Good afternoon, and welcome to the Leap Therapeutics Virtual KOL Event. At this time, all attendees are in a listen-only mode. A question-and-answer session will follow the discussion. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player. As a reminder, this call is being recorded, and a replay will be made available on the Leap website following the conclusion of the event. Just as a reminder to everyone, this presentation will include forward-looking statements. I'd now like to turn the call over to Dr. Cyndi Sir, Chief Medical Officer at Leap Therapeutics. Please go ahead, Cyndi.
Thank you. It's a pleasure today to be joined here with Dr. Zev Wainberg. Dr. Wainberg is a Co-Director of the GI Oncology Program at the University of California, Los Angeles, UCLA. He is a Professor of Medicine and an Academic Medical Oncologist at the David Geffen UCLA School of Medicine, specializing in gastrointestinal malignancies. In addition to being the Co-Director of the GI Oncology Program, he is also Medical Director of the Pancreas Cancer Center at UCLA and the Director of the Early Phase Clinical Research Program at the Johnson Comprehensive Cancer Center at UCLA. Dr. Wainberg has treated patients with Sirexatamab for several years in our clinical trials and is the lead principal investigator in our ongoing DEFIANCE study of Sirexatamab plus bevacizumab and chemotherapy in patients with colorectal cancer who have received one prior line of therapy for their advanced disease.
Dr. Wainberg, most of our listeners are aware that colorectal cancer are aware of colorectal cancer and have probably experienced a colonoscopy and had a relative or friend diagnosed with this deadly disease. To set the stage to talk about the clinical trial and Sirexatamab, can you provide some background about what colorectal cancer is and what is happening to cause a patient to come to the clinic for treatment?
Hi, and thanks for welcoming me here. I'm happy to chat about colon cancer generally and in particular on the DeFianCe trial. I mean, obviously, colon cancer is the most common GI malignancy in the United States, and we diagnose about 150,000 people a year on the basis of usually either symptoms or colonoscopies. Patients are about 40% of those patients present with stage four metastatic disease, which means they're treated from the get-go with palliative chemotherapy combinations. We try to, in those circumstances, provide effective therapies both to shrink existing tumors, to relieve symptoms, but also to prolong progression-free and overall survival.
Great. Thank you for that background. When a patient with colorectal cancer presents, what are their options for initial treatment, and what are your expectations for how a patient may benefit from this first-line therapy? In addition, what are the current expectations for overall survival in newly diagnosed patients with advanced colorectal cancer?
In advanced colorectal cancer, we try to assess a number of biomarkers from the get-go to see if they may be patients that would benefit from one of several targeted therapy combinations, whether that includes immunotherapy, such as in the rare subtype of MSI high or BRAF mutant patients, which is also rare. The reality is that the large majority of patients do not have any actionable biomarkers in either first or second line. Patients are generally treated with combination chemotherapy, which for the most part in the United States has revolved around a regimen of FOLFOX, the majority of whom are treated with bevacizumab. There are some patients treated with an EGFR inhibitor upfront. It all depends on, again, some of the clinical characteristics, but most, the majority of patients are treated with combination chemotherapy with a very standard regimen of FOLFOX bevacizumab.
That probably covers about 70% of the patients.
Yeah, perhaps you can mention a little bit about the paucity of new agents that have entered into the paradigm or the treatment paradigm for colorectal cancer in the recent decade.
We've had some success, obviously, but it's been limited by rare subgroups. The challenge is we haven't been able to move beyond, let's say, a BRAF inhibitor or MSI high, either in front or second-line metastatic colon cancer, because these biomarkers are very rare. The reality is that the majority of patients, up to 60%-70%, don't have any actionable biomarkers that we're aware of in this disease. One of the challenges has been, how do we develop drugs for the biomarkers that we're not aware of? Those include any number of patients, both from RAS wild type and RAS mutant tumors. We have been stuck here in this disease, and in particular in second-line therapy, where the standard of care hasn't changed for close to 20 years.
