Good day, everyone, welcome to the Leap Therapeutics DKN-01 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 Dr. Cynthia Sirard, Vice President of Clinical Research and Development of Leap Therapeutics. Please begin.
Thank you, operator. Welcome, and thank you to those of you joining us today for an update on Leap Therapeutics' DKN-01 development program. I'm Cynthia Sirard. With me today are Douglas Onsi, the Chief Financial Officer at Leap, Walter Newman, a Vice President of Research at Leap, Dr. Samuel Klempner, an Assistant Professor of Massachusetts General Hospital Cancer Center and Harvard Medical School, and Dr. Rebecca Arend, an Assistant Professor and Associate Scientist in 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 two. 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 10-Q, as well as other reports filed with the SEC. Any forward-looking statements represent our views as of today, August 6th, 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 three. Good day. Today, we are hosting a call to allow our investigators to share their clinical insights on our DKK-1 targeted antibody, known as DKN-01. 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, Dr. Walter Newman will start by providing a brief overview of the biology of DKK-1, its role in cancer, the preclinical data which supports our development program, and our understanding of the mechanism of action of DKN-01. I will transition the presentation to two investigators participating in our clinical studies. Our first speaker is Dr. Samuel Klempner, Assistant Professor at Massachusetts General Hospital and Harvard Medical School. Dr. Klempner will discuss treatment of patients with esophageal gastric cancer and present data from the clinical study evaluating DKN-01 in combination with pembrolizumab, marketed by Merck as KEYTRUDA. Dr. Klempner will also review the data from the combination of DKN-01 and paclitaxel chemotherapy in the study. We will hear from Dr. Rebecca Arend, Assistant Professor and Associate Scientist, Gynecologic Oncology Clinic, University of Alabama Comprehensive Cancer Center Experimental Therapeutics Program.
Dr. Arend will provide background on endometrial cancer and carcinosarcoma and review her clinical experience with DKN-01 as a monotherapy and in combination with paclitaxel. We will end the call by opening the floor to questions for Dr. Klempner, Dr. Arend, or any of us from Leap. Turning to slide five and Dr. Newman.
Thank you, Dr. Sirard. Referring to slide five then, DKK-1 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, DKK-1 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 DKK-1 being produced by the tumor cells. We are developing an antibody that binds and inhibits the activity of DKK-1, known as DKN-01. We have evaluated DKN-01 in a variety of preclinical and clinical studies. We believe that DKN-01 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 six. High levels of DKK-1 correlate with shorter overall survival. When we began working on DKK-1, we decided to focus our efforts on cancer indications where DKK-1 was known to be associated with a poor prognosis. Published data demonstrated that patients whose tumors expressed elevated levels of DKK-1 had worse survival outcomes, as can be seen in this TCGA analysis of over 10,000 patient samples where patients with high levels of DKK-1 had two and a half years shorter overall survival than patients with low levels of DKK-1. Similar data had been published for esophageal gastric cancer, biliary tract cancer, and non-small cell lung cancer. As a result, we targeted these indications first. Turning to slide seven. DKK-1 can promote tumor growth in several ways.
At Leap, we have been extremely interested in studying how DKN-01 works in order to provide support for the clinical program. DKN-01 and its murine version has anti-cancer 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 DKN-01 requires a functioning immune system in order to work in shrinking a tumor, and that specifically, DKN-01 requires the activity of Natural Killer cells that can target the tumor. In addition, DKN-01 also upregulates PD-L1 expression on myeloid-derived suppressor cells and tumor cells. These immune mechanisms give us insight into the best combination strategies for anticancer activity. Now turning to slide eight. Natural Killer cells are part of the innate immune system.
Drugs that target the innate immune system are expected to provide additional antitumor benefit to PD-1 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-01 and PD-1 antibodies have additional activity over either antibody alone. This provides preclinical support for the clinical efficacy of DKN-01 in combination with Merck's PD-1 antibody, KEYTRUDA, which will be presented in a few minutes. Now please turn to slide nine. We study DKN-01 in tumor models that produce high levels of DKK-1 in order to most closely resemble patients whose tumors are producing high levels. We have also seen that DKN-01 has high anti-angiogenic activity, which reduces blood vessel density feeding the tumor and contributes to the antitumor response.
In these models, such as the A549 model of non-small cell lung cancer shown here and the PC3 model of prostate cancer, DKN-01 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 DKK-1-positive prostate cancer. We will now transition to Dr. Klempner to discuss the treatment of patients with esophagogastric cancer and present data from our clinical study evaluating DKN-01 in combination with KEYTRUDA.
