Immuneering Corporation (IMRX) Earnings Call Transcript & Summary

Welcome to the Immuneering conference call to discuss a positive data update from the company's ongoing Phase IIa trial of atebimetinib in first-line pancreatic cancer patients. [Operator Instructions] As a reminder, this call is being recorded today, Tuesday, June 17, 2025, I would now like to turn the conference over to Laurence Watts of New Street Investor Relations. Please go ahead.

Thank you, operator. Joining us on the call today from Immuneering are Chief Executive Officer, Ben Zeskind; Chief Scientific Officer, Brett Hall; Chief Medical Officer, Igor Matushansky; Chief Accounting Officer and Treasurer, Mallory Morales; and E.B. Brakewood, our Chief Business Officer. During this call, management will make forward-looking statements, including statements related to its Phase IIa trial of atebimetinib as well as the timing of additional data from the study and the company's development plans. Our actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of risks and uncertainties. Factors that could cause these results to be different from these statements include factors the company described in its security filings, including its annual report on Form 10-K and our quarterly reports on Form 10-Q. Immuneering undertakes no duty or obligation to update any forward-looking statements as a result of new information, future events or changes in its expectations. With that, I will turn the call over to Ben Zeskind, Chief Executive Officer of Immuneering. Ben?

Thank you, Laurence. Good morning, everyone, and thank you for joining our conference call. Our goal is to help cancer patients live longer and longer and longer and eventually live so long that they outlive their disease. So cancer becomes a nonfatal condition like cardiac disease, diabetes or HIV today. Now that's a big goal, but today's data shows that it's within reach. It's also a different goal. Everyone's focused on curing cancer and we say, let's be a little more patient. Let's control it first, then cure it. Everyone kind of wants to squash tumors like a bug, and we say, maybe you need to be a little more patient, maybe you need to whittle away at them until they collapse. Everyone wants to kill the tumor, kill the tumor, kill the tumor. We say, let's focus on preventing the tumor from killing the patient. And this is a different goal, but it's important because if, as a field, we keep doing the same thing, we're going to keep getting the same result and patients are going to keep dying of cancer. So we want to change that. We want to help cancer patients outlive their disease. And as a result of this different goal, we have different priorities. Our first priority is durability. Durability, durability, durability. We want to help patients live longer. We want to maximize overall survival. There's too much focus out there on just shrinking tumors quickly, shrinking tumors quickly. And the challenge is frequently, if you shrink tumors quickly, the effect only lasts for a few months. It's temporary. It's not durable and then the tumors come back, resistant to that treatment, worse than before, and you don't have that durability. So our priority is durability, overall survival. Our other key priority is tolerability. We want patients to live better. We want to minimize adverse events. We want to make drugs with very few serious side effects. And frankly, this is too often an afterthought in the development of oncology drugs. Patients deserve better, especially for drugs that can help patients live for long, long, long periods of time, they have to be really well tolerated. So patients are not only living longer, but they're also feeling better. This tolerability also helps with performance status, which is directly linked to durability, and it also helps with combinability, which is how most cancer therapies are used most effectively. So not surprisingly, with these different priorities of durability and tolerability, we're taking a very different approach. Our approach is focused on not outsmarting the tumor, not killing the tumor but outpacing the cancer. We want our therapies to change faster than the cancer can adapt, faster than it can develop resistance. And so with this different approach, we've created a very different drug. Atebimetinib, formerly known as IMM-1-104, this is an oral once-daily inhibitor of MEK in the MAP kinase pathway, a pathway that drives the majority of all cancers. Already, as a monotherapy in later-line settings, atebimetinib has shown durability and tolerability with very few side effects. But not surprisingly, given our different goal, our different priorities, our different approach and our different drug, we also have a different focus. Our initial focus is first-line pancreatic cancer. First line, this is where there are the most patients in pancreatic cancer because sadly, many of them don't make it past the first-line setting. Oncologists always say, the first shot is the best shot. And so first line is really the place we're focused in pancreatic cancer. It's also a place where you need to combine. And so our Phase IIa is focused on atebimetinib in combination with modified gemcitabine/nab-paclitaxel chemotherapy in first-line pancreatic cancer. And it's an incredibly urgent need. There are about 52,000 deaths each year in the U.S. alone, and the 5-year relative survival is only about 13%. So there's an urgent need for medicines that can help patients with pancreatic cancer live longer and live better. So different goals, different priorities, different approach, different drug, different focus. Not surprisingly, we have very different results. And let's start with durability. And when you talk about durability, the first and most commonly asked question is, what's the median overall survival. So the first piece of wonderful news I can share today is that our median overall survival has not yet been reached, meaning that the majority of our patients are still alive. Median overall survival not yet reached. This is great. But so then how do you go about assessing overall survival when the median survival has not yet reached. Well, kind of the next most common approach is to use landmarks, such as looking at the probability of surviving 6 months with pancreatic cancer. And unfortunately, the answer for many pancreatic cancer patients treated with standard of care gemcitabine/nab-paclitaxel is only 67%. That's right. A full 1/3 of these patients don't make it past 6 months. We set out to change that. By prioritizing durability and tolerability by building a different kind of drug that's designed to outpace cancer, we have achieved a truly unprecedented 94% overall survival at 6 months. That's right. 