Good morning. Welcome to the Leap Therapeutics conference call to discuss new data from Part A of the DeFianCe study that was presented at the ASCO GI conference. At this time, all participants are on listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star one one on your telephone. You will then hear an automatic message advising your hand is raised. I will now pass the conference call over to Cyndi Sirard, Chief Medical Officer of Leap Therapeutics. Cindy?
Thank you, operator. Welcome, and thank you to those of you joining us today for an update on Leap Therapeutics' DKN-01 development 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. 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 of the company's most recent annual report on Form 10-K, as well as other reports filed with the SEC. Any forward-looking statements represent our views as of today, January 23rd, 2024 only.
A replay of this call will be available on the company's website, www.leaptx.com, following this call. I am Cynthia Sirard, the Chief Medical Officer for Leap Therapeutics, and with me today are Dr. Meredith Pelster, the Associate Director, GI Cancer Research Program at Sarah Cannon Research Institute in Nashville, Tennessee, and Dr. Zev Wainberg, Professor of Medicine and Co-Director of the GI Oncology Program at UCLA in Los Angeles, California. Dr. Pelster and Dr. Wainberg will first provide an overview of colorectal cancer and the considerations for treating patients with second-line therapy. Next, Jason Baum, the Chief Scientific Officer at Leap, will introduce our monoclonal antibody, DKN-01, and its mechanism of action and preclinical data in support of its use in colorectal cancer patients.
Then Dr. Pelster and Dr. Wainberg will present the data from the DeFianCe study of DKN-01 in combination with bevacizumab and chemotherapy in patients with advanced colorectal cancer. Finally, we will open the line to questions.
Colorectal cancer is a highly prevalent and impactful disease. All general oncologists see patients with colorectal cancer, and most individuals know someone who has dealt with this disease. It is the third most frequently occurring cancer globally and the second leading cause of cancer-related deaths. In 2020, there were nearly 2 million cases of colorectal cancer diagnosed and nearly 1 million deaths worldwide. Specifically in the U.S., there are approximately 150,000 new cases per year, with more than 50,000 deaths. Colorectal adenocarcinoma can arise in the right or the left colon. The right colon is defined as the cecum, the ascending colon, and the transverse colon, whereas the left side is defined as the descending colon and the sigmoid colon and rectum.
I highlight this difference because it is known that right-sided cancers tend to have a worse prognosis than left-sided cancers, and the molecular features of right and left-sided cancers are different. Various mutations occur with different frequencies on the right and the left, and impact on the WNT pathway is different on the right versus left side of the colon. So it's a very important characteristic of the cancer, and it's important to note both prognostically and for treatment decisions. In the U.S., national guidelines recommend screening for colorectal cancer to try to catch this disease early. However, many patients will still present symptomatically with issues such as rectal bleeding, anemia, or abdominal pain, at which time they may already have advanced stage disease.
Patients who were treated with curative intent for localized disease may also recur later with metastatic disease, and when disease is metastatic, it is typically incurable.
We have come to realize that tumor characteristics, molecular characteristics, patient preferences due to toxicities or quality-of-life considerations, play an impact on what treatment decisions are made when an oncologist is facing a patient with metastatic colon cancer. These characteristics can include age, comorbidities, prior therapies received in the past, but often the site of the tumor can begin to influence what treatments are administered. Additionally, certain molecular characteristics, such as mutations in KRAS, BRAF, microsatellite instability, and HER2, can impact treatment decision-making.
In the metastatic setting, many factors play into the decision-making regarding treatment, which is tailored according to the individual patient. We take into account the patient's characteristics, such as their age, comorbidities, prior adjuvant treatment, if they were initially diagnosed with localized disease, and performance status. A patient who is 65 years old, playing golf daily, and mowing their yard is a very different patient than an 80-year-old patient who is wheelchair-bound. This treatment flow diagram attempts to simplify the options that we consider for patients in each line of therapy. In the front line, for patients that are microsatellite instability-high, immunotherapy is going to be our preferred option. But this is only a small percentage of patients, and the majority of our colorectal cancer patients are going to receive a chemotherapy combination in the front line.