Thank you, Dr. Newman and Dr. Sirard. My name is Sam Klempner. I co-lead the gastric and esophageal program at Mass General Hospital in Boston. As you can imagine, we were quite attracted to this as a therapeutic compound. If you're not familiar with esophagogastric cancer, it is actually the third leading cause of global cancer-related deaths. You can see from this slide that there is a clear discrepancy between U.S. and outside of the U.S. cases. On the next slide, this is a little more granular. Here we see the data for esophageal cancer from the GLOBOCAN. This is the WHO data colorized by incidence, with the darker colors representing higher incidence areas. You see that in China, esophageal cancer represents a major cancer with 13.9 cases per 100,000 individuals.
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. In the U.S., although this is a lower incidence cancer, there is some data that it's actually increasing in younger individuals. On the following slide, we see that this is a disease that has a very poor prognosis. Unfortunately, by the time we find patients in the United States, over half of them are diagnosed with advanced disease, so cancer that has spread outside the stomach. In those patients, we have limited treatment options. Unfortunately, our standard of care therapies have been met with minimal improvements in overall survival over the last two decades.
If you look at the graph, most of our clinic is focused on the people with distant metastases, where you see the five-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 esophagogastric cancers. 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. 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 quickly. In fact, Medicare claims data suggests that only about 40% of U.S. esophagogastric cancers receive second-line therapy.
Some of that has 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 esophageal cancer. They're actually unique among the GI cancers in terms of the degree of chromosomal instability and molecular heterogeneity. We have a high degree of tumors composed of multiple subclones, where some may have the target and others will not. Single-agent targeted therapies have met with very limited success, with Herceptin being the only approved therapy. Although in absolute terms, Herceptin only adds about two months of overall survival when added to standard of care chemotherapy. Next slide. This is the current status of care in the Western world, primarily U.S. and Europe.
As we said, we're focused on advanced patients with esophageal cancer, which is distinguished from gastric and GE junction cancers because the actual biology is somewhat different. 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 third 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.
On the right side in the gastric space, similar pathway except the anti-VEGFR2 monoclonal antibody ramucirumab is approved in the 2 line, where it's been shown to improve survival when added to paclitaxel. We have the recently approved LONSURF in the 3-line setting. I think the takeaway from this is that there is limited overall options and that the later in lines of therapy you go, the response rates and magnitude of benefit drop off quite substantially. Next slide. To put a little bit of granularity to what I just said with regards to the immunotherapy activity, here you see the benchmark immunotherapy study. 2 line and 3 line. Response rates, you see nothing above 13%. In the microsatellite stable, which is about 96% of the patients, single-digit response rates with PFS.
You're talking six to eight weeks here with overall survivals of half a year at best. Next slide. 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-731 DKN-01 plus pembrolizumab. Relatively straightforward design. You can see there's a small lead-in, and then immediately up to the dosing of every two-week DKN-01 with standard of care pembrolizumab every three weeks. There you can see the proportion of breakdown between PD-1 naive and PD-L1 refractory, both which represent substantial unmet needs in esophageal gastric cancers. Next slide. This will frame the following slides, but this is a heterogeneous population that was included in the trial, all heavily pretreated. This is essentially a real-world reflection of what we deal with.
What we'll see is that patients with high tumoral DKK-1, as you may have predicted from the preclinical data, may have improved outcomes. DKK-1 high GE junction patients, this is perhaps the most interesting aspect. A response rate of 50%, a median progression free survival of five months. That's in contrast to the 1.5 to two months and a median overall survival of 7.3 months. We see that this is actually an independent of PD-L1, CPS scores do not predict efficacy, unlike with KEYTRUDA monotherapy, where there certainly is an increase in activity in the positive patients. DKK-1 high has a strong association with efficacy and outcome along independent of prior therapies. We'll see some data with the paclitaxel trial as well. Next slide. This is the breakdown of the trial 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, a little over 50% in both cohorts. Otherwise, this is a largely representative trial population in second and third-line patients. You see majority ECOG PS1. Almost everyone was diagnosed at stage 4 disease, which is what we see in the U.S. The median time since diagnosis is variable, depending on if they presented with early stage or metastatic disease. Next slide. This is something that's always important to look at when we're evaluating later line therapy trials, how many prior lines of therapy. What you see is the majority of patients have had two or more prior lines of therapy. This is a heavily pretreated patient where the benchmark response rate is around 9% or 10%.
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. On the right-hand side here in the column, again, this is the primary group we'll be focusing on. As per other immunotherapy and non-immunotherapy trials, this is divided between esophagus, both adenocarcinoma and squamous, and GE junction and gastric. That division is based on differential outcomes and biology that has been observed across prior trials. Here you see the biomarker status for the standard biomarkers. CPS1 to less than 10, 48% 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.
