of tumors as they treat them, the tumors come out the other side of that with genetics that are very aggressive. We believe because the acquired alterations we see are spread across other pathways, not in the MAPK pathway. We believe tumors are coming out of treatment with atebimetinib with genetics that may be more indolent, less aggressive. I think that is part of the theme of protecting the patients is do not drive their tumors to have more aggressive genetics.
Mm-hmm. I want to talk about your frontline data, which I thought was quite impressive. You show 17-month OS that is almost doubling the historical chemotherapy seen in front line. Can you just compare and contrast your data with the pan-RAS inhibitor?
Sure. Well, I think the first thing to appreciate is our data is in first-line pancreatic cancer.
Yeah.
Right? So, this is data we shared at ASCO in our oral presentation. Exactly to your point, 17.3 months median overall survival in 55 first-line pancreatic cancer patients treated with atebimetinib plus gemcitabine. The benchmark from the pivotal study of standard of care gemcitabine nab-paclitaxel alone is 8.5 months, exactly to your point. Most of the RAS inhibitor data that's being talked about lately in the media is from second line.
Yeah.
Right? That's just simply a different patient population. Right? It's different patients because there's a survivorship bias in terms of which patients actually make it to second line. Only about half the patients make it to second line. So you get a different population in second line. The genetics are different because the initial therapy shapes the genetics of the tumor. So the tumors that arrive at second line, having been shaped by the first line treatments, are different. So, there's a reason that people run distinct clinical trials in second line versus first line. We're doing that. Of course, our phase III is underway in first-line pancreatic cancer.
The data that has been shared by RAS inhibitors in the first-line setting is limited.
Certainly, no RAS inhibitor has shown 17.3 months median overall survival in the first-line setting.
Yeah.
I think we are the front runner in that sense. I think certainly no RAS inhibitor in the first-line setting has shown only two categories of treatment-related adverse events at the Grade 3 level in more than 10% of patients the way that we did. So, in terms of the two things that matter most to patients and their oncologists, overall survival and tolerability, I think the data shows that we are the front runners in first-line pancreatic cancer.
Mm-hmm. How much of that survival benefit do you think is driven by the patient's ability to receive subsequent therapy? To your point earlier about tolerability.
The ultimate survival that a patient is able to have, it's the sum of the benefit they get in first line, plus the probability that they can go on to second line, times the benefit that they get in second line. I think one of the important metrics that we reported at ASCO was that in our study, 60% of patients were able to go on to second-line treatment.
Now, why that's important is because in the pivotal study of standard of care gemcitabine nab-paclitaxel, the MPACT study, only 40% of patients were able to go on to second-line treatment. I absolutely think that one of the benefits of protecting the patients with fewer side effects is you can actually increase the likelihood that they can go on to subsequent lines of therapy. We certainly think that's a contributing factor, but there's a number of contributing factors, right?
The fact that 84% of evaluable patients in our study were weight stable or gained weight.
I think that's really important. That's another aspect of protecting the patient and pancreatic cancer patients frequently lose weight. When they do, the hazard ratio is 1.55 in the literature relative to those that are weight stable or gaining weight. Weight loss, which is driven, it's not just the patients don't have an appetite or it's a side effect of the chemo, there's actually the tumor. One of the other insidious things that tumors do is they secrete soluble factors that break down a patient's muscle. It's called cachexia. They do this for energy, essentially. But it not only causes the patients to lose weight, they lose stamina, they feel weaker, it affects their appearance. All these things were part of our design goal to address, to counteract that cachexia when we were designing atebimetinib.
It is really encouraging to see that 84% of the evaluable patients were weight stable or gained weight at three months. I think that also contributes to the survival that we are seeing. Then, of course, the fact that we are shrinking tumors and controlling the disease, that certainly contributes. We believe there are essentially multiple mechanisms that are all contributing to the survival. It goes all the way back to our intent from the start, which is to make a drug that achieves survival, not just by attacking the tumor, but by attacking the tumor while also protecting the patient.
Mm-hmm. Can you talk a little bit about patient baseline characteristics in the phase II study, and how does that compare to some of the historical controls? Then how do we know the survival benefit that you observe in the study is not a function of patient selection?
Yeah. It is a great question, and I think there is a bare thesis out there that somehow we just got lucky and we got the good pancreatic cancer patients, and frankly, that is just a total flat earth kind of fallacy. If we had set out, which we did not, but if we had set out to choose the pancreatic cancer patients most likely to survive longer, we did a really bad job of that.
