Good morning, welcome to the Leap Therapeutics DKN-01 Clinical Data Conference Call. At this time, all participant lines are in listen-only mode, if you require operator assistance, please press star then zero. After the presentation, there will be a question and answer session. To ask a question during the session, you will need to press star then one. Please be advised that today's conference may be recorded. I will now turn the call over to Cynthia Sirard, Chief Medical Officer. Please go ahead. Good morning, and welcome. This morning, I would like to introduce a couple of my colleagues who have joined me to help present the data. I have Dr. Jay Baum, who is Vice President and Head of Translational Medicine at Leap Therapeutics, as well as Dr. Rebecca Arend, who is an associate professor at the University of Alabama at Birmingham O'Neal Comprehensive Cancer Center. She was also our principal investigator on the trial that we will discuss today. Next slide, please. DKK1 is a modulator of Wnt signaling that is overexpressed in many cancers, often leading to worse outcomes for patients. It's secreted mainly by tumor cells and known to promote cancer cell proliferation, metastasis, and angiogenesis. DKK1 signals to both tumor cells and immune cells, resulting in an immunosuppressive tumor microenvironment. In multiple oncology models, neutralizing DKK1 signaling has been shown to reverse this pro-tumorigenic environment, in part through an activation of an innate immune response. In addition to the effect on immune cells, there are several ways in which DKK1 can regulate cancer cell signaling. First, DKK1 can inhibit the canonical Wnt signaling pathway. This occurs by blocking Wnt binding to the LRP receptor, resulting in the subsequent degradation of β-catenin. Second, it can indirectly activate non-canonical Wnt signaling. Wnt that cannot bind to the LRP receptor instead may bind to alternative receptors, including Frizzled, impacting downstream pathways including JNK. Most recently, DKK1 has been shown to activate the PI3K AKT pathway through binding of the CKAP4 receptor. In indications such as endometrial cancer, there's a correlation between active Wnt signaling and poor patient outcomes. Shown here on the left is expression of CTNNB1, the gene that encodes β-catenin, separated by high and low levels. Endometrial cancer patients with higher expression of CTNNB1 demonstrated worse overall survival than those with low expression of CTNNB1. Similarly, the right panel looks at recurrence-free survival in endometrioid endometrial cancer patients. Those with CTNNB1-stabilizing mutations had a faster recurrence of their disease and a shorter survival as compared to those with wild-type CTNNB1. Enhanced Wnt signaling due to activating mutations has been associated with higher expression of DKK1. To take a closer look at this in endometrial cancer, we worked with Tempus. Tempus has one of the world's largest libraries of real-world evidence, including access to molecular sequencing and clinical outcome data. Here we observed a significant correlation between Wnt-activating mutations and increased expression of DKK1, as shown on the left, largely driven by CTNNB1 mutations, as demonstrated by the middle panel. This was further corroborated in an independent data set of uterine cancer patients in TCGA, again showing the significant upregulation of DKK1 in CTNNB1 mutant samples. DKN-01 is an IgG4 monoclonal antibody developed specifically to target DKK1. Blocking DKK1 has both direct anti-tumor effects and indirect effects, including activation of an innate immune response. Preclinical evidence also suggests that DKN-01 may have anti-angiogenic activity. Previous clinical data from the combination of DKN-01 and pembrolizumab in esophageal gastric cancer demonstrated that high tumoral DKK1 was associated with improved survival. This included a 50% response rate and 80% disease control rate in DKK1 high patients treated with the combination of DKN-01 and pembrolizumab. I'll now turn it over to Dr. Arend to talk more about the endometrial cancer. Good morning. I'm Dr. Rebecca Arend from the University of Alabama. A little bit of background on endometrial cancer. It's by far the most common cancer that we see in the clinic, and honestly, the majority of them have symptoms such as premenopausal bleeding and are usually diagnosed at a pretty early stage. A lot of times we can just cure them with surgery alone. There is a subset that recur, and those initially present with an aggressive histological subtype or metastatic disease have a very poor five-year overall survival. Additionally, based on some of the data that you just saw, a lot of the patients, even with a stage one or two disease that recur, we now know have upregulation of the β-catenin pathway and increased mutations in CTNNB1. Next slide. We used to consider endometrial cancer really based on the histological subtype, and more and more, actually, we just recently published a couple white papers in GYN Onc, really discussing the fact that we are looking at endometrial cancer more according to actual molecular subtypes. You can see here the four molecular subtypes, POLE, MSI hypermutated, copy number low or endometrioid, and