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. Tumor mutational burden, which has actually some data in gastric cancer suggesting a cutoff of around 14 to predict response to immunotherapy. Unfortunately, that's a very small minority. What we see here is that most of these patients have a low tumor mutation burden with a 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. This is the safety data, and we'll see that this drug has been well-tolerated, and I can certainly speak to that clinically. Any treatment emergent 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-01. You see 8.2% and 9.8% related to pembrolizumab. This is sort of first snapshot to suggest that this is a safe drug. Next slide. Again, this is confirmed in the breakdown of the toxicity based on DKN-01 attribution versus pembrolizumab related attribution. Really what we look for here is not only the frequency of events but the severity. What you can see is the greater than three, grade 3 events is uncommon. This is consistent with a single agent monotherapy data. 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, et cetera. Next slide. We'll get into the meat of the trial here, and this is the waterfall plot that's broken down both by, of course, response, but also by tumor type as colorized here. 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. Similarly, you see the stable disease patients. Those are the purple lines within the RECIST kind of error bars. Again, those are all GE junction and gastric cancers. We see that the progressive disease is, again, that's based on the sheer numbers.
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. 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. Here on the prior, we had depth of response, and now we're looking at durability. Again, what's highlighted in green bars and the purple is the GE junction and gastric cancers. You see that the majority of the lines are falling below with some decrease in tumor change. 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 six, seven, eight, nine 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 DKK-1. This is something that's feasible and also has relative clinical utility. Here, IHC was a consideration, but RNAscope has emerged as perhaps a preferential biomarker. This slide is showing you the difference between a positive and negative DKK-1 H-score. 163 you see up top is a DKK-1 high tumor and a negative control. You see a patient, a non-responder with low DKK-1. We'll see more about this on the next slide. This is a graphical way of showing the response based on biomarker status. What is very clear here is that the responding patients are grouped based on an elevated level of DKK-1 expression.
You see the H score increasing there. You see the GE junction and gastric cancers. You see the majority of responders, the blue dots are grouped in the high DKK-1 score. This to me, when I saw this was perhaps the most exciting thing because what we've been lacking is an ability to identify patients reliably who are really going to derive the most benefit and perhaps spare people who are not going to derive any benefit. The logical questions was, is this just something that's in the tumor or in the stroma or in the immune cells? What you see here is that this is clearly a tumor-side biomarker. All of the DKK-1 staining is essentially localized to the tumor. You see very little expression in the stroma or in the immune cells. Next slide.
When you try to examine those DKK-1 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. You see the overall population, the GE junction and gastric cancers represents a significant portion of them. This is actually quite good for an early phase trial in order to get specimens and collect them for analysis. Often we expect 70%-ish rates of biopsies, here we see actually substantially better than that. Another thing that this 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.
Here we see this is actually quite a clinically relevant incidence of a biomarker. Out of those 31 patients, 11 of them are DKK-1 high. That's a substantial portion of any gastric and esophageal population. What you see here in the waterfall plot, which is now color-coded by DKK-1 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 DKK-1 high. This is really interesting data. You show the same thing in the spider plot, the DKK-1 high tumors, you see the durability of response. The scale has changed 200 days and over. These are durable responses, which is of course what we want to see and is hard to come by in the later line settings. Next slide.
These are just smaller numbers but important to see. The progression-free survival here clearly associated with DKK-1 high status. These curves separate quite substantially early on and stay quite separated. This is exactly what you want to see. Again, comparing to those benchmark studies we talked about in the beginning, a median PFS here in the biomarker-enriched population, the DKK-1 high, median PFS of 22 weeks. That is almost tripling of the median PFS of six to eight 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. What you see here from the evaluable data set is that this holds true for overall survival. What's important to note is that this is not just a good prognostic biomarker.
We saw from Dr. Newman's presentation earlier that these are actually patients who inherently do worse. DKK-1 high tumors have a shorter overall survival. This is an aggressive disease population, and here their outcomes have been substantially modified by the drug. This is a substantial improvement in survival. We see 31.6 weeks, which is over six months, which is an improvement well beyond what is seen with our currently available options. Next slide. This is a slide really showing that looking at the anti-PD-L1-naive population, this is the majority of patients on the trial. You see that in some prior IO studies, it's emerged that people who have had 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 1 line of prior therapy, so people who are on the trial in the second line versus people who've had more than one, both of those groups you see responders in. Not only just a couple but durable responses. 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 were going to respond to KEYTRUDA and the DKK-1 is adding unclear benefit? That turns out not to be the case at all. These are patients who actually cover all the bases of CPS expression.
