Immuneering Corporation (IMRX) Earnings Call Transcript & Summary

Welcome to the Immuneering conference call to discuss positive top line results from the Phase I portion of the company's Phase I/IIa trial of IMM-1-104. [Operator Instructions]. As a reminder, this call is being recorded today, Thursday, March 14, 2024. I would now like to turn the conference call over to Laurence Watts of Gilmartin Group. Please go ahead.

Thank you, operator. Joining us on the call today from Immuneering are Chief Executive Officer, Benjamin Zeskind; Chief Scientific Officer; Brett Hall; Chief Business Officer, E.B. Brakewood; and Chief Accounting Officer and Treasurer, Mallory Morales. Please turn to Slide 2. During this conference call, management will make forwarding statements, including statements related to the guidance and timing of data readouts for IMM-1-104. These forward-looking statements are based on the company's current expectations and inherently involve significant risks and uncertainties. Our actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties. Facts that could cause results to be different from these statements include factors the company describes in the section titled Risk Factors on annual report on Form 10-K filed with the SEC on March 1, 2024. 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. Please note that the press release and slides that accompany today's call can be found on the company's IR website at www.immuneering.com. With that, I will turn the call over to Chief Executive Officer, Benjamin Zeskind. Ben?

Thank you, Laurence. Good morning, everyone, and thank you for joining our conference call to discuss the positive top line results from the Phase I portion of Immuneering's Phase I/IIa trial of IMM-1-104. I'm excited to share with you that the data reported today show that IMM-1-104 has been well tolerated and showed preliminary signs of activity. You may recall the initial pharmacokinetic, pharmacodynamic and safety data we presented last April was the first demonstration of our novel Deep Cyclic Inhibition mechanism in humans with IMM-1-104 achieving significant levels of PK Cmax and a half-life of approximately 2 hours as we predicted. We believe today's data now provides initial proof of concept that IMM-1-104 through its Deep Cyclic Inhibition mechanism can achieve universal RAS antitumor activity. Please turn to Slide 3. Before I dive into today's results, let me take a moment to remind everyone that Immuneering's goal is to create medicines for broad populations of cancer patients. And that specifically in this Phase I for IMM-1-104, we enrolled a broad, universal RAS patient population. Our all-comers trial was literally that. And in the chart on the left-hand side of this page, you can see quite a few differences in both -- quite a few different mutations in both KRAS and NRAS. Clearly, some of the more common ones are well represented, such as KRAS-G12D and KRAS-G12V. But you can also see a host of less common KRAS mutations as well as a number of different NRAS mutations. So this trial was really set up to assess IMM-1-104 for broad activity. The schematic on the right-hand side of this page is a reminder of how we're able to do that. IMM-1-104 is a Deep Cyclic Inhibitor of MEK in the MAP kinase pathway. MEK is downstream of RAF and it's also the downstream of RAS. So in theory, a MEK inhibitor should be able to achieve broad universal RAS activity. But to date, chronic inhibitors of MEK have been very poorly tolerated and their use has been limited mainly to RAF mutant disease and mainly in combination with BRAF inhibitors. IMM-1-104 is designed to be an entirely different MEK-inhibitor with a fundamentally new mechanism we call Deep Cyclic Inhibition. On the next slide, we'll remind you precisely what we mean that. Please turn to Slide 4. Deep Cyclic Inhibition is designed to both improve tolerability and broaden activity compared to prior approaches which centered on the chronic inhibition of MEK. Here, our approach is shown in purple versus chronic inhibition shown in brown. Deep Cyclic Inhibition works through a dramatic PK Cmax pulse where the objective is to break tumor addiction, but then reach a near-zero drug trough with the goal of making every day cancer's worse day while also making it a drug holiday for the patient. Additionally, we also have a unique mechanism of action of target engagement, where we aim to block the CRAF bypass feedback loop. Our design for IMM-1-104 was fundamentally new, but we hypothesized that could enable us to dramatically change the safety profile of MEK inhibitors and indeed, MAP-kinase pathway inhibitors more generally. We gave a preview at AACR last year when we shared some data from the dose escalation portion of our Phase I trial and showed that we hadn't encountered any dose-limiting toxicity. But we're going to share a lot more with you today. But first, let me remind you of the trial design for the Phase I portion of our Phase I/IIa study. Please turn to Slide 5. The Phase I portion of our Phase I/IIa study is truly Phase I, as you can see from our prospective primary and secondary endpoints. The primary endpoints were tolerability and a recommended Phase II dose. The secondary endpoint was pharmacokinetics, or PK. As such, the study was designed and the patients were selected with achieving these objectives in mind. That being said, we did also look at exploratory measurements, including pharmacodynamics, blood-based biomarkers such as ctDNA and initial activity, and