Welcome back to the 44th annual TD Cowen Healthcare Conference. I'm Marc Frahm from the biotech team, and we're really happy to have the next session here with Cardiff Oncology and CEO Mark Erlander. Maybe just to start off, Mark, do you want to give a kind of brief just state of the company and kind of what you view as needing to happen to kind of create shareholder value over the next 12, 24 months where major events, and then we can dive into some of the specifics about those events?
That's great, Mark. Thank you so much for the invite here, and it's really a pleasure to be able to tell all of you what we're doing at Cardiff Oncology. If you step back a high level, Cardiff Oncology is now really poised to make a significant impact in the treatment of first-line metastatic colorectal cancer, those patients that have a KRAS mutation. And the reason I say that is for really four reasons. Number one, it's our drug. Onvansertib, it's a small molecule oral drug that is very highly selective for a target called PLK1, which PLK1 is hijacked in tumor cells and allows tumor cells to have uncontrolled growth. Secondly, it's our data.
We reported out originally phase I-B/II data in second line as a single-arm trial, and there we found some very exciting data, which we then just reported out Thursday of last week, which validated that, and we'll probably get into that later today. Thirdly, it's the FDA. We went to the FDA last year. They saw all of our data that we were doing in second line, the original phase I-B/II, and with their recommendation, they recommended that we pivot and transition to a first-line clinical development plan versus a second line. And so that was really one of the reasons for that was that the patients that are in first line, they all are what we'll get into it, bev-naive, and this is a much, much bigger population of KRAS-mutated or RAS-mutated patients. And then finally is the Pfizer.
Pfizer made an initial investment two years ago, 5% of the company, but more importantly, we're working with Pfizer Ignite right now that's actually conducting in close collaboration with our clinical team, really our first-line phase II randomized data, which we'll also speak to a little bit today. So with all of this, we're expecting to see some initial results from that randomized trial mid-time this year. Also last thing to really keep in mind is that we also put out guidance last week that we have cash runway into Q3 of 2025. So that at a high level is where the status of the union is for Cardiff Oncology.
Okay. Great. Thanks for that overview. You started to touch on it a little bit, but can you dive in and just kind of explain the rationale there for that pivot from second line to first line and maybe tie together the drug and the mechanisms of action, but also with that clinical data that you were seeing?
Yeah. Initially, we put out we did a second-line single-arm trial, as you know, where we reported out 66 evaluable patients. And it was within that trial that we found out that there was a huge difference in response rates of those patients who had been previously exposed to bevacizumab, or people know it as Avastin, I'll call it just bev, been exposed to bev in first line versus those patients that were, in essence, never exposed to bev in first line. So they were what we considered bev-naive going into our trial in second line. Now, keep in mind that all patients got bev and FOLFIRI in this single-arm trial in addition to our drug onvansertib.
So what we found there was we had a 73% response rate in patients that were bev-naive, which was really a huge response rate in a second-line trial where you normally would see for bev-naive maybe in the 20%-25%. So it was like a threefold jump. And so that was really we had that data. And then really importantly, because we got that data, we asked the obvious question at the time. We said, "Well, why? Why are we seeing these huge response rates? Is there an underpinning science or mechanism that we just are not aware of at this point that would be between our drug onvansertib and bev?" And it turned out that there was. And it's an incredible story, actually, which I think we will probably touch on a little bit.
But with that, we were armed with that, and we went to the FDA in June of last year and said, "What do you think of our clinical development plan in second line?" And they said, "Looks okay, but actually we would recommend, given your data, to go to first line." And so in first line, instead of only 1/3 of the patients being bev-naive, which is what you see in second line, in first line, all patients would be bev-naive, so all would benefit from this combination. And secondly, the number of patients that are RAS-mutated is much bigger. It's about 48,000 patients in first line are RAS- mutated. So it was really that combination. And then it was really what came out of that outcome of the FDA was not only that, but also a plan that they agreed upon.
And that was really a two-trial plan. The first trial is what we call CRDF-004, which is ongoing today. And that really is a randomized trial, which we'll talk a little bit more about, that looks at two different dose levels and also is a randomized trial, so we'll also look at efficacy. And that's the trial I was talking about that we'll report out some initial data mid this year. And then secondly, they agreed upon the registrational trial that would happen right after that with a single dose of onvansertib. And that's going to be a seamless one trial for both accelerated approval and full approval. And really what we thought was a great win there was the FDA agreed to us allowing ORR, response rate, be the primary endpoint for the accelerated approval. So that's a big win.