As you can see in the bottom left, the waterfall plot, there is no correlation really between CPS status, high expression versus low expression and outcome. There is clearly a correlation between DKK-1 status and outcome, but not PD-L1 status. Again, we see this in two figures, the left and right showing the same thing, in terms of incidence of response and durability of response. In tabular format, we see that there is roughly a real-world breakdown of CPS status within the patient population. The 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. Here you see all of the biomarkers essentially overlaid on each other. Again, this is the same evaluable set of the immunotherapy-naive population.
What you see is clearly the DKK-1 high patients. The blue bars to the right are the responders. 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. CPS score as it has been in some large immunotherapy trials is not really a predictor of PFS at baseline. Here we're seeing the same thing. 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 that population.
If you were to overlay DKK-1 high versus low, you're clearly segregating out the two populations, which is what we're of course trying to do with any biomarker. 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 DKK-1, just driving home the point that clearly DKK-1 high is able to separate these populations. DKK-1 high versus low, clearly you're favoring the DKK-1 population and same thing with all of these other subgroups. The take-home again is that you can segregate out two populations with your biomarker, which is really the goal for any biomarker in 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. 27 patients of the 34 had available PD-L1 status, and you can see the breakdown as it was shown on prior slides. Clearly, these curves are all crossing very early on and frequently, so there's no clear subgroup within the PD-L1 status that's benefiting. Next slide. The other question we would be asking is, does DKK-1 predict for PD-L1 status? The answer is no. Here, DKK-1 expression is not associated with overall survival. This is melanoma data treated with pembro or nivo alone and not significantly differently responding versus non-responding urothelial patients. Here are just two progression-free survival curves and overall survival curves from published data sets. You can see high DKK-1 and low DKK-1 and high DKK-1 and low DKK-1 for these two melanoma populations.
Not separating out the populations. These are not DKN-01 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. As Dr. Newman explained, this is one of the mechanisms that the drug works via. 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-1 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.
Same thing, this is an analysis from public sequencing data looking at beta-catenin scoring and T cell inflamed signature. 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. 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 given pembrolizumab alone. Next slide. There's actually data from a prior DKN-01 study looking at a similar patient population with standard of care paclitaxel. To me, this is an equally important data set. This is the trial design where patients were enrolled.
We see the demographics on the right, get a biopsy, standard of care paclitaxel with every two-week DKN-01, the same schedule that was given in the prior study. Here we see similar breakdown, primarily GE junction, a little bit fewer gastric. Prior therapy, you see these are also heavily pretreated patients, substantial portion of which have received prior taxane. Responding to taxane after prior taxane is something that's always a problem. Also prior ramucirumab. Again, this is a trial attacking a unmet need in a heavily pretreated population. Next slide. Again, here is the same slide, this time including some chemotherapy-based studies, because this was a chemotherapy-based trial. You see KEYNOTE-181 and KEYNOTE-061 response rates in the second line for immunotherapy are quite poor.
This is the PAC monotherapy arm, also showing the sort of benchmark rates for response for single agent paclitaxel around the 15%-17% rate is what you see in the RAINBOW trial as well. Here you see PFS average second line, again, in that 8-10 week range in the chemo-based studies and overall survival around seven months. If we look on the next slide, this is the waterfall plot of the DKN-01 plus paclitaxel trial. 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. That's something that we really haven't seen that often in later line esophageal trials. Chemo-based third line trials, you're talking single digit responses. Next. Here is sort of the summary slide of all the data. Overall survival of 14.1 months.
This is, take it with what it is, but it's an 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 prior trials have not because the squamous patients have done poorly historically. 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. Still, the ability to salvage some activity of a taxane after a prior taxane is a clinically relevant tool in a space where we have very limited options.
What we see in the group of patients who are treated in this 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, around 61.1 weeks, so 14 months, which is a substantial improvement from prior second-line studies. In the patients who are more heavily pre-treated, the bottom row of the prior therapy line, you see this is still encouraging activity, 11.8-week progression-free and a six-month overall survival is certainly comparable or better than historical controls. Next slide. This is just looking at the overall survival. 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.
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. You see the response rate to paclitaxel and ramucirumab, which is arguably the gold standard in the second-line setting, is around 27%. Here we see a response rate of 46%. 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. This is showed graphically along the bottom with the PFS and OS curves, where you can see that there is an impact on the line of therapy. In the true second-line setting, you see the greatest level of activity, and that's to be expected. Next slide.
