Can you describe the company today and what aspects of the Immuneering story investors still misunderstand about the MEK inhibitor atebimetinib?
Absolutely. Yeah. In terms of where the company is today, we are in phase III with a third generation MEK inhibitor. The phase III is well underway. We have over 40 sites already listed on ClinicalTrials.gov, and that is in first-line pancreatic cancer, which is just a huge unmet need. It is the largest number of patients in pancreatic cancer. We are excited to have that underway. We are excited to have funding through that top line readout, which we have guided to in mid-2028. Now you asked about what some of the misunderstandings may be about the company, and I think there is a number of them, the first one being related to news flow. I think people hear top line readout of the phase III in mid-2028, and maybe they wonder how much is happening between now and then. The reality is quite a bit.
Starting in just a few weeks on September 26th, we have a poster at the AACR Special Conference on Pancreatic Cancer. There we have guided to expanding on the finding that we reported at ASCO this year that 84% of the evaluable patients in our phase II study in first-line pancreatic cancer, were weight stable or gained weight at three months. I think that is so important because in pancreatic cancer, patients frequently lose weight. We are going to be expanding on that finding, providing additional context. That is coming up. We have a lung cancer study, a phase II in combination with cemiplimab. We have a supply agreement with Regeneron. We have guided to dosing the first patient in that study by the end of this year and sharing top line results by the end of next year. We have a lot of studies that are ongoing.
I mean, the study that we talked about at ASCO, the 55 patients treated with atebimetinib plus gemcitabine nab-paclitaxel in first-line pancreatic cancer, that study is ongoing. We continue to see that data. Not guiding anything yet. We are still thinking about it, but that is certainly data we have. Similarly, the combination with FOLFIRINOX. Another standard of care treatment in first-line pancreatic cancer, that is another arm of the phase II-A. So far, all we have shared from that is a single case study of a patient with a complete response to that combination. That whole arm is ongoing and again, no decisions yet. We're thinking about when to share that. I think there's a misunderstanding about news flow.
Yep.
We're going to have a lot. I think there's a misunderstanding about MEK inhibitors. Historically, the first generation MEK inhibitors got a bad name. They worked in BRAF mutant disease. They didn't work in RAS mutant disease, including pancreatic cancer, and they were quite poorly tolerated. Second generation MEK inhibitors solved the issue of working in RAS mutant disease. That was a good step forward, but they were still pretty toxic. What we did with our third generation MEK inhibitor was, we believe, to solve that second issue of the toxicity. So, we think MEK has always been a great target. It's just had these two challenges and we think it took three generations to solve it. But we believe we're there. The paper that we published in July, in Cancer Research top journal.
I think that really laid out how we're a next generation MEK inhibitor. I think some of that baggage from prior generations is misunderstood. Then, look, there's a lot of excitement around RAS these days.
Sure
... and well there should be. But I think people mistakenly view RAS inhibition and MEK inhibition as an either/or.
Yep.
T he reality is it's both/ and. In fact, where the RAS inhibitor field is heading is to mutation-specific RAS inhibitors like G12C inhibitors, KRAS G12D inhibitors, and we've shown preclinical data that demonstrates a lot of synergy.
where if you can combine a MEK inhibitor like atebimetinib, a third generation MEK inhibitor, with a mutation-specific RAS inhibitor.
I think there's just a lot of aspects of what we're doing that are perhaps misunderstood and fundamentally the data that we shared at ASCO.
Yeah. We'll get into it.
The overall survival-
Yeah, no.
talk more about that as we go along here.
Absolutely. To piggyback on the comment on news flow, I think the ASCO data set is one worth revisiting. Particularly, obviously the top line was a 17.3 month OS, but can you maybe explain to us some of the more underappreciated aspects of that data set and how it fits in the overall narrative that the oxygen in the room is being sucked out by a lot of the RAS companies?
Yeah, absolutely. Let's talk about this. Again, we're talking about the data that we shared at ASCO this year. So it's 55 first-line pancreatic cancer patients treated with atebimetinib in combination with gemcitabine nab-paclitaxel. Just to remind everyone of the top line result that you mentioned, 17.3 months median overall survival. Now, look, with all the excitement about RAS inhibitors, all the media coverage and the talk of breakthroughs and miracles and revolutions. No RAS inhibitor has ever shown a 17.3-month median OS in any setting in pancreatic cancer. Period. I'll say it again. No RAS inhibitor has ever achieved 17.3 months median overall survival in pancreatic cancer. So I think it's important to put aside the hype and put aside the publicity and really look at the numbers.
Obviously, you got to be careful comparing across trials in the different settings. But when it comes to first-line pancreatic cancer, and when it comes to this pathway and median overall survival, we are the front runners.
