Good afternoon, everyone, and welcome to the Elicio Therapeutics virtual KOL event. At this time, all attendees are in a listen-only mode, and a question-answer session will follow the formal presentations. As a reminder, this call is being recorded, and a replay will be made available on the Elicio website following the conclusion of the event. I'd now like to turn the call over to Dr. Chris Haqq, Chief Executive Officer and Head of Research and Development at Elicio Therapeutics. Please go ahead, Chris.
Great. Thank you very much. It's a pleasure today to welcome you to our discussion of neoadjuvant and metastatic applications of camupepimut, the clinical development in KRAS-mutated pancreatic ductal adenocarcinoma. I'll introduce here just that we will today be making forward-looking statements, and if you have any further questions about that, please refer to the Elicio website. Today in our agenda, we're very privileged to have two speakers that are immensely knowledgeable in the treatment of pancreatic cancer, with Dr. Kevin Soares, Assistant Attending Surgeon on the Hepatopancreaticobiliary Service at Memorial Sloan Kettering Cancer Center. Dr. Soares is the principal investigator of the neoadjuvant phase I study incorporating camupepimut, and he'll speak about that, as we've received so many questions about the recent startup of that study. In addition, it's a pleasure to be joined today with Dr. Eileen O'Reilly.
Eileen is the Winthrop Rockefeller Endowed Chair in Medical Oncology at Memorial Sloan Kettering. She's the section head for Hepatopancreaticobiliary and Neuroendocrine Cancers in the GI Oncology Service, and she co-directs the David M. Rubenstein Center for Pancreatic Cancer Research at MSK. Today, we'll begin with the discussion of the neoadjuvant study design, and after the presentations today, we'll have time for a discussion and question and answer session. With that, let me please invite Dr. Soares to speak about the neoadjuvant study that's begun.
Great. Thank you, Chris, and thank you everyone for the opportunity to be here and discuss our ongoing work. I'll be really focusing on our ongoing phase I trial looking at neoadjuvant FOLFIRINOX and camupepimut and tislelizumab in the resectable, borderline resectable pancreas cancer. Next slide. You can hit that slide ahead a little bit there, Chris, please. You'll see here the survival curves for pancreas cancer. This is a lot of what drives Dr. O'Reilly and I's work every day. What we see is a large number of patients with this disease, and Chris, you can hit the slide one more time.
And what we constantly are running into is the fact that in these survival curves, when you look at these, the higher this tail of the curve is, the more patients are living a long time, and this X-axis is the amount of time they are alive from diagnosis. What becomes clear is that over the years, and this study looked from 1997 up to 2016, we have seen very little improvement in pancreas cancer, most importantly, very little improvement in long-term survivors. We are clearly in need of novel therapies, which is what we are here to discuss and push forward through our research work. Next slide. When we look at classically how novel therapies have been introduced, not just pancreas cancer, but cancers in general, we typically are focused in the metastatic setting.
We are trying to assess safety and then efficacy, but the reality is, when you look at pancreas cancer especially, 50% of patients are metastatic at the time of diagnosis, and we cannot cure those patients. That leaves the other 50% of patients with potentially curable disease, 20% of which can be removed at diagnosis, the other 30% which is advanced but localized. This is really the patient population where we have a chance for cure, and this is really where over the years, as novel medications have come up, where we have seen improvements in overall survival over the years, and this is a patient population that is highly motivated to give themselves the best shot through undergoing combinatorial therapies like surgery, chemotherapy, and other novel and promising therapies. Next slide.
Granted surgery is the approach combined with chemotherapy that offers us the chance at cure, but what is clear is that chance is not nearly as high as it needs to be for these patients, particularly when they are undergoing these major operations with significant risk associated with them. What do we take away when we resect a pancreas cancer patient? Technically, when I am done with an operation, that patient has no more evidence of cancer, but the reality is, that is probably not realistic. This cancer tends to spread very early on in its course, and distant spread ends up being a very common occurrence with five-year survival, even after surgery, just 17% in some series.