94% overall survival with atebimetinib plus modified GnP. These are the kind of odds that patients deserve. By thinking differently, we were able to drive a different outcome and it's game changing for these patients. You can see why our investigators say atebimetinib is having a transformative impact on their practice, 94% overall survival at 6 months, transformative. Here is the Kaplan-Meier plot for atebimetinib plus modified GnP in first-line pancreatic cancer which essentially shows the probability of surviving as a function of time. And it really couldn't look much better than it does right now. Now how robust are these results? Well, over the course of the talk, there's about 18 pillars of robustness that support these results, 18 pillars of robustness. So let's talk through some of them. There's a few key points right here on this slide. The first is that the curve doesn't drop after 6 months, right? It's not like we got to 94% and then shortly thereafter, it tails off. No, the curve stays at 94% all the way to the right. So that's the first pillar of support. That lends robustness to this 94% overall survival that we've observed at 6 months. The second thing to notice is that the median follow-up time is 6 months. That means we've had enough patients on study for long enough to confidently talk about these results. The third thing to notice is the number of patients, n equals 34. This is the full intent-to-treat population at 320 milligrams. This is a sizable number of patients, it's not a small group. It's enough to really say something about survival in this population. And then another thing to notice about robustness here is that we report the 95% confidence interval for that 94% 6-month overall survival. And essentially, a 95% confidence interval is a statistical way of assessing the range of likely outcomes. And you can see that even the lower limit of that is well above the benchmark for standard of care. Finally, you can see that we have a very recent data cutoff of May 26. Now this also gives robustness. We're not showing you stale data. We're showing you recent, recent data, and that's important to note. Look, for over a decade, our company has been talking about taking these survival plots and making them run straight across the top and it's deeply humbling to be able to share these data today. It's an overnight success over a decade in the making. The study is ongoing, and you can see that all the patients with blue marks are still alive and on study, so we're very excited to see how this continues to develop over time. And we're so very grateful to the patients, their families, our investigators, the incredible Immuneering team that made this possible and to our shareholders. Everyone has a lot to be proud of today. Our next step is to run a pivotal study with this combination, randomized against standard of care, and we'll talk more about that in a few minutes. But in the meantime, what we can do is to plot our results together with the results from the pivotal studies of the 3 standard of care treatments for first-line pancreatic cancer. Now you have to take this with a grain of salt because every study is a bit different, but you can instantly see why pancreatic cancer is such a terrible disease with such limited outcomes and how atebimetinib changes that. You can drive a truck through the gap between that blue line and the other lines. Again, we're very excited to see how this continues over time. And look, that's another pillar of robustness that supports our overall survival results. The fact that they not only exceed the standard of care gemcitabine/nab-paclitaxel, they exceed the 6-month OS for every single standard of care, all 3, you can see it's dramatic. So that fact also lends robustness to the overall survival results that we're reporting. It's also worth noting that we actually used less chemo. We used the modified gemcitabine/nab-paclitaxel which is every other week as opposed to 3 weeks on, 1 week off. So over the course of the month, we're using 1/3 less chemo even than they used in that pivotal study for gemcitabine/nab-paclitaxel. So that fact also adds robustness to the 6 months OS of 94% that we're observing here today. Now the most important metric is overall survival. That's what matters most to patients is how long they live. But another important metric is progression-free survival or how long patients stay on study drug without seeing substantial tumor growth. And in terms of progression-free survival, we're seeing a truly unprecedented 72% progression-free survival at 6 months. Again, this adds robustness to the overall survival results that we're seeing. It's another pillar that supports those results because, again, we're seeing progression-free survival that's dramatically higher than what you would expect for the benchmark. In fact, the benchmark for patients on standard of care gemcitabine/nab-paclitaxel is 43%, 43% PFS at 6 months with gemcitabine/nab-paclitaxel versus 72% in our study. Just another huge gap that further lends robustness to the overall survival results that we're seeing. But how about the tumors themselves. What's happening to the tumors? Well, first, just to point out again that if we plot them together, our PFS is dramatically higher than all 3 standard of care treatments. But again, what's happening with the tumors? What's going on there? Well, here, you can see our waterfall plot. You can see each blue line here is a patient. And what you can see is that the vast majority of patients in our study have their tumors shrinking. Their tumors are reducing in size. And a metric that a lot of people like to use, the overall response rate, which is essentially how many patients have their tumors shrinking by more than 30%. And on that overall response rate, we are at an incredible 39%, 39% overall response rate, where the benchmark for standard of care gemcitabine/nab-paclitaxel is only 23%. So we're seeing just an excellent overall response rate. And then the other metric people use when looking at these kind of data is the disease control rate, which is how many patients have their tumors either shrinking or stable? And there, we're looking at a disease control rate of 81%. 81% versus 48% in the pivotal study for gemcitabine/nab-paclitaxel. So these are 3 more pillars that add robustness to the incredible 94% overall survival we're seeing at 6 months. The fact that our overall response rate is dramatically higher, the fact that our disease control rate is also excellent at 81%. And then the third thing to notice on this chart is there's actually a patient over on the right, where the bar goes down to 100%. That's a complete response, a confirmed complete response, which is exceedingly rare in pancreatic cancer. In fact, there was only 1 complete response out of 431 patients in the benchmark study of gemcitabine/nab-paclitaxel. So the fact that we're seeing such unusual things as a complete response just lends further robustness, another pillar of support to the 6-month overall survival that we're seeing of an incredible 94%. But okay, these waterfall plots, it's a snapshot. It's a moment in time. But how are the tumors, how are they changing over time in terms of their size, right? What's the -- do we have a bunch of tumors that have been growing in a bunch of patients that are sort of about to have