Thank you, Molly, and thank you to Jefferies for this opportunity for me to talk to you about what we're doing at Cardiff Oncology. The forward-looking statements will be made today. So Cardiff Oncology, in a nutshell, is this is really the slide that tells you what we're doing at a high level. And if you go from left to right, Cardiff Oncology is positioned to improve the first-line RAS mutated metastatic colorectal cancer treatment. And you know, why do I say that? I say that because if we go left to right, number one, it's our molecule, our investigative molecule called onvansertib.
It specifically inhibits PLK1, and PLK1 is, overexpressed and hijacked by tumor cells, and so, and it really enables tumor cells to have uncontrollable growth, and because of that, that is why, this is such a good target. Secondly, is that we are coming off some very robust data, two different trials. I'm gonna tell you a little bit about, in the next couple 20 minutes. And then also, we had, last year, we had a terrific meeting with the FDA, a Type C meeting, where they, in essence, looked at our data and, suggested and recommended that we, pivot our clinical development path from a, a second line to a, a first line.
And then finally, we've had investment by Pfizer as well as right now, currently, our first-line trial of Pfizer Ignite is executing the clinical operations of that. We expect to release initial data from this first-line trial later this year, and from a cash runway point of view, we have cash into Q3 of 2025. We have more in the pipeline. What I'm gonna talk to you today about is really our lead program, which is in, like I said, RAS -mutated metastatic colorectal cancer, but we do have other programs in pancreatic, small cell, and triple-negative breast cancer, which I will not be speaking about today. So let's talk a little bit about how PLK, how we inhibit PLK1 and why is this important in metastatic colorectal cancer.
As I said, onvansertib is our molecule. It's an oral drug. It is a, has very high specificity for a serine/threonine kinase, PLK1. As you can see here on the right-hand side of the slide, we have a 5,000-fold greater selectivity for PLK1 versus 2 and 3, and this is we think is very important. One of the things that I would mention as well is that onvansertib is well tolerated. The onvansertib has been given to over 300 patients across seven different clinical trials, and we're showing it's well tolerated, and we believe part of the reason for that is because of its selectivity and also its 24-hour half-life. So in metastatic colorectal cancer, I think, a lot of you know it's a very common diagnosis.
On the left side, it's the fourth most common, and on the right side, it's the second most killer in the United States. Today, as we sit here today, about 50% of metastatic colorectal cancer patients have a RAS mutation, and there has not been anything new for these patients for 20 years. Really, a generation has passed, and these patients are still receiving a chemo a cocktail plus bevacizumab or Avastin, and there has been no targeted therapies to the actual tumor. Now, when you look at the landscape that we have in metastatic colorectal cancer and the RAS -mutated, there's quite a bit of talk and people are very familiar with the G12C inhibitors, mostly in non-small cell lung cancer, but in colorectal cancer, G12C is a very small sliver of the patient population.
On the right-hand side, showing you that we are going after all the different RAS -mutations. So over 50% of metastatic colorectal cancer does have a RAS mutation, so we're able to target all of these different RAS -mutations. So let's talk a little bit about the clinical data. Now, today I'm gonna talk to you about three different trials. The first trial is where this was the genesis of this entire program. And this is where we saw this really very robust data in the bevacizumab naive patient population, which I'm gonna get to in a couple minutes.
Secondly, talking to you about an actual randomized trial that we discontinued based on the FDA recommendation, and that's when we pivoted to this first-line trial, which I will tell you about, that we are actually, it's ongoing as I speak. And so let me, let's get into it a little bit. So in the Phase 1b/2 trial, this was really how we started this entire CRC program, and this was a single-arm trial that was going after the RAS mutated patient population, which is approximately 50% of all metastatic colorectal cancer. And we were really focused on second-line, where onvansertib, we were combining it with the standard of care.