I'm excited to be sharing some of that data with you today as well. All data we are reporting today is from our data cutoff date of February 20, 2024. Consistent with the study's primary endpoint, where we focused on safety and getting to the recommended Phase II dose as quickly as possible. On the right-hand side of the slide, you can see that we enrolled a very broad, inclusive group of patients, nearly 2/3 of whom had pancreatic cancer. Sadly, these were very sick patients, 82% of whom with prior treatment history available had never had a response to any prior therapy. Furthermore, approximately 2/3 of the patients were receiving IMM-1-104 in the third line setting or later, actually including up to the seventh line setting. That's highly relevant, particularly in pancreatic cancer, where the earlier lines of therapy are chemotherapy, which is known to be immunogenic, causing additional mutations outside the MAP kinase pathway that IMM-1-104 is designed to treat. In particular, in this late-line setting, there can be extensive lesion to lesion heterogeneity, so that different lesions have different genetic profiles and differ in how dependent they are on the MAP kinase pathway. Nevertheless, we were able to generate compelling data that points to IMM-1-104's antitumor activity, and which we will look to build upon in the Phase II portion of our study. So let me now share with you the top line results from our study, starting with one of our primary endpoints, Safety. Please turn to Slide 6. Here, you can see our safety table in the typical format, reporting all treatment-related adverse events observed in 10% or more of patients. What's not typical about the table is how empty it is. There is 1 single Grade 3 event, which was a rash that was resolved with topical cream. You can count on one hand the number of Grade 2s in any category, and no treatment-related adverse events were deemed serious. This should go without saying but I'll belabor the point anyway, we believe this is a truly dramatic improvement over any prior MEK inhibitor and in fact, highly differentiating relative to any other clinical stage inhibitor targeting the MAP kinase pathway. Of course, the end reported here is 41 patients, but we are very encouraged by what we have observed in our reporting today. So having shown that with deep cyclic inhibition, MEK can be a target that can be inhibited in a way that's exhibited a well-tolerated profile, the next question would be, is IMM-1-104 active? We believe the answer is a resounding yes and we'll show you why on the next few slides. Please turn to Slide 7. The first reason we believe that IMM-1-104 is active is by looking at the PK/PD patient data. IMM-1-104 inhibits the MAP Kinase pathway more than [indiscernible] where we see a more than 90% reduction in phosphorylated levels of ERK. And importantly, you can see that there's a dose-dependent effect. The blue line here is our highest evaluated dose of IMM-1-104 at 320 milligrams taken once daily. At a 320-milligram dose, IMM-1-104 spends approximately [ 2.7 hours above the IC90 line ], meaning it inhibits the pathway at a level greater than 90% for that duration of time. At 240 milligrams in [indiscernible] our dose exploration portion, IMM-1-104 spends 1.9 hours above the IC90 line. We believe that 2.7 hours is better than 1.9, and that together with the fact that there was a lower variance in the PD at 320 milligrams are two of the reasons we selected 320 milligrams as the candidate RP2D. In each case, levels returned back to down below 10 nanograms per milliliter before the 24-hour mark. We believe affording patients the daily drug holiday and pathway reset that's so important in the concept of Deep Cyclic Inhibition. From this then, you can see that IMM-1-104 is active in suppressing the MAP kinase pathway, but how is this translating to our universal RAS goal? To help answer that question, I'm going to show you using circulating tumor DNA data or ctDNA data. But before I do, I want to provide you with some context by sharing the ctDNA data from someone else's trial with you. So please turn to Slide 8. These data are from 20.3 New England Journal of Medicine Article that Genentech published on Divarasib, their KRAS-G12C inhibitor. It's a great article. What they -- acquired alteration. These are not baseline mutations but rather newly arising mutations or amplifications or CNVs that appear following treatment, [ pivot ] as a sign of how each tumor was able to get around therapy. It makes sense that with a KRAS-G12C inhibitor, you're sort of blocking one lane of the MAP kinase superhighway, which helps, right? It slows down traffic, but the tumor can eventually switch lanes to get around it. And as you see, it switches lanes to a KRAS-G12B or other KRAS mutation or QRAS or an NRAS mutation. So acquiring alteration data is important because it tells you how the tumor is able to get around a particular therapy. So with that as context, let's look at the data for 104. Please turn to Slide 9. Now you might think the contrast on your screen is broken at this point because the RAS down here is entirely blank, but it's actually what we observed in the evaluable patient data, and it's striking. We did not see a single acquired alteration in RAS in any of the patients who we have ctDNA data. I'll let that sink in for a minute. What that means is that there were no mutations in KRAS, NRAS or HRAS that a lesion used to get around IMM-1-104. Moreover, the only place [ we saw ] acquired alterations