copy number high, serous-like. The ones on the left are considered hot tumors, and those notoriously are MSI high tumors or mismatch repair deficient tumors and have an excellent response to pembrolizumab alone. Those on the left are considered more cold tumors, and as was reported at this year's SGO, now lenvatinib and pembrolizumab as a combination agent are probably going to be second-line therapy for those patients because the response rates to immunotherapy alone are extremely low. Next slide. Here shows you a little bit of a treatment paradigm for advanced endometrial cancer as clinicians, how we think or how we deal with it. At diagnosis, whether it's advanced, then we go straight to first-line, or if it's recurrent, they're observed in the upfront setting, and first-line is considered at the time of recurrence. Most of the time we go to chemotherapy. The preferred regimen is carboplatin. Second-line therapy, I think we are now discovering is really more of a biomarker-directed therapy than it used to be. It used to be that it was just sort of a catchall. We would give everybody the same thing, but now that we know sort of the phenotypes, that bases our decision on what our second-line systemic therapy is going to be. Even though it's extremely rare, we do have targeted therapy for patients with NTRK gene fusions. Again, extremely small numbers. More commonly, it's going to be our MSI-high, MSI-low or stable patients, like we saw on the previous slide, or mismatch repair proficient. That's going to be about 60%. Those patients are going to receive lenvatinib, pembrolizumab as a combination therapy. In about 20% or 40%, depending on what you read, either MSI-high, most of those are going to be tumor mutation burden-high. They're not always mutually exclusive, but a lot of times there's a huge overlap. Those patients will receive immunotherapy as a single agent. It's going to either be pembrolizumab or now nivolumab with response for overall response rates as high as 57%. Next slide. Single-agent activity endometrial cancer actually has not been very successful, I would say the least. The highest overall response rates are in cytotoxic chemotherapies, but those again are cytotoxic and extremely toxic to patients. Interesting, the paclitaxel, which here is 27%, and the data that was presented at SGO is actually much lower than that. I think probably because most patients who receive paclitaxel on the second-line setting now have received it front line, which didn't used to be the case in these historic trials. As you can see in the single-agent targeted therapy, response rates are extremely low, more in the teens. Next slide. Here, I want to point out the pembrolizumab, lenvatinib data, which again was presented at this year's SGO. I think one of the most important aspects of this data, and as a clinician, I can tell you, it is an extremely poorly tolerated regimen. I will start at a much lower dose, in the trials they started at 24, which they found was too toxic, then 20 milligrams was tested. We don't have any prospective trials using any doses lower than 20. Approximately 20% were discontinued for pembrolizumab toxicity, 14% for both drugs. The other options, as control arms, such as pembrolizumab in the mismatch repair deficient or platinum again, or other things have really low response rates. You can see here that the overall response rate in the proficient is 30%, but again, as high as 60% are going to have to dose reduce the lenvatinib due to the toxicity. Next slide. It's clear that a significant group of patients fail to respond to the therapies that we currently have available, and identifying the source of that resistance, I think can really help us direct them to more efficacious treatment options. DKK1 may represent one resistant mechanism to standard therapies. Again, using real-world evidence from Tempus, we looked at time to treatment discontinuation for patients with high versus low DKK1 expression. On the left, we see a statistically significant difference where patients with high DKK1 come off of VEGF treatments such as bevacizumab faster than patients with low DKK1. Similarly, we see a trend towards higher DKK1 patients on the right having poor response to anti-PD-1, PD-L1 therapies. Now I'm going to turn it back over to Cyndi. Thanks, Rebecca. What we did, we conducted a phase II basket study in which we were evaluating DKK1 as a monotherapy as well as DKK1 in combination with paclitaxel. This study enrolled patients with endometrial cancer, ovarian cancer, as well as carcinosarcoma. As the basket study, it was required that 50% in each group had a Wnt signaling alteration. I'll describe in a subsequent slide what constituted a Wnt signaling alteration. The primary objective of the study was overall response rates, with some secondary objectives exploring genetic mutations in the Wnt signaling pathway, as well as expression of tumoral DKK1, and better to identify patients for subsequent trials. The study design is below. They were 28-day cycles. The patients received DKK1 on days one and day 15, and then weekly if it was paclitaxel was used in combination, it was administered on days one, eight, 15, and 22. Next slide. As mentioned, the