progression? Absolutely not. This is our spider plot. Essentially, what this shows is deepening tumor responses with time. You can see the vast majority of patients have lesions that are shrinking and continue to shrink. Now what's important here is we don't shrink the tumor slowly. I'll say that again, we don't shrink the tumor slowly -- quickly. We don't shrink them quickly. We shrink them slowly. And if you shrink tumors too quickly as many targeted therapies do, you essentially select for resistant cells and you ultimately get a tumor that's worse, the patient progresses and it becomes harder to treat. So by shrinking tumors slowly, shrinking them slowly, we actually get, I would believe, much better durability and you can see that here. It's a little bit like the old fable of the tortoise and the hare, right? I think too much of oncology is rooting for the hare, the rabbit, to go sprinting out ahead and sort of not worrying about what happens at the end. With us, with atebimetinib, slow and steady is what wins the race. Shrinking those tumors slowly but surely, more and more over time, and you can see that the vast majority of our patients have their tumors shrinking and steadily reducing. Slow and steady wins the race. And these spider plots that show deepening tumor responses over time are yet another pillar of robustness that supports the incredible 94% overall survival at 6 months that we're seeing. Really remarkable to see those deepening responses over time. All right. So we've talked a lot about durability. We've talked a lot about durability. But what about our other top priority, tolerability. Let's take a look at the data there. Now it's probably not surprising to hear that standard of care chemotherapy has quite a few adverse events. And here you can see a table of the 10 or 11 sort of most common serious or grade 3 and above adverse events observed in the 3 pivotal studies of the standard of care therapies, gemcitabine/nab-paclitaxel, FOLFIRINOX and NALIRIFOX. Now look on the right, what you can see is that in the majority of those 11 categories, 6 out of the 11 categories are a combination of atebimetinib plus modified gem/nab at 0 grade 3 or higher adverse events. That's right, 0. There are just so few serious adverse events that we're seeing with this treatment. And that's critical for many reasons. It's critical because it helps patients not only live longer but live better, live more normal lives, be able to enjoy their lives, be able to go out and do things. And this is really what's so special about the tolerability that we designed from the beginning. That was a key priority from the beginning with atebimetinib. This tolerability is also important for the durability. They go hand-in-hand for a few reasons. Tolerability affects performance status or how well the patients are doing, which is directly correlated with survival. So ultimately, by keeping the patients in better shape, it also helps them live longer. Performance status is key. And it also enables combinations and combinations are another very powerful strategy to prevent tumors from developing resistance. So the fact that we can so readily combine and don't take this for granted because there's a lot of targeted therapies that can't. But the fact that atebimetinib has a tolerability profile where it can so readily combine with chemotherapy and go straight to that first-line setting is truly remarkable. It's another pillar of robustness that supports the overall survival results that we're reporting to you today. Really just remarkable tolerability and we're so pleased for the patients that are able to experience this. So the next question people often ask is what was the population of patients that we had in this study? And how did it compare to the patients in these 3 benchmark studies. And there, we get another pillar of robustness. Take a look here. Take a look at these patients, the median age of our patient population in this study was 69 years old versus the 3 benchmark studies where the patients were in their low to mid-60s. Only 2/3 of our patients were over the age of 65, whereas it was half or less for the 3 benchmark studies. Now unfortunately, age is associated with overall survival in general and particularly in pancreatic cancer. So the fact that we were able to achieve a 94% overall survival at 6 months, even with a group of older -- meaningfully older patients lends further robustness to the result that we're seeing. Not to mention the fact that we actually had a higher percentage of patients with elevated CA 19-9, a blood-based biomarker that's associated with pancreatic cancer, tumor burden and prognosis. So just the fact that we had these older patients, and we're very thrilled that we were able to help them. It just lends even more robustness to the overall survival results that we're seeing. So let's zoom in a little bit and talk about a couple of those patients because it's 1 thing to look at the numbers and the aggregate plots, but it's another thing to understand the kind of experience that individual patients are having on this treatment. So this is a patient, a 65-year-old male treated in this study with -- in the first-line setting with pancreatic cancer with atebimetinib plus the modified gemcitabine/nab-paclitaxel. This patient had a baseline tumor burden. You can see the baseline sum of longest diameters or SLD of almost 10 centimeters. Think about that. That's a very substantial tumor burden. This patient has been on treatment over 7.5 months as of the data cutoff. He's gained weight. He's seen a 98% reduction in CA 19-9 levels. That's that blood-based biomarker, you can see in the left, it's basically normalized. 37 is considered normal. But look at the tumors, look at the pod on the right. The tumors have been reduced. They've shrunk, slowly but steadily, right? 20%, close to 30%, but not quite there. On the third scan at 5 months, 30%, and then further down and staying down. This is a confirmed PR with a deep 46.5% reduction in the tumors. This is really just a remarkable outcome for this patient. And I think what's -- but what's most remarkable is that sum of longest diameters is composed of 3 target lesions, and we have the scans for this patient. So we can show you exactly what's happening with the 3 target lesions that make up that sum of longest diameters that you see. And the first target lesion was the largest. It was a pancreatic cancer mass, a mass in the pancreas. And what -- and you can see, over the course of these 3 scans, the baseline scan 2 and scan 4, you can see what we mean. The tumor is shrinking slowly but steadily on both axes, on both dimensions, as you can see on the top. And that's hard to do. In pancreatic cancer, these pancreatic primary tumors often form a thick fibrotic husk. So the fact that you can whittle away at that is really excellent. And that's part of what drives the overall reductions that you saw on the prior slide. But what's particularly remarkable about this patient is the 2 other target lesions, which we'll show on the next slide. This patient had 2 metastases, 2 lesions, at 2 different spots in the liver. And what you can see is that over the course of 6 months, not right away, but slowly, surely, our treatment whittled away those tumors to the point that they were no longer detectable. That's right. 