Good day, everyone, and 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, Chief Medical Officer of Leap. 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, and with me today are Dr. Samuel Klempner, an associate professor at Harvard Medical School who leads the Gastric and Esophageal Cancer Program at Massachusetts General Hospital Cancer Center, Jason Baum, Vice President and Head of Translational Medicine at Leap, and Douglas Onsi, President and Chief Executive Officer at Leap. 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 21st, 2022 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. Today, we are hosting a call to share updated results from our clinical study of DKN-01 in combination with BeiGene's anti-PD-1 antibody, tislelizumab, and capecitabine and oxaliplatin in patients with advanced gastric and gastroesophageal junction cancer.
To provide a brief overview of the data that will be presented in detail this morning, DKN-01 in combination with tislelizumab and chemotherapy demonstrated a compelling 68.2% overall response rate and 10.7-month progression-free survival as a first-line treatment for advanced gastric and gastroesophageal junction cancer, with a 90% overall response rate and 11.9-month progression-free survival in patients whose tumors expressed high levels of DKK1. This updated data, taken together with our understanding of DKK1 biology and our previous clinical studies, which demonstrated the activity of DKN-01 as a monotherapy and in combination with a different anti-PD-1 antibody, pembrolizumab, and with paclitaxel chemotherapy, should establish DKK1 as an important new target in gastric cancer and DKN-01 as a promising new therapy for patients with this deadly global disease.
We will start with an overview of the biology of the DKK-1 protein and the mechanism of action of DKN-01 from Jay Baum at Leap. Our clinical data presentation will be given by Dr. Samuel Klempner of Massachusetts General Hospital, who is an investigator in this study. Dr. Klempner will review the data from the study and his experience with treating patients with DKN-01. We will end the call by opening the floor to questions for Dr. Klempner or any of us from Leap. With that, I'll hand it over to Jay and ask that you please turn to slide four.
Thank you, Cindy. DKK1 is a broadly expressed marker with high levels seen across indications. Shown here is a range of DKK1 expression from the TCGA database separated out by cancer type. In the majority of cancers, we observe either elevated median levels of DKK1 expression or a subset of patients with high DKK1. In addition to stomach adenocarcinoma, which you can see towards the left side, there are several other indications that we're very interested in and have elevated DKK1. This includes endometrial and lung cancers, where we've already demonstrated single-agent activity with DKN-01, prostate, where we have an ongoing investigator-sponsored trial, and CRC, which includes a large subset of patients who have very active Wnt signaling. Slide five nicely illustrates the pro-tumorigenic mechanism of DKK1.
It is secreted mainly by tumor cells and signals to several different cell types, including tumor cells, immune cells, and endothelial cells, to promote cancer development. On the tumor cells, DKK-1 binds to CKAP4 receptor to activate the PI3K/AKT pathway and drive cancer cell proliferation. DKK-1 also has a significant impact on the immune cells in the tumor microenvironment. It signals directly to myeloid-derived suppressor cells, or MDSCs, to enhance their activity, while also decreasing the activity and number of natural killer, or NK, cells. This combines to create an immunosuppressive tumor microenvironment. Evidence also suggests that DKK-1 can promote angiogenesis through increased VEGFR2 expression in the blood vessels to further drive cancer progression.
As a result, high DKK-1 expression is often found in patients with the most aggressive cancers who have rapid progression of disease and poor survival, and this is shown on slide six. On the left side is an analysis of DKK-1 expression across the TCGA pan-cancer dataset, comparing patients with high versus low levels of DKK-1. You can see significantly shorter overall survival in high DKK-1 patients, as illustrated by the red line. This data set is made up of many cancer types, including gastric cancer, which is separated out on its own on the right side. Again, here we see patients with high DKK-1 demonstrate shorter survival than those with low DKK-1. In addition to being an overall poor prognostic marker, DKK-1 is also believed to be a key resistance mechanism to standard of care therapies as shown on slide seven.
To examine this closer, we've been working with Tempus, who has one of the world's largest databases of real-world evidence containing clinical outcome and molecular data. Using Tempus's data, we've looked at several common treatment regimens in GEJ and gastric cancer, including platinum and fluoropyrimidine-based therapies typically used in frontline patients. Across different cutoffs of DKK1 expression, you can see the same trend towards high DKK1 patients in red, discontinuing treatment faster compared to those with low DKK1 in blue. Slide eight illustrates how DKN-01 was designed to neutralize and reverse the pro-tumorigenic effects of DKK1. It does this through several mechanisms, including a downregulation of PI3K/AKT signaling on tumor cells, as well as a decrease in angiogenesis.