Most often, this is a doublet chemo regimen with either an anti-VEGF or anti-EGFR antibody added, pending the sidedness and the molecular profile of the cancer. Some patients will receive triplet therapy, particularly young patients, patients that have particularly bad prognosis related to their molecular profiling, or patients that we are potentially trying to get to a resection and want to maximize response rates. In the second line, patients with a mutation for which there is a targeted therapy available may receive this. Patients that are BRAF mutated have encorafenib with anti-EGFR therapy as an option, and HER2-amplified patients have available HER2-directed therapies. But for most patients who do not have an available targeted therapy, the second line will involve more chemotherapy.
For many of our patients, they will start on a FOLFOX backbone and then move to a FOLFIRI backbone, or for a smaller percentage of the patients, the reverse, FOLFIRI followed by FOLFOX.
However, we still are in sore need of novel therapies that will expand the treatment options for patients, and more importantly, expand the biomarker options for oncology considerations. Where we've not seen a lot of progress, unfortunately, is in second-line metastatic colon cancer. The majority of the biomarker development has been in front line, and that has left patients with so-called second line with fewer options. One option that has emerged is the sense that the side of the tumor, the side of the colon where the tumor originates, can have an impact in both prognosis and consideration of targeted therapies. Unfortunately, after patients progress on frontline therapy, second line treatment options are still lacking. In particular, the patients who are microsatellite stable and not candidates for immunotherapy are often lacking when it comes to novel therapeutic approaches.
Recent studies have shown us that the disease heterogeneity, treatment diversity, and an emerging incidence of this cancer in young people, has led to urgent consideration of novel therapies for this patient population.
Looking specifically at therapy in the second-line, as we reviewed in the prior treatment flow diagram, patient characteristics and prior therapy really drive the choice of second-line therapy, as well as the anticipated outcomes of that therapy. Features that impact this choice and the anticipated results include prior use of bevacizumab, and whether patients received induction or maintenance therapy, tumor characteristics, notably the genetic profile, the sidedness of the tumor, things such as the molecular subtype. Prior chemotherapy used in the front line in the front-line setting also, of course, plays a role. The site of metastatic disease, patients that have liver metastases versus patients that do not have liver metastases. Another important characteristic is whether or not a patient was a rapid progressor on their initial therapy.
We know that patients that progressed within six-12 months after they completed neoadjuvant or adjuvant therapy for an initially localized disease, those patients tend to not do as well, and patients who have rapid progression on first-line therapy similarly have a worse prognosis. Given that there are so many different factors that influence our treatment choices and outcomes, it's clear that this second-line population is a very heterogeneous group. It follows that the historical efficacy for second-line treatments in phase lll trials is quite varied. Response rates range from 4%-22%. Disease control rates in these studies range from 62%-78%. Progression-free survival ranges from 2.5-6.9 months, and overall survival ranges from 11.2-15.5 months.
It makes sense that we see these types of ranges because these different trials were including so many different subpopulations of patients. Another important thing to note on second-line treatment is that in the past decade, we have really had no paradigm-changing treatment options. We have seen data on bevacizumab maintenance, and we have seen data on therapy in targeted patient populations, but still, for most of our patients, it is going to be FOLFOX to FOLFIRI as their progression from first-line to second-line treatment, and really highlighting the fact that we need more options in this area.
DKK1 is a protein that plays a critical role in the development of cancer, where it's often overexpressed, leading to worse outcomes for patients. It's secreted largely by tumor cells and is able to promote cancer cell development through an induction of proliferation, metastasis, and angiogenesis. DKK1 does this through a few different mechanisms illustrated here. Evidence suggests it can promote angiogenesis, resulting in an increased number and size of blood vessels. DKK1 can also bind to the CKAP4 receptor on tumor cells and activate the PI3 kinase AKT pathway to drive cancer cell proliferation. But importantly, DKK1 also has a significant impact on immune cells in the tumor microenvironment. It signals directly to myeloid-derived suppressor cells to enhance their activity and promotes the presence of M2 macrophages. In parallel, DKK1 is able to decrease the activity and number of natural killer cells.