patients who were enrolled, 50% were required to have Wnt signaling alterations. Those alterations are identified in the box to the left. This is a group of genes, about 20 in total, in which there's association to the Wnt signaling pathway. We were most interested in those patients with Wnt-activating mutations, which have been described both by Jay and Rebecca to date, in which we expected a higher level of DKK1 expression in patients who had true Wnt activating mutations. The genes identified in green, including β-catenin, APC, Axin one and two, RNF43, ZNRF3, and the R-spondins, were the genes that we felt represented true activating mutations. Next slide. Importantly, in this study, we did see an association of higher levels of tumoral DKK1 expression in patients whose tumors had Wnt activating mutations. Overall, 21% of patients across the three disease indications had Wnt activating mutations. The most common mutations were identified in patients with endometrial cancer, and the most common mutation within those patients with endometrial cancer was in fact the β-catenin mutation at 16%. Overall, the patients who had the Wnt activating mutations had roughly 14.4-fold higher expression of tumoral DKK1 than those patients who did not. Next slide. Here you can see also the patients who had endometrial cancer had higher levels of tumoral DKK1 expression than those patients with ovarian cancer, for example. Here you can see we evaluated 42 patients with endometrial cancer versus 29 patients with ovarian cancer, and the median age score or histology score was higher at 14, compared to ovarian cancer at five. The images on the right represent our chromogenic in situ hybridization assay, in which you can see the staining of the red represents the DKK1 in the tumor itself. Slide. Here I will turn it back over to Dr. Arend to describe the toxicity of the monoclonal antibody. Thanks, Cynthia. Here are the most common treatment adverse events in both arms. As you can see, adverse events were similar for monotherapy in combination, with GI disorders being the most frequent, and combination therapy had a higher frequency of anemia. Severe adverse events in the monotherapy arm were five point eight percent, and in the combination arm, six point eight percent. DKK1 was very well tolerated, both as monotherapy and in combination with paclitaxel. I can tell you as a clinician, as witnessing how patients looked when they received DKK1 was pretty remarkable. Me and my partner would joke about the fact that we thought maybe the patients were just drinking water that were on monotherapy because they had such good safety profile, you didn't even know they were on monotherapy. I have one patient who's been on it for over two years, and she's doing fantastic. That's very different from something like lenvatinib, where I see extreme severe toxicities. I would say this is an extremely strong selling point for patients, especially those who've received multiple lines of treatment, specifically chemotherapy, where they've lost their hair, they get sick all the time. Additionally, this makes DKK1 an extremely good partner, not only for chemotherapy, but other possible combinations just because it's so well-tolerated. Even seeing patients in the combination arm, it almost seems like the DKK1 actually helped with some of the side effects, because the side effect profile was actually less than what I usually see with single-agent Taxol. This makes it much easier discussion with patients during informed consent when discussing their treatment plans, especially for those who are receiving monotherapy, which was great in the trial that the physicians got to decide. I really think it was a beautifully designed trial that made it very easy for us to accrue, too. Now I'm going to discuss a little bit of the results from the trial, specifically in the endometrial cancer patients. Next slide. Slide 22. I hope we're all on it. Here you look at the demographics and the baseline tumor characteristics of the endometrial cancer patients on the trial. I think one of the important things to note is how heavily pretreated these patients were. Over 50% had more than two prior systemic lines of therapy. This truly was a very high pretreated population, and the majority of them are microsatellite stable, as you can see on the right. Next slide. I'm going to present the DKK1 monotherapy next. Next slide. Here is the DKK1 monotherapy, and this is endometrial cancer overall response. Endometrial cancers with alterations in the Wnt signaling pathway had greater clinical activity than those without the Wnt pathway alterations, with an overall response rate of 10% versus zero percent, and a disease control rate of 48% versus 13%, as demonstrated in the waterfall plot below. Next slide. Here's the spider plot showing a DKK1 monotherapy. Endometrial cancers with alterations in the Wnt signaling pathway not only had a better response, but they had a more durable clinical response than those without the Wnt pathway alterations. As you can see, the green lines represent those with Wnt alterations and the blue without Wnt alterations. Next slide. Now I want to go through a couple case vignettes just to highlight some of