Welcome to the Immuneering Conference Call to Discuss a Positive Data Update from the Company's Ongoing phase II-A trial of atobemetinib in First-line Pancreatic Cancer Patients. At this time, all participants are in listen-only mode. Following management-prepared remarks, we will hold a Q&A session. To ensure that we have ample time to address everyone's questions, we would ask each person to limit themselves to one question and one follow-up. As a reminder, this call is being recorded today, Tuesday, June 17, 2025. I would now like to turn the conference over to Lawrence 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 Matyshensky, Chief Accounting Officer and Treasurer Mallory Morales, and E Brakewood, our Chief Business Officer. During this call, management will make forward-looking statements, including statements related to its phase II-A trial of atobemetinib, 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 describes 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, Lawrence. 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 non-fatal 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." 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. We want to change that. We want to help cancer patients outlive their disease. 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. The challenge is, frequently, if you shrink tumors quickly, the effect only lasts for a few months. It's temporary. It's not durable. The tumors come back resistant to that treatment, worse than before, and you do not have that durability. 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. 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 are 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. 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. With this different approach, we've created a very different drug, atobemetinib, formerly known as IMM-1104. 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, atobemetinib has shown durability and tolerability with very few side effects. 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." First-line is really the place we're focused in pancreatic cancer. It's also a place where you need to combine. Our phase II-A is focused on atobemetinib in combination with modified gemcitabine chemotherapy in first-line pancreatic cancer. It's an incredibly urgent need. There are about 52,000 deaths each year in the U.S. alone, and the five-year relative survival is only about 13%. There's an urgent need for medicines that can help patients with pancreatic cancer live longer and live better. Different goal, different priorities, different approach, different drug, different focus. Not surprisingly, we have very different results. Let's start with durability. When you talk about durability, the first and most commonly asked question is, "What's the median overall survival?" 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. Then how do you go about assessing overall survival when the median survival is not yet reached? Kind of the next most common approach is to use landmarks, such as looking at the probability of surviving six months with pancreatic cancer. Unfortunately, the answer for many pancreatic cancer patients treated with standard of care gemcitabine nab-paclitaxel is only 67%. That's right. A full one-third of these patients do not make it past six 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 six months. That's right. 94% overall survival with atobemetinib 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 atobemetinib is having a transformative impact on their practice. 94% overall survival at six months. Transformative. Here is the Kaplan-Meier plot for atobemetinib plus modified GNP in first-line pancreatic cancer, which essentially shows the probability of surviving as a function of time. It really could not look much better than it does right now. Now, how robust are these results? Over the course of the talk, there's about 18 pillars of robustness that support these results. 18 pillars of robustness. 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 six months. 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. That's the first pillar of support. That lends robustness to this 94% overall survival that we've observed at six months. The second thing to notice is that the median follow-up time is six 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. Another thing to notice about the robustness here is that we report the 95% confidence interval for that 94% six-month overall survival. Essentially, a 95% confidence interval is a statistical way of assessing the range of likely outcomes. 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 26th. This also gives robustness. We're not showing you stale data. We're showing you recent, recent data. 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. It is deeply humbling to be able to share these data today. It is 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. We are very excited to see how this continues to develop over time. We are 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. We will talk more about that in a few minutes. In the meantime, what we can do is to plot our results together with the results from the pivotal studies of the three 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. You can instantly see why pancreatic cancer is such a terrible disease with such limited outcomes and how atobemetinib 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. 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 six-month OS for every single standard of care, all three. You can see it's dramatic. 