This helps to create an immunosuppressive tumor microenvironment, preventing the immune system from being able to target and remove the cancerous cells. These mechanisms explain why when DKK1 is expressed or present in the context of cancer, those patients often have shorter overall survival and faster time to treatment progression on standard therapies. DKN-01 was designed to inhibit the function of DKK1. It is able to reverse the harmful pro-tumorigenic effects of DKK1. DKN-01 targets DKK1 in the tumor microenvironment, blocking the signaling through CKAP4. This causes a downregulation of AKT/PI3K signaling on tumor cells, which in turn leads to reduced proliferation. In addition, it can reduce angiogenesis, resulting in fewer and smaller blood vessels. As a result, DKN-01 potentially contributes to the benefit of a combination with a VEGF inhibitor, such as bevacizumab.
However, the key mechanism of DKN-01 involves creating a more favorable immune response to attack the tumor. Preclinical data suggests that this is characterized by a reprogramming of the tumor microenvironment, in part by reducing the activity of suppressive MDSCs, converting M2 to M1 macrophages, and promoting the activation of NK cells. The immune modulatory mechanism of DKN-01 also allows it to synergize well with other drugs, including anti-PD-1 antibodies. Each of these combines to create a multipronged attack on the cancer cells, the microenvironment around them, and the blood vessels running through them, contributing to DKN-01's activity. Colorectal cancer is characterized by high activity of WNT signaling, which is modulated by DKK1. Approximately 80%-90% of CRC tumors contain alterations in the WNT pathway genes such as APC. WNT pathway activation is enriched in the CMS2 subtype, commonly found in left-sided tumors.
Real-world evidence demonstrates that DKK1 is elevated in later-stage CRC patients and is highest in the metastatic rectum. In terms of the treatment landscape, 5-FU-based chemotherapies are the backbone of first and second-line therapies in colorectal cancer. We know from our gastric cancer experience that DKN-01 synergizes well with 5-FU-based therapies, and DKK1 has been associated with resistance to 5-FU and CRC. Preclinically, DKN-01 has shown activity across different CRC models, both alone and in combination. Some of this preclinical data is shown here using an HCT116 model of colorectal cancer. In a wild-type model on the left, DKN-01 and bevacizumab as monotherapies each show moderate inhibition of tumor growth. However, an enhanced effect is seen in combination, with tumors no longer growing. On the right is the 5-FU-resistant version of the HCT116 model, generated by Ajay Goel lab at City of Hope.
We believe this to be reflective of a second-line setting in which patients have already seen and are no longer responsive to 5-FU. Here it's clear that 5-FU on its own has no effect. However, upon treatment with DKN-01, even as a monotherapy, we observe striking tumor regressions.
The DeFianCe study includes patients with microsatellite stable, BRAF wild-type, advanced colorectal cancer who have received one prior 5-FU-based chemotherapy regimen. In part A, the safety run-in, patients received DKN-01 with either FOLFOX or FOLFIRI, whichever regimen they did not receive in the first line, and bevacizumab. Part B is the randomized phase ll controlled trial in which patients are randomized in a one-to-one fashion to DKN-01 with chemo and bevacizumab or to chemo and bevacizumab alone. 33 patients were enrolled in the safety run-in and treated with the combination of chemo, bevacizumab, and DKN-01, and we will be discussing more on the results from this group today. For the randomized portion of the study, the primary outcome is progression-free survival, with key secondary outcomes of response rate, duration of response, and overall survival. 33 patients were included in part A.
As you'll note, 25 patients had left-sided colon cancer and eight had right-sided. Of the left-sided patients, 15 had a rectal or rectosigmoid primary cancer. As far as prior treatments, 17 patients in this group had received prior anti-VEGF therapy, 23 patients had liver metastases, and six patients out of this group of 33 were non-evaluable for response. Four patients due to discontinuation of therapy during cycle one, and two patients had passed away prior to their first imaging. Regarding treatment, patients received their chemotherapy on day one of each cycle, along with bevacizumab and DKN-01. DKN-01 was also administered on day eight of each 14-day cycle. Baseline characteristics are presented here. Again, talking about some key characteristics, 76% of patients had a left-sided cancer, with 45% having a rectal or rectosigmoid cancer. 52% of patients had received prior bevacizumab.
75% of patients had KRAS mutations, which I do think is very important to highlight, as this is a well-known negative prognostic feature. 70% of patients had liver metastasis, which is very consistent with the general population of colorectal cancer patients. Looking at the safety summary from part A, the most frequent treatment-related adverse events included diarrhea, fatigue, neutropenia, and nausea, as well as the others noted in this figure. Overall, I would highlight that patients had expected adverse events given the chemotherapy and bevacizumab backbone, and there was really nothing unexpected or unmanageable that arose for patients on this study. Getting into the outcomes from part A, the best overall response for the evaluable population is shown here, with 8 patients achieving a partial response, yielding an overall response rate of 30%.