the reasons, or some of the responses that we are seeing clinically. To me, as a treating physician, and as to this patient, this has been like an absolute miracle drug. This woman with recurrent endometrial cancer who came onto the study suffering from severe neuropathy and thrombocytopenia, now has no evidence of residual disease after 21 months of being on monotherapy, and she really continues to do great. Treatment with the Leap drug reversed the expected aggressive behavior. Defects in DNA mismatch repair or MSI-high. Some people would say those patients are more aggressive to endometrial cancer, which can certainly be debated. Nonetheless, this patient continues on DKN-01 monotherapy with no evidence of residual disease and is doing great. Next slide. Here's an example of another lady with recurrent endometrial cancer who experienced such horrible toxicity from Taxol she actually had to discontinue it. After two cycles of monotherapy, she had a 41% reduction in her tumor, which was confirmed after four cycles, and she remained on therapy for over six months, when otherwise she definitely would have been dead in my mind. She's still alive, and she remains in follow-up. It's important to note that this patient did not have high DKK1 score, with 38 being the threshold. Hers was actually only 19, which shows that even some without high DKK1 scores do show benefit. I think it's important to note that she did have a PI3 kinase mutation, which we're still trying to sort out what the contribution is that with this monotherapy drug. Next slide. Now I want to highlight some of the tumoral DKK1 as a biomarker in this trial. Next slide. Endometrial cancer with DKK1 high tumoral expression have a better overall response rate, 14% versus zero percent, and clinical benefit of 57% versus seven percent after DKN-01 treatment compared with low DKK1 tumors. There, seven patients with unknown DKK1 expression had an additional complete responder and an overall disease control rate of 86%. We know that three of these patients with durable, stable disease had WNT activating mutations. You can see in the waterfall plot below and also on the slide, the DKK1 high, as we put the cutoff here, is greater than or equal to 18%, had a response rate of 14%, which was equivalent in the patients with unknown, which were also seven patients. Showing that we need further data to really tease out exactly the DKK1 as a biomarker. We're seeing pretty remarkable response rates to monotherapy in a heavily pretreated population. Next slide. High tumoral DKK1 expression have more durable clinical benefit after DKN-01 monotherapy compared to DKK1 low tumors, as you can see in the spider plot below. You can see the green is the high, low is the blue, and then the unknown is the gray. Highlighting the importance of really being able to tease out this data that was missing in the trial going forward. Next slide. Here again, we can see tumors with high DKK1 have a longer progression-free survival of three months compared to only one point eight months in the low, with a hazard ratio of zero point three percent and a 95% confidence interval of zero point one four to one point one after DKN-01 monotherapy compared to DKK1 low tumors, with the unknown in gray, green being the high, and blue being the low. Next slide. We did a sensitivity analysis trying to reflect three patients with known WNT activating mutations, and we considered them in this sensitivity analysis as DKK high, which then strengthens the PFS compared to DKK1 to five point eight months versus one point eight months with a hazard ratio of point five six. Next slide. Endometrial cancer with DKK1 high tumoral expression have more durable clinical benefit after DKN-01 plus paclitaxel compared to DKK1 low tumors, as you can see in this spider plot below, showing the high in green again and the low in blue and the unknown in gray. Next slide. Looking at the combination, we see that an improved progression-free survival in high tumoral DKK1 expressing tumors. Five point four months versus 1.8 months after DKN-01 plus paclitaxel compared to the DKK1 low tumors, as you can see in the Kaplan-Meier curve below. Next slide. DKK1 expression is higher in endometrial carcinoma, as was discussed before. You can see in this RNAscope that the DKK1 expression in endometrioid tumors versus non-endometrioid tumors have a median H-score of 18 versus 11. You can see on the right-hand side, using the Tempus data, the increase in the DKK1 high expression in endometrioid tumors. Next slide. Looking at pooled endometrial cancer data, the overall response rate and the endometrioid histology by tumoral DKK1 expression. Tumors with high DKK1 have a better overall response rate of seven percent versus zero percent and a disease control rate of 57% versus 15% after DKN-01 treatment compared with DKK1 low tumors. You can see on the right-hand side the RNAscope or the H-score according to response and the DKK1 expression showing DKK1 high with greater responses. Again below you can see all endometrial cancer patients, DKK1 high greater than or equal to 18%, an overall response rate of seven, but a disease control rate of 57%. Again, highlighting this unknown population with a 