Alex, and I serve as an equity research analyst here at Sidoti & Company. Today, we're pleased to be in conversation with CEO Mark Erlander of Cardiff Oncology, ticker CRDF. During the presentation, please feel welcome to submit questions using the Zoom Q&A interface at the bottom of your screen. After the presentation, we'll open to your questions. And with that, Mark, I'll turn it over to you.
Well, thank you very much, Alex. And it's really a pleasure. It's really a pleasure to be able to speak at the Sidoti Conference today. And I'm really excited to be able to talk to those of you that are listening, to give you an update of where we are at Cardiff Oncology and why we think you should be excited about what we're doing. With that, I'm going to start the conversation with you. Okay. We have certain forward-looking statements. So let's get started. So onvansertib. Onvansertib is really a first-in-class PLK1 inhibitor for first-line RAS-mutated metastatic colorectal cancer. And why do I say that? So on the top left, really talking about the actual molecule, it's a highly selective PLK1 inhibitor. PLK1 is a serine/threonine kinase, so it's an enzyme. It drives the tumor cell division, DNA repair, angiogenesis, survival.
In essence, tumor cells overexpress this enzyme, PLK1, and that allows tumor cells to have uncontrollable growth and be able to metastasize. So it is really a great and well-known target for cancer therapy. On the top right side, really, what are we talking about here? Well, we've shown very strong efficacy signal in RAS-mutated metastatic colorectal cancer. And that really started, and I'm going to get into that in a second, but really seeing a very robust activity in Bev-naïve patients in our second-line trial. And then, of course, now in our first-line trial, what I'm going to talk to you today about is the exciting results that we have in CARDIV-004, which we initially released back from July 29th of this year.
Now, on the bottom left is really very important because we believe that onvansertib is going to be a practice-changing. It will be basically a practice-changing potential in a very large underserved population, and on the far right, bottom right, we have also already received clear FDA alignment as far as the clinical path, so let's get started, and all of the things I've just talked to you about, I will be touching on in much greater detail as we go through this presentation. Onvansertib, just to remind you, it is a small molecule in the middle. There's the structure, and on the far right, you can see those of you who are pharmacologists know that this is showing that we have a 5,000-fold greater activity of PLK1 versus the other evolutionary-related PLKs.
We believe that's very important and one of the reasons why this molecule is so well tolerated when combined with chemotherapies. So let's talk about the actual disease state that we are targeting here. On the left-hand side, I think everybody knows colorectal cancer is a rather common diagnosis, the third most common. And then look on the bottom left there. That's really the big problem we have in colorectal cancer. Only 15% survival at five years after being diagnosed. And on the right side, you can see gives you kind of a timeline of what's happened for these patients, these RAS-mutated metastatic colorectal cancer patients, what's happened as far as therapies. And you can see that the last targeted therapy was bevacizumab or Avastin, and that was over 20 years ago. And so really, what we're talking about here is we need new therapies in first line.
I know that the people I'm talking to right now, myself included, we have loved ones that we know that have been diagnosed with metastatic colorectal cancer. And 50% of those patients that are newly diagnosed will have a RAS mutation. And what we're saying here is that for the last 20 years, there's been nothing new. And we've got to collectively, we've got to change that 15% five-year survival. We need to make a change so that these patients have a much greater survival. So with that, let me go to the next slide. And that really just kind of reiterates what I just said. Right side's a pie chart showing that really for the vast majority of RAS-mutated patients, there is really nothing new under the sun for these patients in over 20 years.
And so this is a huge market, but quite frankly, more importantly, it's a huge unmet need that we believe here at Cardiff Oncology that we're going to be able to address this. So let's talk a little bit about sort of the genesis of this program. Really, how did we get started in colorectal cancer? And it really began with a phase 1b/2 trial, but it was in second line. And it was really KRAS-mutated. So still the RAS, we started with the RAS-mutated population. And in that phase 1b/2 trial, which I'm going to talk to you about, we discovered synergy with bevacizumab. And I'm going to talk a little bit more about that. That led to really a deep dive into the identification of a novel mechanism of how onvansertib works in concert with bevacizumab or Avastin to shut down angiogenesis in tumors.
And then really, with conversation with the FDA, led to a pivot of our clinical development path from a second line to a first line and subsequent trial 004, which we're going to talk to you about as well. But really, to get things started, let's talk about the beginnings of this whole program, which was in second line in the left-hand side, second line, KRAS mutated, unresectable, with ORR being the primary endpoint. And on the right-hand side is the dosing schedule. Onvansertib is oral. Patients take five doses daily for five days. Then they have nine days off. And they, in essence, overlay the standard of care infusions that happen every two weeks at the hospital, which would be the FOLFIRI + BEV.