Hopefully what I've shown you over the last few minutes is that this is a very difficult, but very important disease space. It's a huge global market, the third 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 two DKN-01 studies in combination, we see clearly that the Taxol combination has substantial activity, particularly in the second-line setting. The exciting combination of DKN-01 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. Not only that, but you can narrow it down within a biomarker selected population. The DKK-1 high subgroup, that progression-free survival and overall survival in later-line is really quite impressive in my opinion.
The totality of the data, the monotherapy, chemo combination, and PD-1 combination, I think it's built quite a nice story for further development. 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. There's a lot of excitement in the GE and gastric community about how to build upon this. I will turn this over to the next speaker and happy to take questions toward the end.
Thank you, Dr. Klempner. Now I would like to introduce Dr. Rebecca Arend at the University of Alabama at Birmingham Comprehensive Cancer Center, who will be giving a presentation on endometrial cancer and carcinosarcoma and her clinical experiences with DKN-01.
That introduction. That was a presentation by Dr. Newman and Dr. Klempner. 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 heterogeneous. 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. It's the fourth most common cancer in women in the U.S. Interestingly, the incidence is actually increasing. More specifically than that, it's categorized into two types. Type 1 is sort of your traditional type that we think of. It's obese women. We have signs such as post-menopausal bleeding. We catch it early. Type 2 is more aggressive. That's more of your carcinosarcoma and your non-endometrial histologies.
Those are actually specifically the ones that are increasing in incidence and also increasing in the death rate, specifically in earlier age women. It is significantly an unmet need in our area. If you look at the five-year overall survival rates, this chart right here shows you both type 1 and type 2 endometrial cancer. While localized disease, 95% survival at five years, and it's 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. 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.
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 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 two physicians to agree on whether or not just to give chemotherapy, combine chemotherapy with radiation, do sandwich therapy. There's a lot of controversy there. Almost always, if it's spread beyond the pelvis, we start with surgery, and then there is some sort of adjuvant therapy following that.
Cancer that's spread beyond the uterus and it can't be removed with surgery, in those circumstances, sometimes we will do chemotherapy or radiation first, followed by surgery. There are patients that can't undergo surgery alone, and we just do chemotherapy, followed by hormonal therapy or a combination of the two. Next slide. 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 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?
If you look at the Wnt pathway mutations, endometrioid cancer, 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. This is extremely exciting. More specifically, honestly, if you look at ARID1A mutations, which is as high as 35%-40% in endometrioid, I think more exciting is the fact that if you look over to carcinosarcoma, the type 2, 25% have ARID1A mutations. 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 ARID1A mutation. I think these are all sort of exciting areas. Then I also wanted to put that into the context. If you look at the serous cancers, which are just as aggressive as carcinosarcoma, ERBB2 amplification, which is HER2, is about 25%-30%. We just recently had a trial that was presented showing the benefit of Herceptin maintenance therapy in the upfront setting. While Herceptin is already FDA approved for multiple tumors, that probably will be the new paradigm shift for serous cancer. I do see this as potentially the future of these sort of biomarkers.
It's 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. This is based on some of the GE or the esophageal data, which obviously is much more mature than the GYN studies. The remarkable response that was seen with DKN-01 with a patient with CTNNB1 mutation, showing the baseline CT scan on the right of 40 mm shrinking down to 14 mm. 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.
If you look at the rationale, similar to what was discussed previously, the fact that DKK-1 levels are correlated with poor prognosis, and we have seen that in all GYN cancers. The higher the expression is of DKK-1, the higher the stage is and the poorer the overall survival is. The fact that those are the patients that are responding is even more exciting. We also see that malignancies that have activated Wnt beta-catenin signaling mutations, such as the ones we saw in the previous slide, such as CTNNB1, show higher levels of tumoral DKK-1. 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.
That might be why we're seeing these durable responses with the combination with immunotherapy. 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. Activated beta-catenin signaling mutations seem to occur early in the process, and like I said, or what's been said 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. 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.
This is just sort of a schematic of the mechanism of action of why DKK-1 potentially leads to immune invasion. The left-hand side, you see cell death occurring. DKK-1, 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 is sort of a negative feedback loop. When you get an upregulation of the Wnt pathway, your tumor tries to secrete more DKK-1 to automatically turn your tumor off. The higher your Wnt pathway is turned on, higher levels of DKK-1 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 they lead to these huge micrometastasis.
If we can figure out how to target those cells, that is extremely exciting in the field. Next slide. 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. 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-01 does as a single agent, not only in terms of efficacy, but also in terms of side effects. From my experience, my patients who have been on single agent DKN-01 have zero side effects. It's extremely well-tolerated.