DKN-01 is also able to remodel the tumor microenvironment, creating a more favorable immune response to attack the tumor by reducing the activity of MDSCs and promoting the release of cytokines to activate NK cells. It's a multipronged attack on the cancer cells, the microenvironment around them, and the blood vessels running through them, all of which contribute to DKN-01's activity. Slide nine shows how DKN-01's mechanism of action also allows to synergize well with other agents such as anti-PD-1s. As I mentioned, DKN-01 helps to create a more favorable tumor microenvironment, in part due to the activation of NK and dendritic cells, as well as the inhibition of suppressive MDSCs. In addition, we've seen both in preclinical and clinical data that DKN-01 increases the expression of PD-L1 and brings T cells into the tumors.
The establishment of a T cell-rich environment with increased PD-L1 expression may further enhance the activity of anti-PD-1s, especially in settings where those molecules are normally not effective on their own. I'll now turn it back to Cindy to review some of the previous clinical data demonstrating the synergy between DKN-01 and standard therapies on slide 10.
Thanks, Jay. DKN-01 has been administered in a prior clinical trial to unselected patients for esophageal gastric malignancies. DKN-01 was administered as a monotherapy or in combination with paclitaxel or pembrolizumab in this phase I trial. As a single agent, DKN-01 had a response rate of 10% identified by a central imaging vendor in patients with heavily pretreated esophageal gastric cancers. This slide demonstrates the activity of DKN-01 when used in combination with paclitaxel as a second-line therapy or in combination with pembrolizumab as a second-line or later regimen. We will first focus on the combination of DKN-01 plus paclitaxel as a second-line therapy. Here you can see that the combination was active with an overall response rate of 47% and a disease control rate of 73%.
A progression-free survival of 19.6 weeks and an overall survival exceeding one year. This data is comparable to the current second-line standard of care ramucirumab plus paclitaxel, where the overall response rate is 27%, disease control rate of 79%, progression-free survival of 4.4 months, and an overall survival of 9.6 months. The combination of DKN-01 plus pembrolizumab was active, in particular in biomarker-high or DKK1-high patients. In this study, we evaluated second-line or later GEA patients treated with DKN-01 plus pembrolizumab according to tumoral DKK1 expression. We were able to identify a threshold of DKK1 expression which correlated with clinical activity.
Here you can see a clear separation of responders with DKK-1 high or an H-score of 35 or greater compared with DKK-1 low at 50% compared to 0%, and a clinical benefit rate in the DKK-1 high patients of 80% compared to 20% in the DKK-1 low. In addition to the higher overall response rate, we were also able to demonstrate an improvement in progression-free survival and overall survival in DKK-1 high patients when compared to DKK-1 low patients. It is this DKK tumoral to DKK-1 tumoral expression threshold with an H-score of 35 or higher that we have carried into our subsequent trial, the DisTinGuish trial, as a predefined cut point in the study that Dr. Klempner will discuss next.
Thank you, Cynthia. I have the pleasure of presenting the clinical data from the ongoing DisTinGuish trial. What you can see here on slide 12 is the schema, and this was really designed to build upon the data in the later-line in DKK-1 high populations that Dr. Sirard just mentioned. As you can see, there's two parts. A first-line trial, which is standard 5-FU and platinum-based therapy with the anti-PD-1 agent tislelizumab with the addition of DKN-01, and the second-line study including DKN-01 plus tislelizumab in a DKK-1 high population.
The goals here in the first line are to gain further characterization and response data in the front-line setting up for potential subsequent development and in the second line to validate some of the previous findings, looking at response rate in a chemo-free regimen consisting of an anti-PD-1 in DKN-01 in DKK-1 high biomarker-enriched patient population. Slide 13 here shows the patients who went on to the trial, and certainly, there's a lot of data here, but I think some of the highlights are
One, we always look at the prevalence of the biomarker when we're interested in biomarker development. Certainly, it's encouraging to see a DKK-1 high score in 57% of the front-line patients who entered into the trial. We see that DKK-1 high is more frequently associated with liver involvement in previously untreated patients, and this seems to be consistent with perhaps the more aggressive biology of DKK-1 elevated tumors. This next slide simply is showing examples of DKK-1 expression using RNAscope and digital pathology, looking at the reliability and robustness of scoring system. Here you see that tumor specimens were stained for DKK-1 expression and quantified using a digital analysis platform, which is shown in the two figures.