2 liver metastases rendered no longer detectable in a patient treated with atebimetinib plus modified gemcitabine/nab-paclitaxel. That is an extremely unusual outcome, and it just lends robustness, another pillar of robustness to this overall survival that we're seeing, 94% overall survival at 6 months. Patients with lesions that are rendered undetectable in the liver. That's remarkable. You don't commonly see that in pancreatic cancer. Let's look at another patient on this study. This is a patient, a 77-year-old male who's been on treatment as of the data cutoff over 6 months, 5-centimeter tumor burden at baseline and you can see, again, slowly but surely, right? You can see the reduction in the tumor on the right there, first scan, second scan, a little bit more. Third scan a little bit more, we've whittled away at it. And then it starts to collapse. Look at that drop from the third scan to the fourth scan. And so this is a 65% reduction in the sum of longest diameters. Patients had improved quality of life, they've gained weight. And most remarkably, 1 of the target lesions that makes up that sum of longest diameters is a pancreatic lesion, and it's completely resolved. It's no longer detectable. Just remarkable. Again, highly uncommon. But the fact that we've seen not only liver lesions in 1 patient be rendered undetectable by this treatment in this study, but also a pancreatic lesion in a different patient rendered undetectable by atebimetinib plus modified gemcitabine/nab-paclitaxel in our study. That just lends another pillar of robustness to the incredible overall survival that we're seeing with this treatment. That does not commonly happen. So those are 2 case studies of patients who were treated with the combination of atebimetinib plus modified gemcitabine/nab-paclitaxel. But there's 1 more patient we want to show you, 1 more case study. And this was actually a patient from way back in Phase I. Now why are we showing you a patient from way back in Phase I? We're showing a patient from way back in Phase I because this patient is still on treatment as of the data cutoff. That's right. This is a third-line pancreatic cancer patient, third line, treated with atebimetinib monotherapy. So just to be clear, this patient had progressive disease with FOLFIRINOX treatment in the first-line setting, standard of care, had progressive disease with a gemcitabine-containing regimen in the second line and came to our Phase I study in the third-line setting and began receiving atebimetinib monotherapy. Now in that setting, the median PFS is only 2 months. You would only expect the patient to stay on treatment for only 2 months with standard of care. And the median OS, the median survival in third-line pancreatic cancer is only 5 months. You wouldn't expect this patient to live more than half a year. And in fact, what we're seeing in this 70-year-old male treated with atebimetinib monotherapy is over 15 months, approximately 16 months of progression-free survival to date, to date, on treatment as of the data cutoff. And again, you can see on the right, we did not shrink these tumors quickly. We shrink them slowly, and it's a massive tumor burden at baseline. Look at that baseline SLD 18.6 centimeters, 14% reduction, 17%, 22%, 25% we shrank it slowly, slowly but surely. And then at the 14-month mark, it crosses over to 31% at the 14- month mark and then confirms on the next scan as well after the 15-month mark. This is incredible. You just don't see this with targeted therapy, a PR after 14 months, just remarkable, atebimetinib monotherapy, third-line pancreatic cancer. Patient has an improved quality of life, patient has a 98% reduction -- sorry, 96% reduction in their peak CA19-9 levels. They've seen their KRAS mutant circulating tumor DNA reduced and most recently, complete resolution of a bone lesion, a bone lesion that's completely resolved. Now this case lends yet more robustness, another pillar of support for the 96% overall survival we're seeing at 6 months, right? This just doesn't happen in pancreatic cancer, to see an 18-centimeter tumor burden reduced by over 30% to see a patient on treatment 15, 16 months. And the best part is we hear from the investigator that this patient has been living a normal life. That's right, living a normal life with third-line pancreatic cancer, thanks to atebimetinib, living a normal life. This patient [indiscernible] and really all the data, the 94% OS at 6 months that we're seeing. This gives us a glimpse into a future where pancreatic cancer and other cancers could be controlled, where patients could outlive their disease, where it could become a chronic condition that's controlled, that's managed, that no longer is fatal. And that's the future we're working towards. And the next step towards that future is our pivotal study. So we're planning a global randomized pivotal trial designed to facilitate accelerated approval in first-line pancreatic cancer for atebimetinib plus the modified gemcitabine/nab-paclitaxel, randomized against gemcitabine/nab-paclitaxel standard of care therapy. Now this plan, of course, is subject to ongoing data and regulatory authority feedback. But we're really excited to move forward with this in 2026 and really take the next step to bringing this really remarkable treatment to pancreatic cancer patients everywhere. So I've walked you through this incredible durability, overall survival, patients 94% overall survival at 6 months. This incredible tolerability. Patients living better. 0 grade 3 adverse events in 6 of the 11 categories commonly seen with standard of care. We believe patients can outlive their cancer. But so how does it work? How are we doing this? How are we changing the paradigm for targeted therapy to improve durability and tolerability? Well, the first thing we're doing is achieving durability by outpacing cancer. Now as I alluded to earlier, most targeted therapies are designed for sustained inhibition. They're designed to shut down the pathway 24/7 and the challenge with that, as Robert Gatenby at Moffitt and others have really shown with their research is you drive cancer to adapt, you drive cancer to adapt, and it develops resistance, right? Cancer is not -- it doesn't work by magic. It's not some paranormal force, but it just has a couple of good tricks. And 1 of its tricks is that it adapts, it adapts well. And so the result what you see over and over with targeted therapies is they look great at first, they knock down the tumor, it shrinks 50%. But what you're doing is you're selecting for resistant cells, the orange cells you can see there. It's Darwinian, Robert Gatenby at Moffitt and others use Darwinian theory and mathematical modeling. And you can see you select for the resistant cells and the