Now, one thing that we didn't know going into this second-line trial several years ago was that actually the patients who came into our trial came in two different flavors. One was patients who had received bevacizumab in first line. It is approved for first line and second line. And then those patients who actually did not receive bev when they were in first line. In our second-line trial, all patients got the standard of care, which would be FOLFIRI + bev + onvansertib. Now, cutting to the chase, what was the data? When you looked at the data from patients who came into our trial with no prior exposure to bev, that is to say bev-naïve, you can see right away that this is a traditional waterfall plot where going down is good news. The tumor is shrinking.
If you cross the 30% reduction of the tumor versus baseline, it is an official response in terms of that teal color you're seeing. You can see right away that there's just a lot more responsive patients in the bev-naive than bev-exposed to the tune of 73% response rate on the left-hand side versus 16%. What we were expecting is on the far right, the historical controls of bev-naive should be around 25%. We were clocking it at 73%. Something was going on here that we didn't know about when we started this trial. This also translated to much greater progression-free survival, nearly doubling in the bev-naive patients and nearly doubling of what we were expecting on the far right with the historical controls. This really led us then to really do a deep dive into what was going on.
Really, the question really was, okay, so you have patients that come into our second-line trial. The tumor has not been exposed to bev, so it's bev- naive. They obviously have not been exposed to onvansertib. So is there something going on between onvansertib and bev that we just didn't know about before? And so that really allowed us to ask some very fundamental questions in mouse models where you, in essence, grow up the human tumor on the hind leg of a mouse. And you can see here right away, these are basically curves showing tumor volume over time in the x-axis. And when you add onvansertib and bev together and administer it to a mouse that's harboring a RAS-mutated tumor, you can see that there is a much greater effect, stat-sig effect on the tumor growth versus either agent alone or the vehicle.
Now, we said, well, let's look at a couple more. We did. And we got the same answer over and over again. So then we called up the CRO that was actually running the experiment for us and said, hey, by the way, on those last two experiments, two models, can you do a gross dissection of the actual tumor from the mouse and take a photograph of it and send it to us? And the reason we asked that is because when you look at the photos, and if your eyes at the top look at, you look at the vehicle, the control, pretty big tumors, but also really red, lots of vascularization. And when you had bev and onvansertib administered to mice with these tumors, you can see that there was a smaller tumor, but also decreased. But really, your eyes go down to the bottom.
You can see that not only do you, when you have the combination, not only do you have smaller tumors, but you also have really pale tumors. That means there's not really shutting down the vascularization or angiogenesis. This was really a hit and clue for us, and this is what really propelled us into a year of research to understand the mechanism because it had not been known before. What it came down to was the following. I'm going to cut to the chase because in this short presentation. On the left-hand side, a cartoon. We all know that tumors, when they grow, they outpace. They grow so fast that they outpace the blood vessels supplying nutrients and oxygen. So they become hypoxic in the middle. That is to say, no oxygen. Now, normally, those cells would die, but no, tumors can adapt.
And they adapt to this hypoxia by turning on a whole new set of genes through this HIF-1 alpha pathway. And we know that bev actually neutralizes one of the outputs of this pathway, which is the VEGF, which is basically the growth factor trying to attract new vascularization. But what we didn't know was that onvansertib actually works in concert on the same pathway and actually shuts it down at the beginning. It really inhibits the ability to even be able to have this adaptation. So what that really led to was the clinical data as well as this translational, this preclinical data led to a publication in the ASCO flagship journal called JCO, Journal of Clinical Oncology.
And even more excitingly than that was the fact that because it was a novel finding and we were actually identifying a patient population, it really enabled the issuance of two brand new patents from the USPTO, which really extended runway out to at least 2043. Now, with that, really kind of in summary, what we really now know about onvansertib is, and it's really a perfect match for combining it with chemotherapy and colorectal cancer because, number one, we have the right patient population. It has synthetic lethality with RAS mutant background. That is to say, RAS mutant tumor cells are much more sensitive to inhibition of PLK1. They get killed much more easily. We have synergy with the chemotherapy. In this case, FOLFIRI, we showed you that. That's the IRI part of FOLFIRI is irinotecan that causes DNA damage. We have synergy with that.