Great. Thank you. As you think about first-line options for patients, let's specifically discuss bevacizumab, what its mechanism of action is, what percentage of patients do you think might receive this agent in the front line, and what might be the reasons or risks that patients wouldn't receive bevacizumab as part of their front-line regimen?
I mean, the majority of patients receive bevacizumab for a few reasons. Number one, because it's well tolerated, and we have a huge amount of data over a better part of 20 years. Nowadays, most people are using bevacizumab biosimilars, not necessarily the trade name or the originator drug. It's well tolerated. There are very, very few patients who have absolute contraindications. The comfort of the community, both with respect to tolerability and consistent data showing overall survival advantages, which is admittedly old data but still relevant to the field, has led it to become the de facto standard of care. That has not changed, and we do not expect that to change because it is such an entrenched standard.
Yeah. Do you think that there are geographic differences in the pattern of uptake of the use of bevacizumab in the front line?
I don't know. I mean, my sense is no. I think pretty much there are some patients who you would maybe consider an EGFR inhibitor upfront, but that's got to be a very rare patient population, usually RAS wild type, left-sided tumor. In the United States, even though there has been some suggestion that there's some benefit in that group, it hasn't had the uptake, primarily because of toxicity. The majority of patients do get bevacizumab globally.
Great. Speaking specifically of bevacizumab, what are your expectations on how a first-line patient may do on bevacizumab plus standard of care chemotherapy as it relates to your standard clinical efficacy endpoints, such as response rate, progression-free, and overall survival? To follow on that, do you think that there's a need for additional therapies that could perhaps enhance these clinical outcomes for patients moving forward?
I mean, we definitely need new therapies for, that's the easy question. We definitely need new therapies for pancreatic cancer, excuse me, for colon cancer and pancreatic cancer. For colon cancer, certainly we need new therapies. We haven't had anything new for a long time in this disease outside of rare subsets. We need something that's going to complement the existing standard of angiogenesis inhibitors with bevacizumab. We know that the majority of patients are treated upfront with FOLFOX- Bev, second-line FOLFIRI- Bev, third-line TAS-102- Bev. The continuity of angiogenesis inhibition isn't going away. We have to complement that somehow with new drugs.
Great. This is a disease also when you approach second line or even as they're in first line that is slightly different from other malignancies, whereby there are a number of potential curative or thought to be curative type surgeries or interventions that can be used in this disease, such as oligometastatectomies or other local curative therapies. Clearly, it impacts survival outcomes, both in progression and overall survival. I would bet that you see kind of some of those impacts kind of target or kind of assess it when you're in a clinical study. It's kind of hard to necessarily assess progression-free survival because physicians are opting to put some of their patients on or use some curative intent therapies.
Yeah. I mean, we do a lot of procedures in colon cancer nowadays, generally speaking, whether it's surgeries or whether it's ablations or whether it's chemoembolizations. There's all sorts of procedures going on. The linear transition between first and second line is usually cobbled with multiple procedures along the way. It's not as straightforward, let's say, paradigm as some other cancers where they transition from one regimen to another. There's a lot of sidesteps.
Right. Right. Despite these intended front-line potential curative therapies, unfortunately, most patients with advanced disease do see their tumors relapse. What is the conversation that you have with patients who are considering second-line therapy, and what treatments—we've already talked a little bit about the treatments that you offer them—but when do you really think it's necessary to start second-line therapies?
I mean, a very large majority of patients, obviously all virtually, progress on front-line therapy. We need to have a good effective standard of second-line therapies. We approach them with that as we see evidence of disease progression. Now, the majority of patients who progress in colon cancer actually still have a really good performance status and are strong and healthy and can get effective multi-agent chemotherapy in second line. In the United States, like I suggested earlier, the majority of patients are treated with irinotecan, FOLFIRI-based regimens. Again, rare subsets are treated sometimes with other things like the BRAF cohort. The very large majority of patients are treated with FOLFIRI, bevacizumab, and second line.
Great. Do the outcomes for the patients treated with second-line agents depend upon what they've received in the front line? We've mentioned on several occasions that bevacizumab is continued frequently throughout the course of a patient with colorectal cancer and adding in with different combinations. Do you expect the patient's clinical outcomes for those treated, for example, with EGFR or with prior VEGF or those with or without RAS mutations to have different clinical outcomes when treated with a second-line regimen?