It was not going to have to be PFS, it could be ORR. So that's kind of what was the pivot and why we pivoted and then the outcome of that with the FDA.
Maybe dig a little bit further on that. I mean, you mentioned the kind of you did some went back to the lab. It's like you did some translational work on the to figure out the mechanism and make sense, bev-naive, the signals there. But looking across oncology, we generally see people start in later lines and that's their first approval and then move up, right? You could have, in theory, said, "Okay, the signal's all bev-naive. There is a meaningful population of bev-naive patients in the second line, right? Why not start with them and then go to first line?" What was kind of the rationale there?
Well, I mean, we did talk to the FDA about that. And I think, number one, it is a small patient population because when you whittle it down, it's only about 1/3 of the second-line patients have RAS mutation. So we're looking at about 7,500 patients a year. And their argument was that you've got 48,000 in first line. And the biology would be the same. So why would you be in second line when you could be in first line? So that was really their big argument was, at Cardiff, you have the opportunity here to make a much bigger impact in a much shorter period of time. We think you should do it, but it's up to you.
You also touched on this a little bit, but that while you were kind of coming to that conclusion with the FDA to pivot to the first line, of course, the second-line trial was open where we just saw the data the other day, some of the data that had accumulated before you fully made that pivot. Can you just maybe provide a summary of that data, and then we can dive into some specifics about it?
Yeah. Just to give you context, so when we finished the original single-arm trial in second line and then we had that data where we had these bev-naive patients that were doing so much better, we did start a randomized trial in second line that had three arms. It was a control arm, a FOLFIRI plus bev, and then the same thing with onvansertib at two different doses of 20 mg and 30 mg plus the FOLFIRI and bev. So it was a trial designed to demonstrate the contribution of onvansertib as you compare it to a control arm of the same backbone of FOLFIRI and bev. So we started that trial, and we went to the FDA, and then, of course, we decided to discontinue that trial. It just didn't make sense to run two different trials testing the same hypothesis. So it made sense to discontinue that trial.
But before we discontinued it, there were 23 patients. If you looked on ClinicalTrials.gov, there's 23 patients that were enrolled in that trial. Of the 23 patients, there was, in essence, 22 evaluable for safety and 21 patients evaluable for efficacy. In the 21 patients, they were pretty much covered across the three different arms. So you had a control arm, and then you had two different arms of 20 mg and 30 mg onvansertib. And what was interesting was that within that, there was about 1/3 of patients in each arm, in essence, that were bev-naive, and the 2/3 were bev exposed. When we looked at that, it was really very revealing. And we released this data on Thursday after hours, as you mentioned.
It was a very stark contrast of a bev-naive patient getting onvansertib on top of FOLFIRI and bev versus a bev-naive patient that was getting just standard care, FOLFIRI plus bev. You could see that of the four patients that were bev-naive that were getting the experimental, they're getting the onvansertib, two of them had confirmed PRs of tumor reductions of greater than 40%, 43%, 44%. The third patient that had a - 27%, and I could talk more about that, that went off trial for actually the wrong reason, but they went off trial because they had PD, but it turned out that they thought they had progressive disease, but it turned out that the patient actually had a valley fever lesion, which by biopsy showed it was not cancerous, but they'd already left the trial because of the initial mistake.
But that patient was going down. It was -27%, so it was getting close to that -30%. And in the control arm, we had three patients that were bev-naive, and none of them had any kind of responses. They were all right around the single to double- digit, but no response at all, nothing even close to that. So it was very obvious looking at that that the signal was only in the patients that were both getting onvansertib and the chemo and plus bev in the bev-naive patients.
Okay. And then maybe as we kind of look at that accumulated second-line dataset, right, across the two different trials, are there any baseline factors we should think about that may also be contributing to some of the enrichment of maybe some of that is driving the bev decision in the first line or even within the trial as to kind of where you're seeing responses or not, whether it's sidedness of the tumor, the particular KRAS mutation they have, anything like that that's jumping out?