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 three weeks on, one week off. Over the course of the month, we're using a third less chemo even than they used in that pivotal study for gemcitabine nab-paclitaxel. That fact also adds robustness to the six-month 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. Another important metric is progression-free survival or how long patients stay on study drug without seeing substantial tumor growth. In terms of progression-free survival, we're seeing a truly unprecedented 72% progression-free survival at six 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 benchmarks. In fact, the benchmark for patients on standard of care gemcitabine nab-paclitaxel is 43%. 43% PFS at six 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. How about the tumors themselves? What's happening to the tumors? First, just to point out again that if we plot them together, our PFS is dramatically higher than all three standard of care treatments. Again, what's happening with the tumors? What's going on there? Here you can see our waterfall plot. You can see each blue line here is a patient. What you can see is that the vast majority of patients in our study have their tumors shrinking. Their tumors are reducing in size. A metric that a lot of people like to use is the overall response rate, which is essentially how many patients have their tumors shrinking by more than 30%. 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%. We are seeing just an excellent overall response rate. The other metric people use when looking at these kinds of data is the disease control rate, which is how many patients have their tumors either shrinking or stable. There, we are looking at a disease control rate of 81%. 81% versus 48% in the pivotal study for gemcitabine nab-paclitaxel. These are three more pillars that add robustness to the incredible 94% overall survival we're seeing at six months. The fact that our overall response rate is dramatically higher. The fact that our disease control rate is also excellent at 81%. 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 one complete response out of 431 patients in the benchmark study of gemcitabine nab-paclitaxel. The fact that we're seeing such unusual things as a complete response just lends further robustness, another pillar of support to the six-month overall survival that we're seeing of an incredible 94%. These waterfall plots, it's a snapshot. It's a moment in time. How are the tumors? How are they changing over time in terms of their size? Do we have a bunch of tumors that have been growing and 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 do not shrink the tumors quickly. We shrink them slowly. 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. By shrinking tumors slowly, making them slowly, we actually get, we believe, much better durability. You can see that here. It is 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 atobemetinib, slow and steady is what wins the race. Ranking those tumors slowly but surely, more and more over time. You can see the vast majority of our patients have their tumors shrinking and steadily reducing. Slow and steady wins the race. These spider plots that show deepening tumor responses over time are yet another pillar of robustness that supports the incredible 94% overall survival at six months that we are seeing. Really remarkable to see those deepening responses over time. All right. We've talked a lot about durability. We've talked a lot about durability. 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. Here you can see a table of the 10 or 11 most common serious or grade 3 and above adverse events observed in the three pivotal studies of the standard of care therapies: gemcitabine nab-paclitaxel, FOLFIRINOX, and NALIRIFOX. Now look down the right. What you can see is that in the majority of those 11 categories, six out of the 11 categories, our combination atobemetinib plus modified gemcitabine nab-paclitaxel had zero grade 3 or higher adverse events. That's right, zero. There are just so few serious adverse events that we're seeing with this treatment. That is critical for many reasons. It is 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. 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 atobemetinib. 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. Ultimately, by keeping the patients in better shape, it also helps them live longer. Performance status is key. It also enables combinations. Combinations are another very powerful strategy to prevent tumors from developing resistance. The fact that we can so readily combine, and do not take this for granted because there are a lot of targeted therapies that cannot but the fact that atobemetinib has a tolerability profile where it can so readily combine with chemotherapy and go straight to that first-line setting is truly remarkable. It is another pillar of robustness that supports the overall survival results that we are reporting to you today. Really just remarkable tolerability. We are so pleased for the patients that are able to experience this. The next question people often ask is, what was the population of patients that we had in this study? How did it compare to the patients in these three benchmark studies? 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 three benchmark studies where the patients were in their low to mid-60s. Only two-thirds of our patients were over the age of 65, whereas it was half or less for the three benchmark studies. Now, unfortunately, age is associated with overall survival in general, and particularly in pancreatic cancer. The fact that we were able to achieve a 94% overall survival at six months, even with a group of 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. 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. Let's zoom in a little bit and talk about a couple of those patients because it's one 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. This is a patient, a 65-year-old male treated in this study in the first-line setting with pancreatic cancer, atobemetinib 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 seven and a half 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. Look at the tumors. Look at the plot on the right. The tumors have been reduced. They've shrank slowly but steadily, right? 