Yeah. I mean, there's obviously a lot of heterogeneity in the disease. People are going to do differently. In second line, we haven't changed the paradigm for a long, long time. I think the biomarker stuff has helped some patients, but not a large majority of them. It's often pretty reflex that patients are started on second-line therapy with FOLFIRI, bevacizumab, almost regardless of what they get in front line.
What would you say on average, how long do patients remain on second-line therapy with your experience?
I mean, six months. I mean, that's not a long time. Now, second-line therapy is often also interrupted here and there, but we don't see patients necessarily lasting beyond that in the large majority of cases. It's also something that they tend to progress, and we get ourselves in a situation where we're scrambling for what to do because the durability isn't there as much as we would like.
Okay. Great. All right. With that as the background, let's then transition a bit to talk about Sirexatamab or DKN-01, which is Leap's antibody that targets DKK1. You were one of the physicians who early on suggested that this drug should be evaluated in colorectal cancer patients. What was it about Sirexatamab that interested you, and why did you think it could help patients with colorectal cancer?
I mean, first of all, we know it's a well-tolerated drug. If you're adding to an existing standard of care, you have to make sure that your drug is well tolerated. Having been involved with this compound from the phase one days, I do know full well that tolerability is not an issue. It's an easy antibody to combine with existing antibodies, whether they're bevacizumab or other bevacizumab-based therapies or otherwise. Obviously, early on, we had some hint of a biomarker that could assign patients based on some preliminary results that certainly inhibition of DKK1, including theoretically blocking some activation of the Wnt beta-catenin pathway, is an obvious interest for this disease.
The fact that it is a huge unmet need is also really critical because anytime you can have a drug that shows an increased response rate or signal of progression-free survival is encouraging for further development.
Great. Overall, how many patients have you treated with Sirexatamab? You mentioned this already, but I think your experience with the tolerability and the safety of the agent has been that it's been well tolerated, both as a single agent and in combination, as you discussed. Roughly, overall, how many patients?
I mean, over the years, it's probably been 20-30 patients or so. Had some good enough experience, get a feel for the drug, both in combination, both in a single agent. You get a feel after 20-30 patients what's going on and whether there's something to be worried about from a tolerability angle, which I've not experienced.
Great. Yeah. No, thank you for your perspective there. Before we get into the overall clinical trial data, how would you describe the outcomes for your CRC patients treated with Sirexatamab in particular in terms of impacting their disease?
I mean, anecdotally, I've been pleased with the results. I've had a number of patients who have lasted on this combination much longer than I would have expected that the standard of care would have provided. Obviously, as any individual investigator will tell you, we're all subject to anecdotal experiences, but mine have been favorable. I mean we know which patients get the drug, so we have a feel for whether those patients are doing better than we might expect. Remember, the patients who are enrolling in the study are a large percentage, at least KRAS mutant patients who have a poor prognosis. You know that you get to know after a while what FOLFIRI- Bev gets you.
Yeah. No, understood. Now maybe we can dig into the DEFIANCE study itself. As I think everyone on this call knows, the DEFIANCE study enrolled a total of 188 patients with metastatic colorectal cancer. They were microsatellite stable and BRAF negative. They had all received one prior line of therapy for their advanced disease. In March of this year, we announced that in patients who had high DKK1 plasma levels, either at the upper quartile or above the median, those that were treated with the Sirexatamab arm had a significantly improved response rate, progression-free survival, and overall survival compared to the control arm. In the upper quartile specifically, the Sirexatamab arm had a statistically significant 32% higher overall response rate, a three-and-a-half-month longer progression-free survival, and overall survival that was compared to the control arm.
Additionally, another subgroup that we reviewed in March was those patients who had not received prior anti-VEGF therapy. In the VEGF naive patients, the Sirexatamab arm had a statistically significant 22% higher overall response rate, a 2.6-month longer progression-free survival compared to the control arm, and an early advantage in overall survival. There's a lot of study data to talk about, but let's start with discussing the study population as a whole and then focus in on the two major subgroups that have the strongest outcomes, that being the DKK1 biomarker and the VEGF naive patients. In the overall population, the Sirexatamab experimental arm had a 10.7% higher overall response rate at 36.2% compared to the control arm at 25.5%.