In each of these arms, it's broken up into basically two major groups, which is the endometrial and the ovarian. Sorry, let me take a sip of water. Within that, it's broken up into patients with mutations and without. Similar to what we had seen previously, we're able to pull out how much is the mutation benefiting. Excuse me, beyond that, it's the single agent versus the combination. Next slide. Got it. This is showing you the response. This is the waterfall plot, again, small numbers. It's showing you the response of the monotherapy. 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.
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 two, and the stable disease, which is five, so that's more than 50% which are getting some clinical benefit. These are heavily pre-treated patients where we don't even really have a good second-line option, much less a third-line option, with what looks to be a durable response and a potential biomarker. Next slide. 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.
This is a patient that I was referring to before. She's a heavily pre-treated 60-year-old patient. Sometimes we are actually putting these patients, because the physician gets to choose whether we put them on combination or monotherapy. 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. 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. Shows she was enrolled in July of 2018, and then initially, we saw a 37.5% reduction after eight cycles, and then after 10 cycles, she actually had a 56.2% reduction. Again, tolerated the treatment extremely well. Next slide. Here we see the combination.
This is including both the monotherapy and the combination paclitaxel plus DKN-01. Again, in the waterfall plot to the right, we see more response in the DKK-1 high patients, and less of the DKK-1 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. Here, as was mentioned before, patients with beta-catenin activating mutations, we know express higher levels of DKK-1. 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 ARID1A, may be correlated with higher levels of DKK-1.
We can see that if you look at the right-hand side, that shows you the beta-catenin APC or RNF43 mutations, and the higher levels of DKK-1 H-scores. 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. 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 in the survival curves. If you look at the chart on the bottom, the progression-free survival, and if we had similar charts in showing you previous data, your progression-free survival with recurrent endometrial cancer is going to be less than six months.
The fact that we have 31.6 weeks, which is much longer than six months, in our patients with mutations, is exciting. 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. 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 Wnt beta-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. 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. 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 endometrial cancers. They do not respond well to our traditional chemotherapy. They almost always recur and have a very poor progression-free and overall survival historically. The fact that this is one patient, she's a 46-year-old female. She had recurrent uterine carcinosarcoma, previously heavily pre-treated. She received DKN-01 and paclitaxel, and her first scan revealed a partial response of 61% with a complete resolution of her lung nodules, which I can guarantee we would not have seen with single-agent Taxol. This is likely driven by her beta-catenin mutation in that nodule. Next slide. A little bit more on uterine carcinosarcoma.
It's very interesting because it's sort of two types of cancer that kind of merge as one. What we didn't know previously was whether it was actually two cancers coming together or one that just morphed into something extremely poor and aggressive. We know that it probably starts as sort of a well-differentiated cancer. The reason why it looks like two 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. The five-year survival is on the order of 15% for advanced stage disease. Even in patients with stage 1 disease, we always treat them with adjuvant chemotherapy because of the aggressive nature.
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 IFOS and Taxol, to CarboTaxol, which is much better tolerated. Now the new paradigm will be to treat all patients with carcinosarcoma in the upfront setting with paclitaxel. Then it becomes what to give them at the time of first recurrence. 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. Ifosfamide would be the best choice, although as a single agent does not have great efficacy. Next slide. Again, limited numbers, but we've had four patients that enrolled in our original study.
Three patients that were treated with the combination, one that was treated with the monotherapy. Two patients had clinical benefit and both had beta-catenin mutations. One actually had a partial response, and then one had a prolonged stable disease with monotherapy alone, which is quite remarkable. Three patients have DKK-1 high tumors. Now we've opened it to an additional arm V and VI, in order to look at the same sort of schema in carcinosarcoma specifically. 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. In conclusion, endometrial cancer and carcinosarcoma 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 DKK-1, 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. 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. Thanks for giving me the opportunity to present it.
Thank you, Dr. Arend. You can go to the next slide. We are very excited about the clinical data for DKN-01 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 Dr. Klempner provides the foundation for late-stage development programs in esophageal gastric cancer. Specifically, we intend to combine DKN-01 with paclitaxel in esophageal cancer patients and to combine DKN-01 with an anti-PD-1 or PD-L1 antibody in DKK-1 high GE junction gastric cancer patients. Our emerging data in endometrial cancer and carcinosarcoma could provide another important therapeutic opportunity for DKN-01. 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 Dr. Arend'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-1 or PD-L1 antibodies, we have supported a series of investigator-initiated studies. These studies will be providing data over the next six to 24 months and could open up new patient populations in prostate cancer, hepatobiliary cancer, and esophagogastric cancer. We believe that the studies allow for the broad exploration of DKN-01 in a capital-efficient manner. Due to the broad potential applicability of DKN-01 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 Dr. Klempner and Dr. Arend for their participation in today's program. 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. If you would like to ask a question, please press star then one. If your question has been answered and you'd like to remove yourself from the queue, please press the pound key. Once again, to ask a question, that's star then one. Our first question comes from Wangzhi Li of Ladenburg. Your line is open.