20%. Close to 30, but not quite there. On the third scan at five months, 30%. 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. I think what's most remarkable is that that sum of longest diameters is composed of three target lesions. We have the scans for this patient. We can show you exactly what's happening with the three target lesions that make up that sum of longest diameters that you see. The first target lesion was the largest. It was a pancreatic cancer mass, a mass in the pancreas. You can see over the course of these three scans, the baseline scan two and scan four, 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. That's hard to do. In pancreatic cancer, these pancreatic primary tumors often form a thick fibrotic husk. The fact that you can whittle away at that is really excellent. That's part of what drives the overall reductions that you saw on the prior slide. What is particularly remarkable about this patient is the two other target lesions, which we will show on the next slide. This patient had two metastases, two lesions at two different spots in the liver. What you can see is that over the course of six months, not right away, but slowly, surely, our treatment whittled away those tumors to the point that they were no longer detectable. That is right. Two liver metastases rendered no longer detectable in a patient treated with atobemetinib plus modified gemcitabine nab-paclitaxel. That is an extremely unusual outcome. It just lends robustness, another pillar of robustness, to this overall survival that we are seeing: 94% overall survival at six months. Patients with lesions that are rendered undetectable in the liver. That is remarkable. You do not commonly see that in pancreatic cancer. Let us 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 six months, 5 cm tumor burden at baseline. You can see, again, slowly but surely, right? You can see the reductions 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. It starts to collapse. Look at that drop from the third scan to the fourth scan. This is a 65% reduction in the sum of longest diameters. Patients had improved quality of life. They've gained weight. Most remarkably, one of the target lesions that makes up that sum of longest diameters is a pancreatic lesion. It's completely resolved. It's no longer detectable. Just remarkable. Again, highly uncommon. The fact that we've seen not only liver lesions in one patient be rendered undetectable by this treatment in this study, but also a pancreatic lesion in a different patient rendered undetectable by atobemetinib plus modified gemcitabine nab-paclitaxel in our study just lends another pillar of robustness to the incredible overall survival that we're seeing with this treatment. That does not commonly happen. Those are two case studies of patients who were treated with the combination of atobemetinib plus modified gemcitabine nab-paclitaxel. There is one more patient we want to show you, one more case study. This is actually a patient from way back in phase one. Now, why are we showing you a patient from way back in phase one? We're showing you a patient from way back in phase one 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 atobemetinib monotherapy. So just to be clear, this patient had progressive disease with sulfuran oxide 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 atobemetinib monotherapy. Now, in that setting, the median PFS is only two months. You would only expect the patient to stay on treatment for only two months with standard of care. The median OS, the median survival in third-line pancreatic cancer is only five months. You wouldn't expect this patient to live more than half a year. In fact, what we're seeing in this 70-year-old male treated with atobemetinib monotherapy is over 15 months, approximately 16 months of progression-free survival to date, to date on treatment as of the data cutoff. You can see on the right, we did not shrink these tumors quickly. We shrank them slowly. It is a massive tumor burden at baseline. Look at that baseline SLD, 18.6 cm, 14% reduction, 17, 22, 25. We shrank it slowly, slowly but surely. At the 14-month mark, it crosses over to 31% at the 14-month mark. It confirms on the next scan as well after the 15-month mark. This is incredible. You just do not see this with targeted therapy. A PR after 14 months. Just remarkable. Atobemetinib monotherapy, third-line pancreatic cancer. Patient has an improved quality of life. Patient has a 98% reduction, sorry, 96% reduction in their peak CA 19-9 levels. They've seen their KRAS mutant circulating tumor DNA reduced. 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 six months, right? This just doesn't happen in pancreatic cancer to see an 18 cm tumor burden reduced by over 30%, to see a patient on treatment 15, 16 months. The best part is, 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 atobemetinib, living a normal life. This patient, and really all the data, the 94% OS at six 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. That's the future we're working towards. The next step towards that future is our pivotal study. We're planning a global randomized pivotal trial designed to facilitate accelerated approval in first-line pancreatic cancer for atobemetinib plus the modified gemcitabine nab-paclitaxel, randomized against gemcitabine nab-paclitaxel, standard of care therapy. This plan, of course, is subject to ongoing data and regulatory authority feedback. 