What is your impression of a 10.7% improvement in overall response rate for the experimental arm in the intent-to-treat population and the 36.2% specifically response rate in the Sirexatamab arm? How do you think that that compares with really historical studies, historical benchmark studies for what you would expect in this heterogeneous disease?
Yeah. If you look at response rate, I mean, we have a decent-sized randomized phase two here with almost 100 patients in each arm. We also have a response rate, in my view, that probably exceeds the historical controls of what we would expect from a control arm. Here we have 26%, and the majority of randomized phase two, phase three studies, it's not even 20% in the large majority of patients. Our control arm did a little better, perhaps, than we might have expected. To have more than 10% improvement in response rate, to me, is meaningful. It means that we're onto something. It suggests, of course, that the addition of Sirexatamab to standard control is adding a response rate in a second-line patient population, which has never been demonstrated to date.
If you look at the number of randomized trials in second line, we do not have too many that exceed response rate by 10% in second-line colon cancer. That, to me, is encouraging.
Do you believe specifically in colorectal cancer that response rates are a good surrogate for survival outcomes?
I mean, it's a fair question. I think that it has been our threshold in the past to determine success or failure. I think we need to complement response rate with PFS. I think it's a clue, and it's certainly something we can't ignore. Obviously, hopefully, we're also going to see a PFS advantage shortly here as well in the intent to treat.
Yeah. Yeah. That's a great segue, actually. I mean, we can speak a little bit to the ongoing patients. At the time of the recent data cut back in March, there were 58 patients who remained on study drug with 10 more patients in the experimental arm compared to the control. There were 34 in the experimental compared to 24 in the control arm. Today, there remain 48 patients on study, and the difference between the two arms has increased to now there being 12 more patients that remain on study therapy in the experimental arm with 30 compared to only 18 in the control arm. Overall, that means roughly one-third of all Sirexatamab-treated patients are still on study drug compared to about one-fifth of the control patients.
At the time of the March data update, we noted that the KM curves for progression-free survival were showing an increased separation over time with the potential to continue to mature favorably due to the higher number of patients who continue to be treated with Sirexatamab. Now, just one month later, we see that trend continuing with a larger difference in the number of ongoing subjects favoring the experimental arm. How difficult is it to show a benefit in progression-free survival in patients with colorectal cancer with such a heterogeneous population? How important is it to wait to see the PFS mature in a situation such as this?
I mean, it's trending good. I would agree. I'm pleased by the trend, and we always sort of have these benchmarks in our mind of what we want to see, and we're headed in the right direction. I think it is important. I think we always want to see the PFS complement what we showed in response rate. It bodes well. I'm quite optimistic. I don't think we don't have too many studies where we've had a PFS advantage in second line, I'll point out. To my knowledge, outside of probably the EGFR inhibitors, it's hard to think of one. None to my knowledge that have added to FOLFIRI, BEV-based therapy. This is a well-powered randomized phase two study.
If this study meets its endpoint for progression-free survival, which hopefully it will, this will be a real signal to do a phase three, in my opinion, without question. The PFS, we certainly know, is predictive of OS to a large extent here. If we have a PFS benefit, which hopefully we will in the next short while, that will bode well for the overall survival too.
Yeah. You mentioned that there were very few randomized phase two studies in second line that had been successful in progression-free survival. I'm just wondering, can you think of examples of other drugs where there has been perhaps a delayed effect on PFS similar to what we're seeing here with the tail population really doing better longer term? Are there other examples in colorectal cancer where you may be seeing a similar trend or in other cancers?
Not to my knowledge. I mean, I think immunotherapy, right, has the promise of this kind of tail of the curve situation. I mean, in colon cancer in particular, where immunotherapy doesn't seem to work, and even in PFS studies didn't really clearly show benefits, there aren't too many that are sort of that are great examples of this field. There may be. I'm just off the top of my head, I can't think of one. I would say that what you want is, when you have a response rate improvement, to have that PFS be materially improved. I think we're headed in the right direction for sure.