in the MAP kinase pathway was in 2 patients at the 160-milligram level, which we believe is below the therapeutic dose and only half the dose amount of our RP2D. So if you take those out, you can see that we have no new alterations in either RAS or any other MAP kinase pathway genes. This means that for the patients in our 104 trial to date, dosed at 240 or 320 milligrams, it blocked every lane of the MAP kinase superhighway, consistent with our goal of universal RAS activity. Importantly, we believe due to our Deep Cyclical Inhibition mechanism, we did so in a way that was well tolerated and has the potential for a clearly differentiated safety profile. As such, we believe that ctDNA data is an incredible proof of concept for IMM-1-104. But what does that mean for IMM-1-104's impact on the tumors themselves? Well, despite this being a very late-stage population, mostly pancreatic, mostly third line or later and mostly never having responded to any prior treatment. And despite activity not being an endpoint of our study, we nevertheless have some exciting antitumor activity to report. So please turn to Slide 10. In the Phase I data reported today, IMM-1-104 as monotherapy [ shrank ] at least 1 target lesion in half of the patients. We all know that pancreatic cancer lesions don't just shrink our own, and they certainly don't shrink by 35.7% which we saw as the best individual lesion regression in 2 separate patients, each of whom were treated with IMM-1-104 at 320 milligrams. Both of these were second-line patients, which we see as playing to the importance of the line of therapy and we believe bodes well for the Phase IIa portion of our Phase I/IIa study, where we will move into earlier lines of therapy. In this later line setting where there is so much genetic heterogeneity among the lesions in a given patient, we believe that these individual lesion measurements are the best way to assess a targeted therapy. That being said, we, of course, also looked at the effect across all target lesions, the RECIST sum of longest diameters or SLD. And there too, we are pleased to observe a minus 18.9% as the best RECIST SLD reduction to date. That was also at 320 and also in a second-line patient. These observations lend additional support to 320 milligrams as our recommended Phase II dose. Our longest duration on therapy was 162 days or 5 months. That was at 240 milligrams. And interestingly, that patient had no treatment-related adverse events whatsoever. And returning the headline for this slide. Overall, 53% of patients, 320 milligrams or 240-milligram had at least 1 target lesion regress. When you consider that 82% of the patients in our trial had never responded to a prior therapy, we are very encouraged by these results. We believe the fact that lesion shrank in so many patients and up to 35% provides clear evidence that IMM-1-104 is active. As such, we believe this study serves as very clear proof of concept for IMM-1-104 with data that makes us excited for our ongoing Phase IIa study. So please turn to Slide 11. On this last slide, I'll run through our top line conclusions as well as go through our next step Phase IIa plan. In this study, IMM-1-104 has been well tolerated, which we believe shows its potential for a differentiated safety profile. We saw 100% suppression of acquired RAS alterations in the data report, which we believe stands as proof of concept for our stated goal of universal RAS activity. Moving forward, our recommended Phase II dose of IMM-1-104 will be 320 milligram, which is supported by tolerability, PK, PD, ctDNA data and initial activity. And importantly, we saw individual target lesion regression in about half of the patients in our study, up 35.7%. We believe this bodes very well as we head into the Phase IIa portion of our Phase I/IIa study. You will have seen from the press release we issued on Monday, we recently dosed the first patient in the Phase IIa portion. Our IIa trial will have 5 arms, and you can see that we're moving to specific types of cancer and to earlier lines of therapy, where we believe IMM-1-104 will have the greatest benefit. We have both monotherapy and combination therapy arms, and let me just emphasize that with the kind of tolerability profile we've observed for IMM-1-104, it really opens up a very wide array of different combination therapy opportunities. Let me also point out that as you will have seen on a prior slide in this deck, we did not have many [ melanoma ] patients in Phase I, and that was a function of having just 5 sites in Phase I study. We have, however, expanded the number of sites for our Phase IIa, and we have strong preclinical data in melanoma that we previously shared. So we're very excited to see how IMM-1-104 does in melanoma and similarly for non-small cell lung cancer as well. With IMM-1-104, we set out to do something fundamentally new. We set out to make a drug that inhibits the MAP kinase pathway at the level of MEK, but does it in a well-tolerated way with broad universal RAS activity. I believe these top line results stand as proof of concept for that mission and we couldn't be happier with the results or prouder of the team that achieved them. In particular, we'd love to thank the patients, investigators and study sites who participated in this clinical trial. We look forward to providing you with updates from our Phase IIa study later in 2024 during what looks to be a data-rich year for Immuneering. With that, I thank you for your attention, and I'm happy to take questions.