tumor ends up coming back. You end up getting resistance. And now you have a bigger problem. Now you have a worse tumor than before and we see this over and over. The reason that cancer patients die frequently is you don't have the durability of the treatment. So we're doing something completely different. Our therapies are designed for deep cyclic inhibition. They pulse faster than the cancer can adapt. And the result of that is tumors shrink slowly but durably. So our drug has a short half-life, about 2 hours in humans. It has fast binding kinetics and it shuts down the path actually more completely than you could with a sustained approach. It shuts down the path more completely, we're above our IC90 or we're suppressing the pathway well more than 90% for several hours a day whereas most targeted therapies against MAK, our target, can only get to around their IC50 values. They can only suppress the pathway about 50%. So that's the deep part. We're shutting down the pathway more completely, but we're doing it cyclically. We're pulsing at every 24 hours from a peak of deep inhibition down to a complete release, and that pulsing is faster than the tumor can adapt. We showed that with transcriptomics before we even began to develop atebimetinib. So the result by outpacing cancer by pulsing faster than the cancer can adapt, the result is the tumors shrink slowly but durably, you can see how we've illustrated that. 20%, 20%, then maybe over time, they start to collapse. And we showed you several case studies where that happened because we're not driving the development of resistance in the same way. Deep cyclic inhibition, achieving durability by outpacing cancer. And this mechanism, we believe, is a key reason we see the kind of durability we're seeing with 94% overall survival at 6 months. But what about the tolerability. Well, the remarkable thing is that this deep cyclic inhibition mechanism not only drives durability, but it also drives tolerability. And here's why. We have the MAP kinase pathway for a reason other than for cancer to hijack it. In healthy cells, it serves a really important function, but it's transient. It turns on and off, it says grow and divide, grow and divide, grow and divide, there's gaps, there's pauses. But in a malignant cell with an oncogenic mutation, that signaling becomes sustained. It's always on. It's saying grow and divide, grow and divide, grow and divide, grow and divide, grow and divide, grow and divide. And that's really what drives cancer. So what everyone else has done, what the kind of conventional wisdom is, is sustained inhibition, shut down the pathway 24/7. You can see it here. You can only get up to about the IC50 often. You can only suppress the pathway about 50% and the challenge is you're suppressing also -- you're suppressing the tumor signaling, but you're also suppressing the transient signaling that those healthy cells need and the result is many adverse events. You're really depriving those healthy cells of the signaling they need. So what's so different about deep signaling inhibition? Well, as I said, we can get down to our IC90 or more. So we're really shutting down the pathway completely, but we're doing it in a pulsatile way. So we're basically restoring that, grow and divide, grow and divide, grow and divide. We're restoring that cadence, that transient signaling to the healthy cells, and we believe that's the reason we see so few adverse events with atebimetinib. So the beauty of this deep cyclic inhibition mechanism has enabled us to achieve both durability and tolerability. All right. Now as we mentioned, we're targeting MEK in the MAP kinase pathway to outpace cancer with durability and tolerability. I mentioned this pathway is altered or inappropriately activated in a majority of cancers. So this has applicability well beyond pancreatic cancer. But this is -- pancreatic cancer is the right place to start. It's a huge unmet need, and the vast majority of pancreatic cancers are driven by the MAP kinase pathway. And here's how our drug works relative to approved MEK inhibitors. Now in Phase I, we showed that atebimetinib monotherapy had activity, durability and tolerability and we showed in acquired alterations that we actually see very few acquired alterations in MAP kinase pathway genes. This is from the Phase I. And this is really showing you in a different way, how we don't drive the kind of resistance that sustained inhibitors do. Now we do see acquired alterations in other pathways, non-MAP kinase pathways. So we're kind of blocking all the lanes of the highway, forcing the tumor off onto the dirt roads. And there's a reason most tumors use the MAP kinase pathway. It's more effective. So already it's helpful to force the tumors under those non-MAP kinase pathways. But then by combining -- by combining with gemcitabine/nab-paclitaxel, we kind of mop up those non-tumor or non-MAP kinase resistance mechanisms. And you can see that in the preclinical data that we shared last year, last year at AACR, you can see that when you combine atebimetinib with gemcitabine/nab-paclitaxel, it essentially flatlines the tumor. So that's yet another pillar of robustness supporting the overall survival, the 94% overall survival at 6 months that we've seen is that we saw it preclinically. We predicted this would happen, and it's exactly what happened. Now targeting the MAP kinase pathway has broader relevance. In fact, this pathway is used in most cancers. So there's really an expansive opportunity. Pancreatic cancer is just the beginning. We're going after lung cancer next. We announced a supply agreement with Regeneron to evaluate our drug in combination with their anti-PD-1 Libtayo, we're looking at colorectal cancer, melanoma and many more. So the incredible durability and tolerability that we're seeing with atebimetinib in pancreatic cancer is really just the start. We want to bring this unique approach ultimately to cancer patients with a variety of cancers. So let me sum up. Our goal -- our unusual goal is to help cancer patients outlive their disease. To achieve that goal, we developed different priorities, durability and tolerability, a different drug, atebimetinib to target the MAP kinase pathway with a different approach, deep cyclic inhibition aiming to outpace the cancer. We went after a different initial focus, first-line pancreatic cancer, first-line pancreatic cancer with atebimetinib in combination with the modified gemcitabine/nab-paclitaxel. And what we saw is extraordinary. A 6-month overall survival of 94% and a 6-month progression-free survival of 72% in first-line pancreatic cancer with a highly favorable tolerability profile. So what's coming next? What are our planned catalysts? Regulatory feedback on the pivotal study plans in the fourth quarter, a data update in the fourth quarter and starting the pivotal study next year, and there are many additional opportunities in a pathway that drives the majority of cancers. So with that, I thank you for your attention, and we're happy to answer questions.