Hey, good morning. Thanks for taking my question. How are you? Starting with the question on the KEYTRUDA combo in esophageal and gastric cancers. Dr. Klempner showed KEYTRUDA alone showed about 10% OR in both the esophageal and the gastric subtype of cancers. The DKN-01 plus KEYTRUDA combo should enhance the OR by 18% in the gastric subtype, but I think 0% in the esophageal subtype. I know it's a small number for the esophageal cohort, about 16 efficacy evaluable patient. Could you share some thoughts on why the difference and show enhancement in the gastric but no effect on the esophageal subtype? Do you think that kind of indirectly supports DKN-01 as a main contributor to the benefit seen in the gastric subtype rather than the KEYTRUDA?
Yeah, 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 junction has worse outcomes in general with immunotherapy. When you look at the KEYNOTE-181 compared to, say, 061, which are really probably as close a data set as we'll have to compare. What we also don't have complete data about is the DKK-1 status of all the esophageal patients. The data that I presented is the DKK-1 status for the GE junction and gastric cancer patients, where clearly that looks like a predictive biomarker. 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. 14 patients, 18 esophageal of the PD-L1 naive, and we don't have DKK-1 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 is 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 something to not ignore. They also have a 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 cadherin pathway mutations and molecular subtypes, particularly the squamous being entirely different than the adenos. I don't know if I answered your question completely because I think it's limited by the amount of data that we have.
Yeah
certainly. Sorry, go ahead.
Yeah, it's helpful. Thank you. Another question is about the PD-1, PD-L1 refractory patient. I know it's always a small number. You have six efficacy evaluable patients out of three stable disease, right? Could you share more information about these three patients? What their baseline conditions look like before the DKN-01, and how long or the duration of their stable disease status? Any further color?
Yeah, I know from being involved in the trial that certainly there's been clinical benefit in those stable patients, and it's a patient population that really we don't know what to do with at all. Within the patients with stable disease. What I do know is that those are DKK-1 high patients. Perhaps the combination may be able to salvage the patients who are refractory to monotherapy, particularly those with DKK-1 high. You're talking about three patients, so we can't really say a lot more than that. It's quite interesting to hypothesize if PD-L1 refractory patients who are DKK-1 high could be salvaged with the addition of DKN-01. That would be something 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.
You actually mentioned, and my next question is: for these three stable disease patients, the refractory cohort, are they DKK-1 high or low? Do we know the status?
High.
They're all high?
Yes.
Okay. Any further thoughts on DKN-01 showed benefits in the PD-1 naive patient, independent of the PD-L1 status, but stable disease in the refractory patients?
I think both of those are equally exciting observations. The PD-L1 negative patients who are immunotherapy naive, the expectation for that patient from KEYTRUDA monotherapy from KEYNOTE-059, for example, the response rate was about 6%. If you can expand the proportion of patients who are responding with the 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. If you can even narrow that even further with DKK-1 status, then I think that's even more interesting. The separate observation that the stable disease in PD-L1 refractory as sort of best response, those are patients who really have no options, and they often have a higher burden of disease and aggressive disease.
I think the fact that there was 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 three patients.
Got it. Okay. One more question also about the paclitaxel combo. If we compare the paclitaxel combo versus the KEYTRUDA combo, in the esophagus subtype, the chemo clearly showed-- it's a cross-trial, but it showed a better outcome so far. If you look at the gastric or gastro junction subtype, also showed, I think around 80% for the KEYTRUDA and 25% of paclitaxel combo. It looks pretty comparable. What do you think in terms of which combo is better for the gastric subtype, the chemo or the KEYTRUDA? The KEYTRUDA combo is mostly for the DKN-01 high patient? Also, do you know, have ever looked at the DKN-01 score in the paclitaxel combo patient? Is any correlation also the responses mostly occur in the DKN-01 high patient?
Don't have DKK-1 status on the paclitaxel DKN-01 combination, the biomarker data sort of emerged over time, there's a small subset I think that will be reported at a later date. To get back to your question, this is really a problem of comparing two trial populations. It's not exactly the same patients in the two different studies. Certainly, there was 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 DKN-01 study. Only future trials are going to answer your question, 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.