Our patients were older, on average than the patients in the pivotal study of gemcitabine nab-paclitaxel. Our median age was 68, whereas it was 62 in that study. Patients with lung mets do generally survive a bit longer than patients who don't have lung mets, and we actually had fewer of those patients. We had 27% lung met patients, whereas in the pivotal study, it was 35%. That was another headwind on our patient selection. Then, if you look at the other locations of the metastases, liver and peritoneal mets generally have equivalently bad survival.
We had 51% liver met patients and then another 20-something percent of peritoneal mets. Between those two, it was comparable to what you see for liver and peritoneal together in the pivotal study of gemcitabine and paclitaxel.
Comparable in that sense. When you really dive into it's a flatter hypothesis. But even if you look at the studies where they have only lung met patients, which are the ones with the best survival, they only get up to around 11.8, 11.9 months survival. That is what you could achieve even if you did have perfect patient selection. To have 17.3 months median OS, it is just really hard to make the math work to say that that is a patient selection bias.
Mm-hmm. On subsequent therapy, I know in your phase II study, very few patients receive targeted therapies like pan-RAS, but now adagrasib is approved in second line, and we think the adoption here will be pretty rapid. How do you think that could impact your OS readout in the Phase III study?
Yeah, it is a great question. Just to reiterate, on the data we shared at ASCO, only one of the 55 patients went on to a RAS inhibitor in the second line. That absolutely did not impact our median OS. In fact, if you take that patient out of the analysis, the median OS is unchanged. You are right that now that there is a pan-RAS inhibitor that is approved in the second line, it is good news for second-line patients. We certainly applaud that. The nice thing is that will have a balanced effect on our control arm and our active arm.
Right? Because patients on both the control arm and the active arm can go on to receive a pan-RAS inhibitor in the second line setting. But the effect is going to be relatively modest because it will mostly be in the U.S., right? We are running a global phase III. So, to the extent we see that most likely be in the United States., and it will most likely be a balanced effect. So, if anything, I think with atebimetinib and bevacizumab what we have shown in phase II, we are delivering patients to the second line, in good shape, both physically and molecularly, to benefit from new and emerging second-line options.
Mm-hmm. I think for frontline, I think there is also some expectation that drugs rest may be adopted there as well. Do you think that might impact the types of patients that are coming to your study in the frontline, or you do not think that is going to be a huge factor?
Look, there is our phase III that is running now in first line and hey have a phase III that is running in first line as well. We are pretty much neck and neck.
Right. They dosed their first patient, they announced in April, we announced it in June. If you look on clinicaltrials.gov today, we have 43 sites already active. Feel free to compare that to the other guys. I think compares favorably. In terms of how first line trials are pursued, if you look at the guidance on timing, I think it's pretty comparable.
Ultimately, this is about choices for patients, right?
Yeah.
You can't get the same treatment in first line and second line.
Right? Once a drug stops working, it stops working. Once a patient has resistance mutations to a drug, they're resistant to it. I think there's an irrationality in the market right now that because of the excitement around pan-RAS, they think, "Oh, they're going to get it in first line and second line and third line and fourth line." That's just not how it works. We think creating options for patients is a good thing. We think creating options that have, again, no RAS inhibitor has shown 17.3 months median OS in the first line setting. We're the front runner in that sense. No RAS inhibitor has shown so few categories of adverse event, only two categories of treatment-related adverse events at the Grade 3 or higher level in more than 10% of patients. We think those things are going to provide a differentiated profile.
Ultimately, if you are in a situation where patients have multiple options in the first-line setting, we think a substantial number of them will choose the option. In the scenario where you have comparable survival and much better tolerability, we think a substantial number of patients will choose the option with fewer rashes, less diarrhea, l ess stomatitis, less fatigue.
Can you share any physician feedback just on potential sequencing or maybe their segment of patients, more suitable for pan-RAS versus for atebimetinib, just given the tolerability advantage. There may be sicker patients or healthy patients more suitable for maybe either drug.
Well, let us talk about our base case, right?
Our base case would be that we show superior OS in the first-line setting and superior tolerability. In that case
That would be a no-brainer.
I think that would be a no-brainer. That is our base case. Again, I think the phase II data that has been released today supports that. Again, no RAS inhibitor has shown a median OS as good as 17.3 months overall survival in any setting, first line or later lines. No RAS inhibitor has shown as few categories of treatment-related adverse events at the Grade 3 level in more than 10% of patients that we have. So that is our base case. Even if you want to take a different case, which is that another possible outcome is you see comparable survival.