14% overall response rate and 86% disease control rate. Next slide. Again, the pooled endometrial cancer showing durable clinical benefit in the endometrioid histology by DKK1 tumoral expression. Endometrial cancer with DKK1 high tumoral expression has a more durable clinical benefit after DKN-01 treatment compared with low DKK1 tumors, shown in the spider graph below. Next slide. Here you can see the Kaplan-Meier curves. Tumors with high DKK1, better progression-free survival of four point one after treatment compared with low DKK1 tumors. Again, this is the pooled endometrial cancer analysis. Next slide. In conclusion, DKN-01, which is an anti-DKK1 antibody, is extremely safe. It's extremely well-tolerated, both as monotherapy and in combination with paclitaxel, such that it might even decrease the side effects of the paclitaxel when given with chemotherapy. DKN-01 monotherapy demonstrated clinical activity in an unselected, extremely heavily pretreated endometrial cancer patient, including a complete response such that we would not see even with chemotherapy, and that was with monotherapy. High tumoral DKK1 expression in endometrial cancer population demonstrated greater response, and we saw a durable clinical benefit and progression-free survival. DKN-01 monotherapy in the DKK1 high versus DKK1 low, showing an overall response rate of 14% versus zero percent, showing that it likely is going to be an excellent biomarker once we gather more information. With a disease control rate as high as 57% and certainly a difference in the progression-free survival depending on whether the tumor was DKK1 high or DKK1 low. The greatest benefit in the highest tumoral DKK1 expression was seen in the endometrioid histology. If you look at the pooled endometrioid data with DKK1 high tumors demonstrating, again, a longer progression-free survival compared to the DKK1 low tumors. Here, the confidence interval does not cross-run with a hazard ratio of point three four. Future gynecologic development will focus on DKK1 high endometrial cancer patients with monotherapy, but I'm also extremely interested to see where this drug leads in combination with anti-PD-1 therapy, especially in this DKK1 high population, especially considering how toxic lenvatinib is and the fact that we know Wnt β-catenin pathways are upregulated in this cold population where lenvatinib/pembro is probably going to be the next standard of care. Now I'd like to open up to questions and answers. Our first question comes from James Delorme with Piper Sandler. Good morning, guys. Congratulations on the data presentation. I was just wondering, could you provide any more information regarding the seven unknown DKK1-expressing patients? What was the cause of the data missing from the trial? Sure. I'll take that one. The patients, as you know, as the study design required, that the tumor was first sent for genetic analysis to ensure that we had the 50% in each of the cohorts be enrolled with Wnt signaling alterations. While we obtained tumor on all patients, at times, and in particular, these seven patients, we didn't have enough tumor to assess beyond the genetic analysis for the entry onto the trial. We tried very hard to get tumor tissue on these patients. As you can imagine, as we knew that three of the seven in the monotherapy cohort did have Wnt activating mutations. That's why we ran the sensitivity analysis, because the expectation would be from pure biology of the tumors that those patients would have likely had DKK1 high disease on the basis of the 14-fold higher expression in patients with Wnt activated. Yeah, that's exactly right. Part of our reason for putting the presentation together the way we did was to show you what we were doing, is trying to understand what was the likely DKK1 expression of those unknown patients. We knew that they had β-catenin mutations, and we showed you both from this study and from real-world evidence that patients with β-catenin mutations, 14-fold higher increase in DKK1, very significantly likely to be DKK1 high patients. The patient with the complete response we showed you had a Wnt signaling alteration, had a PIK3CA mutation with endometrioid histology. We showed you in the endometrioid histology, they were more likely to be higher DKK1. As we looked and considered the biomarkers over the analysis of the study, we did consider the mutations that underlied it, but ultimately came back to DKK1 as being based on all of the evidence we had and the information about these patients to be the most likely explanation that ties all of the data together, given it's the target for the antibody, and that there was such a striking, in the patient for whom it was known, such a striking difference between those with known high and known low, both as monotherapy and in combination with paclitaxel, and it mirrored up with what we saw in the gynecologic or sorry, in the gastric cancer study with pembrolizumab, that we'd seen in monotherapy, chemo combination, PD-1 combination, that fundamentally as we think about, We knew the drug as a single agent had these results, and so being able to Present in this presentation and in the work at SGO, all of the evidence that lead us to the DKK1 biomarker