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. I've walked you through this incredible durability, overall survival, patients' 94% overall survival at six months, this incredible tolerability, patients living better, zero grade 3 adverse events in 6 of the 11 categories commonly seen with standard of care. We believe patients can outlive their cancer. How does it work? How are we doing this? How are we changing the paradigm for targeted therapy to improve durability and tolerability? The first thing we're doing is achieving durability by outpacing cancer. As I alluded to earlier, most targeted therapies are designed for sustained inhibition. They're designed to shut down the pathway 24/7. 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. It develops resistance, right? Cancer's not, it doesn't work by magic. It's not some paranormal force. It just has a couple of good tricks. One of its tricks is that it adapts. It adapts well. 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%. 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. You can see you select for the resistant cells, and the tumor ends up coming back. You end up getting resistance. Now you have a bigger problem. Now you have a worse tumor than before. We see this over and over. The reason that cancer patients die frequently is you don't have the durability of the treatment. We're doing something completely different. Our therapies are designed for deep cyclic inhibition. They pulse faster than the cancer can adapt. The result of that is tumors shrink slowly but durably. Our drug has a short half-life, about two hours in humans. It has fast-binding kinetics. It shuts down the pathway actually more completely than you could with a sustained approach. It shuts down the pathway more completely. We are above our IC90, or we are suppressing the pathway well more than 90% for several hours a day. Whereas most targeted therapies against MEK, our target, can only get to around their IC50 values. They can only suppress the pathway about 50%. That is the deep part. We are shutting down the pathway more completely. We are doing it cyclically. We are pulsing every 24 hours from a peak of deep inhibition down to a complete release. That pulsing is faster than the tumor can adapt. We showed that with transcriptomics before we even began to develop atobemetinib. The result, by outpacing cancer, by pulsing faster than the cancer can adapt, is the tumors shrink slowly but durably. You can see how we've illustrated that. 20%, 20%. Maybe over time, they start to collapse. 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. This mechanism, we believe, is a key reason we see the kind of durability we're seeing with 94% overall survival at six months. What about the tolerability? The remarkable thing is that this deep cyclic inhibition mechanism not only drives durability, but it also drives tolerability. 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. It is transient. It turns on and off. It says grow and divide, grow and divide, grow and divide. There are gaps. There are pauses. In a malignant cell with an oncogenic mutation, that signaling becomes sustained. It is always on. It is saying, "Grow and divide, grow and divide, grow and divide, grow and divide, grow and divide, grow and divide." That is really what drives cancer. 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 really only get up to about the IC50 often. You can only suppress the pathway about 50%. The challenge is you're suppressing the tumor signaling, but you're also suppressing the transient signaling that those healthy cells need. The result is many adverse events. You're really depriving those healthy cells of the signaling they need. What is so different about deep cyclic inhibition? As I said, we can get down to our IC90 or more. We're really shutting down the pathway completely, but we're doing it in a pulsatile way. 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. We believe that's the reason we see so few adverse events with atobemetinib. The beauty of this deep cyclic inhibition mechanism is it enables us to achieve both durability and tolerability. All right. Now, as we mentioned, we're targeting MEK and 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. This has applicability well beyond pancreatic cancer. Pancreatic cancer is the right place to start. It's a huge unmet need. The vast majority of pancreatic cancers are driven by the MAP kinase pathway. Here's how our drug works relative to approved MEK inhibitors. In phase one, we showed that atobemetinib monotherapy had activity, durability, and tolerability. We showed in acquired alterations that we actually see very few acquired alterations in MAP kinase pathway genes. This is from the phase one. 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. We are kind of blocking all the lanes of the highway, forcing the tumor off onto the dirt roads. There is a reason most tumors use the MAP kinase pathway. It is more effective. Already, it is helpful to force the tumors onto those non-MAP kinase pathways. By combining with gemcitabine nab-paclitaxel, we kind of mop up those non-tumor or non-MAP kinase resistance mechanisms. You can see that in the preclinical data that we shared last year, last year at AACR, you can see that when you combine atobemetinib with gemcitabine nab-paclitaxel, it essentially flatlines the tumor. That is yet another pillar of robustness supporting the overall survival, the 94% overall survival at six months that we have seen, is that we saw it preclinically. We predicted this would happen, and it is exactly what happened. Now, targeting the MAP kinase pathway has broader relevance. In fact, this pathway is used in most cancers. 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. The incredible durability and tolerability that we're seeing with atobemetinib in pancreatic cancer is really just the start. We want to bring this unique approach ultimately to cancer patients with a variety of cancers. 