Yeah. No, that's great. I think we agree that let's keep watching the PFS mature over time for the full ITT population, certainly. That's also a great segue into the discussion of these two important subpopulations that I previously described. Those patients who have high plasma DKK1 levels or those patients who have not seen a prior VEGF therapy previously. We'll start with the DKK1 biomarker population. DKK1 is the target of Sirexatamab. Before discussing the data itself, how important is it to you to understand the impact of the protein that is the target of the drug in assessing the activity of such drug?
I mean, it's always great. I think we know that we have an impact on the DKK1 population. I think that's clear. Selection of patients is something that is not usually done until you're ready for the phase three. I mean, the fact that we have a retrospective improvement in response rate, in particular in the extreme high patient populations, is a good sign. I mean, to be fair, this is always an exploratory biomarker. When you look at exploratory biomarkers, you have to be careful how to interpret all the information. Whenever you have a big difference, like we seem to do here in the high quartile, you can't ignore it. You have to chase it down with more longer follow-up. One would imagine that that's something that we'll want to look at in any phase three study. It's not just about response rate.
It's about, are we able to correlate that with a PFS and maybe down the road, potentially an OS advantage in that high quartile group, which I would be optimistic based on the Kaplan-Meier curves to date.
Yeah. Yeah. No, that's great. I think it's just important perhaps to discuss a little bit on what we've seen so far. We know DKK1 is a secreted protein. We know that it's produced from a number of different factors such as bone, platelets, and it's obviously present systemically in the bloodstream. Here, it's important to understand what the control arm does in the patients with the high DKK1 because obviously, others are not studying this particular subgroup because they don't have antibodies that target this protein. In this study, we've seen as DKK1 levels increase, the control patients actually have worse outcomes than the overall population. Overall, again, the control arm had a response rate of roughly 26%. In the patients with the highest amount of DKK1, the upper quartile, the response rate drops to 16%.
The PFS also is shorter in these subjects with higher DKK1. It drops from around eight months to under six months in the patients with the highest DKK1. This also appears to be a consistent effect regardless of whether or not a patient is VEGF naive or VEGF experienced, has RAS mutations, or is wild-type, RAS wild-type, is left-sided, or has liver or lung metastasis. The control arm response rate is lower in the patients in the DKK1 upper quartile and usually also lower in the patients who are above the DKK1 median. I think it's pretty fair to say perhaps that DKK1 has a negative prognostic effect, and it appears to be a bad thing to have present if there's a lot in circulation. The next question, obviously, is whether inhibiting or blocking it can be beneficial. Let's dig a bit more into that data.
As you mentioned, we have analyzed the data based upon whether the patients were in the upper quartile, the highest 25%, or the upper median, the highest 50% of subjects. In the upper quartile, let's talk a bit about the experimental arm here. The Sirexatamab-treated patients have a statistically significant 32% higher response rate, again, a three-and-a-half-month longer progression-free survival. In the overall survival analysis, there are eight death events in the control arm compared to only one in the patients treated with Sirexatamab. In the upper median analysis, the Sirexatamab arm has a statistically significant 16% higher response rate and longer progression-free survival compared to the control arm. In terms of the upper quartile of patients who remain on study therapy today, there are nine patients in the Sirexatamab arm and only one in the control arm.
What are your overall thoughts on this biomarker, DKK1 biomarker results?
Yeah. I think it's provocative. I mean, I obviously think that it's experimental still, but very encouraging that, number one, it represents the DKK1 population, represents a decent chunk of the patients. The response rate and corresponding progression-free survival improvement in that patient is certainly something good to see even at this early time frame. It's something that we'll need to dive in a lot more, to be fair, when we sort of analyze the final results of the study because we'll want to compare the frequency of this biomarker across multiple variables. I'm encouraged that we seem to have a signal of a few better efficacy endpoints in the particularly high patient population.
