Good morning, and welcome to the Leap Therapeutics VK001 Clinical Data Conference Call. At this time, all Please be advised that today's conference maybe recorded. I will now turn the call over to Cynthia Sarard, 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 Doctor. Jay Baum, who is Vice President and Head of Translational Medicine at Leap Therapeutics, as well as Doctor. Rebecca Arend, who is an associate professor at the University of Alabama at Birmingham O'Neill Comprehensive Cancer Center. She was also our principal investigator on the trial that we will discuss today.
DKK1 signals to both tumor cells and immune cells resulting in an immunosuppressive tumor microenvironment. In multiple oncology models, neutralizing VKK1 signaling has been shown to reverse this protumorigenic 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, CKK1 can inhibit the canonical Wnt signaling pathway. This occurs by blocking Wnt binding to the LRP receptor, resulting in the subsequent degradation of beta catenin.
2nd, it can indirectly activate non canonical Wnt signaling. WntZek cannot bind to the LRP receptor instead may bind to alternative receptors including Frizzled impacting downstream pathways including JUNE kinase. And most recently, DKK1 has been shown to activate the PI3 kinase AKT pathway through binding of the CCAP4 receptor. In indications such as endometrial cancer, there's a correlation between active win signaling and poor patient outcomes. Shown here on the left is expression of CTNMB1, the gene that encodes beta catenin separated by high and low levels.
Endometrial cancer patients with higher expression of CTN and B1 demonstrated worse overall survival than those with low expression of CTN and B1. Similarly, the right panel looks at recurrence free survival in endometrioid endometrial cancer patients. Those with CTN and B1 stabilizing had a faster recurrence of their disease and a shorter survival as compared to those with wild type CTN and B1. 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 TEMPEST.
TEMPEST 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 CTN MV1 mutations as demonstrated by the middle panel. And this was further corroborated in independent data set of uterine cancer patients in TCJA, again showing the significant upregulation of DKK1 in CCNMP1 mutant samples. DKN01 is an IgG4 monoclonal antibody developed specifically to target DKK1. Blocking DKK1 has both direct antitumor effects and indirect effects, including activation of an innate immune response.
Preclinical evidence also suggests that DK101 may have anti angiogenic activity. Previous clinical data from the combination of DK101 and pembrolizumab in esophagogic cancer demonstrated that high tumor of 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 DK101 and pembrolizumab. I'll now turn it over to Doctor. Arendt to talk more about the endometrial cancer.
Good morning. I'm Doctor. Rebecca Arendt from the University of Alabama. So a little bit of background on endometrial cancer. So 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. And a lot of times we can just cure them with surgery alone. But there is a subset that recur and those initially present with an aggressive histological subtype or metastatic disease have a very poor 5 year overall survival. Additionally, based on some of the data that you just saw, a lot of the patients even with a stage 1 or 2 disease that recur, we now know have up regulation of the beta catenin pathway and increased mutations in CTNNV1. Next slide.
So we used to consider endometrial cancer really based on the histological subtype, and more and more actually we just recently published a couple of white papers in guide onc really discussing the fact that we are looking at endometrial cancer more according to actual molecular subtypes. And you can see here the 4 molecular subtypes, poly, MSI hyper mutated, copy number low or endometrioid and copy number high, serous like. So 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, 2nd line therapy for those patients because the response rates to immunotherapy alone are extremely low. Next slide.
So 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. So 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. And most of the time, we go to chemotherapy, the preferred regimen is carboTaxol. And then 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 get 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. So even though it's extremely rare, we do have targeted therapy for patients with intra gene fusions, again, extremely small numbers. More commonly is going to be our MSI high, I'm sorry, MSI low or stable patients, like we saw on the previous slide or mismatch repair proficient, and that's going to be about 60%. And those patients are going to receive lenvatinibpembrolizumab as a combination therapy. And then 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. And those patients will receive immunotherapy as a single agent. So it's going to either be pembrolizumab or now nivolumab, with response for overall response rates as high as 57%. Next slide. So single agent activity in 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 SGL is actually much lower than that. And I think probably because most patients who receive paclitaxel in the second line setting now have received it frontline, which didn't used to be the case in these historic trials. But as you can see in the single agent targeted therapy, response rates are extremely low, more in the teens. Next slide.