In the second-line space, there is a benchmark gold standard, it is not that great. It's been able to beat single-agent pembrolizumab and single-agent paclitaxel. I think combinations both with pembro and Taxol with DKN-01 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. I don't know if I can tease out an answer from the available data if pembro plus DKN-01 is better for gastric than Taxol plus DKN-01. There's a lot of attraction in having a chemo-free potential regimen. I think what you can say is that within the GE junction and gastric cancer, that does seem to be where pembro and DKN-01 had a greater activity, particularly in the DKK-1 high patients.
Within the Taxol plus DKN-01 patients, response rate was around 25%, which is comparable to the paclitaxel plus CYRAMZA standard of care. We don't know if the benefit would be substantially better in DKK-1 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 Dr. Klempner. 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. The four patients or so that had high DKK-1 also experienced progressive disease compared to the five that experienced partial response. Is there a difference in the other biomarkers or anything else?
Yeah, that is a fair question. I think that on that waterfall plot, among the patients who progress, certainly there are a fair amount in the stable disease area. Within the two error bars, + 20, - 30 for RECIST. You're right, there are some DKK-1 high patients that progressed, and I think 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 a 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. Certainly, that's a fair question.
I would say that within the esophageal gastric 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 DKK-1 high progressing patients.
Okay. The other question I have for you is, I believe the KEYNOTE-062 study had shown pembro in CPS greater than or equal to 10, there was an improvement in overall survival. 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 or you as a physician can try to figure out what's the right kind of treatment? Would you go for the combo or just the monotherapy on either one of these drugs?
Yeah. First, let me say, KEYNOTE-062 was a first-line study in combination with platinum and 5-FU. The trial was negative. Although there was a subset that looked like there may be a benefit in the CPS greater than 10, the overall trial is negative. I would be very surprised if the FDA used that data to approve pembrolizumab in the first-line setting. In terms of the overall treatment landscape, I don't think KEYNOTE-062 is going to change anything, which means that immunotherapy is still relegated to the greater than two lines in the United States, except for esophageal CPS greater than 10 squams, where it was just recently approved. Again, that represents an extremely small minority in the U.S. where we don't see a lot of squams.
In terms of broad biomarker development in esophageal gastric cancers, 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-01 in combination with pembrolizumab and whether or not you would have DKK-1 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. We have a fairly large data set of pembrolizumab-treated patients to suggest that PD-L1 alone is not a great biomarker. If your biomarker separates a 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 DKK-1 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's 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 II 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. I think it's important to note in the DKN-01 study that the average mutation burden was 5.5 mutation per megabase.
These are patients who would not have been the responders based on either PD-L1 or mutation burden. I think there's a lot to do with biomarkers, but I think this 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 question. Some very nice durable responses shown here today. Just one question from me, and Dr. Klempner, you sort of touched on this with the previous analyst, but in the DKN-01 plus pembro gastric GEJ cohort, I'm also just trying to reconcile the few DKK-1 high non-responders, and I think there are also a few DKK-1 low responders. 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.
Yeah. First, I can say that if you look at the slide that was referred to, slide 29, I assume you guys can see that as well. One thing that falls out is the response rate of 0% in the DKK-1 low and 50% in the DKK-1 high. Equally clinically relevant is the durable or the clinical benefit rate or disease control rate. 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 DKK-1 low. Even those DKK-1 high patients who are not in the RECIST response category, which you see are the three 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 more important in terms of hard clinical outcomes. I don't have the data in front of me to look at the two patients who had progressive disease and the one non-evaluable DKK-1 high patient. I agree with you that other clinical factors, including liver metastasis and overall tumor burden, location of disease, duration of response to prior therapies. As I mentioned before, this is a very heterogeneous population. 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 Leap side.
Great. Thanks for the additional color. I'll hop back in the queue.
Our next question comes from Yale Jen of Laidlaw. Your line is open.
First, thanks for asking. Congrats on the very good outcomes from both indications. Just a quick question for Dr. Arend. As I mentioned in the GI tumor, that seems to be two-thirds of the high and one-third was DKK-1 low. Is that the same sort of breakdown for the gynecological cancers or that different from different sort of subset 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 DKK-1 high, just because it hasn't been looked at extensively. 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. Maybe just one follow-up question here, which is that I came in a little bit late, I might have missed that. In terms of the safety profile of DKN-01, could either of you maybe just give some overview of their safety profile, their AE profile? I appreciate that.
I can say from GYN, I've had almost zero adverse events at all in monotherapy. It's been extremely well-tolerated. Not even a touch of nausea or lab abnormalities or anything.
Okay, great. Thanks a lot. Again, congrats on the readout.
Once again, if you'd like to ask a question, please press star then one. We are showing no further questions. Thank you again for dialing in to today's call.