Good day, everyone, and welcome to the LEAK Therapeutics, DKN-one Clinical Investigator Conference Call. Following the presentation, there will be an opportunity for questions. Please be advised that this call is being recorded at the company's request. At this time, I will now turn the call over to Doctor. Cynthia Serraard, Vice President of Clinical Research and Development of LEAP.
Please begin.
Thank you, operator. Welcome and thank you to those of you joining us today for an update on LEAP Therapeutics DK101 development program. I'm Cynthia Serard and with me today are Douglas Honsie, the Chief Financial Officer at LEAP Walter Newman, the Vice President of Research at LEAP Doctor. Samuel Klempner, an Assistant Professor of Massachusetts General Hospital Cancer Center and Harvard Medical School and Doctor. Rebecca Arond, an Assistant Professor and Associate Scientist and Gynecologic Oncology Clinic, the University of Alabama Comprehensive Cancer Center experimental therapeutics program.
This call is being accompanied by a slide deck. So I will ask you to please turn to our forward looking statements on Slide 2. Before we begin, I would like to remind you that any statements made during this call that are not historical are considered to be forward looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these statements as a result of various important factors, including those discussed in the Risk Factors section in the company's most recent quarterly report on Form 10Q as well as other reports filed with the SEC. Any forward looking statements represent our views as of today, August 6, 2019 only.
A replay of this call will be available on the company's website, www.leaptx.com, following this call. With that, please turn to Slide 3. Good day. Today, we are hosting a call to allow our investigators to share their clinical insights on our BKK1 targeted antibody known as BKN-one. We will discuss the biology and treatment paradigms of the indications we are pursuing and provide their thoughts on the opportunities ahead for the program.
During our presentation, Doctor. Walter Newman will start by providing a brief overview of the biology of DKK1, its role in cancer, the preclinical data which supports our development program and our understanding of the mechanism of Our first speaker is Doctor. Samuel Kumpner, Assistant Professor at Massachusetts General Hospital and Harvard Medical School. Doctor. Kumpner will discuss treatment of patients with esophagal gastric cancer and present data from the clinical study evaluating VK101 in combination with pembrolizumab, marketed by Merck as KEYTRUDA.
Doctor. Klempner will also review the data from the combination of DK101 and paclitaxel chemotherapy in this study. Next, we will hear from Doctor. Rebecca Aron, Assistant Professor and Associate Scientist, Gynecologic Oncology Clinic, University of Alabama Comprehensive Cancer Center Experimental Therapeutics Program. Doctor.
Iran will provide background on endometrial and cancer in carcinosarcoma and review her clinical experience with DK101 as a mono therapy and in combination with paclitaxel. We will end the call by opening the floor to questions for Doctor. Flintner, Doctor. Aran or any of us from Lee. Now turning to Slide 5 and Doctor.
Newman.
Thank you, Doctor. Surard. Referring to Slide 5 then, DKK1 is a secreted protein that modulates cell signaling pathways known as the Wnt signaling pathways as well as the PI3 kinase and AKT pathways. In cancer, pathways. In cancer, DKK1 has been implicated in facilitating tumor growth and metastasis as well as promoting immunosuppression in the tumor microenvironment through the activation of myeloid derived suppressor cells and the suppression of natural killer cell anti tumor activity.
In addition, some patients' tumors have mutations in their Wnt signaling pathways that lead to higher levels of DTK1 being produced by the tumor cells. We are developing an antibody that binds and inhibits the activity of DKK1 known as DKN01. We have evaluated DKN01 in a variety of preclinical and clinical studies. We believe that PKN01 therapy causes tumor reductions through both changes in the tumor cells and activation of the innate immune system in the tumor microenvironment. Let me now turn to Slide 6.
High levels of DKK1 correlate with shorter overall survival. When we began working on DKK1, we decided to focus our efforts on cancer indications where DKK1 was known to be associated with a poor prognosis. Published data demonstrated that patients whose tumors expressed elevated levels of DKK1 had worse survival outcomes as can be seen in this TCGA analysis of over 10,000 patient samples where patients with high levels of DKK1 had 2.5 years shorter overall survival than patients with low levels of DKK1. Similar data had been published for esophagogastric cancer, biliary tract cancer and non small cell lung cancer. Tract cancer
and non small cell lung cancer.
As a result, we targeted these indications first. Now turning to Slide 7. DKK1 can promote tumor growth in several ways. At LEAP, we have been extremely interested in studying how DKN-one works in order to provide support for the clinical program. PKAN-one and its murine version has anticancer activity in many different cancer cell lines and cancer models as shown in the first panel on the top row in a B16 melanoma model.
What we have learned through the next two figures on the top row is that tKNO1 requires a functioning immune system in order to work in shrinking a tumor and that specifically DKN-one requires the activity of natural killer cells that can target the tumor. In addition, DK101 also upregulates PD L1 expression on myeloid derived suppressor cells and tumor cells. These immune mechanisms gives us insight into the best combination strategies for anti cancer activity. Now turning to Slide 8. Natural killer cells are part of the innate immune system.
Drugs that target the innate immune system are expected to provide additional anti tumor benefit to PD-one and PD L1 antibodies that target T cells and the adaptive immune system. We and our academic collaborators have demonstrated in several cancer models that DKN-one and PD-one antibodies have additional activity over either antibody alone. This provides preclinical support for the clinical efficacy of DK101 in combination with Merck's PD-one antibody KEYTRUDA, which will be presented in a few minutes. Now please turn to Slide 9. We study dK101 in tumor models that produce high levels of dKK1 in order to most closely resemble patients whose tumors are producing high levels.
We have also seen that DKK1 has high anti angiogenic activity, which reduces blood vessel density feeding the tumor and contributes to the anti tumor response. In these models, such as the A549 model of non small cell lung cancer shown here and the PC3 model of prostate cancer, CK-one has monotherapy activity and additive efficacy in combination with paclitaxel. These data support the clinical activity that we have seen in the esophageal cancer and endometrial cancer patients with paclitaxel and the design of the investigator initiated study at NYU in DKK1 positive prostate cancer. We will now transition to Doctor. Kleptner to discuss the treatment of patients with esophagastric cancer and present data from our clinical study evaluating DKN1 in combination with KEYTRUDA.
Thank you, Doctor. Newman and Doctor. Surrard. My name is Sam Krumper. I co lead the gastric and esophageal program at Mass General Hospital in Boston.
And as you can imagine, we were quite attracted to this as a therapeutic compound. But if you're not familiar with esophagogastric cancer, it is actually the 3rd leading cause of global cancer related deaths. But you can see from this slide that there is a clear discrepancy between U. S. And outside of the U.
S. Cases. And on the next slide, this is a little more granular. So here we see the data for esophageal cancer from the global can. This is the WHO data colorized by incidents with the darker colors representing higher incidence areas.