So here, I want to point out the pembrolizumablimvatinib 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 is an extremely poorly tolerated regimen. I will start at a much lower dose, but in the trials they started at 24, which they found was too toxic and then 20 milligrams was tested. But we don't have any prospective trials using any doses lower than 20. And approximately 20% were discontinued for pembrolizumab toxicity, 14% for both drugs.
And 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. And you can see here that the overall response rate in the Perficient is 30%, but again as high as 60% are going to have to dose reduce the lenvatinib due to the toxicity. Next slide. So it's really 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. So, DKK1 may represent 1 resistant mechanism to standard therapies.
Again, using real world evidence from Tempest, we looked at time to treatment discontinuation for patients with high versus low dKK1 expression. And on the left, we see Similarly, we see a trend towards higher dkk1 patients on Similarly, we see a trend towards higher dkk1 patients on the right having poor response to anti PD-onePD L1 therapy. Now I'm going to turn it back over to Cindy.
Thanks, Rebecca. So what we did, we conducted a Phase 2 basket study in which we were evaluating DK101 as a monotherapy as well as DK101 in combination with paclitaxel. This study enrolled patients with endometrial cancer, ovarian cancer as well as carcinosarcoma. And 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 tumor DKK1 and better to identify patients for subsequent trials. The study design is below, they were 28 day cycles, The patients received DK101 on days 1 day 15. And then weekly, if it was paclitaxel was used in combination, it was administered on days 1, 8, 15 and 22. Next slide. As mentioned, the patients who are enrolled, 50% were required to have Wnt signaling alterations.
Those alterations are identified in the box to the left. This was a group of genes about 20 in total in which there is 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 the genes that we felt represented true activating mutations. Next slide.
Importantly, in this study, we did see an association of higher levels of tumor DKK1 expression in patients whose tumors had BLINK activating mutation. Overall, 21% of patients across the 3 disease indications had linked activating mutation. 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 beta ketene mutation at 16%. Overall, the patients who had the Wnt activating mutations had roughly 14 point 4 fold higher expression of tumor VKK1 than those patients who did not. Next slide.
Here you can see, also the patients who had endometrial cancer had higher levels of tumor VKK1 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 5. The images on the right represents our chromogenic Incytru hybridization assay in which you can see the staining of the red represents the DKK1 in the tumor itself. Slide. And here, I will turn it back over to Doctor.
Arendt to describe the toxicity of the monoclonal antibody.
Thanks, Cindy. So here are the most common treatment adverse events in both arms. So 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 5 point 8% and in the combination arm 6.8%. EK-eight zero one was very well tolerated, both as monotherapy and in combination with paclitaxel.
And I can tell you as a clinician as witnessing how patients looked when they received DK-one was pretty remarkable. I mean, me and my partner, we 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 mean, I have one patient who's been on it for over 2 years and she's doing fantastic. So that's very different from something like lenvatinib where I see extreme severe toxicities. So 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've been sick all the time.
Additionally, this makes CK-one an extremely good partner, not only for chemotherapy, but other possible combinations just because it's so well tolerated. And even seeing patients in the combination arm, it almost seems like the DK101 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. So this makes it much easier discussion with patients during informed consent when discussing treatment plans, especially for those who are receiving monotherapy, which was great in the trial that the physicians got to decide. So I really think it was a beautifully designed trial that made it very easy for us to accrue to. So 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. So 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. I mean over 50% had more than 2 prior systemic lines of therapy.
So 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. So I'm going to present the DKN-one monotherapy. Next slide.
So here is the DKN-one monotherapy and this is endometrial cancer overall response. So endometrial cancers with alterations in the Wnt signaling pathway had a great had greater clinical activity than those without the Wnt pathway alterations with an overall response rate of 10% versus 0% and a disease control rate of 48% versus 13% as demonstrated in the waterfall plot below. Next slide. So here's the spider, plot showing a DK101 monotherapy. Endometrial cancers with alterations in the WIT signaling pathway not only had a better response, but they had a more durable clinical response than those without the Wnt pathway alteration.
As you can see, the green lines represent those with Wnt alterations and the blue without Wnt alterations. Next slide. So now I want to go through a couple of case vignettes just to highlight some of the reasons or some of the responses that we are seeing clinically. So to me as a treating physician, and as to this patient, this has been like an absolute miracle drug. I mean, this woman with recurrent endometrial cancer who came onto the study suffering from severe neuropathy and thrombocytopenia now has evidence of has no evidence, sorry, residual disease after 21 months of being on monotherapy.