There were really two reasons why we got into this from a scientific rationale, and one of them was that there was synthetic lethality between RAS mutations and PLK1 inhibition, i.e., onvansertib. And secondly, was synergy with DNA-damaging agents, which is the irinotecan part of FOLFIRI. So this is really how we started, and that was our rationale. And the actual trial is shown here, and on the left side, it's a single-arm trial. It was second line.
All had to be KRAS -mutated, and all had to be unresectable. In the middle, you see the actual dosing schedule, and there you can see that onvansertib is superimposed onto the standard of care scheduling of every two weeks, the patients receive an infusion of the FOLFIRI plus Bev, and then also they take orally our drug, onvansertib, for five days within nine days off. And the primary endpoint was ORR. Now, one thing just to mention very quickly is that, and we didn't know it at the time when we started this trial, but you, you'll see why it becomes important, is that patients could, two different types of patients came into our trial.
One type of patient was a patient who received the FOLFOX, the chemotherapy, but did not receive Avastin or bevacizumab, which we just will call from now on bev. But also, then you have patients who actually did receive FOLFOX and bev. So they were bev-exposed. Those that didn't receive bev in first line, we call bev -naive. Now, the reason that's important is shown on the next slide. So here's a waterfall plot showing best response from this trial, 66 evaluable patients, out of 68, and you can see right away on the left-hand side that this is where there's a lot more activity. We have, in essence, a 73% response rate within patients who came into our trial and were bev -naive. And the bev -exposed was really much less response rate, 16%.
So also you'll notice that, the reason that we really sat up and took notice of this was because we knew that, historical controls for these kinds of patients that are bev -naive was more in the 25% response rate, and we were seeing nearly triple that in this trial. So the other thing that we observed in this trial is that we saw activity across all the different RAS mutations. So we were really, truly, agnostic, as you can see that here. We broke it out into bev -naive and bev -exposed.
And also, when this high ORR extended into a much greater median PFS, and you can see here on the right-hand side of the Kaplan-Meier curve, that quite a separation between a bev -naive patient population and Bev exposed, with the bev -naive having a median PFS of 15 months, which, if you look at the bottom right of the slide, the historical is more in the 7-8 months. So we had nearly a doubling of PFS as well. So the question we had when we saw these results was, was there a bias in the trial? Was there something that went wrong in this trial that made us be able to see an artifact such as a high response rate in the bev -naive?
So we looked at all of the different patient characteristics, looked at a lot of the different known good and bad prognostic factors, and what I'm showing you here is that we did not see any kind of bias. Every time you looked at each one of these characteristics, the dark blue is the bev -naive patient population, the light blue is the bev -exposed. It didn't matter what characteristic you looked at, there was just a lot more clinical activity or efficacy in a bev -naive patient population. So then the question came down to is, okay, the trial is not biased, but what's the scientific underlying mechanism of this?
There really had not been any literature to suggest that there was some sort of interaction between a tumor that's receiving, that's bev-naive, that's receiving bev, and onvansertib, a PLK1 inhibitor. So we did the really obvious experiment. We went in. So we really did the reverse order of what you normally do. We went back to the bench to try to understand what that mechanism, what that underlying mechanism is for the clinical findings. What I'm showing you here is three different in vivo models, and what we did is we said, "Let's look at single agent, onvansertib and bev, and then let's put them together and look at how that affects on the Y-axis tumor growth." Well, it's pretty obvious when you look at that every single model we looked at had the same answer.
The combination had a much greater effect on inhibiting tumor growth than either agent alone. And where you really can see this obviously at a naked eye level is we asked the CRO that was running this, we said, "Look, do a gross dissection and take it out, take the tumor out of the mouse, and take a photo of it, and send it to us." And they did. And you can see right away is that in the control, large tumors, a lot of vascularization, red, right? And if you look at the bev and the onvansertib, they both have smaller tumors and less vascularization. But really what made us sit up and notice was the onvansertib plus bev. Take a look at that, you can see that it's a lot more pale, a lot less vascularization.