Additionally, as we look to understand how to implement novel therapies in patients before surgery and even after, we are very limited with what we have been able to accomplish, particularly when we look at these tumors and they are removed, we are not seeing significant responses consistently that would implicate that these therapies have been very effective. It is hard to move the field forward because we are not seeing a lot of data or analyses that can really tell us, okay, well, why is it not working or why is it working, and who are the patients we should target and how should we move forward to the next step? This really is our interest in trying to move promising therapies, more specifically like immunotherapy, into a neoadjuvant setting where we can answer a lot of these questions. First of all, can we help patients live longer?
Can we make this surgery a curative event more often than not, which is currently not the case. In addition to that, can we understand what's happening at the tumor level with these novel therapies so that we can actually understand what are stronger preoperative and perioperative strategies to combine surgery with other promising therapies? In doing so, we need studies that really understand what's happening clinically, but also biologically. How are these medications working? Next slide. This just gives you a sense of what's been done thus far in this setting.
I look first at the regimen, and you can see the regimens that have been used most often in a neoadjuvant setting are basically the same chemotherapies we've been using for years now that have produced the numbers that I showed you in that first slide, and it's really reshuffling the different types of systemic chemotherapies. Not until recently are we seeing an interesting development of using targeted therapies and immunotherapies. If you go to the next red box, what you can see there in the CR is complete response or pathologic complete response. It's essentially, at best, 10%, but realistically 0%-3%. Even the median path response, where you get an overall higher response throughout the tumor, is still limited to about 20% of all the patients.
In doing so, what we're seeing at the end of the day is very minimal improvement in overall survival and disease-free survival, meaning we're still not curing a large percentage of patients. Next slide. This is really the thought process behind the current trial we have ongoing, where we have patients who have a high chance of being able to get to surgery, but they need neoadjuvant therapy first in order to control their disease and control for the potential for spread, even though the scans do not show it. This is a patient population we target with this study where we implement not only the standard of care chemotherapy, but add neoadjuvant immunotherapies, which could potentially shrink the tumor, facilitate surgery, but more importantly, potentially help activate the immune system and help it understand it needs to attack these cancer cells throughout the body.
That, by far, is our best defense against these microscopic cells that might be elsewhere that we can't address with surgery. By educating the immune system while the tumor's intact before surgery, we hope those T cells then go attack the tumor. We take the tumor out. We can understand if it's attacking the tumor once we analyze it. On top of that, then when the cancer's all gone and we realistically have microscopic disease left over, can address that with further immunotherapy and standard of care systemic therapies, all leading to what we hope is higher percentage of long-term cures, which come with a reduced chance of having the cancer come back, which ultimately can improve survival. Next slide. This approach is not something that's unique to pancreas cancer. We've actually seen the potential benefit of neoadjuvant immune approaches in other cancers.
This is a graph or a table demonstrating non-small cell lung cancer trials, triple-negative breast cancer trials, and even melanoma trials, all used in the neoadjuvant setting. The benefits here both being clinical, but understanding the biology where we can really understand how to implement these combinatorial therapies that we have at our disposal. Next slide. With that, I'll introduce the design that we have ongoing for our trial, which is a collaboration through Break Through Cancer and Lustgarten Foundation. It's a multi-institutional trial that's targeting patients, as I mentioned, with resectable or borderline resectable cancer. You can go onto the next slide. These patients, per standard of care, get full FOLFIRINOX, which is a standard of care chemotherapy. We typically do approximately four months of chemotherapy.
In this design, we are able to get their genetic testing done in the first two months while they get their standard of care chemotherapy, and then enroll them as their third month of treatment begins so that we can then give them chemotherapy combined with vaccine in one arm. In the second arm, it's chemotherapy combined with vaccine along with tislelizumab, which is an anti-PD-1 inhibitor. You can go to the next slide, Chris. That is completed all before surgery, and we have a window of opportunity between chemotherapy and surgery where we're able to give the immunotherapy on its own in those three weeks while the patients await surgery. Next slide. They then go on to potentially curative surgery, and then next slide, followed by adjuvant immunotherapy combined with chemotherapy, staying on the same paradigm that they were preoperatively.
Ultimately, once their chemotherapy is complete, next slide, we have the opportunity to do booster vaccinations. At the end, should their, when their cancer or if their cancer recurs, we have the opportunity to do biopsies. So we have a spectrum here of what's happening in these patients from beginning to end, meaning a biopsy prior to surgery and a biopsy at the time of surgery, which is a surgical resection, and then a recurrence, helping us understand resistance and response to the treatments we're implementing. Next slide. This is a two-arm study with 10 patients in each study, and the inclusion criteria, that's good, Chris, we can move to the next one, include patients with borderline resectable and resectable pancreas cancer containing these KRAS mutations with adequate performance status. Obviously, any patients with metastatic disease or unresectable disease are excluded. Next slide.