And she really continues to do great. So treatment with the lead drug reversed the expected aggressive behavior, just defects in DNA match repair or MSI high. Some people would say those patients are more aggressive in endometrial cancer, which can certainly be debated. But nonetheless, this patient continues on DKN-one monotherapy with no evidence of residual disease and is doing great. Next slide.
So here's an example of another lady with recurrent endometrial cancer who experienced such horrible toxicity from taxol, she actually had to discontinue it. So after 2 cycles of monotherapy, she had a 41% reduction in her tumor, which was confirmed after 4 cycles and she remained on therapy for over 6 months, when otherwise she definitely would have been dead in my mind. She's still alive and she remains in follow-up. So 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 BKK1 scores do show benefit. But 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 at with this monotherapy drug.
Next slide. So now I want to highlight some of the Temoral DKK1 as a biomarker in this trial. Next slide. So individual cancer with DKK1 high to moral expression have a better overall response rate, 14% versus 0% and clinical benefit of 57% versus 7% after DKN-one treatment compared with low CKK1 tumors. There are are 7 patients with unknown dkk1 expression had an additional complete responder and an overall disease control rate of 86%.
So we know that 3 of these patients with durable stable disease had Wnt activating mutations. And 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 7 patients, showing that we need further data to really tease out exactly the DKK1 as a biomarker, but we're seeing pretty remarkable response rates to monotherapy in a heavily pretreated population. Next slide. So high TOMORROLDKK1 expression have more durable clinical benefit after NO1 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. So here again, we can see tumors with high DKK1 have a longer progression free survival of 3 months compared to only 1.8 months in the low with a hazard ratio of 0.3% and a 95 95% confidence interval of 0.14 to 1.1 after DK101 monotherapy compared to DKK1 low tumors with the unknown in gray, green being the high and blue being the low. Next slide. So we did a sensitivity analysis trying to reflect 3 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 5.8 months versus 1.8 months with a hazard ratio of 0 point 56. Next slide.
So, endometrial cancer with DKK1 to moral expression have more durable clinical benefit after DKN-one 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. So looking at the combination, we see an improved progression free survival in high tumorlDKK1 expressing tumors, 5.4 months versus 1.8 months after DKN1 plus paclitaxel compared to the DKN1 low tumors, as you can see in the Kaplan Meier curve below. Next slide. So, DKK1 expression is higher in endometrioid endometrial carcinoma as was discussed before.
You can see in this RNA scope that the DKK1 expression in endometrioid tumors versus non endometrioid tumors have a median H score of 18 versus 11. And you can see on the right hand side using the TEMPEST data, the increase in the DKK1 high expression in endometrioid tumors. Next slide. So looking at pooled endometrial cancer data, the overall response rate in the endometrioid histology by tumorlDKK1 expression. So tumors with highDKK1 have a better overall response rate of 7% versus 0% and a disease control rate of 57% versus 15% after DK101 treatment compared with DKK1 low tumors.
And you can see on the right hand side, the RNA scope or the H score according to response and the DKK1 expression showing DKK1 high with greater responses. And again, below you can see all endometrial cancer patients, CKK1 high greater than or equal to 18% and overall response rate of 7%, but a disease control rate of 57%. And again, highlighting this unknown population with a 14% overall response rate and 86% disease control rate. Next slide. So again, the pooled endometrial cancer showing durable clinical benefit in the endometrioid histology by DKK1 tomorrow after DK101 treatment compared with low DKK1 tumors, showed in the spider graph below.
Next slide. So here you can see the Kaplan Meier curves, tumors with high DKK1, better progression free survival of 4.1 after treatment compared with low DKK1 tumors. And again, this is the pooled endometrial cancer analysis. Next slide. So in conclusion, DKN-one, 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.
DK101 monotherapy demonstrated clinical activity in an unselected extremely heavily pretreated endometrial cancer patients, including a complete response such that we would not see even with chemotherapy and that was with monotherapy. High temporal DKK1 expression in endometrial cancer population demonstrated greater response and we saw a durable clinical benefit and progression free survival. DK101 monotherapy in the DKK1 high versus DKK1 low showing an overall response rate of 14% versus 0%, 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 DKK1 high or DKK1 low. The greatest benefit and the highest moral DKK1 expression was seen in the endometrioid pathology.