Yeah. We looked at that, and we also, in our phase I-B/II trial, have more patients to look at that. We had 15 patients that were bev-naive. First of all, just to go down your list, I mean, number one, there's no real clear reason, one reason why a patient doesn't get bev in first line. A lot of it is physician-directed. They perceived risk maybe for a patient. One of the reasons, one of the main reasons that patients are—they think they're too old to handle Avastin or bev. So when we looked at the data, we have not seen anything. We've also looked at the RAS mutations. Now, clearly, we see activity across all the different RAS mutations. Sidedness, we have not seen any relationship between a right-sided, which has a worse prognosis than a left-sided.
Having said that, one sidebar on sidedness is that the difference in the prognostic difference of a right-sided versus a left-sided colorectal cancer tumor, that difference is seen in wild type, but not seen in RAS- mutated. RAS mutation, in essence, dominates the prognosis of that patient. So it really does not have a play. Even though, having said that, we looked at it, we didn't see any difference.
Okay. Maybe now the first-line trial is open. You want to run through? You touched on a few elements of it, but just kind of run through the design of that first-line trial that is open.
Yeah. This is a really exciting trial, like I was mentioning to you earlier. This is CRDF-004, and this is a 90-patient trial. It's randomized into three arms. Those arms are a control arm versus a standard care, which is FOLFIRI plus bev or FOLFOX plus bev. And I'll come back to that because I think we want to know about the two different chemos. So you have a FOLFIRI plus bev or FOLFOX. Those are the two that are approved in first line. So that's our control arm. And then we take those same two standard of cares, a FOLFIRI and FOLFOX plus bev, and add on either 20 mg or 30 mg of onvansertib. So it's identical to the ONSEMBLE trial that I just talked to you about that was in second line.
This is identical in the sense of a three-arm and two different doses of onvansertib. But what's new is we're adding a FOLFOX as well as a FOLFIRI. And let me just deviate a little bit and talk a little bit about that. We do call it a three-arm trial, but in reality, it's actually a six-arm trial because you get randomized to the backbones as well. So each patient, there will have equal distribution of a chemo background of either FOLFIRI plus bev or FOLFOX bev in the trial.
That's randomized from the CROs directing it, or is that the physician says, "I'm going to use FOLFIRI," or, "I'm going to use FOLFOX"?
It's actually randomized by actual randomization. It's just harder to show the all six, so we blew the three, but then it is randomized into each chemo backbone.
Okay. You said 90 patients, so kind of 15 per regimen, right?
Yeah. Really, it's going to break down to in the control arm, you have FOLFIRI plus bev and FOLFOX with bev, 30 patients total. It'll be 15 and 15 of the two different chemo backbones. Same for the other arms.
Yeah. And maybe, I guess, what gives you comfort? I think most of the experience with this drug is with FOLFIRI. Just gives you comfort that weird things aren't going to happen from a safety perspective or whatever with FOLFOX.
I mean, we have preclinical data that shows that we see synergy there. We don't see safety issues. In the protocol, there is a safety lead-in for the FOLFOX patients who are getting FOLFOX. So we will evaluate that. There is a safety committee that will be looking at that after a certain number of patients go in just to make sure. So we do have our eyes on it as a safety lead-in, but it will not disrupt the trial.
Okay. And then you're planning on reporting data in the middle of the year, the initial data from that. Maybe review what's the triggering event to showing data, and what endpoints do you think you'll be able to show and which ones clearly like OS, clearly not going to show that?
I mean, right now, as we look at it, we're very bullish to be able to report out initial data mid-year this year. And we say that for two reasons. One of them is that Pfizer Ignite, who is running the trial, but we are working very closely with them, our clin-ops team, feels very bullish about that timeline. And then secondly, as of February 29th, so that's a couple of days ago, we had 20 sites already activated. And within those 20, 16 of them were trial sites that had been involved in our previous two trials. And they know the drug. The investigators know the drug. They're excited and very enthusiastic about the trial and the drug. And the other thing to keep in mind is that a lot of these sites that have been activated are big enrollers.
For example, all three Mayo Clinics are activated, and they were big enrollers in our last trials. So there's that part of it just from that point of view. Now, to get to your answer to your question, so what we're looking at is right now, we think that approximately half the patients if half the patients can be dosed and have one post-baseline scan, that this would be we think this would be enough to be able to see the difference in signal. Clearly, that's what we're projecting, but that's our plan at this point. And I'm sorry, that would be ORR. Yes.