This is really first evaluating the safety of combining chemotherapy with vaccine, with and without tislelizumab. Additionally, it gives us the opportunity with this design to understand the biology so we can understand, are we creating these T-cell responses, and a number of exploratory questions, which I'll get to in the next slide, to better understand what PD-1 may actually also contribute to the vaccine's effectiveness. Next slide. I'll finish with this. We design these studies in a way that no matter what we find here, it should be of interest and help us understand what our next steps are in this disease with this modality.
And these are a number of questions that we are hoping to understand, is specifically. Knowing that this is a systemic disease, even in patients that have localized disease, can we use the vaccine to activate these cancer-fighting immune cells and act as the police throughout to not allow these metastases to develop? Can they also reach the tumor? This is why we can go to surgery and then understand, are these cells that are being activated by the vaccine getting to these tumors and helping us get more patients to surgery? What do these cells look like when they get there? How good of a job can they do to fight the cancer? And when these patients get these cancer-fighting cells, do they do better? That is the ultimate question, right?
Because then we say, "Okay, well, we are implementing something that seems rational and seems to be helping, or at least associated with a better response." And then finally, and very importantly, vaccines have constantly been included with other agents, but the rationale behind that is not clearly known. This study is going to really help us better understand what checkpoint inhibitors can do with vaccine therapy. With that, I will now transition back to Chris and Eileen, and look forward to the question and answer session.
Thank you so much, Dr. Soares, and it is my pleasure to invite Dr. O'Reilly to update now on the recent results from the presentation at ESMO and the simultaneous publication in Nature Medicine. After she covers this part, she will also speak on the new trial in the metastatic setting that is coming up that so many have asked about.
Great. Thank you so much, Dr. Haqq, and pleasure to be here this afternoon. If we could go to the next slide, please. As mentioned, going to start with just summarizing the data from ESMO and link back to a little bit of what Dr. Soares said both before and after this, and you will hopefully see the themes as they build out. To describe the study, the AMPLIFY-7P study was a randomized phase II trial that was conducted in resected pancreas cancer. So individuals who had localized disease, who had received neoadjuvant or adjuvant therapy, had surgery, and were free of disease. That was the key eligibility requirement. They had to have a known KRAS mutation that matched the seven peptides of camupepimut, and they had to have no overt metastatic or residual disease.
It could be agnostic to whether or not they had elevated CEA, CA19-9, or ctDNA, and as we will show shortly, that turned out to be very important. The trial design was observation being the standard of care, and a 2-to-1 randomization to camupepimut versus observation, stratified by nodal status with an option for crossover if there was a change in disease status. Primary endpoint was disease-free survival, and then secondarily looking at tumor biomarker response, overall survival, and exploratorily immunogenicity. Next slide, please. These are the summary demographics, and a few points to note here. From the perspective of age and disease stage and nodal status, noting that nodal status was the stratification factor, the stratification worked well, and they were well-balanced. There was a notable imbalance in terms of the number of individuals who had ctDNA positivity, 20% in the camupepimut versus 12.5% in the observation arm.
Largely similar with regard to details of what their neoadjuvant and adjuvant therapy was, and slight differences related to radiation and resection margin. Next slide, please. Primary endpoints here was disease-free survival as adjudicated by investigator. That was not met on the intent-to-treat analysis, but I will draw your attention to the curves on the left, that there was an early separation here that translated into a 14% higher disease-free survival for the camupepimut-treated individuals versus those observation. So 75.7% versus almost 62%. Those curves kind of collapsed over time, but also point out a couple of things, that the median survival for both arms were 23.8 and 21.2 months, and this was significantly better than the original study design suggested, just indicating this is a subgroup after completion of all therapy who can do well. Next slide, please.