And you see that in China, esophageal cancer represents a major cancer with 13.9 cases per 100,000 individuals. And on the next slide, we see the same data for gastric cancer, where Asia certainly has an endemic along with some parts of South America. And in the U. S, although this is a lower incidence cancer, there is some data that it's actually increasing in younger individuals. And then on the following slide, we see that this is a disease that has a very poor prognosis.
Advanced disease, so cancer that has spread outside the stomach. Advanced disease, so cancer that has spread outside the stomach. And in those patients, we have limited treatment options. And unfortunately, our standard of care therapies have been met with minimal improvements in overall survival over the last 2 decades. But if you look at the graph, most of our clinic is focused in the people with distant metastases where you see the 5 year survival rates are generally quoted around 5%.
The next slide. These are the main issues that we address when we're trying to take care of patients with advanced esophageal gastric cancers. And so part of the reason that these patients have limited options is that they are sick from their disease. They're highly symptomatic because the disease impacts the ability to eat. Nutritional status is a problem.
And unfortunately, what this boils down to is that although patients may be somewhat robust when they're first diagnosed, they can fall off a cliff relatively to do with residual toxicities from first line therapy and some of that has to do with decrement in performance status. Unlike lung cancers and some other diseases where targeted therapies have a firm hold, this has not been the case for gastric and esophage geocancer. And they're actually unique among the GI cancers in terms of the degree of chromosomal instability and molecular heterogeneity. So we have a high degree of tumors composed of multiple sub clones where some may have the target and others will not. So single targeted therapies have met with very limited success with Herceptin being the only approved therapy.
Although in absolute terms Herceptin only adds about 2 months of overall survival when added to standard of care chemotherapy. Next slide. So this is the current status of care in the Western world, primarily U. S. And Europe.
So as we said, we're focused on the advanced patients, patients with esophageal cancer, which is distinguished from gastric and GE junction cancers because the actual biology is somewhat different. So on the left hand of the slide, we see if the patients are HER2 positive, this represents about 15% or less in the esophagus. They receive chemo with Herceptin. If they're fit for second line therapy, they go on to receive single agent paclitaxel or immunotherapy in the subgroup that is CPS greater than 10 and that is a minority of patients. In the 3rd line, KEYTRUDA is again available as an option and the activity has been greatest in the microsatellite instability high patients, which again only represents about 4% of the patients.
Clinical trials is of course the preferred option. And on the right side in the gastric space, similar pathway except the anti VEGFR2 monoclonal antibody ramucirumab is approved in the 2nd line, where it's been shown to improve survival when added to paclitaxel. And then we have the recently approved LonServe in the 3rd line setting. I think the takeaway from this is that there is limited overall options and that the later end lines of therapy you go, the response rates and magnitude of benefit drop off quite substantially. Next slide.
So to put a little bit of granularity to what I just said with regards to the immunotherapy activity, here you see the bench mark immunotherapy study. So 2nd line and third line response rates you see nothing above 13 percent and in the microsatellite stable, which is about 96% of the patients single digit response rates with PFS. You're talking 6 to 8 weeks here with overall survivals of half a year at best. Next slide. So enter much needed improvements in therapy.
There's certainly an unmet need in this space in the second and third line setting. This is the overall schema for the KEYNOTE-seven thirty one, DKN01 plus pembrolizumab, relatively straightforward design. You can see there's a small lead in and then immediately up to dosing of every 2 week DK101 with standard of care pembrolizumab every 3 weeks. And there you can see the proportion of breakdown between PD-one naive and PD L1 refractory, both which represent substantial unmet needs in esophagogastric cancers. Next slide.
So this will frame the following slides, but this is a heterogeneous population that was included in the trial, all heavily pretreated. And this is essentially a real world reflection of what we deal with. What we'll see is that patients with high tumoral DKK1, as you may have predicted from the preclinical data, may have improved outcomes. DKK1 high GE junction patients, this is perhaps the most interesting aspect. A response rate of 51 50%, a median progression free survival of 5 months.
So that's in contrast to the 1.5 to 2 months and a median overall survival of 7.3 months. And then we see that this is actually an independent of PD L1. So CBS scores do not predict efficacy, unlike with KEYTRUDA monotherapy where there certainly is an increase in activity in positive patients. And then DKK1 high has a strong association with efficacy and outcome along independent of prior therapies. And we'll see some data with the paclitaxel trial as well.
Next slide. So this is the breakdown of the patients included in the study. I will be focusing primarily on the GE junction and gastric cohort. And as you can see, that represents a substantial portion of the patients, little over 50% in both cohorts. Otherwise, this is a largely representative trial population in 2nd and third line patients.
You see majority ECOS PS1, almost everyone was diagnosed at stage 4 disease, which is what we see in the United States. And the median time since diagnosis is variable dependent on if they presented with early stage or metastatic disease. Next slide. So this is something that's always important to look at when we're evaluating later line therapy trials, how many prior lines of therapy and what you see is the majority of patients have had 2 or more prior lines of therapies. This is a heavily pretreated patient, where the benchmark response rate is around 9% or 10%.
And then you can see that these patients have all received essentially standard of care based on the algorithm that I presented before, with everybody receiving 5 FU and platinum essentially standard first line therapy. Next. So on the right hand side here in the column, again, this is the primary group we'll be focusing on. But as per other immunotherapy and non immunotherapy trials, this is divided between esophagus, both adenocarcinoma and squamous and GE junction and gastric. And that division is based on differential outcomes biology that has been observed across prior trials.
And so here you see the biomarker status for the standard biomarkers. So CPS1 to less than 10, 48 percent of patients. This is very typical for what we see in the real world. CPS greater than 10, which is a group of patients who may have a greater benefit from KEYTRUDA, you see is about a quarter. And then there's a substantial additional quarter that was negative entirely Consistent with the incidents reported, almost everyone is microsatellite stable.
There is no MSI high patients here. And then tumor mutational burden, which has actually some data in gastric cancer, suggesting a cutoff of around 14 to predict response to immunotherapy. Fortunately, that's a very small minority. So what we see here is that most of these patients have a low tumor mutation burden with the medium of 5.5 mutations per megabase. I think that the takeaway from this slide is really to say that these are not patients where you would have predicted high activity from pembrolizumab alone.
Next slide. So this is the safety data and we'll see that this drug has been well tolerated and I can certainly speak to that clinically. So any treatment, emerging adverse events, typical of immunotherapy, monotherapy trials, this is the breakdown that we see, but we can see very few events leading to discontinuation and very few related to DKN-one. You see 8.2% and 9.8% related to pembrolizumab. So this is sort of 1st snapshot to suggest that this is a safe drug.
Next slide. And again, this is confirmed in the breakdown of the toxicity based on DKN-one attribution versus pembrolizumab related attribution. And really what we look for here is not only the frequency of events, but the severity. So what you can see is the greater than 3, grade 3 events is uncommon. And this is consistent with single agent monotherapy data.