[Operator Instructions] Our first question comes from the line of Yaron Werber with TD Cowen.

This is Joyce on for Yaron. The ctDNA data certainly looks very encouraging. I was wondering if you could talk a little bit about what's happening to the baseline mutations? In the context and perhaps in relation to the no new acquired mutations in RAS and MAP kinase. And secondly, do you think there's any potential mechanism here where that underlying mutation is progressing? And maybe the absence of acquired mutations is due to maybe no new mutational pressure.

I'll actually answer them in the reverse order. So in terms of whether the absence of acquired alterations in RAS could be a result of no mutational pressure. I direct you to Slide 9, in particular to the right half of Slide 9. So if there were no mutational pressure, we wouldn't see any acquired alterations or not many, but we actually do see acquired alterations on the right side there in genes associated with other pathways unrelated to the MAP kinase pathway. So what this is telling us is that there is, in fact, mutational pressure. It's just that the tumor has to resort to completely different pathways in order to get around 104. It can't do it using the MAP kinase pathway. So in other words, we're blocking all the lanes of the highway and the tumor has to resort essentially to taking a train or boarding a ferry, right? It has to go to a completely different pathway to get around. And if there were no mutational pressure, the tumor wouldn't have to do that. So this is how -- it's really the contrast between the right half of Slide 9 and the left that we believe shows clearly that we're blocking all the lanes of the MAP kinase highway. And I think that's -- it's particularly relevant in this late-line setting where you have patients who have been through many rounds of [ muted diet ] chemotherapy and have this lesion to lesion heterogeneity. So they have the ability to acquire [ all these ] alterations in different pathways. Currently in the literature are known as mutations that can antagonize MAP kinase pathway inhibitors. So it all kind of makes sense. Let me ask my colleague Brett if there's anything he'd want to add on that?

I think you covered that well, Ben. So, and then, of course, the other question, I'll let you address that, but I'm happy to help on that, too.

Go for Ben. Why don't you take the lead and I'll jump in.

Yes. So your first question is, perhaps you don't see changes in the original diagnosed [ varying to low ] fraction. We actually do see, we see reduction, stabilization or increase in different patients, and it really depends on the kaleidoscope of mutations that appear in those patients. And so when it comes to controlling the pathway, it appears that the ctDNA tell us simply. If the tumor is addicted to RAF, it means that there aren't other compensatory lesions that it can use to bypass 104 then basically, we do see that reduction in [ varying to low ] fraction and associated tumor regression.

Our next question comes from the line of Michael Yee with Jefferies.

This is Kyle Yang for Michael Yee. So a quick question on the PK. You shared that your IC90 coverage around 2 hours, but are you able to also share what is the half-life? And in terms of Cmax, I remember you shared previously at AACR that Cmax was around 2,000 per milliliter. And here, it looks like Cmax is lower. Are you able to share any color on what's the reason behind it?

Sure. Yes. Thanks for the question. So the, at 320 milligrams, we spend about 2.7 hours above the IC90. So we're really crushing the pathway. And in fact, most prior MEK inhibitors really to get up to around their IC50. So I think it's important to appreciate that difference and just how much we're inhibiting the pathway relative to what's come before. The half-life of the drug is around 2 hours. So that's generally been consistent with the data we previously disclosed. And as for the Cmax, keep in mind, this is a log scale on the left. So Brett would maybe want to comment further there.

Yes. This is well above the 2,000 mark. The other thing, too, is this is based on 19 patients in the Phase I study, so this is modeling for a typical PK profile for a patient at each of the dose levels. And just the composite modeling half-life puts IMM-1-104 in the 1.9 hour range, which is really consistent with the 2-hour range that we've been seeing generally as well. So what we're seeing is between 1.9 and 2 hours on average for IMM-1-104 for half-life.

Our next question comes from the line of Jeffrey Hung with Morgan Stanley.