Yeah. In terms of that delta, that's assuming you're going to pool everything together from onvansertib?
Yeah. And that's an important point, Mark, is that and the ONSEMBLE trial, the trial that we discontinued in second-line taught us that when the confirmed PRs that we observed in the bev-naive patients in second-line in the randomized trial that we were talking about earlier called ONSEMBLE, those two confirmed PRs came from the two different doses. One was 20 mg and one was 30 mg. And so we believe that we have activity, clinical activity, at both doses. So we think that that will enable us to combine both doses in this current trial.
As well also combine between FOLFOX and FOLFIRI, or are you going to?
Yes. Yeah. We think that as well.
Yeah. Okay. And the delta you're looking for is what again?
We're looking really for a delta of approximately 20% between the control arm and the experimental arms.
Okay. And do you think you'll be able to talk about obviously, it won't be fully mature, but kind of early PFS data, or is that still just going to be way too immature to even discuss at that point?
Well, we'll have to see. I mean, clearly, we might have some hints at that point, but we'll have to see.
Okay. And I guess if, well, hopefully, at the interim, you see this 20% delta. And then if you see it again with the full 90 patients, that's the threshold that would justify going to phase III, or is it when you get to the full, you're willing to accept a lower gap?
I mean, currently, we're looking at an approximate 20% delta. I mean, clearly, we'll have to make decisions as we get further into the trial. But as we sit here today, that's our goal would be to look for something that's approximately 20%. And we are wanting to get to the registrational trial as soon as possible. We'll want to get back to the FDA as soon as we have enough data to justify the one dose. So that's kind of what our focus is right now. The gating data for the FDA's concern is really the dose.
Your understanding will be that the 30 patients on each of the two doses in this trial will, plus, obviously, there's the phase I/II experience before this. But the sum of all that, that's enough from a Project Optimus perspective to solve the dose optimization?
Yeah. I mean, we had a great interaction with the FDA concerning this. Clearly, we have a 20 mg and a 30 mg. There's not a lot of difference between those two doses. We are now showing clinical activity in both those doses. So if there's going to be an argument about the doses, it might have to be a numerical argument, not a statistical argument. They were totally fine with that.
Okay. And again, you also touched on with the first line, the kind of the phase III that comes behind it, you'll walk through kind of you'll select a dose. Will you select a FOLFIRI versus FOLFOX, or?
Currently, the reason that we are doing both FOLFOX and FOLFIRI in this phase II is to, in essence, de-risk the registrational trial. We want to do both FOLFOX and FOLFIRI backbones because those are the two approved regimens for first-line. So we want to be able to have patients have the opportunity to combine our drug with standard of care irrespective of the chemo backbone. So we want to understand that now before we go into our registrational trial.
Okay. In terms of size of that, the phase III that comes behind, what you're thinking today, obviously, some of it will be informed by the phase II data that comes out.
It's going to be informed by that. I mean, what we've talked to the FDA about is a two-arm study, randomized trial of about 320 patients, 160 in each arm. But that remains to be. We have to see how this data plays out. And if there's a bigger difference, then we don't need as many patients.
Okay. And the anticipation is, again, from that trial, response rate would be accelerated approval, and then PFS or OS is the?
The FDA has agreed to ORR or response rate for the interim look in the trial for accelerated approval, and then PFS as the primary endpoint for full approval plus a OS trend.
Okay. And I mean, I guess just given the timelines of, unfortunately, for these patients, outcomes are not the greatest. I mean, it seems like you would have fairly by the time you read out the response rate, it looks great. By the time you turn that around to a filing and then you're well into the review process, it would seem like the PFS is probably being finalized kind of during the review timeline. Is that the right way to think about it?
Yeah. The right way to think, I think, is that the FDA really wants your in essence, they often like to see all your patients enrolled when you go for accelerated approval. So in other words, when we go for accelerated approval in the registrational trial, all patients will have already started their dosing.
Yeah. Okay. Okay. Maybe on the safety side, right, there were a few blood count events in the phase II that you just read out the other day, as well as there've been a few in the trial before. I think Cardiff's belief is that that's mostly been tied to the 5-FU in particular, not just 5-FU, but the bolus.
Yeah. The bolus, right.