Now, the question that you asked is what are some of the other interesting numbers underlying that 17.3-month median OS? I think one of the most important numbers is two. We only had two categories of treatment-related adverse events at the Grade 3 level in more than 10% of patients. Anemia and neutropenia, both of which are associated with the chemotherapy that we're combining with.
What that means, essentially, is this combination of atebimetinib plus gemcitabine is extremely well-tolerated. That's important. That matters to patients, particularly in the first-line setting. Because first-line pancreatic cancer patients, they have things they want to do. They want to spend time with family, they want to travel, and if they're dealing with the kind of adverse events that you see more frequently when you target RAS or other elements of the pathway, or when you target MEK in a first-generation way, as opposed to the third-generation way that we're doing it it's hard.
When you have serious rashes, when you have diarrhea 5 x a day, which is the definition of Grade 2 diarrhea, these are all things that make it hard for patients to live their lives and to really live in a meaningful way. We believe the fact that we had so few treatment-related adverse events at the Grade 3 level in more than 10% of patients is huge. I think that's important to patients, it's important to their oncologist, and it's important to their ultimate survival.
Because when you look in the literature, when patients have a decline in their performance status, or when they're unable to go on to second-line treatment, there's a substantial increase in the risk of death, about 50%. I think one of the most important and least appreciated numbers that we shared at ASCO was the fact that 60% of the patients in our phase II in first line were able to go on to second-line treatment.
Absolutely.
Whereas in the pivotal study of standard of care gemcitabine, the MPACT study, only 40% of the patients were able to go on to second-line treatment. That matters for survival, and it also tells you something about how the patients are doing.
The last number I would point to is the 84% of patients being weight stable or gaining weight. We believe that also contributes to survival. A lot to like, we believe, about the data we presented at ASCO. But again, the top line is the thing to like most, which is 17.3 months median OS. A survival that has not been shown by any RAS inhibitor in pancreatic cancer.
A follow-on question before we get into some of the nuances of the MAPKeeper 301 study, I think it's important that this is not a MEK inhibitor like we've seen. I think if you can say a few words on the differentiation mechanistically, and as we've spoken in the past, the mechanism is incredibly attractive and very unique. As a recovering med chemist, it is incredible what you guys have done there. If you can just touch upon how you were able to garner such amazing data with that mechanism, I think it would be helpful context for investors.
Yeah, it's a great question. Thank you, Andres. There's four or five key papers that I think an investor needs to read to really understand the arc of MEK inhibitors and why atebimetinib is so unique and showing such different results from what we've seen before. There's the study, the COMBI-d study, was really what showed that MEK inhibitors can contribute substantially to survival. This is in a BRAF mutant tumor setting. What it showed is, compared to a RAF inhibitor alone, adding a first generation MEK inhibitor increased survival by more than six months. All right, so that's the first one. Even a first generation MEK inhibitor can increase survival substantially in a BRAF mutant tumor.
However, there's another paper around the same time, which showed that a trametinib MEK inhibitor in combination with gemcitabine did not extend survival in pancreatic cancer, a predominantly RAS-driven tumor. So those were really the two clinical bases for first generation MEK inhibitors. Works in RAF, doesn't work in RAS. There's a key paper out of Neal Rosen's lab at Memorial Sloan Kettering Cancer Center, where they basically showed why. Very clearly why MEK inhibitors of the first generation worked in RAF mutant disease, but not in RAS. What that paper showed is there's a feedback loop called CRAF bypass.
You block it works in RAS mutant disease. You don't block it doesn't. It's pretty much that simple. There's a second generation of MEK inhibitors that were developed that block that CRAF bypass. Sure enough, they work in RAS mutant disease.
That's been shown. That was shown well before us. You block CRAF bypass, the MEK inhibitor will work in RAS mutant disease. But if you look at that paper, those second generation MEK inhibitors still were very poorly tolerated. Over 90% of patients experienced rashes of any grade. More than half the patients had diarrhea. There was really still a need to correct that tolerability. That's what we built onto. Right? We developed a new technology called Deep Cyclic Inhibition that's both a PK and a PD pulse. We're shutting the pathway down very completely for several hours a day, and then we're releasing it. It's novel composition of matter developed in-house at Immuneering. What we showed is that can dramatically improve the tolerability, and we're also blocking the CRAF bypass, which makes it work in RAS mutant disease.
If you follow this arc, what you have is a third generation MEK inhibitor that our data is showing works in RAS mutant disease and is we believe much better tolerated than what you saw for the prior generation of MEK inhibitors, specifically with regard to any grade rash. If you look at our monotherapy data, we cut that by two thirds. Less than a third of our patients see any grade rash in that monotherapy study versus around 90% for continuous inhibition of the pathway, whether it's with a MEK inhibitor or a RAS inhibitor. Dramatically, rash is important. Then, we cut the diarrhea in half as well.