The H-score, which is a well, and commonly used approach in pathology, is determined by looking at the percentage of cells expressing low, medium, and high levels. Of course, the score then ranges from zero to 300. As Dr. Sirard mentioned, the previous cut point was already established. Again, showing you on the right-hand side of the slide is the prevalence of the biomarker in the overall Part A, and in Part B, everyone was elevated, and you can see the frequency of screening and positivity. There's a little higher rate in stomach than GE junction, but these numbers are small. Overall, encouraging rate of 57% prevalence for DKK1 high in a front-line population.
It's important to look at these patients to ensure that we're not heavily selecting by chance for patients who would otherwise be high rates of response to chemotherapy plus PD-1. What you can see here in part A, the previously untreated population, three-quarters of the patients essentially had a CPS score, a PD-L1 expression score of less than five. This is a subgroup that we already know from very large phase III trials that do not appear to benefit from the addition of PD-1 on top of chemotherapy. The trial is not enriching for PD-1 responders. There's only two patients who had a CPS score of greater than 10 in part A. Similarly in part B, the second-line population, you see that again, roughly three-quarters of patients had a CPS score of less than five.
Similarly, we know some other markers of immunotherapy responsiveness, including microsatellite instability and elevated tumor mutation burden. What you can see is that there were no known MSI-high patients, and there were only four patients with an elevated mutation burden, two in the first-line and two in the second-line parts of the trial. This is essentially a CONSORT diagram looking at the first-line DKN-01 300 mg plus tislelizumab and CAPOX. The front-line arm or part A of the DisTinGuish trial. 25 patients were enrolled. 12 were DKK1 high in the ITT population, nine DKK1 low, and four non-evaluable. You can see the disposition here, and you can see the treatment down at the bottom.
This is standard, CAPOX or capecitabine oxaliplatin, standard dose tislelizumab and DKN-01 dosed at 300 mg on day one and day 15. Here is the drug exposure and duration on therapy. What you can see is that in part A, median treatment duration here now roughly nine months with nine patients remaining on therapy. In part B, which continues to enroll, there are 12 people who remain on therapy. Part B notably contains two doses of DKN-01 as you could see in the two rightmost columns. If we look at the key questions, that the trial is asking, here we see the evaluable DKK1 high patients and partial response rate. Important to note that everyone who was evaluable and had DKK1 high expression, had a partial response.
What you can see here, the best overall response rate in the modified ITT population, the DKK-1 high, there is 10. Everyone who was evaluable, which is those nine patients, had a partial response, and there is one non-evaluable patient there. Here is the overall in the overall modified ITT population. As Dr. Sirard hinted at the very beginning of the call, a very encouraging response rate of 68% in the overall population. In the DKK-1 high, it was 90%. In DKK-1 low, 56%. The 56% is notable. Perhaps there may even be activity in DKK-1 low population due to the potential involvement in 5-FU and chemotherapy resistance, which is of interest. The waterfall plot shows the response by DKK-1 RNAscope score.
Green denoting greater than 35, and you can see that response is clearly enriched in the DKK-1 high population. Then colored and uncolored circles representing anatomically defined tumor types. I'm gonna have the next few slides, and I'm now on slide 20, breaking down a little bit some of the populations into some important groups, and questions that many of you were probably wondering about. First question is about the durability of the response, and this spider plot clearly shows that one, the responses are again enriched, as was seen in the waterfall plot, in the DKK-1 high patients that they're shown in green. Many of these responses are quick and durable, and you see now going on out to a year. You see the shapes denoting the type of response and dotted or solid line denoting tumor types.
Here we see another way of visualizing the similar data. This is again the frontline cohort looking at the swimmer plot of duration of response by DKK1 status. You can see in green are the DKK1 high patients with the red triangle noting partial response. You can see in blue the DKK1 low population. Again, red triangle noting response. I think it's important to see, one, the durability of the response. Two, there are also significant responses in some DKK1 low patients. Although the biomarker does appear to select for a greater response rate as was previously shown. PFS is longer in DKK1 high patients and as Dr.
Dr. Sirard mentioned in the very beginning, median PFS for the overall study population in part A is 10.7 months to date, and the PFS for DKK-1 high is 11.9 months versus 10.7 months. As you can see, the Kaplan-Meier curve here with green, again noting the high expressors. Duration of response has shown a similar trend. You see, these responses tend to be more durable in the biomarker selected patient population, with a median duration of response of 10.7 months in DKK-1 high patients compared to 7.9 months in DKK-1 low patients. Both of these numbers notably compare favorably to current phase III reference standards with platinum and anti-PD-1 agents. Overall survival is not reached, and I won't spend much time shown here.