Yeah.
But I think there we'll still have better tolerability. In a scenario, and again, let me just be clear, we're running our phase III, so the phase III will have to show all this. But in the scenario where our phase III shows comparable survival with better tolerability, again, then the question becomes how do you sequence these things?
Right? And if you have a drug that's already approved in second line and has already demonstrated benefit there, and you have a drug that shows equivalent OS and better tolerability in the first line, I think that's also going to be a pretty obvious sequencing choice.
Especially because in the first line setting, patients who are newly diagnosed with pancreatic cancer, it's obviously a tough diagnosis. And they have things they want to do, right? They want to travel.
They want to visit family. And having fewer rashes, having less diarrhea, having less fatigue, these are all things that are going to help patients live their lives. I think we hear that from oncologists, right? After the presentation of our data at ASCO, Dr. Peter Vu from UC San Diego, who gave the presentation, he was asked, "What does this mean for patients?" Right?
The 84% of evaluable patients being weight stable or gaining weight, the limited harsh side effects. What does it mean? He is quoted in OncLive, so this is public. He said, "In my experience treating a lot of patients in this study, patients have done incredibly well from a quality of life perspective.
It has been remarkable to see.
You do not frequently hear oncologists, particularly in pancreatic cancer, using words like "incredibly well" and "remarkable" to describe quality of life. I think that is something that is going to be attractive to a lot of patients if we can show the same thing in the phase III.
Maybe give us an update on the enrollment of the phase III. Do you think with the adagrasib approval, any risk in terms of enrolling patients?
Yeah. Our phase III is for first line.
Yeah.
Right? We are very pleased with the progress. We dosed our first patient in June. We announced that. We already have more than 40 sites listed on clinicaltrials.gov. You can run the numbers, right? The unmet need here is just vast, right? There is about 60,000 patients a year in the U.S. alone with pancreatic cancer, much more than that worldwide. Our study is hundreds of patients. There is really just a very unfortunately, the unmet need here is vast. Frankly, that is why we targeted first line in the first, right? There is twice as many patients in the first-line setting as there are in second line. It is the biggest unmet need, and that is really why we chose to focus on first line pancreatic cancer. I think there is a lot of interest and excitement based on the data that we presented at ASCO. I think we're thrilled and honored to have Eileen O'Reilly from Sloan Kettering as the lead PI for the study. We're really excited with the progress.
I guess between now and your 2028 top-line readout, what other data updates should we expect from atebimetinib?
Yeah, it's a great question. I'll start with something we announced this morning, which is we're going to have a poster at the end of September at the AACR Pancreatic Cancer conference. That poster really takes the finding that we announced at ASCO of 84% of evaluable patients being weight stable or gaining weight at three months in our study. It really expands on that, and it looks at the survival implications of that. I think that we're excited to share those data, and I think that'll really help people understand that finding in more detail. Then look, we have multiple studies that are ongoing, right? The combination of atebimetinib with gemcitabine and nab-paclitaxel, the phase II, that continues. We're also running an arm in combination with FOLFIRINOX.
Yeah. Are we going to see data from that combination?
We haven't guided yet, and that's something we're thinking about. Certainly that study is ongoing.
Yeah.
I think we've shared a case study of a patient who has a complete response to atebimetinib plus FOLFIRINOX. Look, that study is ongoing. We see the data, and it's something we're thinking about in terms of the right timing. But I do think it'll be of interest to people, even though what we're pursuing as our top priority in phase III is the combination of atebimetinib with gemcitabine and nab-paclitaxel. I think seeing how atebimetinib does in combination with another chemo agent in first line would certainly be of interest.
Absolutely.
Those are two things. Then, I think our monotherapy data has been misunderstood. That's something we're thinking about how to address. Then of course, we have the lung cancer study with atebimetinib in combination with anti-PD-1. We've guided to dosing the first patient in that study by the end of this year and sharing initial data by the end of next year. There's a lot that's happening there. Then look, because atebimetinib has this tolerability profile that's fairly unique for the MAPK pathway, there's a vast number of combination opportunities. We get a lot of inbound interest in that, and we're working through that and thinking about what makes sense and when. But as we make decisions around potentially pursuing combinations, that's also news flow that could occur in the coming months.
Okay, great. Thank you so much, Ben. Appreciate the discussion.
Thank you, Li, and thanks everyone for listening.