So bottom line takeaway is that compared to large monotherapy data sets, we're not seeing any significant addition of toxicity in the combination. This is a typical breakdown for essentially pembrolizumab related side effects where you see some fatigue, some skin toxicities, which are all minor pruritus, myalgias, etcetera. Next slide. So we'll get into the meat of the trial here. And this is the waterfall faucets broken down both by, of course, response, but also by tumor type as colorized here.
And I think the first thing that emerges that all of the light blue lines are clearly falling to the right side of the figure with responders, and those are the GE junction and gastric cancers who have a partial response. And then similarly, you see the stable disease patients, which are the purple lines within the RECIST kind of error bars. Again, those are all GE junction and castrate cancers. And then we see that the progressive disease is again, that's based on the sheer numbers. So I think what this shows is that the first hint here is that there's increased activity in the GE junction and gastric space perhaps relative to esophageal space.
Next slide. So if we dive a little bit deeper into that and show it in a slightly different manner, this is the spider plot suggesting the durability of response. So here on the prior we had depth of response and now we're looking at durability. And again, what's highlighted in green bars and the purple is the GE junction and gastric cancers. And you see that the primary the majority of the lines are falling below with some decrease in tumor change.
And what's more strikingly here is that there's a substantial portion of patients in a heavily pretreated population who are remaining on therapy and you see 25, 30, 40 weeks out from therapy. So 6, 7, 8, 9 months. Again, next slide. When you try to dig in a little bit about what is it about those responders, certainly the preclinical biomarker that was of interest was DKK1. This is something that's feasible and also has relative clinical utility.
And so here IHC was a consideration, but RNA scope has emerged as perhaps a preferential biomarker. So this slide is showing you the difference between a positive and negative dkk1 h score. So 163 you see up top is a dkk1 high tumor and a negative control. And then you see a patient, a non responder with low DKK1. And we'll see more about this on the next slide.
This is a graphical way of showing the response based on hallmarker status. And so what is very clear here is that the responding patients are grouped based on an elevated level of DKK1 expression. So you see the H score increasing there, see the GE junction in gastric cancers, see the majority of responders, the blue dots are grouped in the high EKK1 score. This to me when I thought this was perhaps the most exciting thing because what we've been And then the logical questions was, is this just something that's in the tumor or in the stroma or in the immune cells? And what you see here is that this is clearly a tumor side biomarker.
So all of the DKK1 staining is essentially localized to the tumor. You see very little expression in the stroma or in the immune cells. Next slide. So when you try to examine those DKK1 high tumors, what you would hope to see is, of course, that those are the group of patients who are the responders. And that is exactly, in fact, what has fallen out.
So you see the overall population, the GE junction and gastric cancers represents a significant portion of them. This is actually quite good for a phase early phase trial in order to get specimens and collect them for analysis. Often we expect pops out here is that, if you're going to develop a drug in a space based on a biomarker, it's important to know how frequent the biomarker is because that will reflect how much of the population may be candidates. So here we see this is actually quite a clinically relevant incidence of a biomarker. Out of those 31 patients, 11 of them are DKK1i.
So that's a substantial portion of any gastric and esophageal population. And then what you see here in the waterfall plot, which is now color coded by DKK1 score and an additional layer for response, the black arrows are showing all of the partial responders and you can see that they're all grouping in the DKK1 high. This is really interesting data and then you show the same thing in the spider plot. The DKK1 high tumors, you see the durability of response. Now the scale has changed 200 days and over.
So these are durable responses, which is of course what we want to see and it's hard to come by in later line settings. Next slide. So these are just smaller numbers, but important to see the progression free survival here clearly associated with the DKK1 high status. I mean these curves separate quite substantially early on and stay quite separated. So this is exactly what you want to see.
And then again, comparing to those benchmark studies we talked about in the beginning, a median PFS here in the sort of biomarker enriched population, the DKK1 high, median PFS of 22 weeks, that is almost tripling of the median PFS of 6 to 8 weeks in pembrolizumab monotherapy. This is a substantial improvement. Next slide. Overall survival is of course a little bit harder to measure because there's some post progression therapies that are captured. But what you see here from the evaluable data set is that this holds true for overall survival.
And what's important to note is that this is not just a good prognostic biomarker. We saw from Doctor. Newman's presentation earlier that these are actually patients who inherently do worse dkk1 high tumors have a shorter overall survival. So this is an aggressive disease population and here that their outcomes have been substantially modified by the drug. So this is a substantial improvement in survival.
We see 31.6 weeks, which is over 6 months, which is an improvement well beyond what is seen with our currently available options. Next slide. So this is a slide really showing that looking at the anti PD L1 naive population. So this is fewer lines of prior therapy have been the ones who fewer lines of prior therapy have been the ones who responded. That is not the case in this trial, which is encouraging to see where people who have one line of prior therapy, so people who are on the trial in the second line versus people who have had more than 1, both of those groups you see responders in.
And not only just a couple, but durable responses. And so this is an encouraging thing for us because we don't have that many options either in the second or the third line setting. Next slide. One logical question that would have come up from this is, are these patients who just have very high PD L1 scores and we're going to respond to KEYTRUDA and the DKN-one is adding unclear benefit. That turns out not to be the case at all.
These are patients who are actually cover all the basis of CPS expression. So as you can see in the bottom left, the waterfall plot, there is no correlation really between CPS status, so high expression versus low expression and outcome. There is clearly a correlation between DKK1 status and outcome, but not PDL1 status. Again, we see this in 2 figures, the left and right showing the same thing in terms of incidence of response and durability of response. And then in tabular format, we see that there is roughly a real world breakdown of CPS status within the patient population.
So take home from this slide is really that response is independent of PD L1, which did not predict clinical benefit where it has in single agent studies. Next slide. So here you see all of the biomarkers essentially overlaid on each other. So again, this is the same valuable set of the immunotherapy naive population. And what you see is clearly the DKK1 high patients, the blue bars to the right are the responders.
But when you look at those patients with regards to their CPS, their PD L1 expression, again, there is no clear correlation that emerges. And this is just a way of compositely representing the data that was shown on the previous two slides. Next slide. So CPS score as it has been in some large immunotherapy trials is not really a predictor of PFS at baseline. And so here we're seeing the same thing, so confirming what has been observed previously.
And what you can see is that if you look at CPS 1 to 10 or greater than 10, median PFS is not substantially different in population. If you were to overlay DKK1 high versus low, you're clearly segregating out the 2 populations, which is what we're of course trying to do with any biomarker. And then certainly when you look at this is essentially the forest plot looking at interaction, the hazard ratio by PD L1 CPS status. There is no clear benefit to any subgroup. Next slide.
This is the same thing looking at DKK1, just driving home the point that clearly DKK1 high is able to separate these populations. So DKK1 high versus low, clearly, you're favoring the DKK1 population and same thing with all of these other subgroup. The take home again is that you can segregate out 2 populations with your biomarker, which is really the goal for any biomarker and drug development. Next slide. PD L1 status is not associated with overall survival.