Certainly you can see the number at risk table on the bottom showing there are multiple patients who remain ongoing and under analysis. One of the obvious questions that comes out of this is, does DKK1 simply mark for a group that has an elevated PD-L1 score and would be more likely to respond to checkpoint inhibitor in the first place? I'm going to try to convince you over the next few slides that that does not appear to be the case. We're now on slide 25 and looking at DKK1 high patients and response regardless of PD-L1 status. As I mentioned, most of the patients were PD-L1 low with a CPS less than five, and you can see that the response rate in the PD-L1 low population is 79%.
Which is substantially better than what would be expected with platinum chemotherapy and checkpoint inhibitor in this group. It is 100% in the DKK-1 high and PD-L1 low patients. In the PD-L1 high expressors, so CPS score of greater than five, the response rate is 67% in the PD-L1 high and 75% in the DKK-1 high, PD-L1 high. In my mind suggesting that the contribution of response may be more driven by the DKK-1 status. Here is again, similar way of showing that response is not necessarily correlated with PD-L1 expression. Here is the modified ITT response by PD-L1 status. You see green is the PD-L1 greater than five, and blue is less than five.
As you can see, there does not appear to be any clear relationship here in the waterfall plot between the CPS score and response. DKK-1 status here is noted by plus for the high expressors and a negative sign for the low expressors. The next two slides look at some formal analyses of this. Here is looking at a Spearman correlation plot comparing DKK-1 and PD-L1 expression. As you can see here, the correlation coefficient is low, and there does not appear to be any clear correlation between PD-L1 expression and DKK-1 expression. Similarly, if one were to look at multivariable analyses, we would show the same thing.
Here response is correlated with—clearly the strongest predictor is DKK-1 RNAscope H-score, and then next to that PD-L1 score and tumor types do not appear to be clear predictors of response. Again, suggesting that it's the elevated tumor or DKK-1 expression is associated with a better response, but not the PD-L1 status here. Obviously, the next question is when we add this drug on top of chemotherapy and checkpoint inhibition, do we generate synergistic or additive toxicity? Certainly in my own experience, I can tell you from treating several patients that this has been a quite well-tolerated combination. The toxicity profile here is shown. The most common DKN-01 related events were generally low-grade fatigue, nausea, some diarrhea, and some cytopenias. You can see here there were no grade 4 events.
There were some treatment related adverse events within 30 days of the last dose shown here. One pulmonary embolism and one aspiration pneumonia and LFT elevation and noted hepatic failure as possibly related. In my own personal experience, I have not seen this degree of toxicity and certainly feel this to be a well-tolerated drug. Looking at the second line group, first the data is relatively early, but here is part B. This is DKN-01 at 300 mg or 600 mg with the anti-PD-1 tislelizumab in advanced GE junction, GE adenocarcinoma patients with elevated DKK1 expression. So you can see there's 30 patients. This is the disposition. B1 and B2 just reflect the DKN-01 dose level as is shown in the bottom. You can see that there are patients still on treatment in both disease.
As a reminder, the second-line space is difficult space in gastric and esophageal cancers. Many of our patients, despite being at academic centers, only about 50% of patients will proceed from first line to second line, in this aggressive disease. Here is the objective response by PD-L1 expression. Again, you can see that there is 12 patients who remain on therapy, several of whom have not yet had their first imaging assessment. The overall response rate in the evaluable patients is five partial responses and one immune-related partial response. Here you can see on the right, there is responses in both the CPS greater than five and less than five populations. Here is the response rate again shown graphically. We can see that there are responses.
Not unexpectedly, the response rate is a little bit higher in PD-L1-positive patients. That's known, as PD-L1 positivity is a known predictor of checkpoint inhibitor responsiveness. Certainly, there are responses shown here, in PD-L1 CPS less than five population as well. Down here, we're looking at the durability of the benefit in DKN-01 dose. As you can see, part B2, there are fewer patients with less follow-up. That's the green looking at the 600 mg dose. The blue shows the 300 mg dose. You can see that there are several partial responders and some of these patients with stable disease, which are the uncolored white triangles, have had durable stable disease, including a patient now out to roughly seven months.
Here is the spider plot, again looking at a similar comparison to what I showed you in part A, looking at the durability of clinical benefit by PD-L1 expression. You can see that, in the CPS positive population, and the negative population, in limited numbers and a relatively short follow-up, we can see that some of these responses are tending to be durable in a second-line population, which is an early and encouraging sign. Again, similar type analysis to what was looked at in part A, looking at DKN-01 and PD-L1 expression and correlation with activity. There is not a correlation here between DKN-01 expression and PD-L1 expression in this patient population. That is consistent with the part A analysis as well, and maybe suggesting that this biomarker is relevant across lines of therapy.