Multivariate analysis model was constructed to account for all of the known prognostic factors and to look at the impact of treatment. The factors that we would expect were adversely prognostic, indeed were so in this model. Again, just to illustrate how adversely prognostic detectable ctDNA is after completion of all therapy, just it has a ratio of almost six and a significant p-value. We would expect, and we did see, that higher CA19-9 and higher stage would also predict for less favorable outcome. We will talk about the radiation data in a few minutes, but just also to draw your attention that in this model, camupepimut versus observation was a hazard ratio of 0.47 and a p-value of 0.0086, translating into 53% reduction in risk of recurrence of or death. Next slide, please.
Looking at ctDNA, and this is a pooled analysis of both study arms, just stratified by whether ctDNA positive or negative prior to enrollment at completion of their standard therapy. You can see again how significant this is. This is not a surprise, but it is not something that has routinely been utilized in terms of stratification for patients enrolled in adjuvant clinical trials in pancreas cancer. But those who had a negative ctDNA had a median survival of 24 months, versus 4.2 months for those who were ctDNA positive, so a very high risk of early radiologic relapse. Next slide, please. Now, taking that information and adding in the impact of treatment. It is a little complex to walk through the slide, but if we start with the top two sets of curves, these are individuals with no detectable ctDNA.
And if you look at the treatment effect of camupepimut versus observation, you will see the median was not reached versus 21.2 months, a hazard ratio of 0.51, and a P of 0.028, suggesting a strong treatment effect. If you look at the bottom two curves, these were individuals who had detectable ctDNA. There was also a treatment effect in favor of camrelizumab, the magnitude less, with the median survivals of 4.3 versus 1.9 months, and a hazard ratio in a similar range, 0.57, and a P-value of 0.048.
Next slide, please. So now, taking that information and lining it up with what we know has proved to be a positive strategy and data presented from later study at ESMO recently in the melanoma world, that is looking at the right. And so the pancreas data on the left, melanoma on the right, and stratified here by ctDNA positivity versus negativity.
And you can see how strikingly similar the trends are in the impact of the addition of immunotherapy in the setting of ctDNA negative versus positive. So, ctDNA negative, again, having a better outcome. So, point here is the consistency of the data. Thanks, Chris. Next slide. So moving now to what does radiation do in this setting? So if we could go to the right, firstly looking at the baseline lymphocyte count of individuals who had received either adjuvant or neoadjuvant radiation, you will see the absolute lymphocyte count at the time of enrollment was lower. Not surprising. We sort of know this, but this is clearly documented here in this prospective study. When one looks at the range of T-cell response, we can also see that this is lower. That is the bar chart on the extreme right.
Nonetheless, if you were an individual who had received radiation and mounted a good T-cell response, and from the previous phase I experience, the threshold of 9.17 segregated those who were going to do significantly better versus those who were not going to do as well. But when we segregate by that, the benefit of treatment was there. And that translates back to the Kaplan-Meier curves on the left.
So looking at the individuals who did not have prior radiation, again, this was a pre-specified analysis for amivantamab-treated individuals, the median disease-free survival was 23.8 months versus 10.4 months for those that did not. So we have shown what the impact of ctDNA positive versus negative, and now, what the impact of radiation might be on this signal. Next slide, please. So this is looking at the immunogenicity here, and the data support a significant T-cell response in the vast majority of patients.
So starting on the left, the pie chart showing that 99% of individuals mounted a T-cell response. And if you look at this splay over baseline, the median increase in T-cell response was 44-fold, and the mean 146-fold, with about 80% plus having above this 9.17 threshold. The second pie chart in the middle, slightly to the right here, looks at the distribution of what that immune response looked like from the CD4 and CD8 perspective. And you can see that both are amplified here in terms of CD4 and CD8 response in 85% of individuals. And then looking at the right, looking at the immune response against specific antigens, and you can see here that there is activity against all antigens.
And just make note in particular, D, V, and R being the three most common antigens in pancreas cancer, and some suggestion in the background from other datasets, not from this, that maybe D is a little bit less immunogenic. That was not observed here. Next slide, please. Looking at mutant KRAS-specific T-cell response by this threshold and outcomes. On the left is the phase I experience that showed that segregation for those that were above the threshold of 9.17, median DFS was not reached versus 3.02 months for those that were below. And similarly, in the phase II, making note that it's an almost fourfold higher number of patients and a broader patient population in that it's a wider set of centers where individuals were being enrolled, that that signal was sustained with the median disease-free survival not reached for those who received amivantamab versus those that did not.