This is clearly shown here in the available patients, which is a substantial portion. So 27 patients of the 34 had available PD L1 status. And you can see the breakdown as it was shown on prior slides. And clearly these curves are all crossing Next slide. And then the other question would be asking is does DKK1 predict for PD L1 status?
And the answer is no. Here DKK1 expression is not responding urothelial patients. So here are just 2 progression free survival curves and overall survival curves from published data sets. You can see high DKK1 and low DKK1 and high DKK1 and low DKK1 for these 2 melanoma populations. Again, not separating the population.
These are not DK101 treated patients. Next slide. This is something I think we'll hear a little bit more about from the next speaker, but activation of the Wnt and beta catenin signaling. So as Doctor. Newman explained, this is one of the mechanisms that the drug works via.
And certainly, we know that beta catenin driven tumors, there's actually some increasing data about this. Increased beta catenin signaling can drive PD L1 and PD-one resistance, partly via immune exclusion from the microenvironment. The ability to manipulate the microenvironment perhaps enhance the immune recognition and penetration via innate and adaptive immune systems is certainly something very, very attractive and there's a lot of strategies involving innate immune activation. This is data just showing what I said where beta catenin positive tumors have decreased levels of immune infiltrates, which reflects the immune exclusion perhaps driven by catenin signaling. And same thing, this is an analysis from public sequencing data looking at beta catenin scoring and T cell inflamed signature.
So T cell inflamed signature is something that's been pretty well validated as a predictor of benefit from immunotherapy, whereas the T cell non inflamed signature patients don't respond as well. So you're picking a population here that is unlikely to benefit from monotherapy. I think that's the message is that these are patients who you would not expect to benefit if they were giving pembrolizumab alone. Next slide. And so there's actually data from a prior DK101 study looking at similar patient population with standard of care paclitaxel.
And this is a to me, this is an equally important data set. So this is the trial design where patients were enrolled. You see the demographics on the right, get a biopsy standard of care paclitaxel with every 2 week DKAN-one, the same schedule that was given in the prior study. And here we see similar breakdown, primarily GE junction, little bit fewer gastric. Prior therapy, you see these are also heavily pretreated patients, substantial portion of which have received prior taxane.
So responding to taxane after prior taxane is something that's always a problem and also prior ramucirumab. So again, this is a trial attacking an unmet need in a heavily pretreated population. Next slide. Again, here is the same slide, but this time including some chemotherapy based studies, because this is a chemotherapy based trial. But you see KEYNOTE-one hundred and eighty one and KEYNOTE-sixty one response rates in the second line for immunotherapy are quite poor.
And this is the PAC monotherapy arm also showing the sort of benchmark rates for response for single agent paclitaxel around the 15% to 17% rate is what you see in the RAINNBO trial as well. So here you see PFS average second line again in that 8 to 10 week range in the chemo based studies and overall survival around 7 months. So if we look on the next slide, this is the waterfall plot of the DKN-one plus paclitaxel trial. And immediately what you see is that there's a substantial response rate in this heavily pretreated population. So 25% response rate with a 60% disease control rate.
And that's something that we really haven't seen that often in later line esophageal trials. Chemo based 3rd line trials, you're talking single digit responses. So next. Here is sort of the summary slide of all the data. Overall survival of 14.1 months.
So this is take it with what it is, but it's impressive data set. Looking at an overall survival, this is essentially almost a doubling of what was seen in some of those prior second line trials. It's also important to note that this trial incorporated squamous cell patients, adeno, GE junction and gastric, of which several of the other trial trials have not because the squamous patients have done poorly historically. So this is actually even a little bit more encouraging. What you also see is on the prior taxane exposure patients, there was activity, albeit a little bit lower, which is what you would expect in a taxane pretreated patient, but still the ability to salvage some activity of a taxane after prior taxane is a clinically relevant tool in a space where we have very limited options.
And so what we see in the group of patients who were treated in the true second line setting, which is the best comparator to what I showed on the slide before, we see a PFS of around 19.6 weeks and that OS, like I said, is around 61.1 weeks, so 14 months, which is a substantial improvement from prior second line study. In the patients who are more heavily pretreated, the bottom row of the prior therapy line, you see this is still encouraging activity, 11.8 week progression free and 6 month overall survival is certainly comparable or better than historical controls. Next slide. This is just looking at the overall survival. So we see the 61 week median overall survival like we talked about.
Again, you see there's no clear grouping here, perhaps there's a little bit of enrichment in the gastric and GE junction patients. But if you look at the response rate and I think response rate is a very important factor when we're looking at these studies, because tumor shrinkage means improved symptom control and better quality of life. So you see the response rate to paclitaxel and ramucirumab, which is arguably the gold standard in the 2nd line setting is around 27%. And here we see a response rate of 46%. And so these are patients who are not only benefiting and having improved progression free survival, but they're actually having better symptom control because they have less tumor.
And then this is showed graphically along the bottom with the PFS and OS curve, where you can see that there is an impact on the line of therapy. So in the true second line setting, you see the greatest level of activity and that's to be expected. Next slide. So hopefully what I've shown you over the last few minutes is that this is a very difficult, but very important disease space. So it's a huge global market, the 3rd leading cause of cancer related deaths in the world.
There's a substantial unmet need and our prior therapies have been disappointing. Looking at the 2 DKN-one studies in combination, we see clearly that the taxol combination has substantial activity, particularly in the second line setting. And then the exciting combination of DKN-one plus pembrolizumab has both a preclinical rationale and then that has borne out in the clinic where we're able to clearly see improved outcomes and not only that, but you can narrow it down within a biomarker selected population. So the DKK1 high subgroup, that progression free survival and overall survival in later line is really quite impressive in my opinion. So the totality of the data and monotherapy, chemo combination and PD-one combination, I think it's built quite a nice story for further development.
And as is highlighted here, some potential spaces to move into, including the triplet combination, because when you have a safe and well tolerated drug, it's actually much easier to build around. So there's a lot of excitement in the GE and gastric community about how to build upon this. So I will turn this over to the next speaker and happy to take questions toward the end.
Thank you, Doctor. Klepner. Now I would like to introduce Doctor. Rebecca Arant at the University of Alabama Birmingham Comprehensive Cancer Center who will be giving a presentation on endometrial cancer and carcinosarcoma and her clinical experiences with DK101.
That introduction and that was a presentation by Doctor. Newman and Doctor. Klefner. Let's start with the first slide. I think similar to what was previously stated about the GI cancers, endometrial cancer is similar in the fact that it is very hetero genius, and we have not seen quite as good of remarkable responses to targeted therapies that we've seen in things like lung cancer.
It's the most common GYN cancer in the Western world and it's the 4th most common cancer in women in the U. S. Interestingly, the incidence is actually increasing. More specifically than that, it's categorized into 2 types. So Type 1 is sort of your traditional type that we think of.
It's obese women. We have signs such as postmenopausal bleeding. We catch it early. Type 2 is more aggressive. That's more of your carcinosarcoma and your non endometrioid histologies.