This is Michael Riad on for Jeff Hung. On cyclic inhibition, how important is it that the 90% inhibition was achieved for 1.9 hours at 240 milligram versus 2.7 hours at 320 milligram? Based on your modeling was 2.7 hours sort of thought about as like the optimal time on? I do have a follow-up.

Sure. Yes. Thanks for the question, Michael. I mean, look, I think one way to -- again, either way, whether it's 1.9 hours or 2 hours, it's a lot more inhibition than sort of with prior MEK inhibitors because we're up above the IC90. But I think you can look at that maybe in the context of Slide 10, actually. So you can see there that the best individual lesion regressions we saw 320 of minus 35.7% were better than the ones we saw at 240 at minus 11.4%. And then similarly for the RECIST SLB, the best we saw at 320 was better [ at ] than what we saw at 240, which was minus 7.1%. So I think those data, while at the low end and it's preliminary, certainly, that 2.7 hours of inhibition is better than 1.9, which is logical, right? It stands to reason. So that's what I would say, but let me again turn it over to Brett for anything he'd like to comment.

Yes, I think, and I would say that this is consistent with what we've seen in our nonclinical, preclinical modeling data. What we wanted to achieve was Deep Cyclic Inhibition which is really driving this binary inhibition pharmacodynamically, with heavy inhibition over 90% for a period of time that gives way with a fast half-life to a near 0 drug trough in order to pick up that full cycle. And so we've achieved this, and we're very comfortable with the PK/PD profile that we're not seeing in patients in our Phase I.

And if I could just a super quick follow-up. So you showed that 53% had target lesion reductions with 104 at 240 mg and 320 mg. Do you know what the breakout was between 320 mg and 240 mg. And what you think is going on in the other 47% of patients.

Brett, do you want to take that one?

Yes, absolutely. So it's slightly favored 320, but it was close between the breakdown. It should be noted that 240 does drive Deep Cyclic Inhibition profile in patients. It's a good fallback dose. But what we did note also on the PK/PD slide, which is on Slide 7, that we did see lower variance in the pharmacodynamic profile, the phospho-ERK inhibition at 320 versus 240, which gave us that more consistent candidate DCI profile, which is part of the reason that we went forward with RP2 dose. As far as the other 47% of patients, in patients that have a large number of alternative mutations with respect to not -- that drive down [ or away ] addiction from the MAP kinase pathway, those patients and tumors are particularly challenging for a single monotherapy that does a good job of blocking the MAP kinase pathway. So as Ben was saying, when the tumor resorts that ferries and trains, it's hard to block -- you're just blocking the road to stop the tumor growth. And that proves particularly challenging in the advanced metastatic setting.

Just to add, so like again, it's really in that later line setting that have this genetic heterogeneity and the ability to take trains or ferries, which is yet another reason we're excited to -- on Slide 11, to move to earlier line settings in the Phase IIa.

Our next question comes from the line of Michael Schmidt with Guggenheim.

Just a follow-up on the clinical efficacy assessment. I was just wondering, it looks like there's about 20 efficacy viable patients in the data set here. Do you have any additional color on the genetic background and histology of patients that did have some tumor reduction? And then as we think about the Phase IIa portion of the study. So what is the expectation for single agent activity in the [ PD ] background? Is the data that we've seen from other [ pan ] RAS inhibitors, [ could die of 320 to 47 lot rate ].

Michael, thanks for the question. Thanks for joining. Keep in mind [indiscernible] end here is really small, right? There's 11 patients with scans at 320, 6 patients with scans at 240 and then another 3 with scans that -- doses that were used in the dose escalation. So we have not seen any particular genetics, certainly not, say, a particular RAS mutation that's more or less associated with response. And we certainly wouldn't expect one, given the fact that we're -- we have this universal RAS design, we're clearly blocking acquired alterations across any ratification. So we've not we've not seen that. I mean the only pattern -- and again, I'd really only call it anecdotal because of the end being smallest, all the best individual regressions in SLBs were in second-line patients, which were, again, less than 1/3 of the patients in our study. But so that's the only pattern I would even kind of suggest based on what we're seeing anecdotally and that one certainly makes sense, right? In all our preclinical data, what matters is how addicted the tumor is to the MAP kinase pathway. The more it is, the better it responds. And so -- but what the specific mutation is does not matter. And so that certainly, I think it's well appreciated that the earlier line the patients are, the earlier lines of mutagenic chemotherapy, they've been through the more homogeneous, their lesions are likely to be in the more dependent on -- the MAP kinase pathway they're likely to be. So that all kind of holds together. In terms of the expectations for the Phase IIa, if we could turn to Slide 11. And it's the right question because this -- the Phase II is the first time we have activity or ORR as an endpoint, right? So, this is the first study we're doing that's designed -- excuse me, to assess that. And so we have specific types of cancer and specific lines of therapy in each of the 5 arms. And there are clear benchmarks. In fact, if we advance to Slide 14, on the left-hand side, you can see in pancreatic cancer, for instance, there are clear benchmarks established by Phase III trials of standard of care. So in the first-line setting, kind of the ORR benchmark ranges from 23% for gemcitabine paclitaxel up to 32% for FOLFIRINOX, 42% for [ Malarifax ]. And then in the second line setting, the benchmark is really 15% to 17% ORR, as you can see in that table on the left side on Slide 14. So that just kind of gives you an example of the benchmarks we'd be looking to -- we would want to clear in the Phase IIa to really demonstrate a difference from the standard of care in these settings. And again, the Phase IIa is the first study we're running, where that's an endpoint, and it's designed to answer that question. And we're certainly optimistic based on what we're seeing so far in the data on Slide 10.