Oh, I think that Dr. O'Reilly might have gone on the mute.
I apologize. I think the headset playing games here. Apologies about that. To recap, looking on the right in the phase II, significantly larger number of patients enrollment across broader number of sites, and again, stratifying by T-cell response, that for those that were above the threshold, hazard ratio of 0.22, much better disease-free survival versus those that were below the threshold. Next slide, please. Looking at the safety profile, this was overall very well tolerated, mild skin side reactions from the injection sites, maybe low-grade fever, mild headache for some patients, but overall, very little in the way of grade 3 related side effects, very low rates of serious treatment emergent side effects. And you'll note observation arm here having a similar number, and none leading to treatment withdrawal and no grade 5 again events. Next slide, please.
Summing up the learnings from the phase II, there was a clear signal identified here. There was an effect of camupepimut during the period of the prime boost administration of the treatment, which fell off with time, suggesting that the ability to sustain and maintain an immune response by a maintenance strategy is going to be important. As Dr. Soares indicated, there's potential for amplifying and further sustaining and expanding that immune response with the addition of an immune checkpoint inhibitor. There are implications with regard to individuals who've had radiation, so less likely to mount the same degree of autoimmunity versus those that did not. All of these suggesting, along with the important stratification of ctDNA positivity versus negativity, are paths forward to a successful phase III. That concludes the randomized phase II portion of the talk.
I'll now discuss the background and the rationale for the phase I. I should mention for those that would like to read in further detail, the data from the randomized phase II were simultaneously published in Nature Medicine, and the QR code there is there for your reference. Next slide, please. Next is the AMPLIFY-103 metastatic phase I trial. This is a trial that we're really excited and looking forward to being activated shortly to build on Dr. Soares' trial and to build on the learnings from the randomized phase II. Next slide, please. I suspect the audience is more than aware, and again, Kevin introduced this very nicely, the pancreas tumors have a very hostile and non-facilitative environment toward an immune response, and this has been known for a long period of time. There are some physical barriers, there's some geographic barriers.
While immune cells are present in the tumors, they're often ones that promote immune suppression, myeloid cells, and not necessarily the ones that support and sustain an immune response in terms of the right T cells. Pancreas cancer has a low tumor mutation burden, and we see low rates of mismatch repair deficiency, all contributing to the fact that, for the large part, immune checkpoint blockade and immunotherapy in general has not been an overtly successful strategy in the clinic. With, however, RAS inhibition, there's optimism that that can be reversed, and that by inhibiting RAS, one can make the tumor cells more immune responsive to facilitate and orchestrate an effective T-cell response to disrupt the adverse myeloid population of cells and the adverse CAFs that are present, and to promote antigen presentation and release, and again, affect an useful immune attack in the tumor. Next slide, please.
There's preclinical data supporting this. These data were published last year, and the left part of the slide looks at a preclinical model which has a low density of T cells. When one looks at RMC-7977, which is the preclinical counterpart of daraxonrasib, the pan-RAS tricomplex inhibitor that's been recently FDA approved in previously treated metastatic pancreas cancer, you can see that responses were induced, the green bars being the responses downward on the waterfall plot on the left. That's in the T-cell low environment. If you now look at the same experiment with the preclinical daraxonrasib version, 7977, in a T-cell rich environment, you can see that those responses are both larger in number and deeper, again, suggesting that there's potential for reversal of degree of immune suppression by inhibiting RAS effectively. Next slide, please.
So, this is additional preclinical support from this showing that having an effective immune response that incorporates both CD4 and CD8, preclinically can maximize that outcome. So, not just CD4 or not just CD8, but both are optimal, and that's illustrated by the green curve in terms of both survival and tumor volume being at its lowest. Next slide, please. So now moving to the design of the phase I, and again, shortly to activate. This is being conducted in previously treated metastatic pancreas cancer in the setting where daraxonrasib represents the new standard. There are two cohorts here looking at camupepimut plus daraxonrasib. So the idea of a small molecule RAS inhibitor plus a complementary immunotherapy targeting RAS, very different mechanisms of action, very different mechanisms of resistance.