[Operator Instructions] Your first question comes from the line of Jay Olson of Oppenheimer.

Thank you for providing this update and congrats on these impressive results. It seems like atebimetinib has really flattened those survival curves with durability that apparently extends even beyond 6 months. So my first question is, can you just talk about how you expect those survival curves, both OS and PFS to evolve as you get out to 12 months and further? And then I had a follow-up question, if I could, please.

Jay, thanks for the question. And you're absolutely right, it's really remarkable what we're seeing. And as you pointed out, the curve is flat, not just at 6 months but well beyond it. Now we don't have a crystal ball, nobody does, but I think the best way you can try to predict that is to really look at the spider plots. Look at the trajectories of these tumors, right? And the vast majority of tumors are continuing to shrink. The vast majority of tumors are continuing to shrink. This is not, we believe, the sort of the picture of a group of patients that are about to have, frankly, either progression events or ultimately survival events. We believe this is a picture of patients that are likely to continue to have excellent durability. And I think some of the case studies and certainly the case study we have from Phase I of the third-line pancreatic cancer patient who's out 15, 16 months with monotherapy, further support that durability. So we're certainly extremely optimistic about how the durability continues to play out over time.

Excellent. And then in addition to the efficacy, I think the tolerability of atebimetinib really stands out. Can you just comment on whether or not you're measuring patient quality of life in the Phase IIa study and how that tolerability may impact the quality of life and what we should expect to see there?

Yes. So the -- we do measure quality of life, and we've reported it for some of the case studies here. I'm just going to show you, right? So in this patient, for instance, we saw improved quality of life on that instrument, same here. We don't have aggregate results to share today. But suffices to say, I mean, to your point, the tolerability is closely linked to quality of life, right? When patients don't have rashes, right? When they don't frequently have serious diarrhea, nausea, vomiting, as many other targeted agents for this pathway do, the fact that we see such low levels of that, such few examples of serious adverse events, rashes, nausea, vomiting, diarrhea. These are all, as we've previously reported for the monotherapy, these are all things that really matter to patients, right? It means we've talked to patients who talk about the -- some of the side effects of standard of care. And it affects how they live their lives, right? I mean just the nausea alone can mean that someone stays in for the weekend versus going out, right? So tolerability matters, it matters a lot. And that's why this was 1 of our key priorities in how we designed 104 and atebimetinib, I should say.

Sorry, go ahead.

No, I was just going to add, we also see weight gain frequently, which is another also associated with how patients are doing and their quality of life, add weight gain to the list. Next question, please.

Your next question comes from the line of Ami Fadia with Needham & Company.

Congrats on the very impressive results and all the progress that you guys have been making. Maybe if you could just sort of comment on any additional thoughts on how this can translate into median overall survival over time. And you talked about the third line patient that actually had a partial response many months into the treatment, could we expect additional improvements in responses with the patients that are ongoing? And how do we compare it to some of the other treatments in development, particularly for example, the Revolution Medicines drug, RMC-6236 that had showed 97% of the patients surviving at 6 months in the RAS mutant population. Maybe if you could sort of talk about how the competitive landscape is evolving? And how do you see your drug sort of position related to that? And then I have just 1 more question.

Ami, thanks for the question. So your first question was about how do the responses sort of play out over time, right? And I think the first thing to point out is that overall survival is what matters most, right? Overall response rate is simply a surrogate endpoint that's used to try to predict what's happening with overall survival. And so I think that that's the first thing to point out. Overall survival is the most important thing. It's what matters most to patients. That being said, exactly as you pointed out, we already have a remarkable high overall response rate of 39% but look at all these patients with stable disease with arrows above them. These are patients that are continuing on treatment. So we absolutely believe that this is likely to continue, we're likely to see these patients continue to have shrinking lesions over time, continuing to see that durability. And that will likely cause the ORR to go up, we believe. And even just -- we did a data cut a month before this one. And even just in the months between that prior data cut and this one, 3 additional patients crossed over that 30% threshold to be partial responses. So just in a month, this went up by 3 additional patients. So we're absolutely optimistic. Again, we don't have a crystal ball, but we're optimistic that many of those stable disease patients continuing on treatment will continue to see their lesions shrink. But now again, this 30% threshold is completely arbitrary, right? Patients don't care about that. They don't care if their tumor shrinks 28% or 31%. What they care about is that they're living longer and that they're having good quality of life. And that's why our priorities are durability and tolerability. That's why we're so excited to have overall survival data, which is much more important than any surrogate endpoint like ORR. And again, in the spider plots too, you can continue to see the tumors shrinking and you see these patients where it will stay in sort of the 10% to 20% range and then drop down quickly later on. So we definitely see these kind of delayed onset responses. I mean, as you pointed out, we now have a confirmed PR from Phase I, 14, 15 months into the study, and that patient is now out about 16 months. So definitely, that we believe we're optimistic about how that continues to play out over time. Now you asked about competitive landscape. And let me speak to that in general. Certainly, we laud every company that's working in pancreatic cancer. There's a huge unmet need. There's a lot of room. But the data that you were referring to, Ami, was from the second-line setting. Neither the company you mentioned, really nor many other companies that we're aware of have shown the kind of data we're showing here in the first-line setting. So that's the first key difference to appreciate. With this data update today, we believe we are the leaders in first-line pancreatic cancer. We've shown the ability to combine with chemo, which other companies, including the 1 you mentioned, have not yet demonstrated. So we have the ability to combine. We've shown really incredible first-line data. And look, I mean, look at our Kaplan-Meier plot, right? If -- just going to that slide. If this continues to play out as it is, right, it really sort of doesn't matter what else is out there, right? You really can't get much better than this, right? No one is going to be able to beat this if it continues as it is. And so even in the best case scenario where you have multiple treatments that all keep almost every pancreatic cancer patient alive. First of all, that would be a wonderful outcome for patients. We'd be thrilled with that. But even then, it would come down to tolerability, right? And tolerability, we see a dramatic difference between our drug and really the other things that are out there for the MAP kinase pathway, including the 1 you referenced. So if you compare monotherapy tolerability, right? We have about a fourfold lower rate of any grade rash. Our levels of nausea, vomiting and diarrhea any grade are about half of the drug you referenced. So really just -- we have a dramatic advantage in tolerability. We have a dramatic advantage in durability. We have a dramatic advantage in combinability and as of today, we are the leaders in first-line pancreatic cancer. Neither the company you mentioned nor others that we're aware have shared a Kaplan-Meier plot like this in first-line pancreatic cancer. So we -- like I said, we welcome the competition. We think there's plenty of room for a lot of great treatments with different profiles in pancreatic cancer. But we're the leaders in first line as of now and really challenge anyone to beat this kind of overall survival with the kind of tolerability that we have, durability, tolerability, I think it doesn't get much better than what we're seeing right now. You had 1 other question, Ami, or maybe not.