And those are actually specifically the ones that are increasing in incidence and also increasing in the death rate, specifically in earlier age women. So it is significantly, an unmet need in our area. If you look at the 5 year overall survival rate, so this chart right here shows you both Type 1 and Type 2 carcinome sorry, Type 1 and Type 2 endometrial cancer. So while like localized disease, 95% survival at 5 years and it's only 67% of all Type 1 and Type 2 endometrial cancer. If we were to separate that into just Type 2s, it would probably look more like the metastatic disease.
So that's where I think really the very early signals that we're seeing in carcinosarcoma, which I'm going to get to later, are extremely exciting. Next slide. So if you look at the NCCN guidelines for patients with endometrial cancer, patients who have localized cancer, usually all we do is a simple hysterectomy and bilateral salpingo oophorectomy and they are cured. Sometimes we will do chemotherapy before surgery, very rarely. If the cancer spreads to distant areas of the body, then usually it's has many modes.
First, we start with surgery almost primarily followed by chemotherapy. There's a huge debate going on right now. You will never get 2 physicians to agree on whether or not just to give chemotherapy, combine chemotherapy with radiation, do sandwich therapy. So there's a lot of controversy there. But almost always, if it's spread beyond the pelvis, we start with surgery and then there is some sort of adjuvant therapy following that.
So cancer that spread beyond the uterus and it can't be removed with surgery and those certain circumstances sometimes we will do chemotherapy or radiation first followed by surgery or there are patients that can't undergo surgery alone and we just do chemotherapy followed by hormonal therapy or a combination of the 2. Next slide. So here's where we sort of get into the nuts and the bolts of it and what we heard a phenomenal presentation previously on sort of the scope of biomarkers in oncology and where we are headed. I mean, I think across all tumor types, that is 100% where the field is headed, is how can we identify patients who are going to respond to certain treatments and then spare others from the toxicity when they won't respond. And if you look at, the pathway mutations, endometrioid cancer, so you see the CTNNB1, which is the beta catenin mutation is as high as 25%.
What's significant to that is if you put it in the context of sort of ovarian cancer, where the field has basically done a 180 and patients are now cured who have even a somatic BRCA mutation with PARP inhibitors and it's completely changed the field. I think that's really going to be where we're headed in all cancers. And so this is extremely exciting. More specifically, honestly, you look at ARID-1A1 mutations, which is as high as 35% to 40% in endometrioid, I think more exciting is the fact that if you look over to carcinosarcoma, the Type 2, 25% had ARID-1 hundred and eighty one mutations. And you'll see in some of my next slides that one of our phenomenal responders with monotherapy, had carcinosarcoma actually that one was endometrial or endometrioid rather, but had an ARID-1A1 mutation.
So I think these are all sort of exciting areas. And then I also wanted to put that into the context. So if you look at the serous cancers, which are just as aggressive as carcinosarcoma, ERBB2 amplification, which is HER2, is about 25% to 30%. And we just recently had a trial that was presented showing the benefit of Herceptin maintenance therapy in the upfront setting. And while Herceptin is already FDA approved for multiple tumors, that probably will be the new paradigm shift for serous cancer.
So I do see this as potentially the future of these sort of biomarkers is potentially not only in the recurrent setting, but kind of moving up into the upfront setting and potentially being able to use these as maintenance therapies and potentially cure some of these patients that we have extremely limited options. Next slide. So this is based on some of the GE or the esophageal data, which obviously is much more mature than the GYN studies. But the remarkable response that was seen with DKN-one with a patient with CTNNB1 mutation showing the baseline CT scan on the right of 40 millimeters shrinking down to 14 millimeters. And then even after the discontinuation of the paclitaxel, remaining on monotherapy, a durable response, which is remarkable with this type of mutation and would not likely be seen otherwise, which we've seen similar results in GYN cancer.
Next slide. So if you look at the rationale, similar to what was discussed previously, the fact that DKK1 levels are correlated with poor prognosis and we have seen that in all GYN cancers. So the higher the expression is of DKK1, the higher the stage is and the poor the overall survival is. So the fact that those are the patients that are responding is even more exciting. We also see that malignancies that have activated wntbeta catenin signaling mutations such as the ones we saw in the previous slide such as, CTT and B1 show higher levels of tomorrow DKK1.
What I think is also very exciting in the preclinical space because I do both preclinical and also clinical is in my lab we're actually trying to really look at how targeting the Wnt pathway potentially could reverse that sort of hot cold signature and that might be why we're seeing these durable responses with the combination with immunotherapy because potentially by targeting the Wnt pathway that's allowing us to take a tumor that's traditionally sort of a cold tumor and turning it into one that looks more like an MSI high or high mutational burden tumor and responding to pembro in a way that it wouldn't otherwise. So activated beta catenin signaling mutations seem to occur early in the process and like I said or what's been stated before really are associated and we're trying to figure out exactly why, but they seem to be associated with immune exclusion, which is why those are also the patients that are not responding to pembro. So more reason why this is such an exciting area in the context of how much immunotherapy has also exploded in the oncology space. Next slide. So this is just sort of a schematic of the mechanism of action of why ZKK1 potentially leads to immune evasion.
So the left hand side, you see cell death occurring, and then DKK1, which is very interesting if you look at the details of how it correlates with the Wnt pathway because it actually inhibits the Wnt pathway. It's sort of a negative feedback loop. So when you get an up regulation Wnt pathway, then your tumor tries to secrete more DKK1 to automatically turn your tumor off. So the higher your Wnt pathway is turned on, higher levels of DKK1 go up. And those lead to further NK cell mediated clearance of proliferative clusters, which we think are really the cells that are not responding to chemotherapy.
So the chemo insensitive cells or cancer stem cells and may lead to these huge micro metastasis. So if we can figure out how to target those cells, that is extremely exciting in the field. Next slide. So just to give you a snapshot into the ongoing trial that we have, again, it's not quite as far along as the GI, but here's the scheme of the trial. So it's a basket study and I think that the design of it is unique and is going to give us a ton of information for two reasons.
One is the fact that each arm also has a monotherapy. So we are able to see what DKN-one does as a single agent, not only in terms of efficacy, but also in terms of side effects. And from my experience, my patients who have been on single agent DKN-one have 0 side effects. I mean, it's extremely well tolerated. So in each of these arms, it's broken up into basically 2 major groups, which the endometrial and the ovarian.
Sorry, let me take a sip of water. And then within that, it's broken up into patients with mutations and without. So similar to what we've seen previously, we're able to sort of pull out how much is the mutation benefiting. And then beyond that, it's the single agent versus the combination. So next slide.
So this is showing you the So if you look at the right hand side, all patients that had any benefit did have a Wnt signaling alteration and the one patient that had the least benefit had no mutation. But if you look at the chart at the bottom, the number of enrolled patients while small 23, the evaluable patients are 12 and if you look at the partial response which is 2 and the stable disease which is 5. So that's more than 50% which are getting some clinical benefit. And these are heavily pretreated patients where we don't even really have a good second line option, much less a 3rd line option with, what looks to be a durable response and a potential biomarker. Next slide.