We had a disease control rate of 93%, with 25 of 27 patients having disease control. This exceeds the 20% response rate target, and overall is very encouraging in the context of prior data, which we've discussed before. Again, we have some patients here, or we have multiple patients that are RAS mutated, and there are other negative features of this population, which I think make this response rate really encouraging. The spider plot here visibly depicts the depth and length of responses and is one of my favorite figures that really highlights the clinical benefit of this regimen. As you can see with the gray bars, the number of primary progressors on this treatment is very limited.
So most patients are not having to hear at the time of their first scan that their cancer is not responding to treatment and that what we've tried is not benefiting them. On the contrary, most patients are receiving a clinical benefit, and a notable portion are receiving this benefit for many months, as you can see by some of these lines, which extend quite a long way out. So I think are one of the best depictions of how the patients on the study are doing. The duration of response in the responder population is a median of 6.1 months, and the six-month duration of response rate is 60%, and we have three ongoing responders on the study, as shown here in this plot.
Looking at progression-free survival, the median progression-free survival is 6.3 months, and the six-month PFS rate is 55.2%. Again, this population is heterogeneous and includes some unfavorable subgroups, so I think this median progression-free survival is encouraging. It is also extremely encouraging that nine patients remain on therapy, and of those patients, a minimum of 8.5 months, they've already been on therapy. Next, we'll move into some subgroup analyses of key groups that we would like to analyze. First, we'll look at tumor sidedness. Overall, we have seen a greater activity in left-sided tumors with this combination. An overall response rate of 33% on the left has been seen, and a disease control rate of 100%. The response rate is increased to 46% in the rectal and rectosigmoid population.
Alternatively, with the right-sided group, the response rate is 17%, with a disease control rate of 67%. That response rate on the right is certainly still higher than we have seen in some other studies, but really, this figure highlights the enriched responses that we're seeing in left-sided tumors. And going back to a spider plot, we again see how many patients are having clinical benefit, and this really highlights the left-sided patients and the rectal patients that are deriving benefit. The preliminary duration of response in the left-sided responder population is 9.9 months, and there are three ongoing partial responders. The preliminary median progression-free survival in the left-sided tumors is 8.6 months, and there are nine left-sided tumor patients that remain on therapy.
So we're looking forward to seeing how those patients continue to do. Looking at these results, and especially the responses in the left-sided population, we can hypothesize that the mechanism of action of DKN-01 is especially impactful in this particular subgroup. Left-sided tumors, as we know, have more frequent aberrations in the WNT pathway that arise due to mutations that are differentially present in left-sided cancers versus right-sided cancers. Also, the enrichment of the Consensus Molecular Subtype 2 in left-sided populations may play a role here as well.
I'd like to go over some of the data about the importance of segregating patients on the basis of tumor location. You've already heard that location does matter and has implications on treatment decisions. But what we've begun to recognize is that in the left-sided colon, even within the left-sided colon, there are differences in tumors that originate in the rectum or rectosigmoid versus the descending colon. One of the things that we observed in the DeFianCe clinical trial, part A, is that six of the eight responding patients were among this group, in the rectosigmoid group. Perhaps an overrepresentation of what we might expect in the rectosigmoid group that had a response rate of 46%, with a number of patients remaining on therapy for a prolonged period of time.
Now, the importance of that is, is that these are patients who originally often progressed quickly. But in this patient population, we had a duration of response of nearly 10 months, with two-thirds of patients having at least six months duration and three ongoing responders at the time of data cut. The PFS for this subgroup is still maturing, as not enough events have occurred, but our preliminary median number is 9.4 months and a six-month PFS rate of 57.1%, which far exceeds the historical controls. Interestingly, higher plasma DKK1 has correlated with improved response, particularly if one looks at the rectosigmoid cancers.