So 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. And here the confidence interval does not cross run with a hazard ratio of 0.34. So future gynecological 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-one therapy, especially in the CK1 high population, especially considering how toxic lenvatinib is and the fact that we know when beta catenin pathways are upregulated in this cold population where lenvatinib timbre is probably going to be the next standard of care. So 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 7 unknown DKK1 expressing patients? What was the cause of the data missing from the trial?
Sure. I'll take that one. So the patients, as you know, as we as the study design requires that the tumor was first sent for a genetic analysis to ensure that we had the 50% in each of the cohorts being rolled with LINT signaling alterations. So while we obtained tumor on all patients, at times and in particular these 7 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 3 of the 7 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 a DKK1 high disease on the basis of the 14 fold higher expression in patients with Wnt activated.
Yes, that's exactly right. So 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 dK1 expression of those unknown patients. So we knew that they had beta catenin mutations and we showed you both from this study and from real world evidence that patients with beta 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. And we showed you in the endometrioid histology, they were more likely to be higher dkk1.
And so as we looked and considered the biomarkers over the analysis of the study, we did consider the mutations that underlie 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 was known, such a striking difference or sorry, in the gastric cancer study with pembrolizumab that we'd seen in monotherapy, chemo combination, PD-one combination that fundamentally, as we think about the it was a known acne. 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 dK1 expression difference in EEC versus EOC. In one of your slide, Slide 19, you showed higher much higher expression in EEC versus EOC. And then another slide, I think Slide 35, you also showed an expression difference.
I just wanted to clarify what's the difference between these two data sets?
Sure. I'll take that one too. So the earlier slide, Slide 19 is showing the difference in DKK1 expression between the 2 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, it's actually breaking down specific histology types of endometrial cancer. So 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 And those patients with endometrioid, endometrial cancer have a higher dkk1 expression than the non endometrioid with a median of 18 versus 11. Got it. So it's just breaking down the specific types.
Yes.
Got it. If you look at the responses or the patient with durable stepper disease, are they mostly enriched in the endometrial cancer or are the Type 2?
Yes. Many of them are in the endometrioid histology. That's correct.
Got it. Great. And if you look at the real world data tempers, any sense about what percentage of patients overall are this type of histology with high DKA expression?
Right. So for the TEMPEST 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. However, in general, for this biomarker, we're targeting about the top tertile or 1 third to be considered as high DKK1.
Yes. And just that TEMPEST data, Wangzhi, is actually RNA seek data too. So the log scale on the left is different than our RNA scope.
Got it. Okay. That's helpful. And maybe one more question is, in one of the slides you showed the response rates and DCR for different type of therapy in this indication, including Avastin? And you also see the one slide that the TegaK1 high to the patient should have poor responses to post PD-one and VEGF inhibitors.
So I just wondered, do you think it makes sense to combine the 3 together PD-one, TKI-one and like Avastin, maybe more synergy?
So I'll take that. I would love to see that because I think that there is pretty much 0 overlap in the 3 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. So 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 Doctor. Darrent. For this indication, if you look at potential registration trial, what do you think of the I mean, OR obviously is the one potential readout and PFS. But how do you think about BCR?
I mean, the response rates, if you look at the PD-one, the volume is kind of low double digits, But the DCR also looks by quite durable benefits too. So what's your view on that?
Yes. I mean, 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. But 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. And so I think that if we get more of a biomarker selected population, potentially within 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 TEMPEST 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. So just wondering how we get comfort that the separation we're seeing here isn't just a sample size effects?
Jay, you want to take that?
So I think we're so 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 1 in the ovarian cancer data set.
So 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. So I think for us, it was reflected also in the efficacy scene. So I think Cindy, anything you'd like to add as you Yes.
I mean, I think it's a very reasonable observation to say that numbers are skewed. I mean, obviously, here we're looking at relatively small numbers and only a third of patients to try and make determinations. But 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 tumor 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 tumor 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. So I think that we could 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. And I think moving towards a Phase 2, 3, something that permits an earlier review of data when looking at the biomarker is the path forward.
Got it. That would be great.
I'll also just chime in on sort of that whole, just in terms of biomarker development. And I think the point about being very low numbers of something like clear cell in the tempest 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. And 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. But if we move forward with this and then you do have a patient, say clear cell or serous or carcinoid sarcoma 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. I mean, 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 Koozie with Baird.