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

One on safety, could you just kind of expand more on what you saw there. The common treatment-related AEs outside of the Grade 3 rash were [ AEs ] were common at the higher dose level, when do they typically rise? Did you see any dose interruptions or changes due to safety? I mean it looks really clean, so I'd assume not. But curious just to hear more. And then secondly, just how does this data kind of inform your thinking on tumor types that might be best suited for combo versus monotherapy?

Sure. Yes. Brett, do you want to take the first one on kind of additional details on the safety data for Slide 6.?

Yes, absolutely. What we can tell you is that the single Grade 3 event which was not curious. And again, quite readily reversed, was on the 320-milligram group. In general, with the Grade 1 and Grade 2, we didn't see a difference, dramatic difference between 240 and 320. There just really aren't that many adverse events, and again, most adverse events are really very low grade, right? I mean on a single hand for Grade 2 and all less than 10 events in Grade 1 for each of these. So extremely well tolerated. It should be noted that there were no IMM-1-104 treatment-related adverse events that were deemed serious at all. And so, and no DLTs, which we had already reported out there in dose escalation. So extremely well tolerated. For most patients coming off -- it was either through the advanced metastatic setting, it was either clinical progression or it was new metastases or nontarget -- changes in nontarget lesions. So it really wasn't a factor on safe -- safety was incredibly clean as you can see on this table.

And turning to your second question, Allison, in terms of the cancer types, I direct you back to Slide 11, right? And this is really what we've prioritized for the Phase IIa. And if you'll recall a few months ago, we announced an expansion of our Phase IIa plans where we increased the number of arms and added a number of additional sites and investigators. And that was really informed by all the data we have in hand, both preclinical and clinical. And it was also informed by extensive discussions with our investigators. We have a great group of investigators and they're really, really thoughtful about what's optimal for patients. So these are the arms we think make a lot of sense right away. Certainly, the combinations, which bring us to pancreatic cancer. We also all note we released our AACR abstract last week. We can't show you the plots until after the conference, but in the text of the abstract, we described animal studies showing near complete responses to 104 plus gemcitabine and paclitaxel. So just really nice animal data as well supporting that combination you see in the lower right on Slide 11. And again, I'll just remind everyone that, the Phase II is underway. We dosed our first patient. We announced that on Monday, and that was in that particular arm. So look, we're really excited about the combination arms for panc. We are very excited about looking at monotherapy, panc and second line earlier. And then melanoma, right? I mean our strongest preclinical data is in melanoma. And we had only 2 patients in the study as of the snapshot date with melanoma. And that was just a function of the fact that we only had 5 sites and we sort of -- you're limited to what the sites have. But very strong preclinical data for melanoma. And we've added a number of new investigators -- great new investigators and sites who are focused specifically on melanoma. And they tell us there's really -- there's not a lot of options sadly for patients with NRAS melanoma in the second line or later setting. So we're really excited to be able to provide that arm of the trial and certainly eager to see how that goes. And then lung cancer as well similarly, just weren't a lot of patients in this study, so excited to really -- really focus in on that. The last thing I'd say about melanoma is just that one of the melanoma patients -- if you go line 10 at the bottom, we described 6 patients who have best sum of longest diameters of 0 to minus 18.9%, and that included one of our melanoma patients, even at a suboptimal dose a patient that started at 160. So even at a suboptimal dose, we saw a really nice kind of SLD numbers in that melanoma patient. So again, really excited for melanoma and then certainly for lung as well. But look, there's only so many arms we can run at once, right? And we think particularly with this -- the tolerability profile that we're showing here, there's really a huge array of combination possibilities that. I think we've shown a number of them in our animal studies, certainly vertical pathway combinations with -- for instance, we have an animal study where we combined with sotorasib and showed a nice improvement in [ ultimate RET inhibition and durability with the combination. So, we think there's really a broad range of both the combination and monotherapy opportunities that are open to 104, and we look forward to pursuing them.