Great. Great. To use your analogy, bridging the preclinical work all the way to the phase III now. Would be great to get some color on the MAPKeeper 301 in terms of design. How did you end up in the design, and how should investors think about some of the differences in maybe the chemotherapy intensity regimen, and what should we be looking at from a design perspective?
Absolutely. Yeah. This is the MAPKeeper 301. It is our phase III study in first-line pancreatic cancer, well underway. We announced dosing the first patient in June. If you look on clinicaltrials.gov today, we already have more than 40 sites up, so we are very happy with the pace of that. We are testing atebimetinib in combination with gemcitabine nab-paclitaxel every other week schedule, same as we did in the phase II.
That is a great schedule because it is shown to be comparable on survival and much better on tolerability than giving the chemotherapy more frequently and giving it three weeks on, one week off, which is the default from the original pivotal study. We think that the tolerability advantages of that play together with the tolerability advantages of atebimetinib that we have shown in monotherapy, and really together, I think create just a very unique opportunity for patients in the first-line setting.
Right? Because, here is an opportunity to have a treatment that has, again, phase II data in first line of 17.3 months median OS, which no RAS inhibitor has shown, and tolerability that is really quite unique. For patients who don't want to lose weight, who don't want to have rashes, who don't want to have diarrhea, I think this trial has the potential to present a really unique option. I think if people look at the data, that's what they'll see.
Great. No, that was very helpful. I guess bringing it all together, the context is so important for the story. As investors think about new therapies that are now available for second-line patients, how important is that preservation of performance status for the atebimetinib thesis?
Yeah. It's vitally important to preserve a patient's performance status. It's vitally important to help them maintain their weight or gain weight. All these things matter in general, and they matter even more in the context of newly approved second line treatments.
Yep.
But I think it's important to emphasize that the newly approved treatments are focused primarily on second line.
Yes.
Right. W ith all the excitement around RAS inhibitors and the media coverage, there were people who were saying, "Oh, they're going to get a blanket approval in first-line pancreatic cancer." Even though that's a completely different patient population.
Yeah.
Right? Different patients at a different stage of disease with different genetics of their tumors. T hat's just not where the data was for that program. So, I think the fact that that approval was primarily for second line. I think that just reiterates that first line is wide open and a distinct setting with different patients. T hat's why we're so excited to have a phase III well underway in first-line pancreatic cancer which it's the biggest unmet need.
It's twice as many patients as the second-line setting. Really important to have first line, and I think that's wide open. Again, I think the best, we believe to our knowledge, the best first-line data that comes from targeting the MAP K pathway is our 17.3 months median OS that we showed. I think having 60% of our patients being able to go on to second-line treatment, that really matters even more so in an era where there are new options in the second line. Because the ultimate benefit a patient gets, it's the sequencing, right? It's not any one treatment or the other treatment. It's both and. The benefit a patient gets is the benefit they get in first line plus the probability of going on to second line times the benefit that they get in second line.
In an era with new options in second line, having the right first-line treatment that can maximize the patient's chances of going on to second line, I think is all the more important. But having the patients be able to have an experience in first line where they're maintaining their weight, they're experiencing relatively few side effects, we believe is important. That profile, which we showed in phase II in the data presented at ASCO, we think that's a unique and differentiated profile, and we're excited about it.
Great. I think as a last question, given the time we have, obviously there's an incredible amount of market dynamics with a lot of entrants in late stages, our first RAS approval. Where do you see in the upcoming years, assuming a positive MAPKeeper 301 study, where do you see atebimetinib fitting in that paradigm? Is it a direct competitor? Is it cooperative? Could it open the doors to more novel combinations outside of chemo? What is your hope there?
It's a great question. I think where the RAS field is going is towards mutation-specific RAS inhibitors. No matter how you look at it, the number of trials, the number of companies working on it, I think there's an implicit understanding that pan-RAS approaches are tough from a tolerability perspective. So mutation-specific RAS is where the field is going. Now, mutation-specific RAS, it's like blocking the top part of a funnel. Imagine a funnel and you're pouring water and you're blocking the top. If the water starts to get around that, you also want to block the bottom part of the funnel.
Yep.
That's what MEK does. We believe MEK inhibitor, particularly a third-generation MEK inhibitor like atebimetinib, in combination with a mutation-specific RAS inhibitor, can be incredibly synergistic.
We've shown pre-clinical data to that effect, greater depth and durability with the combination than either one alone. We think that's where the field is heading the long term. In the meantime, I think when you look at the options for first-line pancreatic cancer and the data that's out there, 17.3 months median OS that we showed at ASCO, no RAS inhibitor has shown that. If we can continue to show the best OS and the best tolerability in the first line setting, I think that'll be a no-brainer.
Great. I think that's all the time we have. I'd like to thank Ben and the whole Immuneering team on behalf of myself and H.C. Wainwright, thank you so much. Congrats on the progress, and we look forward to future updates.