Your next question comes from the line of Michael Lee with Jefferies.

Great. This is Matt on for Mike. Congrats on the update. I wanted to ask about the safety profile. It looks like you've actually improved the safety profile over chemo alone and I want to ask, do you think that's due to the modified gemcitabine regimen you're using? Or just anything else you could add there on how you're seeing this great promising safety profile.

Matt, thanks for the question. Yes, you're absolutely right. So I mentioned earlier in the talk, we're using a modified gemcitabine/nab-paclitaxel, right? So this is every other week as opposed to 3 weeks on, 1 week off. So it's about 1/3 less chemo over the course of a month. This was developed and studied by Dr. Bekaii-Saab and Dr. Ahn at the Mayo Clinic, both investigators in our trial. They published it. It's a great paper, Ahn et al 2017. And they show that you can kind of improve the tolerability while really maintaining the durability with this regimen. So I think that's certainly a part of it. That's certainly why you see the improvements over the gem/nab. But also the fact that atebimetinib as a monotherapy, as I referenced earlier, and as we've reported previously, is just so incredibly well tolerated, right? I mean if you look at our previously reported table of treatment-related adverse events observed in at least 10% of the patients, as monotherapy, you see no grade 3s or grade 4s. And even any great adverse events, as I mentioned, are dramatically lower than other targeted therapies. And in fact, if you look at the Ahn et al 2017 paper, for the safety they saw with the modified gem/nab and you compare that with what we're showing you here on Slide 11, it's really pretty indistinguishable. So I think it's fair to argue that atebimetinib really isn't adding much, if anything, in the way of tox. So that's really why we see this just incredible tolerability profile. And that really also enables the durability that we're seeing with 94% OS at 6 months. Thanks, Matt. I appreciate the question.

Your next question comes from the line of Allison Bratzel with Piper Sandler.

This is Ashley on for Alli. I had a question about the regulatory feedback that you're expecting. So that's being guided to Q4 now. We know a lot is going on with the FDA right now. So we were hoping if you could characterize any interactions that you've had? Have they been timely and what's driving your confidence in having that feedback in hand by that quarter? And also kind of looking forward, I don't know if it's too early to ask this or to be thinking about this. But based on the really encouraging data that you have in hand, how are you thinking about this informing the stat plan going forward with the pivotal study? How is ratio powering? Any color there, I think, would be really helpful as we start thinking about what comes next.

Sure, Ashley. Thanks for the questions. And in a minute, I'll hand it over to our Chief Medical Officer, Igor, to talk about that second question around the powering of the pivotal study. But first, with regard to FDA, I certainly can't comment on our specific interactions. But what I can comment on is more generally I think the philosophy that the agency has been kind of promoting, right? So going back to Project Optimus and Project FrontRunner, I think Dr. Pazdur and his group have really been forward thinking, just really innovative thinking differently around this, around how to make drugs that are more tolerable with Optimus, how to bring more drugs to the first-line setting, even if it's in combination with standard of care because your first shot is your best shot. So we're huge fans of those programs, Project FrontRunner, Project Optimus. And we really believe we're philosophically aligned with those. I think that those just really innovative forward-thinking programs really influenced our thinking. And look, we're also optimistic about Commissioner Makary and the perspective he's bringing to FDA. I attended his talk in person at the Jefferies conference. I think everyone in the industry appreciated him being there and his outreach. And I think he's thinking innovatively about how to get new treatments to patients as quickly as possible, and that's certainly well aligned with our goals. I mean, I think to have a 6-month overall survival of 94% in pancreatic cancer. I mean that's transformative, not our word, our investigator's word, transformative. And I certainly, from what I saw in Dr. Makary's public comments, I think he's philosophically aligned with that. Not to mention, as a clinician, as an oncologist, I mean, he mentioned that what cancer patients care about is not how much their lesions shrink, but actually, how long they live and their quality of life. So I think he gets it. I think we're very optimistic about his leadership. And he wrote a great book, Blind Spots, and it's really about how sometimes the dogma of the medical establishment doesn't align with the data. And I think if you look at our whole approach, it's of the same philosophy, right? How do we follow the data and not necessarily just do the same thing over and over that the industry has been doing, right? It's just -- it's kind of dogma or conventional wisdom that you make these drugs with long half-lives that shut down the pathway permanently. And our data says that, that it's time to update that dogma. It's time to make drugs that can outpace the tumor to help cancer patients outlive their disease. Those are my comments on regulatory. Let me see if Igor wants to comment on your other question around powering of the pivotal study.

Thank you, Ben. I would say to be specific a couple of comments. One is, we will be, of course, doing a global trial. So the FDA, both the EMA and of course, Asia Pac are other considerations, so we are not fully dependent on just what the FDA or when the FDA gets back to us. But we do feel fairly confident that we will be submitting our briefing books in a reasonable amount of time and should have information back for multiple, I would say, agencies, not just the FDA by year-end. In terms of the powering, [indiscernible] hazard ratio of 0.75, and I think it would be reasonable to say if you could expect similar, if not a lower HR in our settings based on our ongoing data.