Here is the toxicity profile of second-line DKN-01 and tislelizumab. As you can see, again, this remains to be a relatively well-tolerated drug at both doses of DKN-01. The 600 mg cohort is currently enrolling, and we expect to have more toxicity data as patient data accumulates. The most common related events are low grade 1 and 2, consisting of fatigue and nausea, similarly to what was seen in part A analysis. There were no grade five toxicities. The full data is shown here in the table. Putting this together, I'm now on slide 37.
We have now shown that DKN-01 at 300 mg plus tislelizumab and standard 5-FU platinum CAPOX chemotherapy is well-tolerated and had encouraging clinical activity as a first-line treatment in part A for advanced gastric and GEJ adenocarcinoma patients. Certainly, the efficacy does appear to be driven by an improved response rate and durability of response in the DKK1-high patients, which we already know are an aggressive subgroup. Response does appear to be associated and predicted by DKK1 expression, and this is independent of PD-L1 expression. The response rate and progression-free survival compares favorably to published standards of care in an unselected PD-L1 population, and overall survival is ongoing and has not been reached.
In the second-line population, DKN-01 at doses of 300 mg or 600 mg plus tislelizumab continues to be well-tolerated with clinical responses as second-line treatment for advanced GE junction and gastric adenocarcinoma patients with elevated DKK1 expression. This study was ongoing, and we expect to have more mature results, particularly in the 600 mg dosing arm. I'd like to thank you for your time and turn it back over to Dr. Sirard.
Thank you, Dr. Klempner, for your participation in today's program, and thank you all for your time and attention today. We'd now like to open the call for questions. Operator?
That concludes our prepared remarks. We will now open the call to your questions. If you'd like to ask a question at this time, please press the star, then the number one key on your touchtone telephone. To withdraw your question, press the pound key. Our first question comes from Joe Catanzaro with Piper Sandler.
Hey, guys. Thanks so much for taking my question and, congrats on the data here. I wanted to first ask about progression-free survival and the difference you're observing between DKK1 high and low patients. I think maybe it was surprising to some that there wasn't more of an absolute difference between the two groups, but wondering if it's fair in the absence of randomized data to think about it more in terms of potential treatment effect, meaning DKK1 high patients are believed to have worse outcomes, as I think you showed on slide six and seven. The treatment effect you're seeing in those patients is actually potentially larger than what the absolute PFS difference implies. Hopefully that makes sense.
Yeah. Thanks, Joe. That's a great question. I think it's a really important point for people to be looking at with respect to this data set, you know, based on everything we know from TCGA and Tempus and evaluating other PD-1 monotherapy studies, you know, consistently see that the DKK1 high patients have shorter overall survival, shorter time to treatment progression, and worse overall prognosis. We would expect those patients to be the ones that are dragging down the median progression-free survival and the response rates. You would normally expect that the DKK1 high patients, you know, would be the ones that have the worst potential outcomes.
Seeing them here being able to be having a higher response rate, having higher PFS and duration of response, we agree means that that is likely to be a group with the highest treatment effect. That, you know, as we looked at the data, we wouldn't have been surprised if, even with the addition of DKN-01, the DKK1 low patients could have had higher PFS due to the truly aggressive nature of the DKK1 high disease.
We're very encouraged to see that particularly in patients where we could get through those first two weeks of dosing, where we could get them that first full cycle of DKN-01, that we could have a very strong effect for those patients and see it, you know, translate even with those patients that couldn't make it through the first few weeks into an overall PFS and duration benefit. I don't know if Sam or Cindy have other things they'd wanna add with respect to, you know, thinking about DKK1 high patients and their disease course.
Yeah, I would agree. I think it's a fair way to put together the data from what's available. I mean, it to me is an indicator that, you know, it warrants more data. I think everybody is very interested to see additional numbers and ultimately randomized data. But I think the way that Doug described it is the way that I would put it together in my own head as well. I got asked that question a few times here at ASCO GI, and that was my general thinking along the lines of the PFS data to date.
Okay, thanks. That's helpful. Then maybe as a follow-up to that, with those comments in mind, I also wanted to better understand the potential next steps in this setting and whether you would pursue all comers or focus simply on just the DKK1-high patients. What are your expectations around closing out the database for the DisTinGuish study, and what would that trigger, as it relates to timing around BeiGene's opt-in decision? Thanks.