The hope and expectation is that these could be very complementary and could add to a higher rate of objective response and a deeper rate of objective response. The second cohort looking at camupepimut, daraxonrasib, and adding an immune checkpoint blockade here, to see if that could be further extended and to try to isolate, to some degree, what the added value of an immune checkpoint blockade and anti-PD-1 might be. Key eligibility criteria are individuals with progressive metastatic pancreas cancer who've had standard of care chemotherapy, typically in the first line setting, and where there would be an intent to receive daraxonrasib as second line. They require measurable disease. As noted from the prior discussion, we're not going to include individuals who've had prior radiation, just again, for maximum signal seeking understanding.
Primary endpoint will be overall response rate and safety, and then secondarily to look at progression-free survival, to look at ctDNA clearance and degree of control of that, to look at biomarker CEA and CA 19-9, and immunogenicity. So, this builds once more on learnings from the randomized phase II, and will further refine what will be the best populations to evaluate this strategy in the clinic. So thank you very much. I will stop there and turn it back to Dr. Haqq.
Great. Thank you so much, Dr. O'Reilly and Dr. Soares as well. See if I can advance here. So now we'll begin our discussion and question and answer session. I'll turn it back over to the operator to let us know how to proceed.
Great. Thank you, Chris. At this time, we will be conducting our Q&A session with our three speakers. Please hold for a brief moment while we pull for questions. Our first question comes from Michael King at Rodman & Renshaw. Please go ahead, Michael.
Hey, guys. Thanks for taking our questions and for the call. This is Snehal for Michael. Just a quick one for Dr. Soares, on the neoadjuvant study. Are you enriching the population for dMMR or pMMR patients or TMB high, or any checkpoint scores? For Dr. O'Reilly, on the metastatic study, RASONQUE, as we all know, causes a lot of rashes. Is there any prophylactic ointment or anything anti-rash perhaps? Thank you.
Thank you for your question. No, we are not enriching for mismatch repair proficient. These are mismatch repair stable, microsatellite stable patients who have a documented KRAS mutation. That is the genetic testing that we are looking for for enrollment, but mismatch repair proficient or not.
Great. I will respond to the second part of your question. They asked what do we do for prophylaxis for cutaneous toxicity or skin toxicity for daraxonrasib? There are standards that are emerging, but typically we will utilize prophylaxis, which includes topical steroids. I will just make note, topical steroids on the skin. We utilize oral antibiotics, counsel patients to use a lot of moisturization, to avoid sun exposure, and to use sunblock. In parallel, work closely with our dermatology colleagues to address rash if it breaks through beyond that.
Got it. Thank you, guys.
Thanks for the questions. Our next question comes from Robert Burns at H.C. Wainwright. Please go ahead.
Hi, guys. Thanks for taking my questions. When I think about the potential combination with RASONQUE, we saw a different combination therapy, specifically the Tango PRMT5 combined with daraxonrasib. They used a lower dose of daraxonrasib. So we saw a lower rate of daraxonrasib-specific AEs. Do you think that there's also the potential to combine camupepimut with daraxonrasib, but at a lower dose to reduce those RASONQUE-related side effects?
Thanks for the question. I'll try to address that. From the safety profile of camupepimut, I think we have, at least in principle and in theory, low concerns about any adverse effects that would be limiting in the clinic. The question of dosing of daraxonrasib is a very hot one, as you're more than aware. And the dose that is planned to be used is the dose that is standard of 300 milligrams orally once a day. The issue with PRMT5 inhibitors is that there can be, depending on which PI3K inhibitor one is utilizing, there may be drug-to-drug interactions that actually makes the effective dose of daraxonrasib higher with a lower dose, if you see what I'm saying.
I do think that for individuals who we treat, we do end up either adjusting by short pauses, by augmenting what we're doing to address the rash, or in maybe up to a third of patients, possibly adjusting the dose. But from the purposes of this study, this is a fit population, and we're planning to proceed with further the labeled dose recommendation to start, and then treat as we would for clinical care and current best standards.
I'll just add that in the protocol, as it is a phase I design, the first few patients are part of a safety run-in, and we'll be reviewing, together with the monitoring committee, the initial safety experience with the combination. If needed, we could make an adjustment. But as Dr. O'Reilly mentioned, there's no scientific basis for a drug interaction, because the camizestrant is not in the same pathway in terms of the metabolism of the P450s in the liver that affect daraxonrasib and other small molecules.