Okay. Thank you. As you know, the levels of DKK1 in our study are measured using a plasma-based assay. This is not part of a standard clinical practice today. Do you think that physicians would be willing to use a plasma-based diagnostic test to make treatment decisions if Sirexatamab were approved for biomarker-specific population?
In theory, yes. In theory, yes. It would have to be something that is correlated with a validated assay. We have some work to do still in that regard, to be fair. Yes, I mean, I think everybody's looking for every which way we can for novel biomarkers. Certainly, you always want to see something, a good lead for sure.
Okay. Great. Let's now transition and look at the other major subpopulation driving the overall results. That's whether or not a patient had received prior anti-VEGF therapy. In patients who had not had prior anti-VEGF therapy, the Sirexatamab arm had a statistically significant 22% higher overall response rate and a 2.6-month longer progression-free survival compared to the control arm, with an early advantage in overall survival. Why would you think that a patient who had not had prior anti-VEGF therapy might have improved outcomes when Sirexatamab is added to bevacizumab and chemotherapy?
I mean, it's a fair question, and it is an interesting finding. I think the reality is when you're adding to novel VEGF inhibitors, you expect a little more bang for your buck out of both the VEGF inhibitor and whatever you're adding to it. There could be some synergy, nice synergy going on in that patient population here. While in the U.S., we tend to treat almost every patient upfront with VEGF inhibitors, I should mention it's not uniform. Globally, where the study was conducted, there are certain countries certainly where people are VEGF naive. It's a relevant question. I would imagine that there's some enhanced synergy in that patient population between the two antibodies.
You're on mute, Cyndi.
I'm on mute. Sorry. What are your specific impressions on the progression-free survival data in this population? Much like the other biomarker population, there are more subjects continuing on the experimental arm at 20 Sirexatamab-treated patients compared to only seven patients in the control arm. Does this data suggest perhaps there would be a path to moving into the frontline therapy here where everyone is bevacizumab naive?
Yeah. I mean, I think that's the when you have synergy with the antibody, which makes sense that you would see that in the VEGF naive, then you would have to think about moving upfront. It's a more complex study, obviously, moving upfront because now we'd have to look for much longer duration of treatment. There is something to be considered in that context. If we hit our endpoint, that's going to be a big decision to be made about a frontline patient population.
Great. Thank you. I frequently get asked, what is the is there overlap between these two populations, the subpopulations that we've been discussed, the VEGF naive and the DKK1 high population? I think this is a really important question. Notably, these two populations are clearly independent, meaning that when you do a multivariate analysis, which evaluates the impact of one variable on another, the DKK1 high patients have improved outcomes regardless of the covariates. Furthermore, the anti-VEGF experienced patients who are DKK1 high also do very well on Sirexatamab. It was a 33% overall response rate compared to a 0% overall response rate for the control patients in those DKK1 high VEGF experienced group. This is likely the negative effect of the DKK1 protein. Similarly, the benefit in the patients who are anti-VEGF naive is not limited to just those who are DKK1 high.
Our thoughts are that if you have a lot of DKK1 in circulation, it could be very bad regardless of any other factor or prior therapy that the patients have received. Inhibiting the harmful effects of DKK1 has therapeutic benefits across these DKK1 high patients, including those who have had prior anti-VEGF therapy. In the context of patients who have not had prior anti-VEGF therapy, prior anti-angiogenic therapy, the additive anti-angiogenic effects of Sirexatamab drive patient benefit in a much larger range of DKK1 levels. I don't know if you have more or thoughts on what I just discussed.
No, I think it's plausible and makes sense that that's the hypothesis. We obviously need more of that patient population. To me, it might be worth doing a study looking at that frontline patient population, a signal-seeking study, because those are true VEGF naive patients frontline.
Yep. Yep. Fair enough. Okay. The data that we've been discussing so far has come from the investigators' assessment from the 44 different trial sites across three countries, the United States, Germany, and in South Korea. We've also been sending these scans to Blinded Independent Central Review to confirm the results. In this study, we've seen that the BICR, or the Blinded Independent Central Review, data has been largely concordant with the investigator results. If there are variances, it tends to increase the treatment effects of the Sirexatamab-treated patients. The ORR difference in the ITT population increases from 10.7% up to 17%. What additional confidence does BICR provide to these results, in your opinion?