So this is the spider plot showing you a similar thing. You see that greater than 50% of the patients with the Wnt signaling alteration at the bottom of the line are showing efficacy, decrease in tumor size with a durable response with just the monotherapy, if they have a mutation. Next slide. So this is the patient that I was referring to before. So she's a heavily pretreated 60 year old patient, who sometimes we are actually putting these patients because the physician gets to choose whether we put them on combination or monotherapy.
So a lot of times the patients that we're putting on monotherapy, the reason why we're doing it is because they can't tolerate Taxol. So the fact that this lady was put on monotherapy basically because she's chewed through other types of chemotherapy, and had this kind of durable response with just monotherapy is actually quite remarkable. She was enrolled in July of 2018, and then initially we saw a 37.5 percent reduction after 8 cycles and then after 10 cycles, she actually had a 56.2% reduction, and again tolerated the treatment extremely well. Next slide. So here we see the combination of this is including both the monotherapy and the combination paclitaxel plus DKN-one.
And again, in the waterfall plot to the right, we see more response in the DKK1 high patients, and less of the DKK1 low patients, again suggesting that potentially this is, a good biomarker for this population in figuring out which patients will and will not respond. Next slide. And here, as was mentioned before, patients with beta catenin activating mutations we know express higher levels of DKK1. What would be interesting is and that we will be able once we have all the data, we'll be able to dive into this a little bit deeper. But my suspicion is that more than just beta catenin mutations, but other mutations such as ARID-1a1 may be correlated with higher levels of DKK1.
And we can see that if you look at the right hand score or the right hand side, that shows you the beta catenin APC or RNF43 mutations and the higher levels of DKK1H scores. And we have seen in both of these trials or all of these trials that we've discussed thus far that those patients seem to have a better response. And this is exciting to have this type of biomarker for patients moving forward. Next slide. So if you look at the breakdown between progression free survival in patients with activating mutations versus those with no mutations, you can see the separation and the survival curves.
And if you look at the chart on the bottom, the progression free survival, and if we had similar charts and showing you previous data, your progression free survival with recurrent endometrial cancer is going to be less than 6 months. So the fact that we have 31.6 weeks, which is much longer than 6 months in our patients with mutations, is exciting. And similar to what was seen in the GI cancer on the right, the hazard ratio of 0.5 if you have a Wnt activating mutation showing that that is a good biomarker for these patients and they are getting a significant durable response. So this is equally unprecedented and equally as exciting as what was discussed previously with, the GI cancer in this space. Next slide.
If you look at the wntbeta catenin activating mutations in prior IO therapy, similar trends, that more important than whether or not you had prior IO is whether or not you have a wnt mutation. So the green and yellow showing a separation with longer, more durable responses with an activating mutation versus the red and blue with no Wnt mutation. Next slide. So here's where the sort of very exciting for me because uterine carcinosarcoma is an extreme area of unmet need. This is the most aggressive of all of our progression free and overall survival historically.
So the fact that this is one patient, she's a 46 year old female, she had recurrent uterine carcinosarcoma, previously heavily pretreated, she received DKN-one and paclitaxel, and her first scan revealed a partial response of 61%, with a complete resolution for her lung nodules, which I can guarantee we would not have seen with single agent taxol, and this is likely driven by her beta catenin mutation in that nodule. Next slide. So a little bit more on uterine carcinosarcoma. So it's very interesting because it's sort of 2 types of cancer that kind of merge as one. What we didn't know previously was whether it was actually 2 cancers coming together or one that just morphed into something extremely poor and aggressive.
Now we know that it probably starts as sort of a well differentiated cancer. And the reason why it looks like 2 cancers is because it's become so poorly differentiated, which accounts for its aggressive nature. While it's less than 5% of all uterine cancers, it's by far the most aggressive. 50% are diagnosed with metastatic disease beyond the pelvis, and the 5 year survival is on the order of 15% for advanced stage disease. But even in patients with stage 1 disease, we always treat them with adjuvant chemotherapy because of the aggressive nature.
So just very, very hot off the press recently published data, actually not published, presented at ASCO, but not published yet, was our upfront trial comparing what was the historic control, which was ifosyntaxol to carbotaxol, which is much better tolerated. And so now the new paradigm will be to treat all patients with carcinosar sarcoma in the upfront setting with paclitaxel. So then it becomes what to give them at the time of first recurrence. And this trial is an excellent option for patients all over the country if they recur, which most will, because we really don't have a second line. Ithosfamide would be the best choice, although as a single agent does not have great efficacy.
Next slide. So again, limited numbers, but we've had 4 patients that enrolled in our original study. So 3 patients that were treated with the combination, one that was treated with the monotherapy. 2 patients had clinical benefit and both had beta catenin mutations. 1 actually had a partial response and then one had a prolonged stable disease with monotherapy alone, which is quite remarkable.
3 patients have DKK1 high tumors. So now we've opened it to an additional arm 56 in order to look at the same sort of schema in carcinosarcoma specifically. So looking both the monotherapy and the combination in patients with and without an alteration, so that we can really tease out which patients benefit from the monotherapy and from which mutations they potentially have. Next slide. So in conclusion, endometrial cancer and carcinoid sarcoma patients clearly are a small subset, but are an aggressive population with very limited number of chemotherapy agents.
The fact that we've seen benefits from monotherapy and that there is a potential biomarker is extremely exciting. We know that when beta catenin mutations lead to higher levels of DKK1, those patients traditionally do worse and those patients are the ones that we're seeing the most durable response. It's extremely safe, in addition to the fact that it's safe in combination with paclitaxel with no additive toxicities, which was similar to what the prior speaker had mentioned, and is extremely well tolerated. So I will be updating all of our data, in September in Brazil at IGCS, but this is just a snapshot into our data thus far. So thanks for giving me the opportunity to present it.
Thank you, Doctor. Arend. You can go to the next slide. So we are very excited about the clinical data for DK101 and the potential that the drug has to treat patients with difficult to treat cancers for which the current therapies are not very effective. We believe that the data presented by Doctor.
Kleffner provides the foundation for late stage development programs in esophagogic cancer. Specifically, we intend to combine DK101 with paclitaxel in esophageal cancer patients and to combine DK101 with an anti PD-one or PD L1 antibody in DKK1 high GE junction gastric cancer patients. Our emerging data in endometrial cancer and carcinosarcoma could provide another important therapeutic opportunity for DK101. We are pleased by the initial responses and the disease stability and are continuing to follow the long term outcomes and enroll new carcinosarcoma patients. The next data update will come from Doctor.
Arendt's presentation at the International Gynecologic Cancer Society Annual Global Meeting in September in Brazil. In order to aggressively evaluate new biomarker directed populations and to test different anti PD-one or PD L1 antibodies, we have supported a series of investigator initiated studies. These studies will be providing data over the next 6 to 24 months and could open up new patient populations in prostate cancer, hepatobiliary cancer and softgastric cancer. We believe that the studies allow for the broad exploration of DKAN-one in a capital efficient manner. Due to the broad potential applicability of DKAN-one in several cancer indications and the prevalence of many of these indications in China and the rest of Asia, we are undertaking a business strategy to obtain a partner or partners for late stage development and to expand our capabilities in China and Asia.