and an understanding of what the results would be if that was a known outcome, I think was an important objective for us in the last few months of data analysis. Thank you. Our next question comes from Wangzhi Li with Ladenburg. Hi. Thanks for taking my question. Maybe a clarifying question on the DKK1 expression difference in EEC versus EOC. In one of your slides, I think slide 19, you showed much higher expression in EEC versus EOC. Another slide, I think slide 35, it also showed a expression difference. I just want to clarify, what's the difference between these two data sets? Sure. I'll take that one too. The earlier slide 19, is showing the difference in DKK1 expression between the two different cancer types, the endometrial cancer versus the ovarian cancer, and it's showing a higher level of expression in patients who have endometrial cancer. The later slide you referenced, slide 35, is actually breaking down specific histology types of endometrial cancer. Endometrioid endometrial cancer is the most common endometrial cancer. In fact, it represents roughly 80% of patients who are diagnosed with endometrial cancer. Within that histology, we also see higher DKK1 expression compared to other histologies that are non-endometrioid. Non-endometrioid histologies include things such as serous or clear cell or mixed epithelial tumors. Those patients with endometrioid endometrial cancer have a higher DKK1 expression than the non-endometrioid, with a median of 18 versus 11. Got it. It's just breaking down the specific types. Yeah. Got it. If you look at the responses or the patient with durable stable disease, are they mostly enriched in the endometrioid endometrial cancer or other type 2? Yes. Many of them are in the endometrioid histology. That's correct. Yep. Got it. Great. If you look at the real-world data, Tempus, any sense about what percent of patients overall are this type of histology with higher DKK1 expression? Tempus data. Right. For the Tempus data, we did not set a cutoff here for what we consider to be high versus low. We just wanted to look at the relative. In general, for this biomarker, we're targeting about the top tertile, or one-third, to be considered as high DKK1. Yeah, just that Tempus data, Wenxi, is actually RNA-Seq data too, so the log scale on the left is different than our RNAscope. Got it. Okay. That's helpful. Maybe one more question is, in one of the slides, you showed the response rates and DCRs for different type of therapy in this indication, including Avastin. You also showed one slide at the DKK1 high to the patient, showed poor responses to both PD-1 and VEGF inhibitors. I just wondered, do you think it makes sense to combine the three together, PD-1, DKK1, and Avastin, maybe more synergy? I'll take that. I would love to see that because I think that there is pretty much zero overlap in the three agents, and they all work differently. I would love to get some preclinical data suggesting that, but we certainly see synergy with VEGF inhibition and IO agents. I can only imagine. We also know that there's synergy between Wnt and IO, and being able to explore this a little bit more with anti-angiogenics, I think would be an extremely interesting avenue forward. Great. Maybe last question for Dr. Arend. For this indication, if you look at potential registration trial, what do you think of the OR obviously the one potential readout and PFS? How do you think about DCR? The response rates, if you look at the PD-1, they all in the kind of low double digits, but the DCR also looks like quite durable benefits too. What's your view on that? Yeah. I would say, being on the other side, discussing with the FDA registration, I think the disease control rate, obviously, I think you need kind of both. More and more we're seeing the need to have those high percentages in the disease control rate, which I think is promising when we look at the data here compared to the overall response rate. I think that if we get more of a biomarker-selected population, potentially with immunotherapy and in patients that haven't received so many prior lines, I'm very optimistic that we'll see response rates and disease control rates that will lead to registration. Great. Thanks for taking my questions. Our next question comes from David Novak with Raymond James. Hi, folks. Thanks for taking my question and great presentation. Thanks very much for the analysis here. Just one quick question from me. When I look at the various cluster plots that you present here, specifically the DKK1 expression associated with WNT-dependent signaling from Tempus, or the distribution of H-scores by WNT activating mutation status, clustering definitely does appear to separate. However, the ranges do overlap, and we're comparing an unequal sample size here in both charts. Just wondering how we get comfort that the separation we're seeing here isn't just a sample size effect. Jay, you want to take that? David, great question. Look, in addition to looking at the DKK1 expression as we showed you, we did notice that there was a much lower number of patients with WNT activating mutations in the ovarian cancer data set. I think there was only one. PIK3CA mutation is also very low, I think only one