As mentioned, there is a lot of reason to think that these tumors may have a different profile of biomarkers than right-sided tumors, and therefore, correlation of a biomarker here, even preliminarily, is suggestive that this is something that we should be looking at in a coherent fashion in the next phase of the study. Beyond bevacizumab prior exposures, patients obviously are all tested for the presence of KRAS mutations. In fact, there is durability and activity with this combination, regardless of KRAS status, in either patients with KRAS mutations, even the G12D mutations, which are the most common but associated with a poorer prognosis and other KRAS isoforms. Amongst that group of patients, the median PFS of six months in this poor prognostic group is also quite encouraging.
Not surprisingly, the median PFS is greater in the patients with KRAS wild-type disease, which we've known for some time is an improved prognostic category. The clinical activity of the combination of FOLFIRI, bevacizumab, and DKN-01 is active in both patients with RAS mutations, again, regardless of the isoform, and patients with KRAS wild-type. This is something that the second phase of the DeFianCe study will be exploring in greater detail to see the impact of this therapy on patients with a heterogeneous group of second-line patients. Another variable is whether or not the patient had received prior bevacizumab prior to enrollment. As many of us know, bevacizumab-containing therapy is a standard of care in patients who got newly diagnosed metastatic colon cancer.
But there are many considerations why a patient may not have received bevacizumab, including the fact that they were treated in the adjuvant setting or had a contraindication to bev, such as a bleeding tumor. In this study, among the small sample size in middle E that we looked at, the response rate in PFS is very favorable in the bevacizumab-experienced patients compared to the historical control, which is known as the ML18147 study. Here, the six-month PFS rate of 60% exceeds the historical control expectations, and the preliminary median PFS of 7.3 months in an otherwise perhaps poor prognosis group of patients is encouraging.
Anecdotally, I had a patient on this study who progressed, a young man with who had metastatic rectal cancer, received FOLFOX bevacizumab in the past, and the patient was enrolled on the study in October 2022, due to the presence of extensive retroperitoneal lymphadenopathy. He received FOLFIRI bevacizumab and DKN-01, and he had a fantastic response with a PR at eight weeks and ultimately deepened his response over the next six months. Ultimately, he has remained on study for up to 13 months prior to disease progression. This anecdote perhaps represents an expression of possible additional activity of DKN-01 to FOLFIRI bevacizumab. And in fact, in this patient population of rapid progressors on frontline therapy, six patients had a PFS exceeding eight months.
This is, again, encouraging that in a patient population with so-called rapid progression, which implies progression in a much shorter timeframe than historical control, we are able to arrest some of that disease progression.
We noted a high overall response rate in patients who had not received prior bevacizumab. This population included patients that were rapid progressors on frontline therapy. In particular, many of these patients had received adjuvant therapy for resected disease, a setting in which bevacizumab is not used, and they progressed either while on or quickly after treatment, indicating an aggressive cancer. So in this population, the response rate was 36%, with a disease control rate of 93%. The median progression-free survival is 5.9 months, with six patients without progression for longer than eight months and four patients that are still on therapy. So very encouraging numbers in this population of patients, many of whom were essentially primarily refractory to their first chemotherapy. Now, I wanted to share a patient in this category from our site.
She's a 71-year-old female who was diagnosed with rectal adenocarcinoma in January 2022 and underwent intensive neoadjuvant treatment with four months of FOLFOX, followed by radiotherapy concurrent with capecitabine. After this treatment, she underwent resection, so trimodality treatment, and very quickly recurred after her surgery with multiple liver metastases, and a lung nodule. So you can only imagine what a difficult situation this patient had, had gone through months and months and months of, of therapy with curative intent, only to very quickly thereafter be told that she was, despite all of that, now, now metastatic and incurable. Some other of her tumor characteristics of note, she had APC mutations, and she had a, a TP53 mutation as well.
As you can see from the figure, she has had a very nice response on treatment on the DeFianCe study, achieved a PR on her first restaging scan. So you can imagine that that was a very different scan review conversation than the review after her surgery when she had progressed. Her response has deepened, and she has continued on therapy and is currently on cycle 19. She is tolerating the therapy well. She's had some fatigue, she's had some neutropenia, had some hypertension that was controlled with adjustments in medications, but overall tolerating well, you know, and really able to live her life.
This is one of several patients at our site that have had this type of experience with continued PRs, tolerating treatment well, and really able to achieve what we want patients to achieve on palliative therapy, living longer and living well while they still have cancer. I think, you know, when you see a patient on your schedule that's coming in on study, I think you kind of know, well, you know, this treatment is tolerable. You know, I'm not anticipating going to see a patient that is going to be miserable because they are on this treatment. So not only are they achieving benefit, but they're doing so with toxicities that we're familiar with and that we can help them manage through.