So there's something going on between PLK1 inhibition and bev in the same pathway of vascularization. So we really, to cut to the chase, what we found was that tumor growth, as we all know, usually outpaces the ability of them to get nutrients and oxygen. So in the middle of a tumor becomes hypoxic. They've just run out of. There's not enough oxygen there. But instead of those tumor cells dying, they adapt, and how they adapt is through a very well-known hypoxic hallmark of cancer, of hypoxia response, and they induce a transcriptional factor, showing it here, HIF-1 alpha, and that turns on a whole new plethora of genes, a new genetic program that allows the tumor to attract a new vessel vascularization through angiogenesis and also survive. So we know that bev, how it works, it basically neutralizes the growth factor, VEGF.
But what we didn't know was that onvansertib inhibits the inducibility of HIF-1 alpha. Now, we don't have a lot of time here today, so I'm not gonna go through all the details here, but this is just showing you here, if you focus on the left, top left, these are four different cell lines where we asked that question. We said, "Well, let's induce hypoxia, and let's then see if what happens with onvansertib being added to it." You can see on the left side, if you look at the LoVo cell line, oxygen levels normally are at 20%, as we know. We didn't see anything there, but with 1%, which is hypoxic, you see this huge up-inducibility band, a protein band of the HIF-1 alpha.
But what was startling to us was that when onvansertib was present, it no longer was there. And we saw that over and over again, all the different cell lines you see on this slide gave the same answer. We also asked the question of, well, was there an off-target effect? Is onvansertib hitting something else besides PLK1? So we did the obvious experiment on the bottom, where we used siRNA to PLK1, our target, and knocked it down, and we saw exactly the same thing. When you knock down PLK1, you inhibit the ability of the tumor cell to adapt to a hypoxic situation. Now, the other question that we had was, well, what about the bev-exposed patients? They're gonna get bev in that. They got bev in the trial. What's different about tumors that have been exposed to bev versus those that haven't?
I will say from this slide, this slide shows you we did a very large experiment with Tempus, 135 patients, and we exactly mimicked the type of two different types of patients that came into our trial. Those that were bev -naive, they just got FOLFOX, and those that got bev -exposed, they got FOLFOX plus bev. And we had whole genome transcriptome data post their treatment of first line, and we asked, what's the difference? So in other words, what is the difference between a bev-naive tumor and a tumor that's been exposed to beva? And you can see on the right-hand side, there is the uptick of gene sets that are in essence we already knew some of this.
We knew that bev, pretreatment of bev to a tumor, will cause hypoxia gene sets to be really induced and shown there on the right-hand side. That's in a way that's known as a way a tumor cell can become resistant to bev. But what caught our eye was the mitotic spindle in the G2M checkpoint gene sets that were also really upregulated with bev treatment. Those are gene sets controlled by PLK1, our target, and the fact they were upregulated allows us to make a very strong hypothesis that the reason why you're not seeing clinical activity in bev-exposed patients is because those tumors have been radically changed by pretreatment with bev to have resistant mechanisms to not only bev, but to onvansertib. So let's move to...
Okay, this really gave you understanding of the underlying mechanisms, but what about more clinical data to validate what I'm just talking to you about? Now, as I mentioned to you, we did do a randomized trial. It was. We discontinued it basically because of our feedback from the FDA that recommended we move to first line. However, we did have 21 patients that were on this trial that we were able to evaluate. And this trial was randomized to a standard of care of FOLFIRI plus bevacizumab, and then overlaid in the second and third arm of the randomization were onvansertib at 20 mg and onvansertib at 30 mg with FOLFIRI bevacizumab. Now, on the right-hand side, the dosing schedule was exactly the same.
They were given orally onvansertib for 5 days and 9 days off and overlaid onto a standard of care of FOLFIRI plus bev. Now, this is the data. So what we saw, and if you look at this data, your eyes are gonna go immediately to the left. You'll see where the tumor shrinkage is the greatest is on the left-hand side of this slide. And those are the bev-naive patients that also received onvansertib in addition to standard of care. And you'll notice in the bev- exposed, we don't have any objective responses, and also in, more importantly, in the FOLFIRI bev alone, in bev- naive, we have no objective responses. Now, the other thing that I...