I mean, it's always more scrutiny. I think it's encouraging that in any randomized registrational study, it'll be part of any analysis. It's important to keep it in mind. When it corresponds, it's nice to see because you're not relying on any individual assessment. I think here we have pretty good concordance, which is, to me, encouraging.
Great. Okay. Now that we've spoken about the study results to date, how do these overall results reflect what you've seen in treating your own patients?
They correspond nicely. I have had, as I mentioned earlier, fairly nice anecdotal results. I have been pleased with how the antibody has performed. I have been pleased with the tolerability profile. Obviously, my personal results correspond quite nicely with the overall results of the study population.
Great. As a final question, do you have any final thoughts on how you think that Sirexatamab in this data compares to other drugs that you've seen in development in colorectal cancer, in particular ongoing phase two studies or other drugs in development right now? Would you like to see Sirexatamab become a potential therapeutic option for your patients?
Yeah. I mean, compared to other second-line therapies, this is, I would argue, one of the better ones out there, one of the better data sets out there, provided we obviously see our PFS advantage, which we're waiting for. I would put that up in compared to a lot of other studies. Now, there has been a tendency to move towards biomarker selection in that patient population second line. I think we have to do much more refinement of our biomarker before we're ready to claim that definitively. I certainly think we would want to do a larger study as our next step if these results are confirmed for progression-free. That has to be done because we would have too good a signal to ignore in a very unmet need.
Thank you very much, Dr. Wainberg, for all of your work on behalf of GI cancer patients and your leadership of the Sirexatamab clinical development program. We'll now open it up to any questions that might have been submitted online or from anyone on the line.
Great. Thank you, Cyndi. Yes, at this time, we will be taking questions from our audience. As a reminder, if you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player. To our analysts that are joining us live, please use the raise hand feature at the bottom of your Zoom to indicate you have a question. Please hold for a brief moment. Our first question comes from Kalpit Patel at B. Riley Securities. Please go ahead, Kalpit.
Yeah. Hey, good afternoon, and thanks for hosting this call. I had one call, maybe one question for the doctor. Maybe can you share your experience with patients who have low levels of DKK1 and how they perform? Because we saw the PFS data that the company has so far, and it looks like in the ITT it was comparable. When they break it down to the high DKK1, they did much better. I am curious if the low DKK1 patients, in your experience, did worse on the experimental group.
We're not privy as investigators to which patients of ours are DKK1 high or low. It's an experimental biomarker that is not—I have no idea which one of my patients are high or low. I couldn't answer that particular question. I mean, I agree with you that often the DKK high, or in this case, the DKK high population may be driving a majority of the benefit. It's probably going to be difficult statistically to claim that, obviously, because of small numbers, but it's plausible. I have no idea which one of my patients are high or low.
Okay. Okay. Cyndi, you mentioned you guys have updated numbers today in terms of how many patients still remain on treatment. Do you have what's the plan for updated PFS data and when the curves would be or if there's another hazard ratio available?
Yeah. We continue to look, I mean, this is an open-label study. We continue to look at the data every couple of months. We expect the next look at the data should be towards the end of the second quarter to better understand how this continues to evolve. We are optimistic, clearly, that the data continues to suggest that there are more patients who are treated with Sirexatamab as opposed to that in the control arm. We hope that it will transition to a statistically significant improvement in the intent-to-treat population, similar to what we've already seen for the DKK1 high population, either at the upper quartile or the upper median, as well as the VEGF naive populations.
Got it. Okay. One final question I had. The colorectal cancer, from my understanding, the tumor tissue does not necessarily have as much secretion of DKK1 as maybe gastric cancer or some other cancers. I'm just curious why high circulating levels of DKK1 would be highly beneficial here.