Our next question comes from the line of Jay Olson with Oppenheimer.

Congrats on the progress, and thank you for providing this update. Can you talk about the percent of patients remaining on 104 treatment? And since most patients remain dependent on the RAS MAP-K pathway, does it suggest patients may continue to respond to 104 and then those patients with clinical activity may deepen over time?

Jay, I'll take up half of that, and then I'll get it over to Brett. We haven't disclosed a lot of details on kind of exactly where each of the patients are. But what you can see on Slide 10, certainly the patient to -- as of the data snapshot had started treatment but not yet been scanned, other patients pending data entry. So there's sort of patients that are a variety of stages in the therapy. Again, just in terms of longevity on therapy, I'd point to also Slide 10, a patient that was on therapy for over 5 months. And that was a third line pancreatic cancer patient who had no adverse events whatsoever. I mean just if you think in terms of the [ PF expectations ] for third line pancreatic cancer, that's noteworthy. And I think the other way you can kind of get a sense is on Slide 9, we have the durations of time. Again, this is not a duration on therapy. It's the duration between the baseline and the ctDNA sample that we took. But that can start to give you a sense. I don't know, Brett, feel free to jump in as well.

Yes. So I would -- to answer your first question, Jay, on Slide 10. That the best RECIST SLD, that was actually sequential regression on subsequent scans, to answer your question. Do we see continuing depth -- deepening of regression? We do. We do observe that. I think the biggest challenge has been in this heavily pretreated advanced patients -- metastatic patient population has been just controlling new [ MEKs ] with expansion of nontarget lesions, right? It really hasn't been on the directional change of the regressions we're seeing at the individual lesion. Or even in the case of that minus 18.9%, that was 2 sequential scans of continuing, deepening regression before new metastasis led to progression.

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

Firstly, could you give us some more color on the baseline mutations of the patients? I think in Slide #9, you mentioned kind of the KRAS mutation. But if you could give us some color on the other mutations that these patients carry, particularly the second line patients, that would be helpful. And with regards to the 2 patients that saw lesion regression, could you give us some color on what type of tumor they had?

Sure, Ami. Nice to talk to you. I'll answer the second question, and maybe I'll hand it back to Brett for the first question. But just to be clear, there were many more than 2 patients who saw individual lesion regressions, but the 2 best were at [ 2 agents ] minus 35.7%. Those were both pancreatic cancer patients. So that's -- they were pancreatic cancer. However, if you look on kind of the bottom of Slide 10 where we note that the 6 of 20 patients with scan had sum of longest diameters of 0 to minus 18.9%. And in that group of 6 whose -- [ we saw ] sum of longest diameters was either flat or negative. We had 4 different types of cancer, pancreatic, colorectal, cholangiocarcinoma and melanoma. So kind of nice to see those signs of activity really across a variety of different cancers, especially given that more than 60% of the patients in the study had pancreatic cancer. So that's kind of to your second question. Brett, do you want to speak to the first question about non-RAS baseline mutation?

Yes, absolutely. So yes, basically, as you can imagine in this advanced metastatic cancer setting, we actually saw a whole litany of mutations outside of RAS and these patients at baseline. Just to be clear on Slide 9, these are only newly emergent mutations that we saw after treatment. So these are basically driven by selection bias with the tumors trying to get around the drug. I can say as well that it wasn't surprising to see some of the mutational burdens where basically the more mutations you have in parallel pathways, the less likely you were expecting to see big movements with respect to tumor regression. So there really weren't any surprises. And in fact, in almost every patient, the baseline profile and emergent newly acquired mutation profile really paints a pretty solid picture, where the tumor has to shift its allegiance away from the MAP kinase pathway to try to get around 104.

Great. Could I ask a quick follow-up? So just with regards to the second line patients, and you're running a cohort, which includes baseline patients as monotherapy in your Phase IIa. How should I think about the baseline mutations of those patients? Are they usually sort of burdened with multiple sort of mutations even outside the MAP-K pathway, just based on kind of what you've seen so far?