Just how are you treating that going forward? And just, I guess, what convinces you that it really is truly just the 5-FU? Because I think some other PLK1 inhibitors have been associated with some issues with blood counts.
Yeah. I think, number one, onvansertib is very different than previous PLK inhibitors. We believe that the reason it is so well tolerated is because it's so highly specific for just PLK1. The previous ones where they had a lot of neutropenia, a lot of these kinds of issues, were pan-inhibitors. They hit PLK2, 3, 4. So I think from the point of view of what we've seen so far, onvansertib is very well tolerated. And we did report out in the phase I-B/II trial that we did have some grade 4s, which then when we removed the 5-FU bolus, those then we no longer observed that in those patients. And then I think in the ensemble trial, the one that we reported out on Thursday, actually, there were only two grade 4s. And those were actually in the lower dose of onvansertib, the 20 mg.
The higher dose, 30 mg, there were no grade 4s, and there was no grade 4s in the control arm. So we think that that's, keep in mind, it doesn't make sense that it was due to onvansertib because it's a lower dose. And I think it just is a matter of that FOLFIRI does cause grade 4s as well in the sense. So we think that that's really what's going on here. It's a very well-tolerated drug.
Okay. Maybe leaving colorectal, we just have a couple of minutes left, but leaving colorectal cancer, go to, there's also a trial in prostate cancer. When are you going to just kind of?
Pancreatic.
Oh, sorry. Pancreatic. I was just hosting a session on prostate cancer. That's why. The pancreatic cancer, you want to just refresh on kind of what data you have shown you have provided data updates you have provided, but then importantly, kind of set the stage for when we might see more data, kind of how big of a dataset that's going to be?
Yeah. I mean, we reported out previously data from a phase II trial in second-line pancreatic cancer. The data was very promising. In 21 patients, we had four PRs, three of which confirmed. It was really for pancreatic, it was very encouraging data. We had PFSs that appeared to be doubling what you would normally see in second-line. So from that, I mean, that study is complete. What we're doing now is we've decided to go into first-line pancreatic. In first line, we're going to be combining onvansertib with a standard of care Gem/Abraxane. We're also looking at combining also with the other standard of care, which is FOLFIRINOX, given the recent approval of Onivyde for first line. So stay tuned on that. But these are investigator-initiated trials.
We do believe that this is another area that we can see onvansertib having really a positive.
You want to touch on kind of the rationale for why pancreatic is a focus given what you've been seeing in colorectal cancer?
Yeah. Pancreatic cancer is pretty much all RAS-mutated. I mean, it's greater than 90%, 95%. And so in keeping it's a GI-type tumor. And we are seeing a lot we do have previous data showing synthetic lethality between RAS mutations and PLK1 inhibition, which would be our drug. And so that's kind of the fundamental rationale. And then on top of that is the synergy we see with the irinotecan, which was the second line study that we just finished, the FOLFIRI. And then also, we do have synergy with taxanes. And that would be the Gem/Abraxane, the Abraxane being the paclitaxel or taxane.
Okay. I guess you did mention the recent approval, which was the first one in a while in first-line pancreatic. There's also direct RAS inhibitors being developed in the space, right? Just how do you kind of envision this space evolving? Where does onvansertib fit in?
I think we're able to we've seen in GI as well as in the pancreatic so far that we do have activity across different RAS mutations. And so we do feel that this is the strength of onvansertib is it's downstream of all RAS mutations. And so we believe that that's where it's going to play. And we think in pancreatic cancer, what we did notice is that I think everybody in this room knows this, is that by the time a patient gets to second line, it's pretty the patient has deteriorated, unfortunately. So we think the opportunity for onvansertib to have the greatest impact would be in the first line setting.
Okay. And then there's a couple of IITs running in other tumor types, triple negative, small cell, that you have planned and activated. Just maybe lay out the path there of when we may start seeing some data out of those trials.
Yeah. I mean, they are investigator-initiated trials. The triple negative breast cancer, at this point, they're still in a dose escalation component. In the small cell lung cancer, the investigator has taken a new position at a different university, and that has caused some delays in that. So they do move a little bit slower than sponsored programs such as, obviously, our lead program in metastatic colorectal cancer.
Okay. Unfortunately, we're out of time. We're going to have to cut off there. Thanks a lot for joining, Mark. Thanks for everybody in the room.
All right. Thank you. Thank you. Appreciate it.