Yeah. No. I mean, I'll take that. I mean, obviously, DKK1 is the target of the antibody. As you mentioned, in this particular disease, we do not have a lot of DKK1 expression in the tumor tissue itself. That was expected, actually, based upon the TCGA database. We did look at DKK1 in the tumor. Notably, the vast majority of the patients did not have a lot of DKK1 in the tumors. We moved to look at and explore in the plasma-based assay because, as I mentioned, DKK1 is a secreted protein. It definitely is produced in a variety of places, such as bone platelets. We know it's present systemically.
The hypothesis is, obviously, if we're targeting that particular protein, those patients who have higher circulating DKK1 values would be those patients who would respond and have better clinical outcomes to being treated with an anti-DKK1 antibody.
Okay. Thank you very much for taking the questions.
Thanks, Kalpit. Our next question comes from Madeleine Stone at William Blair. Please go ahead, Madeline.
Great. Thanks for taking the question. One for the doctor. Could you talk about how you see testing for DKK1 expression fitting into your clinical practice? Do you think you would be testing in all patients or specific subsets of patients, for example, those with KRAS wild type or who have left-sided tumors? Thank you.
I mean, I think once we get more granularity about the biomarker, we would test it in all patients. I mean, if it's a serum-based biomarker, it's easy to test. That's the point. We would want to get a lot more information about the prevalence of the biomarker, generally speaking, and then in those specific subgroups because before you embark on a prospective biomarker enrichment program, you need to nail all that stuff down. I think probably we're a little ways away from that still. We want to generate more data about the biomarker. It's a very easy thing to test serum biomarkers in this disease. I wouldn't have any practical issues with it at all.
Great. Thank you.
Great. Thanks for the question, Madeleine. I'm going to pivot back to a question that came from the audience. What is your opinion of success of liver and lung mets patients having such good outcomes?
I mean, that's consistent with the literature. I think we all know that non-peritoneal disease patients tend to do a little better. Patients with liver mets tend to do maybe a little worse historically, and lung mets a little better. I think there's no reason to think that the patients, first of all, with VEGF inhibitors and DKK1 inhibitors would do better or worse depending on site of metastasis. I think this is entirely consistent with general statements about the disease.
Great. Thank you.
I would only add to that that recently, we've looked at patients with liver metastases, and we've been able to identify that those patients actually clearly do slightly better in patients with the experimental therapy as opposed to the control therapy as well. It's something that we'll continue to monitor over time. It doesn't necessarily appear to correlate with DKK1 expression. We do know that the vast majority, I think, as Zev has mentioned, of patients with this disease do have about three-quarters do have liver metastases. We clearly appear to be doing slightly better in patients with liver metastases than the control arm that will need to continue to mature.
Great. Thank you both. Our next question, is there any research that has identified an early predictor of PFS in this population?
I mean, other than the stuff we discussed, obviously, you have a signal here for DKK1 high. You have a signal here for VEGF naive. Those are the two signals that we've looked at so far.
Yeah. Those are pretty mature, knowing the number of subjects who are no longer on, in particular, in the DKK1 upper quartile.
Great. Our next question, can you describe the DKK1 test used in the trial?
Yeah. So we've tested this in actually, we tested it in three different assays, all of which are plasma-based assays. One is the Somologic assay, which is the data that we presented. All of the assays in which we tested this in are all consistent, where the advantage continues. It's pretty consistent across all three assays. We use an MSD platform as well and the Somologic assay. Moving forward, for a companion diagnostic, we would have so the Somologic assay is an assay that's been validated. However, moving forward, we will need to identify an assay that we can use as a companion diagnostic. That work is underway.
Great. Thank you, Cyndi. It looks like those are all the questions. Dr. Wainberg, Cyndi, do you guys have any final comments?
No. I mean, again, I'm encouraged by what I see so far. I think this is kind of where you want to be in a randomized phase two study. The fact that these patients are the data is still maturing and the PFS is encouraging to me is reason to be optimistic and see it through. That'll open lots of doors, hopefully.
I would just like to thank Dr. Wainberg and all the patients who have enrolled on the clinical studies, as well as all the staff across the sites that have been instrumental in getting this study enrolled in continued development with Sirexatamab.
Great. Thank you both for your time today. This concludes our Virtual KOL Event. I want to thank the audience for joining. You may now disconnect.