So I've hoped that we've demonstrated, by taking you through the data from our safety lead-in population, that DKN-01, in combination with standard chemotherapy and bevacizumab, is well tolerated. We're really not seeing any unanticipated side effects. Side effects are manageable and familiar to oncologists that treat patients with these chemotherapy backbones. In addition to it being well tolerated, we've seen promising clinical activity in a heterogeneous group of colorectal cancer patients that do have poor prognostic features, including a high rate of liver metastases and KRAS mutations. The overall response rate for the evaluable population is 30%, with a disease control rate of 93%, with a median progression-free survival of 6.3 months.
Nine patients remain on study therapy beyond 8.5 months, which I feel that, taken into the context of prior work, is very encouraging, given the baseline characteristics of the population included here. Our subgroup analyses have demonstrated the greatest benefit in rectal and rectosigmoid cancer patients, with an overall response rate of 46% and 100% disease control rate. Along with that, preliminary median progression-free survival is 9.4 months. I think we are really interested in the idea that the left-sided population is different than the right-sided population, and the mechanism of DKN-01 may really play to the biologic differences between those groups of patients. And it's something we're very excited to see, you know, further data on.
We did see elevated baseline plasma DKK-1 levels correlating with greater clinical response, which is an interesting finding, and we'll learn more about that in the future as well, I know. Additional subgroups do reflect the breadth of clinical activity of the combination. I think, thinking about Part B, you know, based on our experience in Part A, it's just a very easy decision to put your patient on this study. We're seeing great initial responses. The patients are tolerating treatment well. And so I think we're all really excited to contribute patients to really further understand the promise of this drug.
And we're excited for our patients about this opportunity, and an opportunity that we can, you know, tell them, "You know, this treatment is likely to be tolerable for you. There are going to be side effects, but we can manage them and help you get through it to hopefully gain a real meaningful benefit from this therapy".
One of the things that I find interesting about the Leap DeFianCe study is that, number one, we have not seen additional toxicities with the addition of DKN-01 to standard of care FOLFIRI bevacizumab. That's critically important when we're dealing with a second-line patient population, which is a challenging group of patients, and encouraging that we've not seen enhanced toxicity beyond what we would expect with second-line chemotherapy. We also have to acknowledge that there are very few targeted therapy approaches being investigated in the second line, so having a promising preliminary signal, as we demonstrated in Part A of this study, to me, is encouraging for the second-line cohort.
Of course, we need to do the randomized study to see what the PFS improvement will be in second line, but based on the preliminary evidence so far in the frontline cohorts, we are encouraged that we are having synergistic activity with bevacizumab due to the mechanism of action of DKN-01, which will lend itself to the second-line patient population. We have to acknowledge that this is a small data set, and therefore, doing a randomized trial to look for a signal of PFS is the critical next step before embarking on registrational trials, which we expect to do in the future.
Thank you very much, Dr. Pelster and Dr. Wainberg. Now, we will be happy to open the line to questions.
Thank you. Ladies and gentlemen, to ask a question, you will need to press star one one on your telephone and wait for your name to be announced. To withdraw your question, you may press star one one again. Please stand by while we compile the Q&A roster. Now, first question coming from the line of Joseph Catanzaro from Piper Sandler. Your line is open.
Hey, everybody, appreciate the call here and all the additional details. Maybe my first question, I guess, for the dynamics of prior bev exposure or bev naive, I guess I'm trying to understand whether the left-sided rectal subgroup is enriched for bev naive patients, or if it has a just similar rate as the total population. And if there is enrichment, is that being driven by these patients more likely to undergo resection and receive adjuvant therapy and then quickly recur? So any additional details there would be helpful. Thanks, and I have one follow-up.
So, with the rectal cancer patients, a number of them, as Dr. Pelster described, are not given bevacizumab in the adjuvant setting. So if those patients were the rapid progressors, they wouldn't have received the bevacizumab in combination with the cytotoxic chemotherapeutics at the front line. We have not yet done the formal analysis of bev exposure in the specific rectosigmoid group as a breakdown, as another subset, because the numbers get smaller. So we did just restrict that, but, it is something that we will continue to explore as we advance into Part B.