Then I just showed you our novel finding where we have synergy with bevacizumab and really inhibits new blood vessel formation to support tumor cells. With that, let's kind of move on to really the exciting clinical data that I want to talk about now. That really is the ongoing first-line trial. Now, just as I mentioned earlier, we were in second line. All that data was in second line. We went to the FDA. The FDA really recommended that we pivot the entire program to a first line. Why was that? A lot more patients with RAS mutation, there was a huge unmet need. Secondly, all patients in first line are bev -naive. They've never seen bev before. Perfect storm to really be able to leverage our molecule onvansertib in the first-line setting.
Just to level set before we jump into the data, so what's out there before? What kind of clinical trials and what kind of response rates are you getting that have been practice-changing trials? We've highlighted here the ORR, which is objective response rate or simply the response. And you can see right away that it's really low double-digit, 10%, 11% difference between the response rate of the control arm versus the new experimental arm in these previous clinical trials. Really, what we're seeing here is that led to PFS and events or PFS numbers that enabled practice changing. That's really what we're looking for here is a greater than 10% change in the ORR based on previous studies. Let's get into the actual trial itself. This, like I said, is a first-line trial on the left-hand side. Now, it's really all RAS mutations.
We included both the KRAS, which is the most abundant, but also we included the NRAS, which is rare, much more rare, but we wanted to get them all. Unresectable, no prior bev. In the middle of it, a screen, you can see the actual experimental design, so it's a randomized trial. Really, you can see that it's actually six arms that can be, in essence, looked at as in three major buckets: standard of care alone, 20 mg, and 30 mg onvansertib. Why two different chemos? Well, FOLFIRI, bev, and FOLFOX bev are both approved for first line and have been shown previously to be equivalent from an efficacy point of view, so we wanted to look at both of those in this trial. Right-hand side is a dosing schedule exactly the same as what we did in that second-line trial I just talked to you about.
And then really importantly, as your eyes go to the bottom left as far as the endpoints, what's important here is that it is ORR, with secondary being the DOR and PFS. But all the data you're going to see here was really assessed by a central review. It was a blinded independent central review or what people call BICR. That's important. Really elevates the quality and the data and really gets rid of the biases that can be seen sometimes from site to site. Now, let's jump right into what the data looks like. We've got three rows here. The top row is really now, keep in mind, this is the response rate of an ongoing trial. So what you're looking at here is, in essence, a snapshot of the data.
You can see right away. Your eyes go across. You can see that there's a 19% difference in the 30 mg versus the control with what appears to be a dose effect with the 20 mg being higher than the control. Also, what's interesting is that what we were seeing, we were seeing in this trial that tumors shrunk much more rapidly and quicker with patients who received also the onvansertib. And you can see that in that second row. Confirmed responses at six months. So in other words, when you look at six months as a landmark and you demand that, what is the number of patients who have had a confirmed response? That is to say, they had a 30% or greater reduction, and then the next scan, they showed that again. So they confirmed it.
What you can see right away is that you go from 22% in the control versus 46%, 8 versus 17 patients. So basically, a doubling of patients were seeing much more rapid responses in that first six months, and then because it's an ongoing trial, we also include the last row, which is really the response rate of confirmed PRs or confirmed responses. We call them PRs, partial responses. Confirmed PRs and CRs are complete responses, + any patient who we yet to confirm. That is to say that down the road, they could confirm, and you can see that the numbers all bump up, and then you're now looking at a 43% versus 59% for the 30 mg. Now, another way to look at this data is really through the control and the onvansertib 20 and 30 through a waterfall plot.
You can see right away there is quite a difference in the depth of response when you look at the experimental arms, the 20 and 30, but the 30 especially, and also the presence of complete responses, the tumor totally disappearing. This can be seen better through what we call spider plots, where on the y-axis, yes, that's tumor shrinkage going down is good news. And then on the x-axis is time. And you can see right away that there's quite a difference between the pattern. If you step back and looked at this as you were looking at a Matisse at a basically art venue, you would say, wow, there is quite a difference here, a standard of care versus 20, and particularly the 30 mg.
You can see there's really the slope of the lines of these patients' tumors keep going down, down, down, and many of them, there's quite a few here you can see that are close to 100% or already at 100%. Now, the other way to look at this is through chemo backbone. Like we stated, there are two different chemos, and what we can see here with the data that was released on July 29th of this year is that we are seeing activity on top of both chemo backbones, and we have examples here of different patients, and it's actually quite exciting. You can see that on top left, here's a very young patient, a 47-year-old female with target lesions in the peritoneum and all the way and non-target throughout the entire peritoneum.