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, atobemetinib, 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 atobemetinib in combination with the modified gemcitabine nab-paclitaxel. What we saw is extraordinary. A six-month overall survival of 94% and a six-month progression-free survival of 72% in first-line pancreatic cancer with a highly favorable tolerability profile. 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. There are many additional opportunities in a pathway that drives the majority of cancers. With that, I thank you for your attention, and we're happy to answer questions. The question and answer session. If you would like to ask a question, please press star one on your telephone keypad to raise your hand and join the queue. If you would like to withdraw your question, simply press star one again. If you are called upon to ask your question and are listening via loudspeaker on your device, please pick up your handset and ensure that your phone is not on mute when asking your question. Again, press star one to join the queue. Your first question comes from the line of Jay Olson of Oppenheimer. Your line is open. Oh, hey, guys. Thank you for providing this update and congrats on these impressive results. It seems like atobemetinib has really flattened those survival curves with durability that apparently extends even beyond six months. 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? I had a follow-up question, if I could, please. Hey, Jay, thanks for the question. You're absolutely right. It's really remarkable what we're seeing. As you pointed out, the curve is flat, not just at six months, but well beyond it. We don't have a crystal ball. Nobody does. 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? The vast majority of tumors are continuing to shrink. This is not, we believe, 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. I think some of the case studies and certainly the case study we have from phase one of the third-line pancreatic cancer patient who's out 15, 16 months with monotherapy further support that durability. We're certainly extremely optimistic about how the durability continues to play out over time. Excellent. Thank you, Ben. In addition to the efficacy, I think the tolerability of abetimetinib really stands out. Can you just comment on whether or not you're measuring patient quality of life in the phase II-A study and how that tolerability may impact the quality of life and what we should expect to see there? Thank you. Yep. 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? In this patient, for instance, we saw improved quality of life on that instrument. Same here. We do not have aggregate results to share today. Suffice it to say, I mean, to your point, tolerability is closely linked to quality of life, right? When patients do not have rashes, right? When they do not 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 have previously reported for the monotherapy, these are all things that really matter to patients, right? It means we have talked to patients who talk about 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? Tolerability matters. It matters a lot. That is why this was one of our key priorities in how we designed 104 and atobemetinib, I should say. Great. Thanks for taking the question. Congrats again. Thank you, Jay. Oh, sorry. Go ahead. Absolutely. No, I was just going to add we also see weight gain frequently, which is also associated with how patients are doing and their quality of life. Add weight gain to the list. Excellent. Thank you, Ben. Next question, please. Thanks, Jay. Thank you. Next question, please. Your next question comes from the line of Ami Fadia with Needham & Company. Your line is open. Hi, good morning. 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. You talked about the third-line patient that actually had a positive response many months into the treatment. Could we expect additional improvements in responses with the patients that are ongoing? 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 six 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. I have just one more question. Thank you. Hey, Amy. Thanks for the question. Your first question was about how do the responses sort of play out over time, right? 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. I think 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 remarkably high overall response rate of 39%. Look at all these patients with stable disease with arrows above them. These are patients that are continuing on treatment. 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. That'll likely cause the ORR to go up, we believe. Even just, we did a data cut a month before this one. Even just in the months between that prior data cut and this one, three additional patients crossed over that 30% threshold to be partial responses. Just in a month, this went up by three additional patients. 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. Now, again, this 30% threshold is completely arbitrary, right? Patients do not care about that. They do not 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. 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. In the spider plots, too, you can continue to see the tumors shrinking. You see these patients where it'll stay in sort of the 10-20% range and then drop down quickly later on. We definitely see these kind of delayed onset responses. I mean, as you pointed out, we now have a confirmed PR from phase one, 14-15 months into the study. That patient's now out about 16 months. We believe we're optimistic about how that continues to play out over time. You asked about competitive landscape. Let me speak to that in general. Certainly, we allowed every company that's working in pancreatic cancer. There's a huge unmet need. There's a lot of room. The data that you were referring to, Amy, 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. That is 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 one you mentioned, have not yet demonstrated. We have the ability to combine. We've shown really incredible first-line data. I mean, look at our Kaplan-Meier plot, right? Just going to that slide. If this continues to play out as it is, 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. 