Okay, thanks. And then my follow-up, I guess, with all these sort of subgroup analyses, whether there's any thinking or decision that's going to be made around the enrollment criteria for phase ll, and whether there's an opportunity or thinking to enrich for specific populations. And maybe if not changing enrollment criteria, whether the statistical analysis plan maybe will find focus on sort of a primary subgroup initially and then work its way down. So any updated thinking there would be great.
Yeah. So with that one, actually, as we opened up Part B, we are stratifying the patients with two specific clinical characteristics that we knew were very relevant to outcomes, one of which is tumor sidedness, the other which is prior bevacizumab. So the balance, the arms will be well balanced for both tumor sidedness as well as the presence or absence of prior bevacizumab. Since the study is enrolling so quickly, it would be challenging to change midstream now to reflect only a left-sided population. However, we are continuing to see the majority of folks who enroll it, you know, roughly 75-25 split between the left and the right side.
Okay, got it. That's helpful, and I appreciate you taking my question. Thanks so much.
Thank you. One moment for our next question. Our next question coming from the line of Joel Beatty with Baird. Your line is open.
Great. Hi, thanks for the presentation. The first question is, you know, in these small data sets for initial single arm data, it's always hard to get a sense of how it compares to what might have been expected with the other treatment alone, in this case, bevacizumab. So I guess the question is, could you kind of summarize what the most striking differences, you know, or how you look at it, you know, what stands out the most compared to what would have been expected with bev alone?
Dr. Pelster, maybe you could take that question from your clinical perspective.
Certainly. I mean, I think what stands out in the left-sided population is really the response rate, which is certainly higher than I would expect in a second-line population, kind of whether or not they are Bev exposed. It seems like it is more than just Bev that's driving this, and you know, in my opinion.
Thanks. I appreciate that. Then, maybe taking that a step further, could you discuss survival and maybe how it looks now compared to what might be expected, but then also how much the survival data might be expected to mature over time from where it's at now?
I think that-
Yeah, so we-
Go ahead. Oh, yeah, go ahead, Cyndi.
No, no, no. Go ahead, Meredith. You can go first, and then I'll follow you.
We certainly need to let the survival data mature further. But I think what we're seeing thus far is encouraging. And it's very encouraging how many patients, especially in this subgroup, are still on study, suggesting that there is a group that can have quite a good duration of benefit.
Yeah, and to just add on to that, we are not, we've not been able to calculate a median survival because the number of events is far too few in order to be at a median. So we do know that it will be a year for all subjects, come the April timeframe, at which I think as Meredith described earlier, is the expected kind of survival in second line, somewhere between 11 and 13-ish months. So with that in mind, it's something we continue to follow.
Great. Thank you.
Thank you. One moment for our next question. Our next question coming from the line of Mara Goldstein with Mizuho. Your line is open.
Great. Thanks so much for taking my question. I just had a question on the DKK1 expression levels in the rectal tumors, and were those correlated with any of the favorable or not favorable baseline characteristics? And were expression levels consistent with what, let's say, you have observed in liver cancer? And then the other question I had was just around the sepsis death in the study and whether that was treatment-related to the DKN-01 treatment.
Sure. I can take the tumor DKK-1 question first. So what we've seen in second line colorectal cancer, unlike frontline gastric cancer, is that there is some variability depending on where the tumor was taken and when it was taken. So for example, tumors taken typically from the metastatic site or taken after frontline therapy, tend to have higher DKK-1 expression as compared to those taken from the primary or taken from an archival sample. So with that in mind, you know, I think we have not seen the same correlation that we've seen in the frontline gastric cancer study, which is why we are looking closer at a plasma-based assay, which I think you saw some of the data here, which correlated nicely with response in the rectal patients.
That I think that will give us a better contemporaneous picture of what the DKK-1 expression is looking like, especially since we know that there are other sources of DKK-1 outside of just the tumor, including the bone. So I think that'll give us a nice picture in second-line colon cancer, you know, specifically. So we'll continue to monitor that.
Okay.