Thank you, Igor. Thank you, Ashley,

Your last question comes from the line of Graig Suvannavejh with Mizuho.

Congratulations on the data. I've got 2 questions in particular, if I could. I might have missed this in your prepared comments. But with respect to the data update that we're going to get later this year, can you provide any additional color on what types of data we'll have and in particular, I'm curious if we'll get the FOLFIRINOX combination data there and perhaps any other monotherapy second-line data. And then secondly, with this really excellent data set in hand, what's your current preference on advancing into Phase III with atebi in pancreatic cancer, meaning either is your preference right now to do it on your own, well, where perhaps you might need some additional financing or instead, based on the robustness of the data, do you think instead you prefer a partner? And if the latter, ideally, what are some of the key elements that you'd be looking for in a partnership?

Graig, good to talk to you. Thanks for the question. So we're not really providing additional color on the details of that data update, I think, stay -- that next data update, stay tuned for that. But certainly, I think it's clear from the durability that we're seeing here with atebimetinib plus the modified gemcitabine/nab-paclitaxel and the fact that we've really sort of already -- we're already going full speed ahead, planning the pivotal study for that? I mean that's our top priority. And I think you can read that from everything you're seeing here. But no further guidance today on that data update. But as we talked about earlier, we're certainly optimistic to see how these patients continue to do over time. Yes. In terms of the path forward, I'll simply say that we keep all options on the table, and we're certainly -- we'll do what's best for the patients and for our shareholders, right? So we're certainly had a robust dialogue with a number of really world-class pharma companies. I think the Regeneron announcement was just a good example of that and just sort of the tip of the iceberg. I mean with the tolerability that we have, I mean, with this kind of tolerability and this ability to have a durable blockade on the MAP kinase pathway, the combination opportunities here are vast, right? So I think that Regeneron agreement that we announced is really just the tip of the iceberg. There are so many opportunities to combine atebimetinib with so many different therapies really for the benefit of cancer patients. So we have a lot of discussions around that. Certainly, we want to look to expand to the many different types of cancer, right? We get into our sites, our investigators, word gets around at these cancer centers that there's sort of finally a MEK inhibitor that's really active, really durable and really well tolerated and the ideas flow in for combinations, for different types of cancer, requests for investigator-initiated trials. So there's really just a huge broad potential for this drug to help so many different cancer patients. And we're going to keep all options on the table and really find the path that enables us to bring the benefits, the durability and the tolerability of atebimetinib to as many cancer patients as possible in a way that's also really rewards our shareholders for really making a good bet on a differentiated approach, right? As Don Valentine, right, the legendary Founder of Sequoia Capital, early investor in Apple and Cisco and other great companies. He said great companies are built with different products by different people, right? You really have to think differently, and that's what we've done here, and we're thrilled to see the kind of survival that we're seeing today.

If I can squeeze in just 1 more. I'm intrigued by the potential of atebi in other indications like colorectal cancer and melanoma. And the question is, could you just remind us or remind me of any preclinical data you have where you're combining atebi with another agent that gives you some confidence of potential efficacy in other indications like colorectal and melanoma.

Sure. Yes. I mean we've -- let's take a step back and talk about our kind of deep cyclic inhibitors more generally because some of the preclinical work is done with tool compounds or others. But certainly, with our -- with our preclinical work, we've shared publicly combinations of our -- these deep cyclic inhibitors with G12C inhibitors, where we see really deeper tumor growth inhibition and better durability. We've shared combinations with BRAF inhibitors and RAF mutant disease, where, again, we don't see the kind of resistance and escape that you typically see with a kind of a registered MEK inhibitor because of the durability. We've shared data on combinations with immuno-oncology agents with checkpoint inhibitors. And again, that's really just the beginning, right? This pathway, the MAP kinase pathway it's the pathway of choice for cancer, right? It's cancer super highway. This is the majority of cancers use this pathway. And really all the other approaches that we're aware of, whether it's prior MEK inhibitors, whether it's mutation-specific RAS inhibitors like KRAS G12C even whether it's sort of pan or multi-RAS approaches, right? The tumor still always finds a way to get around it using the MAP Kinase pathway, whether it's a KRAS amplification, it's a BRAF mutation, tumor can get around it. And that we're just not -- we're not seeing that. We see very few acquired alterations in any MAP kinase pathway gene in our Phase I data that we shared publicly. We're blocking all the lanes of that super highway with atebimetinib and we're doing it in a durable, in a tolerable way. And the result as we're forcing cancer onto the side road under these pathways that it less frequently uses because they're not as robust. And so that's -- and then by combining with different agents that help lock those side roads, if you will, that help take out those pathways. We really believe just the sky is the limit. I mean, the range of combinations here and the potential for atebimetinib to really benefit so many cancer patients with durability and tolerability that ultimately helps them outlive the disease. I mean that -- just think of it if cancer could become a disease that's managed rather than fatal. I mean it's not -- it's a big goal, but we think, based on the data we're sharing today, it's an achievable goal. Any other questions?

That concludes our question-and-answer session. I will turn the call back over to Ben Zeskind for closing remarks.

All right. I want to thank everyone for joining our call today. We're thrilled to be able to share the kind of durability that we're sharing, 94% OS at 6 months, to help overall survival to help patients live longer. We're thrilled to have the kind of tolerability that we're seeing with few adverse events. And ultimately, we want to help patients outlive their disease. And with that, we'd like to thank all the patients and the investigators involved in our ongoing studies, and we look forward to updating you on our progress in the coming year. Thank you, everyone.

This concludes today's conference call. Thank you all for joining, and you may now disconnect.