Thank you to Doctor. Klimtner and Doctor. Aran for their participation in today's program, and thank you all for your time and attention today. We'd now like to open the call for questions. Operator?
That concludes our prepared remarks. We will now open the call to your questions. Our first question comes from Wangzhi Li of Ladenburg. Your line is open.
Hey, good morning. Thanks for taking my question. I have a few. Starting with the question on the KEYTRUDA combo in saprogia and gastric cancers. So Doctor.
Glenblis showed the KEYTRUDA alone showed about 10% OR in both the suffragal and the gastric subtype of cancers, But the DKM1 plus KEYTRUDA combo should enhance the ORR by 18% in the gastric subtype, but I think 0% in the suffragile subtype. I know it's a small number for the suffragile cohort, about 16 efficacy value of patients. But could you share some thoughts on why the difference and show enhancement in the gastric, but no effect on the subtype. And does that do you see that kind of indirectly support DGN-one as a main contributor to the benefits seen in the gastric subtype rather than the KEYTRUDA?
Yes, thanks. That's a great question. I think it's going to be a little bit tough to give you a granular answer with pretty small numbers. But as you probably know, true esophageal cancer above the has worse outcomes in general with immunotherapy. When you look at the KEYNOTE-one hundred and eighty one compared to say, 6 1, which are really probably as close as data sets as we'll have to compare.
What we also don't have complete data about is the, DKK1 status of all the esophageal patients. The data that I presented is the DKK1 status for the junction and gastric cancer patients where clearly that looks like a predictive biomarker. So I don't know if I'm going to be able to give you the best answer. If you look back on, say, Slide 22 and some of the demographics, the numbers are really, really small for esophageal. So 14 patients, 18 esophageal of the PD L1 naive, and we don't have DKK1 status to present for all those patients.
I just don't know if I'm going to be able to give you a better answer. I think what we can say is that the activity that's seen in the gastric and GE junction, it's interesting enough, in my opinion, to clearly target development in that area. Plus, it honestly represents a much larger proportion of our patients in general. Certainly in Asia, they do have more esophageal cancer, so it's ton of gastric cancer. And that's probably where we may see activity.
There may be some biological differences. There certainly are in the genetic differences between esophageal and esophagogastric cancers in terms of rates of cutaneous pathway mutations and molecular subtypes, particularly the squamous being entirely different than the adenos. So I don't know if I answered your question completely because I think it's limited by the amount of data that we have. But I can say that certainly within the sorry, go ahead.
That is helpful. Thank you. And then another question is about the PD-one, PDI-one refractory patient. I know it's a very small number. You have 6 efficacy value patients at 3 stable disease, right?
Could you share more some more information about these 3 patients? What their baseline conditions look like before the DGN-one? And how long are the duration of their step of disease status? Any further color?
Yes. I think there's been a little bit of I know from being involved in the trial that certainly there's been benefit clinical benefit in those stable patients. And this is a it's a patient population that really we don't know what to do with at all. And within the patients with stable disease, what I do know is that those are DKK1 high patients. So perhaps the combination may be able to salvage the patients who are refractory to monotherapy, particularly those with DKK1 high.
You're talking about 3 patients, so we can't really say a lot more than that. But it was quite interesting to hypothesize if PD L1 refractory patients who are DKK1 high could be salvaged with the addition of DKN-one, that would be something sort of that we haven't figured out how to salvage PD L1 refractory patients in any setting. I think that's probably about all I can say for the PD L1 refractory patients.
So actually you mentioned that my question is for these 3 step patients, the refractory cohort, are the PKK1 high or low? Do we know the status? High. Still high?
Yes.
Okay. What do you any further thoughts on DGN-one showed benefit in the PD-one naive patient independent of the PD-one status, but stability in the refractory patients.
I mean, I think both of those are equally exciting observations. The PD L1 negative patients who are immunotherapy naive, who are immunotherapy naive, the expectation for that patient from KEYTRUDA monotherapy and from KEYNOTE-fifty nine, for example, the response rate was about 6%. So if you can expand the proportion of patients who are responding with a combination, and in fact, the drug is not even approved for the PD L1 negative population as you know. I think you have something that's very exciting. And if you can even narrow that even further with BKK1 status, then I think that's even more interesting.
The separate observation that the stable disease in PD L1 refractory has sort of best response, those are patients who really have no options and they often have a higher burden of disease and aggressive disease. So I think the fact that there is able to be stable disease and clinical benefit in that population and that the biomarker seems to align with the benefit. I think those are about the most important conclusions we can make from such small number of 3 patients.
Got it. Okay. So one more question is also about the peglitaxel combo. If we compare the peglitaxel combo versus the KEYTRUDA combo in the subtype, the chemo clearly should have I mean, is a cost trial by should have better outcome so far. If you look at the gastric junction subtype, those showed, I think, around 80% for the KEYTRUDA and 25% of Tekzo combo.
So it looks pretty comparable. So what do you think in terms of which combo is better for the gastric subtype, the chemo or the KEYTRUDA? Or the KEYTRUDA combo is mostly for the DKN-one high patient? And also, do you know the however, look at the DKN001 L score in the paclitaxel combo patient? Is any correlation also the responses mostly occur in the TCAN-one high patient?
So don't have DKK1 status on the paclitaxel, DKN-one combination and the biomarker data sort of emerged over time. And so it's there's a small subset, I think, that will be reported at a later date. But to get back to your question, I mean, this is really a problem of trial comparing 2 trial populations. It's not exactly the same patients in the 2 different studies. Certainly, there is a larger proportion in the taxol study of true second line patients.
This is around 16 of the total patients were only one prior line of therapy, which is a little bit different than the pembro plus dK-one study. Only future trials are going to answer your question, but I think that there's enough in the totality of the data to suggest that perhaps both should be pursued or even consideration for a triplet because of the tolerability of the drug. Certainly, in the second line space, there is a benchmark gold standard, but it is not that great. But it's been able to beat single agent pembrolizumab and single agent paclitaxel. So I think combinations both with pembro and taxol with DK101 are interesting.
I think that comes down to sort of a pathway towards ultimate approval and registration, which informs the trial design to some degree. So I don't know if I can tease out an answer from the available data if pembro plus DEACON is better for gastric than taxol plus DEACON. Certainly, there's a lot of attraction in having a chemo free potential regimen. And I think what you can say is that within the GE junction and gastric cancer that does seem to be where pembro and DK101 had a greater activity, particularly in the DKK1 high patients and within the taxol plus dK1 patients, response rate was around 25%, which is comparable to the paclitaxel plus Cyramza standard of care. But we don't know if the benefit would be substantially better in DKK1 high patients because we just don't have that data yet.