You can see that this patient, after six months of treatment, six cycles, they achieved a complete response. Everything's gone. They went into a curative surgery afterwards to get anything that was potentially left. Basically, the tumor and its target lesions were gone. Bottom right is also an example of another patient who also did the same thing in six months. These are all examples. These are great stories. This is one of the reasons why the investigators in our trial are very excited about this molecule and very excited about working with us in the future in our registrational trial, which I'm going to talk to you about in a couple of seconds. At the July cutoff, and when we presented this on July 29th of this year, there was really very, very early to start looking at durability, which would be considered like progression-free survival.
We can see things are going in the right direction here with the control arm and having the worst outcome there being on the bottom, the gold line versus the black line on top, which is the 30 mg. So things look great, but to be fair, this is early, early days, and we will be giving a much bigger update of all this in Q1 of next year. Now, the other way to look at it, and we're not going to go into details, but we have looked at it. It is while we're sitting around waiting for the durability data, we actually, there's other ways that people have in the past looked to see if they can then predict whether or not you would have a durable signal. Two different ways. One is on the top left. There is early tumor shrinkage.
They look at really when the tumor shrinks to 20% or greater within the first scan, which is the first after two months of therapy. That's pretty predictive. In fact, we have quite stellar data with that. And that is in our corporate deck if you want to look at that on our website. Also, depth of response. We see also a much greater depth, as you can see on those spider plots. It's obvious that we have a much greater depth response. And that's also associated with greater durable signals going forward for these patients. What about safety? We are combining onvansertib on top of two different types of chemo, basically, you have the FOLFIRI and the FOLFOX, + you're adding onvansertib on top of that. What we look at is that onvansertib, it is known as a PLK1 inhibitor.
It's known that if you went really, really high in dosing, you would have neutropenia or neutrophil count decrease, like we have highlighted there. What we're seeing, though, is that the doses that we're using and the schedule we're using to see this efficacy, we're really not seeing any increase or incremental increase in safety or in any kind of issues with regards to neutrophil count. And you can see that right there. If you look across there, you can see that what we really look at is grade 3 or greater. And you can see that in the control arm versus the 20 and 30, there really is really not much of a difference at all, particularly when you compare the 30 versus the control. That is good news.
And that is also another reason why the investigators, of all ones that we've talked to, they've always commented about how well tolerated onvansertib is on top of the given chemo. So where are we going? We're talking about 004, still ongoing. We will be updating that in Q1, like I said. But really, where we want to go next is the registrational trial. We've already had a meeting with the FDA a couple of years ago and laid out a roadmap that we agreed with the FDA to, where we would, in essence, in the 004, as you know, we are picking a dose, 20 versus 30. And I think it's pretty obvious to people that we're going for the 30, back to the FDA with the 30 mg. But on the 005, what about that?
The FDA has laid out a single trial that they proposed that we would do and that we agreed with them on that would be really designed for both accelerated and full approval in the same trial. We will be updating our basically clinical development path as well next year. So we'll have much greater clarity on exactly the number of patients once we meet with the FDA early next year. So what are we talking about as far as next steps? So before we kind of talk about that, we also at Pfizer just wanted to mention that Pfizer is an investor in the company. They have about a 3% ownership with their investment. And this was through their breakthrough growth initiative. This was back in 2021.
I think the other thing that's important was that once Pfizer saw the data from that initial second-line trial that I started out this whole conversation with you about, they said, "Hey, we have a program within Pfizer called Pfizer Ignite," which is, in essence, a CRO within Pfizer where we, in essence, will work with biotech companies like yourself that we have an interest in. And we would like to basically run the trial. Now, I want to be very clear. Yes, we are working with Pfizer Ignite, but there's no strings attached. We're paying cash for this. But I think what we get out of it is the fact that Pfizer has a very high bar for quality of data.
We felt that this was important when we were running this trial since so much is weighing on this trial, the 004 trial, as far as our next steps in the registrational trial. We've been very pleased with our relationship with Pfizer. Like I said, there are no strings attached with our relationship with Pfizer. What I'd like to do here is just kind of reiterate what I talked about. If we go from left to right on this slide, what I've introduced you to, some of you may not have known about what we're doing at Cardiff Oncology. We have a first-in-class PLK1 inhibitor. Importantly, we're showing efficacy, and also, it is well tolerated. We really are able to combine this with existing chemotherapies. Secondly, we started the program in second line.