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. Even then, it would come down to tolerability, right? 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 one you referenced. If you compare monotherapy tolerability, we have about a four-fold lower rate of any grade rash. Our levels of nausea, vomiting, and diarrhea any grade are about half of the drug you referenced. We have a dramatic advantage in tolerability. We have a dramatic advantage in durability. We have a dramatic advantage in combinability. As of today, we are the leaders in first-line pancreatic cancer. Neither the company you mentioned nor others that we are aware of have shared a Kaplan-Meier plot like this in first-line pancreatic cancer. Like I said, we welcome the competition. We think there is plenty of room for a lot of great treatments with different profiles in pancreatic cancer. We are 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 does not get much better than what we are seeing right now. You had one other question, Amy. Or maybe not. Next question. Happy to move on if I answered it all. Next question from the line of Michael Lee with Jefferies. Great. Thanks so much, guys. This is Matt. I am from Mike. Congrats on the update. Thanks for taking our question. I wanted to ask about the safety profile. It looks like you've actually improved the safety profile over chemo alone. I wanted to ask, do you think that's due to the modified gemcitabine nab-paclitaxel regimen you're using or just anything else you could add there on how you're seeing this great, promising safety profile? Thanks so much. Hey, Matt. Thanks for the question. Yeah, you're absolutely right. I mentioned earlier in the talk we're using a modified gemcitabine nab-paclitaxel, right? This is every other week as opposed to three weeks on, one week off. It's about a third less chemo over the course of a month. This was developed and studied by Dr. Bakai Saab and Dr. Ahn at the Mayo Clinic, both investigators in our trial. They published it. It's a great paper on Ahn et al. 2017. They showed that you can kind of improve the tolerability while really maintaining the durability with this regimen. I think that's certainly a part of it. That's certainly why you see the improvements over the GENAB. Also, the fact that atobemetinib, as a monotherapy, as I referenced earlier and as we 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. Even the any grade adverse events, as I mentioned, are dramatically lower than other targeted therapies. In fact, if you look at the Ahn et al. 2017 paper for the safety they saw with the modified GENAB, and you compare that with what we're showing you here on slide 11, it's really pretty indistinguishable. I think it's fair to argue that atobemetinib really isn't adding much, if anything, in the way of tox. That's really why we see this just incredible tolerability profile. That really also enables the durability that we're seeing with 94% OS at six months. Thanks, Matt. Appreciate the question. Next question. Next question comes from the line of Alison Ratsnell with Piper Sandler. Your line is open. Good morning. This is Ashley Ahn for Ally. I had a question about the regulatory feedback that you're expecting. That's being guided to Q4 now. We know a lot is going on with the FDA right now. 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? 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 stats plan going forward with the PIPITL study? Has ratio powering? Any color there, I think, would be really helpful as we start thinking about what comes next. Thank you. Sure, Ashley. Thanks for the questions. 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 PIPITL study. First, with regard to FDA, I certainly can't comment on our specific interactions. What I can comment on is, more generally, I think the philosophy that the agency has been kind of promoting, right? Going back to Project Optimus and Project Front Runner, 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 is in combination with standard of care because your first shot is your best shot. We are huge fans of those programs, Project Front Runner, Project Optimus. We really believe we are philosophically aligned with those. I think that those just really innovative, forward-thinking programs really influenced our thinking. Look, we are also optimistic about Commissioner Makari and the perspective he is bringing to FDA. I attended his talk in person at the Jeffries Conference. I think everyone in the industry appreciated him being there and his outreach. I think he's thinking innovatively about how to get new treatments to patients as quickly as possible. That's certainly well aligned with our goals. I mean, I think to have a six-month overall survival of 94% in pancreatic cancer, that's transformative. Not our word. Our investigators were transformative. Certainly, from what I saw in Dr. Makari's public comments, I think he's philosophically aligned with that. Not to mention, as a clinician, as an oncologist, 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. I think he gets it. I think we're very optimistic about his leadership. He wrote a great book, Blind Spots. It is really about how sometimes the dogma of the medical establishment does not align with the data. I think if you look at our whole approach, it is 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 is kind of dogma or conventional wisdom that you make these drugs with long half-lives that shut down the pathway permanently. Our data says that it is time to update that dogma. It is 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. Oh, thank you, Ben. I would say to be specific, a couple of comments. One is we will be, of course, doing a global trial. The FDA, the EMA, and, of course, Asia-Pac are other considerations so that we are not fully dependent on just what the FDA or when the FDA gets back to us. 