in the ovarian cancer data set. I think biologically, as we looked at the difference between endometrial and ovarian cancer patients, we definitely saw the more favorable biology in the endometrial cancer patients and a greater number of patients who were high, even as you looked at the numbers outside of the kind of median or tertile. I think for us, it was reflected also in the efficacy seen. I think Cyndi, anything you'd like to add as you Yeah. I think it's a very reasonable Go ahead. Yeah, I think it's a very reasonable observation to say that numbers are skewed. Here we're looking at relatively small numbers and only a third of patients to try and make determinations. I do think that there is a signal here. I think it's pretty clear that across all the populations we looked at, when you look at tumoral DKK1 expression, you do see improvement in disease control as well as progression-free survival. I should mention that obviously we've discussed that this also parallels the path that we are advancing in esophageal gastric cancer, in which the biomarker, again, there suggests that the patients with high tumoral DKK1 are the patients who derive the greatest clinical benefit, and obviously the biologic rationale is strongest when going after the target of the antibody. I think that to advance, I think to convince ourselves, you would need to conduct further studies, clearly, to better understand if the biomarker high population does better. I think moving towards a phase II, III, something that permits an earlier review of data when looking at the biomarker is the path forward. Got it. That's great. I'll also just chime in on sort of that whole, just in terms of biomarker development. I think the point about being very low numbers of something like clear cell in the Tempus data is important, and that's one of the things that we run into in developmental therapeutics driven by biomarkers is in the rare tumor populations. It's very hard to move that forward. In some ways, I think we're sort of lucky here because endometrioid endometrial cancer is one of the most common GYN cancers, and those typically have the higher DKK1 expression. If we move forward with this, and then you do have a patient, say clear cell or serous or carcinosarcoma, that has a DKK1 high tumor, if there's a path forward in the endometrioid, then that would be a great opportunity to be able to use that combination in DKK1 high tumor, even in tumors that aren't normally DKK1 high. Look at sort of the pembro FDA approval. Once we start really driving these drugs based on biomarkers, it's going to allow us to utilize these combinations in patients with rarer subtypes. Perfect. That's really helpful. Thank you very much, guys. I'll hop back in the queue. Our next question comes from Colleen Kusy with Baird. Hi, good morning. Thanks for taking our question. I think it was the second case study that you highlighted in the monotherapy, the patient did not have high DKK1 expression. I guess if you can maybe just talk about how you're now, if that makes you reconsider the threshold at all, and if there's anything else unique about that patient. I have a follow-up. Yeah. I'm going to jump in. Go ahead. Yeah, no, this patient actually was considered high for this disease indication. Our thresholds across disease indications are likely to differ here. If you noticed throughout the presentation, the H-score that we were considering DKK1 high in endometrial cancer was actually 18. This partial responding patient had high disease with an H-score of 19. Okay. Thank you for clarifying that. For the tolerability of DKN-01, is there a scientific rationale for why DKN-01 could make the tolerability of chemo better? Was that surprising at all? Was that something that you had kind of expected going into this combination? The only thing I can add to that was a preclinical study that we did several years ago in non-small cell lung cancer, an A549 model in which we worked with the Belfer Institute here in Boston, in which we studied across a number of different chemotherapeutic combinations with the non-small cell lung cancer. It was noted as an observation during that study that the mice actually were better groomed and felt better when the DKN-01-01 was used in combination with a cytotoxic chemotherapy. That's anecdotally really all I can suggest. We've conducted, as you know, a number of studies in combination with cytotoxic chemotherapeutics and never added to the toxicity of any of those agents alone. I do think that we've been able to successfully combine across a number of different agents, including cytotoxic chemotherapeutics. Anecdotally, as Rebecca mentioned, even on study, I think the patients have tolerated the regimens quite well. Great. Thank you. For future development, I know obviously you highlighted the potential of a PD-1 combination is really exciting. I guess, are there any initial thoughts you have on sort of the patient population and how you might kind of tease that out as you continue to develop the biomarker? Do you want me to take that, Cyndi? Or you want to? I can start and by all means, please jump in. We're thinking, a less heavily pretreated population, so two or fewer prior therapies, looking