Yeah. No, thanks. Those are a really important question. First is under our contract, BeiGene has a period of time after they receive the final data from this study to make their final opt-in or not decision. You know, we would expect that database lock will be in the summertime, based on the current enrollment in part B and the follow-up to get a good overall survival read on all of the patients in part A. That would put BeiGene's opt-in decision point in the you know in the fall. You know, as we look at next steps, and that is an ongoing conversation that we're having, certainly with BeiGene, with our key opinion leaders, and as Dr.
Klempner just mentioned, you know, we absolutely believe that a randomized trial is the right next step, that we've demonstrated as much as you can demonstrate in single arm studies, having done it as monotherapy paclitaxel combination, KEYTRUDA combination, and now with tislelizumab, that we need to move on to a randomized study and really hone in on that performance of the control group in DKK1 high patients. Your question as to, you know, whether to focus solely on DKK1 high patients, where we would expect the treatment effect to be the largest or to continue to enroll all patients while sort of stratifying and balancing for DKK1.
Given the very strong results we've had in that overall population, having a complete response in a DKK1 low patient, having another patient go on to surgery because their tumor shrunk sufficiently that it could be removed and they be in a pathologic complete response, continuing to be very interested in the potential mechanistic synergy, even in DKK1 lower patients as it relates to 5-FU or the upregulation of PD-L1. It is a very open question that we don't have an answer to yet, but is something we continue to talk about with our investigators and you know, with our partner.
Okay, great. Thanks so much for taking my questions here.
Our next question comes from Timur Ivannikov with Raymond James.
Thank you for taking the question. Maybe asking a PFS question slightly differently because your overall response rate in DKK1 high was much better. In terms of first-line PFS and OS charts, of course, there are three patients who died early on in DKK1 high arm. That's sort of affecting the comparison, but to what extent do you think higher response rate in DKK1 high population can actually translate to improve PFS and OS?
Sam, I think that comment'd be perfect for you.
Sure. You know, the relationship between response rate and harder clinical outcomes, PFS and OS, the correlation is not always perfect. Certainly, response rate is very important in this disease population because these patients at the time of diagnosis are often highly symptomatic related to the location of the tumors, primarily GI bleeds, inability to swallow, et cetera. A response rate is quite clinically important even if it doesn't translate into PFS at times in other studies. This is the exact reason why nobody gives pembrolizumab monotherapy despite the fact that it's technically non-inferior to chemo, but the response rate is significantly inferior. Yes, response rate very important. Does it always translate to PFS? No.
I think in very small numbers here. I mean, you're looking at basically 21-24 patients, 25 patients here. It's a little hard to tease it out and, you know, there was some early censoring, as you suggested, in sort of unrelated events. I think it's just too early to know. I mean, you need, in my opinion, you just need more numbers to really get more granular with that, with that relationship. I would anticipate that, first of all, this median PFS of 10.7 months compares very favorably to the data that's out there in frontline trials. You know, even in the best selected patients for CheckMate 649, for example, the median PFS is around 7.5, 7.6 months.
This is a very encouraging, and to me I think it partly reflects what's happening mechanistically that, you know, if you are able to favorably remodel the microenvironment early on, then you can set this up to be a longer term success story. I know I didn't give you a perfect answer and I just think it's partly we just don't have enough numbers to give a really granular answer around that question. But I'm not concerned that a very high response rate is not translating here to a dramatic difference in the two arms of PFS.
Yeah. Thank you very much for the detailed answer. Maybe just another question then for Dr. Klempner. Just in terms of, you've mentioned you have a few patients under your care. Just in terms of tolerability and safety, you know, some of the grade three events with the DKN-01, elevated LFTs and GI events, are those events sort of ongoing or they're transitory? How do you see the treatment? I don't know if you have any second-line patients under your care, just to compare.
I have a fair amount of experience with the drug from this trial as well as the previous study in later line disease with pembrolizumab. GI stuff is probably the most common experience in symptom in my experience of the drug. It's usually people are not actually throwing up. It's usually GI upset more than nausea. It's a little bit difficult, you know, it's a symptom that's very common to these patients because of the type of cancer they have. I think that it's quite manageable. It seems, you know, relatively transitory, just like nausea is after chemotherapy, you know, usually a couple days after, lasts a day or two, and is manageable with simple antiemetic management. LFTs also a common phenomenon in the management of this population.