I can take the toxicity question, and Dr. Pelster should feel free to chime in for patient. So this was an elderly woman, you know, 84-year-old woman who received full dose irinotecan in context of the FOLFIRI regimen, developed some pretty, pretty significant diarrhea and then unfortunately became septic following her diarrhea. The diarrhea was felt related to all of the entire study regimen, including DKN-01, and unfortunately, she succumbed to her sepsis prior to her first scan. But I don't know, Dr. Pelster, if you have more to add.
I think you summarized it well, Cindy. I mean, this was a chemotherapy toxicity issue. Like you said, she was elderly. She received a lot of chemo and I think that was the ultimate cause.
Thank you very much.
Thank you. One moment for next question. And our next question coming from the line of Timur Ivannikov from Raymond James. Your line is open.
Yeah, hi. Thank you. Thanks for the question. So first, in terms of the nine patients who are continuing on treatment, could you talk about what therapies those patients are receiving?
Are receiving on therapy, on the study or had received prior to? Sorry, I just want to make sure I follow the question.
I mean, have they discontinued any of their chemo, sorry, chemo regimen, bevacizumab? Are they continuing on, DKN-01 only at this point?
Yeah. Okay. No, great question. So again, this is a regimen that we permit the patients to stay on study, provided they continue a component of the regimen. As the patients continue down or continue on in later lines, overall, the patients do tend to either reduce the chemotherapy, such as the irinotecan and the 5-FU, or eliminate them entirely and then stay on the biologics, such as DKN-01 plus bevacizumab for the most part. There have been some patients that have discontinued bevacizumab. There have been some that have discontinued chemotherapy. None of them have discontinued DKN-01, that have been long-term patients on trial.
Okay, great. And then, maybe a question for KOLs and the company as well. So, I think you have around 70% of the patients with liver metastases in the study. And is that sort of typical in general for second-line CRC population? And then specifically for the company, you know, we've seen trials where companies exclude patients with liver metastases in the second-line setting. Was that your decision to be sort of representative of the overall population to include those patients?
I can take the frequency question. Yes, 70% with liver mets is very in keeping with what we would expect, in this line of therapy.
Yeah, and then I'll take the company perspective. So we definitely wanted to be representative of what was being treated in the community for patients with second-line liver cancer. We know that the liver is one of the primary sites of metastasis from colorectal cancer, so eliminating patients with liver metastasis because we're an immunotherapy without knowing what it would have done, I think would have been, you know, a disservice to the agent to see where we could potentially go in the future. We are seeing patients with liver metastases responding, which is unusual for immunotherapy. So I do think we're encouraged there, and moving forward, we're not excluding patients with liver metastasis in Part B, but will be something that we can explore as it relates to a subgroup moving forward.
Okay, got it. And then a final question, maybe for Dr. Pelster. Just in terms of, I think you've already answered it, but just in terms of sort of the outperformance of patients with left-sided tumors, you know, in this study, obviously, obviously you presented the details, but just in terms of the magnitude of how much the patients outperformed, is that something you would expect in practice? I think you mentioned that, you would expect patients to do better if they have a left-sided tumor location, but it's just difficult to understand how in this study, the outperformance relates to kind of the, natural history of the disease.
Sure. Yeah. I mean, I think the outcomes here in this second line, in this particular population of left-sided patients that have a high proportion of KRAS mutations and a high proportion of, you know, primary progression, on first-line therapy, I do think the magnitude of benefit is more than we would expect from standard second-line therapy. I think this agent is adding something, but of course we're really gonna have to get the randomized data to confirm that. But taking into consideration not only their left-sidedness, which is a good prognostic feature, but the poor prognostic features that this population also has, I think the benefit these patients are receiving is more than I would expect.
Okay, great. Thank you very much.
Thank you. I'm not showing any further questions in the queue at this time. I would now like to turn the call back over to Mr. Doug Onsi, Chief Executive Officer of Leap Therapeutics, for any closing remarks.
Thank you very much. We appreciate, Dr. Pelster and Dr. Wainberg for their contributions as investigators on the study and in, preparing this presentation today. Appreciate all of you, listening to the call. We are certainly available, here at Leap anytime if you'd like to ask further questions. And as always, we want to thank all of the physicians and patients who participate in the clinical trials. It's what keeps us motivated every day here at Leap. So thank you all very much, and hope everyone has a wonderful day.
Ladies and gentlemen, that does end our conference call today. Thank you for your participation. You may now disconnect.