Awesome. Thank you.
Thanks for the questions, Robert. Our next question comes from Kevin De Geeter at Ladenburg. Please go ahead, Kevin.
Hey. Yeah. Thanks for taking our questions. I actually just had maybe two, both around ctDNA. Can you just comment currently for your practice with pancreatic cancer patients? I think we can kind of see the prognostic benefit of ctDNA status, but how does ctDNA, high, low, actually historically have changed practice when we're mostly giving patients chemo regimens? Then I maybe have a follow-up.
Yeah. I think ctDNA, thank you, it's a great question and an important one because its use and its role is definitely being more routinely integrated into practice in the setting of pancreas cancer. Starting with chemotherapy, we know if we have an effective treatment, we'll see declines in ctDNA and variant allele fractions of major driver oncogenes like RAS, et cetera. That's been shown. The degree of response, the durability of response can predict for outcome. There's not a huge amount of randomized data in that space, but it's being looked at routinely now as a surrogate to see an early decline, the degree of decline, and again, how durable that is as a marker of how some of these newer agents are working in the clinic, and in terms of how we might utilize those signals to prioritize or deprioritize one approach versus another.
In this setting of the randomized phase II and future phase III, it is clear that we need to stratify by this, and about 20% of patients, and this is hinted at in other studies as well, will have detectable ctDNA and are clearly not going to do as well. I do think for immune-based approaches and in the setting of comparing like with like, having an effective ability to segregate out those two groups is going to be important.
So stratification factor in the phase III in terms of drug development, I think a lot of potential as one marker of outcome. In terms of day-to-day clinical care, we use this, I would say, quite frequently now as an early means of determining whether or not a RAS mutation is present and specifically which allele. We also use it for clinical conundrums to help understand, is something active or not?
Thank you.
Great.
Dr. Soares, did you want to add?
I agree with what Dr. O'Reilly had to say about it, of course. I do struggle with it currently because we do get it a lot more and more. As you mentioned, Kevin, it's hard to know what to do with that information as things currently stand. I think the future is that we will be able to act on ctDNA and modify treatments. But as it currently stands, it's really limited what Dr. O'Reilly described.
That's helpful. My follow-up actually is for Dr. Soares and the neoadjuvant study. Does study protocol allow for any sort of adaptive features if we do see some patients who go from ctDNA positive to negative, following surgery or at some point in the treatment regimen? Just how does that fit into the learning we may be able to derive from the study?
Great question. Thank you. This will all be understood post-treatment. We are not doing it throughout treatment here. We will do the analysis once the trial is nearly complete. What we hope to do with that information is potentially inform the next trial. This is a 20-patient trial aimed at accruing within a year or 18 months at most. We will be able to have that understanding and inform the next trial, but not as this trial currently stands. Patients will continue through their standard of care treatment and investigational treatments as dictated in the protocol.
Great. Thanks for taking our questions.
Thanks, Kevin. Our next question comes from Mayank Mamtani at B. Riley. Please go ahead. You might be on mute.
Can you hear me?
Yes, we can.
Great. Thank you. Sorry, Mike on for Mayank here. Thanks for taking our question and hosting the event. For Dr. O'Reilly, Dara already shrinks tumors on its own. What would you expect camupepimut to be adding to it? Would it be deeper responses, longer PFS, or a ctDNA clearance? For Chris, how will the study show what each drug adds here? That is, does camupepimut on top of Dara and nivolumab on top of the two? Thank you.
Yeah. Thank you. Just to make note that it's a signal-seeking study, right? It, by its design, is not going to be able to be definitive here. I think we would be postulating that we would see more responses with the combination and that they will last longer. Both the overall response rate as the proximate signal, but that durability, right, that's a critical issue in the clinic, is how we can sustain that, and that happens for more individuals. The other endpoints, looking at biomarkers, looking in terms of CEA, CA 19-9, and ctDNA will be supportive, I think, of this. It ultimately will be the totality of the observations that will help inform which of these two, or maybe even both, will have traction in the clinic for moving forward.