We showed really very high response rates in bev-naive patients. That led to two new patents, led to a JCO article. It led to a meeting with the FDA, which then really, from the outcome of all of that, was a shift, a pivot of the company from a second-line to a first-line clinical development path. Why? Many more patients are in desperate need of therapies, particularly the RAS-mutated patients, which is half the population, as well as all patients would be BEV-naive. So we would be able to use that synergy between onvansertib and chemotherapy and BEV. And then I just showed you really some very encouraging signals on the ongoing trial in 004. We believe we've already identified a dose. We'll be going back to the FDA with that and then to really work out the details of that registrational trial.
And we are going to be giving you all an update next quarter, which will then show you much more durable data in the sense that we're looking longer term on these patients now. So we will be able to talk more about PFS and duration of response. The good news there is that we do have cash for another year after that release of data. So we have cash out into 2027. And with that, I've finished my talk, and I'm looking forward to hearing any kind of questions that anybody has. With that, it's been a great pleasure to talk to you all and give you really an up-to-date of what we're doing here at Cardiff Oncology. Thank you.
Great. Well, thank you very much, Mark. Let's start, I think, on something you just talked about, which is the partnership with Pfizer and their investment. Could you talk a little bit about overall how you think about partnerships in terms of subsidizing costs or licensing and generally your approach to that?
I mean, we've been very fortunate. Our relationship, we value our relationship with Pfizer. But really, the relationship has really, in essence, really no strings attached. They did put an equity investment into the company. From that, they got a member on our scientific advisory board, not a board, but our scientific advisory board. And that's actually turned out to be really a great thing because we can tap into some of their expertise in different subjects that we'd like to talk to them about. So it actually has turned out to be a really great relationship. And then, of course, the Pfizer Ignite part of the story is really just cash for service. There's no strings there. But we believe we're leveraging the high data quality that Pfizer does in their trials with that relationship.
So what I'd say is that I think we have, in essence, kind of two unique relationships with Pfizer in the sense that we are leveraging really expertise and execution of a trial, but really with limited strings attached.
Great context. Thank you. And I think you spoke about this a little bit, right, that PLK1 has been a target in oncology for years. But selectivity has been a major challenge. There's been other major challenges. So one of the really interesting and effective things about onvansertib is it's well tolerated. You're seeing great response rates. Can you talk a little bit about how that translates into not just clinical potential, but economic potential? What do these outcomes sort of imply given the pricing and economics of the standard of care today?
Yeah. I mean, I think a couple of things. You're absolutely right, Alex. The story of PLK1 being a target is not a new story. What the new story is, is onvansertib is the first molecule to be shown to be well tolerated. Previous PLK inhibitors were pan inhibitors. They hit PLK1, 2, and 3. They had a lot of toxicity. Couldn't really be combined with anything. Whereas here comes onvansertib, only hits PLK1, able to be well tolerated. So what does that really mean when you think about it? Well, in very simplistic terms, it means that patients can be taking their chemotherapy + onvansertib for a much longer time and don't have to have dose reductions or have to have interruptions and that sort of thing that would maybe be a problem if onvansertib had a toxicity profile that was putting on top of the chemo.
So this will equate to, of course, more drug being used or drug really acquired by hospitals for their patients. So I do think it does have an economic outcome in a positive way in general terms.
Thank you. And maybe as the last question, for investors who appreciate the growing prominence of colorectal cancer and the need to advance the standard of care, and they've seen some of your encouraging data, but they're not sure if now is the right time to invest, what would you say to them about having a conversation or why it might be a good time to invest?
Well, I think we're in a really Cardiff Oncology has been developing onvansertib for several years now, and I think we've gotten to the point where we are showing that onvansertib has great activity in colorectal cancer. We showed it in second line. Now we're showing it in first line, and so we are very bullish, of course, going forward. Very positive conversation previously with the FDA regarding this, and so, I mean, obviously, people have to make up their own minds of when they would want to invest in Cardiff Oncology, but I would say that we have really got a great track record of showing that onvansertib is active in colorectal cancer.
This is really a golden opportunity for us to be able to make a difference in first line, newly diagnosed patients for the first time being able to have something new that will be much greater than what people have received before.
Great context. With that, we are at time. So I'd like to thank you, Mark, for sharing the Cardiff story with us. And also thank everybody listening for spending time with us today.
Yeah. And I would just like to second that, Alex. Thank you so much to you, to Sidoti, for inviting us. And those of you that are sitting there thinking, "Wow, this sounds really exciting," you can check that out at our website, www.cardiffoncology.com. And also, you can also reach out to us as well. So thank you again for listening, and we look forward to talking to you in Q1.