Mechanistically, I'm not concerned about the drug in regards to hepatotoxicity. It's not really the irAEs that we see with PD-1 related, you know, LFT changes. These are transient and don't require any intervention therapeutically in my experience. I was honestly a little bit surprised to see a couple of the attributions of the other adverse events. You know, every investigator is responsible for doing their best judgment about the etiology of a symptom. In my own experience, for example, I have not seen thromboembolic events which are common in this population. It's hard for me to get my head around exactly why this drug would be predisposing to thromboembolic events.
I would suspect those are potentially unrelated events, but I was not the investigator treating those patients, so I can't speak to their thought process.
Okay, great. Maybe one final question, and this is maybe for Doug. In terms of the patient selection in your second line study, you know, you appear to have screened a lot of patients. I see there's 170 patients and the study, obviously second line study is going to be a lot smaller than that. But just in terms of how much do you expect to improve perhaps the outcomes or perhaps the responses if you improve the selection and the screening in the second line study? Any thoughts on that would be great.
No, that's a really interesting question. As we've seen there, you know, we're encouraged to see that we continue to have one-third of patients in the second-line be DKK-1 high. But it's become, you know, as we've seen, we have had a significant number of patients that were screened as DKK-1 high, but who were not eligible by the time it was time to enroll them in the study, were not able to be enrolled due to the continued aggressive nature of their disease.
We do think that as we've seen, you know, more and more patients now, who are high DKK1 coming off of first-line therapy into second line, that it's incredibly important for us to try to get them, enrolled into the study, sooner so that we can, have the best chance of having the drug be able to be successful for the patients. One of the steps that we, you know, have been able to take over time in this study now that it's up and running, is to look for DKK1 expression while a patient is still on first-line therapy.
That we can know a patient is DKK-1 high at one of our sites, follow them until they have progression, and more rapidly, you know, move them into the clinical trial to try to, you know, minimize those patients we lose due to their aggressive disease, you know, waiting for a DKK-1 expression and for the consenting of the patient. Meanwhile, their disease continues to roar on and in many cases, you know, will not allow them to be eligible for the study. I think it's a really good point as we look at those second-line patients the one you know more we can do to pick them up early is important.
The second, I think, as you look at the profile of those patients, is how low the PD-L1 expression is. I think that, you know, with PD-1 antibodies being available, you wind up with a second-line population that is going to continue to be low PD-L1 expression. You know, as you can see there, you know, no patients even at 20 or higher in the second-line setting. You're really getting a group that's in high need, but you know, from a development process having very high disease.
Okay. Thank you very much.
Our next question comes from Mara Goldstein with Mizuho.
Great. Thanks so much for taking the question. The first maybe is a question for Dr. Klempner, just in terms of putting this data, I suppose, in context with published data, because there's been much discussion around CheckMate 649 and really what is the appropriate ORR to look at. Then I also had another question just around the part A and part B, and the decision to dose up to 600 mg in part B, and sort of what your thoughts around the value of that given the 300 mg for part A.
Sure. I'll take the first question. In 649, if you're trying to look at a reference, I would use the overall everyone enrolled for the reference here, because we just don't have enough numbers to really say should you compare. I'm pulling up the supplement so I can give you the exact numbers here. Yeah. If you look at the response rate in the overall population, which is 1,211 patients in the supplement to The Lancet paper, it's 58% for nivo plus chemotherapy, and it's 51% for the CPS low patient. Those are good numbers to keep in reference for a trial that's heavily enriched for CPS greater than five, where the response rate is 60%.
This trial, to me, obviously compares quite favorably to that. To me, it impressively does not appear to be related to the PD-L1 status, which to me is suggesting that, you know, this is a drug-mediated difference. I don't know if that answers your question. You were asking about benchmark response rate. It's tricky. I mean, we at our institution, don't give checkpoint inhibitors to people with a CPS score of less than five. So we often use that as sort of our comparator. I think a 55%-58% response rate benchmark for checkpoint plus 5-FU and platinum is a fair place to compare.
Okay.
I'd just say first, you know, certainly, you know, we all have seen The Lancet publication and the supplement and, you know, do note that there is a difference in the number of patients represented in the supplement and the FDA label. In the FDA label for nivolumab plus chemotherapy, where all of the patients in this study are included, the response rate in the overall population drops to 47%, with 50% in the PD-L1 greater than five population. We certainly acknowledge that there is a difference between the manuscript for the study and the FDA label for reasons that are not clear, you know, are better known to Bristol-Myers Squibb than to us.
With respect to dose, you know, there is, you know, as we look at taking on later line patients, the idea of can we get more drug to patients sooner and continue to fully understand the dose and exposure-response relationship, encouraged us to want to test an even higher dose in the second line patients than we had found to be effective in previous studies.