You can't maybe see it, that really plainly, but I'll just tell you that in the bev-naive patients that got onvansertib, and we saw the clinical activity, those bev-naive patients, there were seven of them there in total across both the study drug plus the standard of care. All of those seven sites were different clinical sites. So in other words, there wasn't a bias in the, you know, when maybe one site had a couple of patients that did really well. The other thing that was interesting was that the two patients that had confirmed PRs there were actually the 20 mg and the 30 mg, so both doses gave efficacy.
Now, the other thing you'll see in the four patients, there's two that had confirmed PRs, and there's one patient with a -27, which is actually kind of a tragic story. And the reason I say that is because that patient, when you look at spider plots here on the left-hand side, you can read it yourself, but what happened was that they thought the patient did have another lesion in the lung, so they had progressed. So they took that patient off the trial. And what happened then was, as you can see, was that then that tumor started to grow again.
The tragic part of this story, of course, is the fact that it turned out when they did a tissue biopsy, that this patient, did not have a new metastatic lesion, they had a fungal infection. But it does point out the fact that once we withdrew onvansertib, you really do see the tumor starting to take off again. So let's just talk about, on the last couple of minutes, talk about where we're going now. Now, the, one of the points of, of the FDA when we had the meeting was that when we go into first line, and you see on the left-hand side, the market size, the patient population is much larger, nearly 50,000 patients in the United States per year.
So also, when we went to the FDA, really, we were able to lay out, and they agreed to a clinical path to accelerate approval and full approval. The trial we're doing today, the 004, is the first randomized trial. It's a 90-patient trial, and there we will, in essence, confirm our dose and look at the efficacy in that trial from a randomized trial. We will then. Once we have the dose, we will go to the FDA, and they've. We've already put in front of them the 005. They agreed to it. They've agreed to a seamless trial for both accelerated approval and full approval, with the accelerated approval, primary endpoint being ORR, response rate. And for full approval, PFS with an OS trend.
So the trial that is ongoing today is the Cardiff 004, and you can see here that looks very similar to what I showed you in second line, where we have a standard of care arm, and then we have onvansertib at 20 mg and at 30 mg. And same dosing schedule as the last two trials I talked to you about, and also, Pfizer Ignite is really, in essence, acting as our CRO and really clinically executing the clinical operations of this trial. We remain, you know, we are very bullish about where we are with this. When you ask about, well, what's the response rates in first line? I've shown you here from a review article, recent review article.
So on the left-hand side, you can see that in first line, we have 45% response rates. As I showed you earlier, in second line, we were showing 73% response rate. We feel very bullish about being able to achieve a delta difference that is in the range of about 20% above standard of care response rates. We also just wanna mention that we do... Pfizer did invest in us back in November of 2021, $15 million investment. This was through their Breakthrough Growth Initiative. We, for that, they have the right to first access to data.
They have no rights to the molecule or first refusal or anything like that, but they do have the right to see the data two days in advance before we release anything publicly. That's been a really also Adam Schaywitz is on our scientific advisory board. It's been a great relationship with Pfizer, and we've been able to really have a very good interaction with them through this growth initiative. Pfizer Ignite, they came to us and asked if we, if they, we'd be interested in having them run our they would run our first-line trial that we're doing right now. And they are, in essence, acting as our CRO. They have Cardiff Oncology, as it says here, retains the full economic ownership and control of onvansertib.
So as I sum up, this talk, this really, I hope really gave you a good view of what we're doing here at Cardiff Oncology. We're very excited about the trial that is ongoing right now. It's a first-line trial, and like I said, we'll be sharing data later this year, a first initial look of that. And we do have, as I'm showing you here, we have cash of $67 million and runway into Q3 of 2025. So thank you very much for your attention, and I'll take any sort of questions at this point. Okay, I stunned you guys. Well, thank you very much.