at patients with endometrial cancer, considering histologies within that realm, and then trying probably to better select for patients on the basis of DKK1 H-scores. Yeah. I would say. Go ahead, Rebecca. Yeah, I was just going to say, as a clinician, I would love to see this drug coming sooner and sooner, in terms of lines of therapy, just because of how remarkable the response is in extremely heavily pretreated populations. In an ideal world and in my heart of hearts, I would love to see in a DKK1 high population or patients with β-catenin mutations for this to substitute the lenvatinib and be able to use this in combination with IO as second line. I even actually mentioned something to Cyndi this morning that in a DKK1 high or a β-catenin mutation patient, we've seen in serous patients with HER2 mutations, now we use trastuzumab in upfront or first line in combination with chemo and then continue it with maintenance therapy. I don't think that that would be out of the realm of possibilities for this drug in this population. I think the sooner the better once we develop the biomarker would be the best for the patients. Great. Thank you for taking our questions. As a reminder, ladies and gentlemen, that is star then one to ask a question. Our next question comes from Arthur He with H.C. Wainwright. Good morning, everyone. This is Arthur from HC. Thanks for taking my question. I have two questions. One is regarding the overall survival data in either the monotherapy or combo therapy. Do you guys can give us more color on that? Cyndi, do you want to take that? Or Doug? We haven't presented that data in this SGO presentation. I think it mirrors what you see in terms of DKK1 expression driving differences. We focused on presenting overall response rate and progression-free survival because they were the least affected by subsequent lines of therapy or by how pretreated the patients were. We tried to, for the sake of building the understanding of how important DKK1 is to select patients who have the best outcomes on DKN-01-based therapy, we really tried to hone in on the point in time that was affected most directly by DKN-01. We can certainly share the overall survival data, and it'll be part of a manuscript downstream. In this heavily pretreated patient population, the data's all consistent with what you'd expect. Thanks, Doug. My second question is regarding the potential, the biomarker for the future study. One is the DKK1, the H-score is kind of finalized at the 18 or there is a future further tweak on that definition? The second, would you consider other biomarker in combination with the DKK1 H-score to better select the patient population? Thank you. In terms of the H-score, I agree with you. It is a fine line. I think we're also considering other ways of looking at some of the data, including percent positive tumor cells, which is more in line with other histology-based diagnostics. I think at this point, the H-score is what we are going forward with. In terms of other biomarkers, I think those would be retrospectively looked at in a future study, but at this point, we're focused on moving forward with DKK1 high. Yeah. I think as we looked at the data so far, 18 was terrific in terms of being an upper tertile across the entire population, so it still gives you one-third. Interestingly, it was the median in the endometrioid histology, so you'd expect greater than half of the patients in endometrioid histology to be DKK1 high. As we do more patients and further studies, we'll be able to make sure those numbers continue to play out in terms of percentage-wise the same way. I think we'll always look at what are the underlying mutations for the DKK1 high patients, whether the DKK1 high patients with β-catenin mutations continue to be a subgroup, whether the DKK1 high patients with PIK3CA mutations are a particularly interesting subgroup. We believe the common focus is around DKK1, the target of our antibody, and being the core biomarker that we use to select patients. As Dr. Arend and Cyndi both said, I think it's a very exciting opportunity to be able to follow a similar path with esophagogastric cancer by looking at a PD-1 combination for these patients. Thank you. Thank you for taking my question. I'm showing no further questions in queue at this time. I'd like to turn the call back to Doug Onsi for closing remarks. Thank you all very much for your participation this morning. I'd very much like to thank Dr. Arend and the P204 study investigators. It was a terrific group that enrolled, I think, a spectacularly well-designed and executed study to tease out the impact of many different biomarkers, whether both mutational and DKK1 expression in a study that I think added a lot of value to our understanding of DKN-01, of the path forward for targeting these patients, and brought some terrific results to many of the women who were enrolled in this study. Thanks also to all the people who participated in the study and their sites and to the entire team at Leap. We appreciate your time today and are available for any questions that people might have who want to reach out to us after the call. Thank you all very much. Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.