Yeah, I think that's exactly right. I'll just add to Dr. O'Reilly's comments that, broadly as a field, what we've learned with RAS inhibitors is that those that are allele-specific inhibitors tend to have a mechanism of relapse where the tumor will grow out a clone that has a different RAS mutation. That's something that camupepimut could address because it is comprised of multiple specific peptide amphiphiles that can direct immunotherapy to those other alleles that could grow out unless they were suppressed by the immune system. With a pan-inhibitor like daraxonrasib, the mechanism of resistance is thought to be an increase in the amount of the RAS protein, the original mutation that was present in the patient's tumor. That's also something that appears well-suited to complement with camupepimut because, of course, that would present more antigen for the immune system to attack.
We are hopeful that this signal that we are seeking will be evidenced by deeper and more durable responses. That will give us something that we would then discuss with regulators in order to determine the path for the potential registration. We model this in our clinical development planning as something that has the potential that it could support an accelerated approval strategy. We will look forward to being able to share the results as patients proceed through the study and then be able to discuss those results for their implications for how we would support potential registration in the future.
Great. Thank you for the questions, Mike. Our next question comes from Boris Peaker at Jones Trading. Please go ahead, Boris.
Great. Thanks for taking my questions. I am just curious, given the data that we have seen on ctDNA, why not just focus on ctDNA-negative patients? I understand it is a small fraction of the market, but does not that give you a significant advantage and probability of success?
I think you talk-
Yeah.
Oh, sorry, Chris. Please.
Oh, no. Please go ahead.
Oh, I will start and then by all means. I think you are talking about in the adjuvant setting in the future phase III. The magnitude of the benefit is going to be more pronounced in a setting of non-ctDNA positive. I do think you want to maximize the benefit and make it available to the biggest population. For something that, in this disease, that is imminently going to relapse, that may be harder for an immunotherapy approach on its own to have the best and the most durable outcome. I would say there is a value in both, and the plan is not to exclude ctDNA negative, but to stratify and to understand the signal best in both populations.
Got it. My second question, I guess, is for the triple combo, where you are doing the daraxonrasib and nivolumab and your treatment, what do you expect, or how do you even interpret the data when you have three active drugs together like this? What would you expect Rexin-G207 plus nivolumab itself to do?
Yeah. I think important question, and to reemphasize again, this is early phase I, signal seeking, safety. These are the critical components to understand. I think we're optimistic and hopeful that the doublet will be safe and will have a signal. The triplets, I think there's optimism and hope that also will be safe. It's going to take some time to understand because the potential impact of an immune checkpoint blockade, it will take a longer period of time to understand that signal as well. But I think if it's safe and the immunogenicity, the totality of the evidence based on the response, CEA, CA19-9, ctDNA, the parameters we were talking about a few minutes ago, looking at the package of the doublet and looking at the package of the triplets, will help again inform what is best to move forwards.
Yeah. I'll just add that I think we're very lucky to have such great translational signals with the development program, in that the correlation of the RAS-specific T cells induced from camupepimut have dovetailed so well with the disease-free survival or relapse-free survival in phase I and II. So, we do expect to be able to look at the two regimens and to be able to compare their biologic effects. If we see the pharmacologic impact being different for the two regimens, that will give us a good guide.
It could be the case that we'll find that the doublet is as effective at producing the kinds of immune effector cells that are thought to have the most impact on tumor cells, in which case we could be efficient in moving things forward. We'll be looking to do more definitive studies in the future that address the contribution of component more formally. But as Dr. O'Reilly mentioned, this is a signal-seeking study, one that will establish the safety of these approaches prospectively and build on the retrospective observations that are so interesting coming out of the studies.
Okay, great. Thanks.
Thank you for the questions, Boris. This concludes today's Q&A session. Chris, I will turn it back to you for closing remarks.
Great. Thank you so much. I wanted to thank everyone for attending today. As you can see from the content that we have shared today, our clinical development strategy has really been designed now to extend the promising observations that we see in the randomized phase II adjuvant setting into the earlier line of therapy in the neoadjuvant space. That is where the intact lymph nodes and antigens draining from the tumor could give us the best opportunity for the use of immune therapy, as well as the observations from phase II in retrospect, motivating the prospective combination in the metastatic patient group. We are very excited to be able to extend the development of camupepimut into those additional areas. And we thank everyone for attending today and learning more about camupepimut. Thanks so much.
Good work, guys.