Our next question comes from Swayampakula Ramakanth of H. C. Wainwright. Your line is
open.
Thank you. Just a question for Doctor. Kempner. When we look at the Slide 29, the waterfall plot, I'm just trying to find out, understand what's the difference in the patients, though the 4 patients or so that had high DKK1 also experienced progressive disease compared to the 5 that experienced partial response. So, is there a difference in that other biomarkers or anything else?
Yes, that is a fair question. I mean, I think that on that waterfall plot, among the patients who progress, certainly, there are a fair amount in the stable disease area. So within the 2 kind of error bars, plus 20 minuteus 30 for RECIST. But you're right, there are some ZKK1 high patients that progressed. And I think that that there is no perfect biomarker and gastric and esophageal cancers are very complex and heterogeneous.
I don't have off the top of my head full clinical data to say that, oh, maybe that person had a substantially higher tumor burden at baseline, some other negative prognostic factors like liver full of tumor. I think those are important things to tease out as biomarker development proceeds. Is it independent beyond other clinical markers? It looks to be so far from what's been tested and from what I've seen. But certainly those are that's a fair question.
But I would say that within the esophagogastric space, we have yet to see any biomarker that has been quite as predictive as this within the immunotherapy markers that we've seen outside of perhaps microsatellite instability and EBV positive tumors, which are extremely uncommon. I think that's probably all that I can say about the DKK1 high progressing patients.
The other question I have for you is, I believe the KEYNOTE-sixty two study had shown pembro in CPS greater than or equal to 10. There was an improvement in overall survival. When you compare that against or when you consider that data against what you're seeing in the current study, how should we think about the biomarkers or biomarker analysis of the patients, so that we can try to figure out what's the right or you as a physician can try to figure out what's the right kind of treatment. Would you go for like the combo or just the monotherapy on either one of these drugs?
Yes. So first, let me say, KEYNOTE-sixty 2 was a first line study in combination with PLATINUM and 5 SEU, and the trial was negative. So the although there was a subset that looked like there may be a benefit in the CPS greater than 10, the overall trial is negative. So I would be very surprised if the FDA used that data to approve pembrolizumab in the first line setting. So in terms of the overall treatment landscape, I don't think KEYNOTE-sixty two is going to change anything, which means that immunotherapy is still relegated to the greater than two lines in the United represents an extremely small minority in the U.
S. Where we don't see a lot of squamous. In terms of biomarker, broad biomarker development in esophageal gastric cancers, I mean there's well established standards, which grant access to currently approved therapies, microsatellite instability, PD L1 and HER2 are the approved biomarkers. The safety of DKN-one in combination with pembrolizumab and whether or not you would have DKK1 high funneled toward a particular therapy is something that remains to be seen. I think you need a little bit more data to tease that out.
But we have a fairly large data set of pembrolizumab treated patients to suggest that PD L1 alone is not a great biomarker. I mean, if your biomarker separates the response rate from 6% in the PD L1 negative to 9% in the PD L1 positive microsatellite stable patients, That is not a particularly discriminating feature. Whereas the DKK1 status early on, you're looking at a response rate of 50% in the high patients, which is a dramatic improvement suggesting that this is a real biologically relevant biomarker where PD L1, I think you can make the argument that it's the poor man surrogate, especially in the low PD L1 patients. Composite biomarkers, I think, are important. We don't know all the ones to use yet.
Tumor mutational burden is another one that has fallen out. And there's a Phase 2 trial that was just published in the Annals of Oncology, suggesting that in gastric cancer patients with a tumor mutation burden greater than 14, it was able to identify the responders to single agent PD L1. And I think it's important to note in the DK101 study that the average mutation burden was 5.5 mutations per megabase. So these are patients who would not have been the responders based on either PD L1 or mutation burden. So I think there's a lot to do with biomarkers, but this is I think this was one looks to be relatively independent thus far.
Thank you. Thank you for the additional clarity.
Our next question comes from David Novak of Raymond James. Your line is open.
Good morning. Thanks for taking my questions. Some very nice durable responses shown here today. Just one question for me. And Doctor.
Klemmner, you sort of touched on this with the previous analysts, but in the DKN-one plus pembro gastric GEJ cohort, I'm also just trying to reconcile the few DKK1 high non responders. And I think there are also a few DKK1 low responders and maybe I'm oversimplifying here, but baseline tumor burden definitely seems like an ideal variable to look at here. Have you specifically looked at baseline tumor burden as it seems reasonable that perhaps lower baseline tumor burden may have been correlated to response, but I'd love to see that data if you have it.
Yes. So first, I can say that if you look at the slide that was referred to Slide 29, I don't assume you guys can see that as well. One thing that falls out is the response rate of 0% in the DKK1 low and 50% in the DKK1 high. But equally clinically relevant is the durable or the clinical benefit rate or disease control rate. And so you see that there the biomarker continues to perform well where you see a durable clinical benefit rate of essentially 80% or disease control rate of 80% versus 20% in the DKK1 low.
So even though DKK1 high patients who are not in the RECIST response category, which you see the 3 patients who have stable disease, stable disease is a clinical win. That's a person who has control of their disease and is able to remain on a well tolerated study and maintain a quality of life. I think that's an important observation to include in addition to response. Response rates are certainly important, but progression free survival and overall survival are also more important in terms of hard clinical outcomes. I don't have the data in front of me to look at the say, the 2 patients who had progressive disease and the one non evaluable DKK1 high patient.
I agree with you that other clinical factors, including liver metastases, overall tumor burden, location of disease, duration of response to prior therapies. I mean, as I mentioned before, this is a very heterogeneous population. So there certainly are some other features, genomic and clinical, which are known to be associated with just an aggressive disease biology that no therapy was going to salvage. I think it's a fair question to look into and perhaps we can look at that on the lead side. Queue.
Our next question comes from Yale Jen of Laidlaw. Your line is open.
First, thanks for and glad you guys have a very congrats on the very good outcomes from both indications. Just a quick question for Doctor. Aaron. As I mentioned in the GI tumor that seems to be 2 third of is the high and 1 third was PKK low. Is that the same sort of breakdown for the gynecological cancers or that different from different sort of subsets of tumors?
I think it's too early to tell in our numbers. I don't think we have data universally to know, across all endometrial cancer, what proportion of ZKK1 high just because it hasn't been looked at extensively. So I think it's too soon to know for sure, but we will be able to have that when this trial is complete.
Okay, great. That's helpful. And maybe just one follow-up question here, which is that I came in a little bit late, I might have missed that. And in terms of the safety profile of PKAN-one, could there of you maybe just some overview of their safety profile, their AE profile and I appreciate that.
I mean, I can say from GYN, I've had almost 0, adverse events at all in monotherapy. It's been extremely well tolerated, not even like a touch of nausea or lab abnormalities or anything.
Okay, great. Thanks a lot. Again, congrats on the readouts.
And we are showing no further questions. Thank you again for dialing in to today's call.