Yes. It's interesting. It's a good question. It really is. So I would say that in the second-line setting, it really depends on what happened in first line. I'm going to give you just an example. So if a patient -- pancreatic cancer patient in the second line was treated with FOLFIRINOX for a year with dropping oxaliplatin along the way, and the best overall achieved response with stable disease, that's a very different patient than a patient who had the second-line pancreatic had FOLFIRINOX in the front line, was treated for 3 months, experienced the PR, but then progressed. The exposure to the mutagenic chemotherapy is different. It's 4x longer in that first patient scenario where that patient only achieved stable disease, suggesting there's probably a more aggressive course for that patient than the other patient. So I think one of the root things, and is a question that someone had earlier as well, is what are your benchmarks that you want to respond? Do you start to set benchmarks based on 20 to 30 studies from kind of an emergent clinical trial? Or do you go to a tried and true Phase III benchmark that's been established? And I think part of this tumor or patient-to-patient heterogeneity, basically is addressed -- better addressing in these registrational studies, which are the ones that tend to pivot -- these [ table ] studies the set the benchmarks. So I think to answer your question, it will really depend on the patient population, but that's why we have 30 patients in each arm, to really get a broader experience on those patients and suseptibility to treatment against an inhibitor like 104.

Our next question comes from the line of Graig Suvannavejh with Mizuho Securities.

Just maybe 2 questions for me. I'm just thinking about the Phase IIa portion and the decision to go into monotherapy as well as combination therapy cohorts. Can you just give us maybe a sense of what gives you the confidence that the drug alone will be able to show some efficacy? And then I'll follow up with my second question.

Yes. Thanks, Greg. Look, I mean, we're shrinking tumors in half for patients. And I think that's generally in a later line setting. I think in the monotherapy arm for pancreatic, we're going to be in the second-line setting or earlier. I'd also point to the number we cited earlier, which is present on Slide 5. Where in this study, we had very broad criteria, and over 80% of the patients never had a response to any prior therapy. Now most companies don't report that number, but every clinician that we've spoken with said, "Whoa, that's unusual, right? Typically, patients at least have a brief response to first-line therapy. And look, I think that's the nature of a Phase I where your end point is safety, and you're really evaluating something new. Whereas a Phase IIa, you generally see kind of a slightly different group of patients. So look, I mean, given less than 1/3 of these patients were in the second line in the Phase I, it's a different group of patients and despite all that, we're shrinking lesions up to 35%. I think we're actually very, very excited for the monotherapy arm in panc, in second and first line. And I'll also point out, too, that we were originally just going to have that be a second-line trial. It was actually our investigators, a great group of investigators. As I mentioned, multiple investigators suggested that we add an option for first line. And we said, how can we do that? And what they told us was there are these first line chemotherapies in pancreatic cancer are so toxic, so tough to tolerate. But they said there's patients that they see who just want a non-chemo option, even in the [ first-line ] setting. So that's -- that was suggested by our investigators. So we're excited for that arm. And then as I talked about melanoma and lung, we really didn't have the patients to do a full evaluation here in terms of the number of patients, but were given all the preclinical data and what we did, being the limited number of patients we had, we're super excited for both of those monotherapy arms as well.

Okay. And then the follow-up. Just second question, you had commented that perhaps there were no specific RAS mutations that were less responsive to the drug. I was wondering the converse, if there were certain mutations that were more responsive to the drug?

Neither, no. I mean there's -- and this is consistent with our preclinical data, we see there's no difference, right? And we're certainly right, we're hitting the pathway at the level of MEK, right? So any RAS mutation is going to be upstream of that. So we certainly didn't see anything, again with the caveat that this was a low end in the trial, certainly wasn't designed to look for those kind of patterns. But everything we've seen in our preclinical data, is it doesn't matter what mutation the lesion is using to be dependent on the MAP kinase. The only thing that matters is how dependent the lesion is on the MAP kinase pathway, right? If the lesion is already using a different pathway, right? If it's already taking the train and the ferry, it's not going to matter that we block the highway. But to the extent the tumor is dependent on the MAP kinase pathway, to the extent that it's on the highway, everything we've seen preclinically, and we believe to date clinically suggest those are lesions that are going to be most sensitive.

This concludes today's question-and-answer session. I would now like to turn the call over to Benjamin Zeskind for closing remarks.

Great. Thank you. I'd just like to thank everyone for participating in today's call. Have a great day.

This concludes today's call. You may now disconnect.