Hi, good morning. Thanks for taking our question. On the I think it was the 2nd 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?
And then I have
a follow-up. Yes. I'm going to jump in there. Yes.
So we're going to hang on one. Yes. No, this patient actually was considered high for this disease indication. Our thresholds across disease indications are likely to differ here. But if you notice throughout the presentation, the age score that we were considering DKK1 high and endometrial cancer was actually 18.
This partial responding patient had high disease with an age score of 19.
Okay. Thank you for clarifying that. And then for the tolerability of DKN, is there a scientific rationale for why DKAN-one could make the tolerability of chemo better? Was that surprising at all? Or was that something that you had kind of expected going into this combination?
So the only thing I can add to that was a preclinical study that we did several years ago in non small cell lung cancer in 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. And it was noted as an observation during that study that the mice actually were better groomed and felt better when the DKN1 was used in combination with the cytotoxic chemotherapy. So that's anecdotally really all I can suggest. I mean, we don't and we've conducted, as you know, a number of studies in combination with the cytotoxic chemotherapeutics and never added to toxicity of any of those agents alone. So I do think that we've been able to successfully combine across a number of different agents, including cytotoxic chemotherapeutics.
And anecdotally, and as Rebecca mentioned even on study, I think the patients have been tolerated the regimens quite well.
Great. Thank you. And for future development, I know obviously you highlighted the potential of PD-one 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 with as you continue to develop the biomarker?
Do you want me to take that, Cindy or you want to?
I mean, I can start and by all means, please jump in. So we're thinking a less heavily pretreated population, so 2 or fewer prior therapies, looking at patients with endometrial cancer, considering histologies within that realm and then trying probably to better select the patients on the basis of DKK1H scores.
Yes. And I was going to say, I mean, yes, 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. So in an ideal world and in my heart of hearts, I
would love to see in a
DKK1 high population or patients with beta catenin mutations for this to substitute the lenvatinib and be able to use this in combination with IO as second line. Even actually mentioned something to Cindy this morning that in a DKK1 high or beta catenin mutation patient, we've seen in serious patients with HER2 mutations, now we use trastuzumab in upfront or first line in combination with chemo and then continue it with maintenance therapy. So I don't think that that would be out of the realm of possibilities for this drug in this population. So I think the sooner the better once we develop the biomarker would be the best for the patients.
Great. Thank you for
taking the
questions. Our next question comes from Arthur Heng with H. C. Wainwright.
Good morning, everyone. This is Arthur for Aki. Thanks for taking my question. So I have two questions. So one is regarding the overall survival data in the either the monotherapy or combo therapy.
You guys can give us more color on that?
Cindy, do
you want to take that or Doug?
Yes. So we haven't presented that data in this STO presentation. I think it was 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. And so we tried to, for the sake of building the understanding of how important DKK1 is to select patients who have the best outcomes on DK101 based therapy, we really tried to hone in on the point in time that was affected most directly by DK101.
But we can certainly share the overall survival data and it will be part of a manuscript downstream. But in this heavily pretreated patient population, a the data is all consistent with what you'd expect.
Thanks, Scott. And my second question is regarding the potential of the biomarker for the future study. So one is the DKK1, the H score is kind of fixed kind of finalized at the 18? Or there's a future further tweak on that definition? And the second, would you consider other biomarker in combination with the dk1hscore to better select the patient population?
Thank you.
In terms of the age 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. But 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.
Yes. I think as we looked at the data so far, 2018 was terrific in terms of being an upper tertile across the entire population. So it still gives you 1 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.
You will 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 beta catenin mutations continue to be a subgroup, whether the DKK1 high patients with PIK3CA mutations are a particularly interesting subgroup. But we believe the common focus is around DKK1, the target of our antibody and being the core biomarker that we use to select patients. And then as Doctor. Wrend and Cindy both said, I think it's a very exciting opportunity to be able to follow a similar path to esophagal gastric cancer by looking at a PD-one combination for these patients.
Thank you. And 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 Aunty for closing remarks.
So thank you all very much for your 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 VKAN-one of the path forward for targeting these patients and brought some terrific results to many of the women who were enrolled in the study. So thanks also to all the people who participated in the study and to their sites and to the entire team here at LEAP. So 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.