You know, you could also imagine that that could be a foundation to move to a less frequent dosing regimen in future studies, so that with experience with 600 mg on day one and 15 of a 21-day cycle, it would be easier to move to a once every three-week dosing cycle that could be more convenient for patients and also more compatible with the once every three-week dosing regimen of tislelizumab. We'll, you know, we continue. It's very helpful to us from a modeling, from a safety, and ultimately to see if there is additional efficacy you can get from higher doses. It's in this type of study, it was a very good time for us to try to explore that.
Thank you.
As a reminder, if you'd like to ask a question at this time, that is star then one. Our next question comes from Joel Beatty with Baird.
Hi. Thanks for this presentation and congrats on the data. My first question is, do you anticipate any changes in protocol in a future pivotal study, mainly related to managing any of those safety and tolerability issues?
Maybe any other comments about safety of the drug, maybe Cindy, from your perspective as you look at the overall safety database for DKN-01 in esophageal gastric cancers or even from its, you know, monotherapy activity.
Yeah, no, this drug has been administered in about 450 patients with cancer to date. I think, you know, as Dr. Klempner described it's very well tolerated as monotherapy. The most frequent adverse events are low grade 1, 2 in severity and typically constitutional or gastrointestinal. I think also as Dr. Klempner mentioned, I think some of these are adverse events that occur quite frequently in this population just due to the location of their malignancies. I think we have not also, as Dr. Klempner described, really seen an increase in any particular event in combination with any therapy, whether it be a chemotherapy or other immunotherapy, in which we do see a transition to really the safety profile of the agents that we use in combination.
For chemotherapeutic agents, we tend to see cytopenias, and for the immunotherapy, we really haven't actually seen an increase, as Sam mentioned in the irAEs as well. It's been very safe to administer. You know, and again, as Dr. Klempner mentioned, even for the more high-grade events that occurred in Part A of this study, the company, in a company assessment on these, did not agree with the investigator that suggested that the thromboembolic disease was related to the drug regimen, given the underlying incidence of thromboembolic disease in patients with gastric cancer.
Okay, great. Yeah, that's helpful. Another question, can you discuss the outlook for DKN-01 beyond gastric cancer and the potential in other indications?
Yeah. No, that's a great question. I mean, we are, you know, we're very enthusiastic about the potential for DKN-01 both inside of gastric cancer, but in other indications. You know, we believe the basic development strategy that we've had, which is to look for tumor types where DKK1 is highly expressed, where that high expression leads to worse outcomes for patients, and where there is a significant unmet medical need that we could be addressing is one that applies to not just gastric cancer. We, you know, as we look at the studies we've done in the past, we continue to believe we saw a very strong single agent signal in endometrial cancer, including our patient with a complete response that's now over three and a half years on a monotherapy CR.
Initially, the overall treatment effect benefit we saw in monotherapy and in combination with paclitaxel and DKN-01, high DKK1 patients. You know, we originally did a single agent study that had an expansion cohort in non-small cell lung cancer, had a patient with a single agent response, and nearly 50% of patients with stable disease. In lung cancer, that's another indication with a high DKK1 population where that DKK1 is associated with worse outcomes, and even one where the PD-L1 low population appears to be a group that's not as targeted by the PD-1 combinations that are currently in phase III clinical trials, so potentially of interest.
Colorectal cancer is a population that has, you know, a high degree of Wnt activation, a high DKK1 in advanced patients, 5-FU-based chemotherapy as a frontline regimen, just like in gastric cancer, and, you know, modest activity for PD-1 antibodies outside of MSI-high patients. Even though we have no current clinical data there, we've done animal models in colorectal cancer cell lines that have shown single agent and combination activity. As we look at the kind of top four indications on our prioritization scheme, it winds up being prostate cancer, you know, where we are still hopeful that we'll have clinical data to show in the middle of this year from Dr. Wise's IST at New York University.
You know, we point people to the research he's published in the past of his identification of DKK-1 as being associated with an immunosuppressive tumor microenvironment in prostate cancer, particularly advanced patients who are, you know, PSA low and androgen receptor negative. You know, we currently have been in a conversation with BeiGene and with other people around what is of those four, which are the next most exciting paths for DKN-01 to take forward. Is it DKN-01 with chemotherapy and a PD-1 again, or do you not need the PD-1 for some of these opportunities? We hope to have, you know, an update for people, you know, over the next few months.
I can say it's a spirited conversation here in terms of people having their favorites of where we go next.
Great. Thank you.
We are showing no further questions. Thank you again for dialing into today's call. Have a great day.