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, the NAPOLI 3 user has a ratio of 0.75. I think it would be reasonable to say that you could expect similar, if not a lower HR in our settings based on our ongoing data. Super helpful. Thank you. Thank you, Igor. Thanks, Ashley. Next question. Your last question comes from the line of Graig Suvannavejh with Mizuho. Your line is open. Hey, thank you. Good morning and congratulations on the data. I've got two 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? In particular, I'm curious if we'll get the full FOLFIRINOX combination data there and perhaps any other monotherapy second-line data. Then secondly, with this really excellent data set in hand, what's your current preference on advancing into phase three with atobemetinib in pancreatic cancer? Meaning, either is your preference right now to do it on your own, where perhaps you might need some additional financing, or instead, based on the robustness of this data, do you think instead you'd prefer a partner? If the latter, ideally, what are some of the key elements that you'd be looking for in a partnership? Thanks. Hey, Graig. Good to talk to you. Thanks for the questions. We're not really providing additional color on the details of that data update. I think that next data update, stay tuned for that. Certainly, I think it's clear from the durability that we're seeing here with atobemetinib 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. I think you can read that from everything you're seeing here. No further guidance today on that data update. As we talked about earlier, we're certainly optimistic to see how these patients continue to do over time. In terms of the path forward, I'll simply say that we keep all options on the table. We're certainly, we'll do what's best for the patients and for our shareholders, right? We're certainly of a robust dialogue with a number of really world-class pharma companies. I think the Regeneron announcement is 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 of the MAP kinase pathway, the combination opportunities here are vast, right? I think that Regeneron agreement that we announced is really just the tip of the iceberg. There are so many opportunities to combine atobemetinib with so many different therapies, really for the benefit of cancer patients. 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. The ideas flow in for combinations for different types of cancer, requests for investigator-initiated trials. There is really just a huge broad potential for this drug to help so many different cancer patients. We are 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 atobemetinib to as many cancer patients as possible in a way that also really rewards our shareholders for really making a good bet on a differentiated approach, right? 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." You really have to think differently. That is what we have done here. We are thrilled to see the kind of survival that we are seeing today. If I could squeeze in just one more. I am intrigued by the potential of atebi in other indications like colorectal cancer and melanoma. The question is, could you just remind us or remind me of any preclinical data you have where you are combining atebi with another agent that gives you some confidence of potential efficacy in other indications like colorectal and melanoma? Sure. Yeah. I mean, 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 preclinical work, we've shared publicly combinations of 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 in RAF mutant disease where, again, we don't see the kind of resistance and escape that you typically see with 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's superhighway. This is the majority of cancers use this pathway. Really, all the other approaches that we're aware of, whether it's prior MEK inhibitors, whether it's mutation-specific RAF inhibitors like KRAS G12C, even whether it's sort of pan or multi-RAF 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, the tumor can get around it. We're just not seeing that. We see very few acquired alterations in any MAP kinase pathway gene in our phase one data that we shared publicly. We're blocking all the lanes of that superhighway with atobemetinib. We're doing it in a durable, in a tolerable way. The result is we're forcing cancer onto the side roads under these pathways that it less frequently uses because they're not as robust. That is, and then by combining with different agents that help block those side roads, if you will, that help take out those pathways, we really believe just the sky's the limit. I mean, the range of combinations here and the potential for atobemetinib to really benefit so many cancer patients with durability and tolerability ultimately helps them outlive their disease. I mean, just think of it. If cancer could become a disease that is managed rather than fatal, I mean, it is not a, it is a big goal, but we think based on the data we are sharing today, it is an achievable goal. Okay. Thank you. Congrats again. Thanks, Graig. 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 six 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. Ultimately, we want to help patients outlive their disease. With that, we'd like to thank all the patients and the investigators involved in our ongoing studies. 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. You may now disconnect.