Okay, perfect. Great. Yeah. Thanks everybody for joining us here. Second day of Piper Sandler's Annual Healthcare Conference. I'm Joe Catanzaro, I'm one of Piper's biotech analysts. It's my pleasure to kick off this session with Cardiff Oncology. Joining us is their CEO, Mark Erlander. Mark, thanks so much for joining us. Maybe before we jump into Q&A, I could give you, like, a minute or two to just sort of introduce Cardiff. You know, let us know what you guys have been up to and what we have to look forward to heading into 2024.
Well, thank you, Joe. Thank you for this opportunity for us to talk about Cardiff Oncology and give you an update. Cardiff Oncology has an investigational drug called onvansertib. And onvansertib is a small molecule, it's oral, and it is a highly specific inhibitor of PLK1. PLK1 is a serine/threonine kinase. It's an enzyme that has a really high, big regulatory role in cell division, and actually tumor cells across many different tumor types overexpress PLK1, and that's how they really have their uncon... It allows them to have uncontrolled metastatic growth. Now, at Cardiff Oncology, our lead program with onvansertib is in KRAS-mutated metastatic colorectal cancer. And currently, as we sit here today, we've now started a trial, a randomized trial in first line.
But really, just to give you a couple, a little bit more about how did we get there? You know, we started really in second line, and we have a trial in second line where it was a single-armed, phase I/II trial. And the results from all available patients, we showed that we had response rates that were about twofold that of standard of care. But actually, that's where it got interesting. Because as we looked at the data, we were able to - we observed that there was a group of patients that had much higher response rate, 73% response rate versus controls of about 25%. And it was really because of this that we in essence looked to see, well, you know, why do we seeing this?
It allowed us to dive into preclinical work, about a year of it, and from there, we had discovered a new mechanism for onvansertib inhibiting PLK1, and really, onvansertib is involved in anti-angiogenesis. We went to the FDA with our clinical results and our preclinical, and the outcome was really. It was a great outcome. What we came out of that was that we have now an FDA agreed upon plan that is actually in first line for KRAS-mutated metastatic colorectal cancer. One of the reasons why that is important is that we'll get into it more, but in first line, all patients are naive to bevacizumab, and also, really about 50% of the patients that are diagnosed with metastatic colorectal cancer are RAS -mutated.
So it's really. And one other thing to keep in mind there is that there hasn't been any new therapy for these patients for 20 years. We also then, we have a relationship with Pfizer. They did an investment in the company two years ago. They looked at the totality of the data and the FDA, and they pitched to us the Pfizer Ignite program, which is a new program that Pfizer has that allows, that in essence, they will be they are gonna be our clinical operations for our first line trial that we've now just started. So that really gives you kind of, I think, a background of where we are right now.
Yeah, that's perfect. I'm wondering maybe if we could actually start with something you touched on there and sort of the new role maybe you've uncovered for PLK1 within the context of angiogenesis. So I'm wondering if you could just sort of speak to sort of mechanistically what PLK1 is doing within angiogenesis, and maybe how that role is similar and/or different to how we think about bevacizumab and how it has an impact on angiogenesis.
Yeah, you know, it really was a... The clinical result really made us go back into preclinical, and that's how we really discovered this new role for PLK1 in angiogenesis. And PLK1, what we saw was that, in essence, onvansertib, which inhibits PLK1, onvansertib was, in essence, inhibiting the expression of HIF-1α. Now, HIF-1α is the hypoxia-inducible factor, which is what tumors turn on because they are growing so fast, they don't have enough oxygen, so they adapt by having the hypoxia-inducible element, which part of that is secretion of VEGF, which promotes vascularization of the tumor. So when you think of them, the way we see it now, how this works is it's really a two hits.
So PLK, onvansertib in essence inhibits the HIF-1α expression at the high level, that's really at the master switch of the tumor being able to survive and be able to live in an anoxic or hypoxic conditions. And then VEGF, it hits it downstream, where one of the outputs of this HIF-1α pathway is VEGF, which promotes vascularization, and that we know that's where Bev hits and, in essence, mops up the Bev.
Great. Super helpful. I wanna maybe go back to something you said in your prepared remarks, and this goes back to, I think, when I first started following your story, and, you know, it still feels like there's been a lot of starts and stops in onvansertib's development. You know, again, I go back three years, and it was sort of really interesting, early single-arm data.
Right.
Great response rates. And it still feels like we're still in the same, like, bucket. More patients. Data, I think, has held up reasonably well. Is 2024 the point at which we get a more definitive answer to what onvansertib's contribution is within the backbone of chemotherapy and bevacizumab in colorectal cancer?
Yeah, I mean, I think the answer is yes, in at a high level. But you know, just to really frame that a little bit, when we started out, we were in second-line RAS -mutated. And you know, we, we looked at the data, and to your point, the data looked very promising. But as that data matured and we went out to 66 evaluable patients, we were able to see this group of patients within that, that had these much bigger response rates. And so that was really. That was the watershed moment for Cardiff Oncology. We realized that, that there was something going on here that we didn't understand, but if we did and we were able to leverage it, we would be able to have really a much greater success in colorectal cancer.
I think, you know, one way to put it is that we follow the data. Now, we, you know, could have just stuck there in the second line, but we chose to really not. You know, it's hard to ignore data when you have response rates that are above 70%. We had to really look at that, and that did take some time. But it also propelled us, based on our interaction with the FDA, propelled us to a first-line clinical development path that which they agreed upon for accelerated and full approval.
So yes, it was a bit of a journey, but I think we really have gotten to a place where we are now at a definitive moment with a randomized trial in first line, and we will have data readout mid next year regarding that.
One question I get every so often is whether that second-line randomized trial that I think you guys first sort of pointed towards in the summer of 2022 ever enrolled any patients? I think it was sort of almost a year from sort of announcing that second-line randomized trial to then now the first-line randomized trial. I guess people are interested in whether, you know, you generated any early randomized data, whether there's any data that you got to help you point towards which dose is maybe the dose to move forward with.
Well, we ended up enrolling 23 patients in that trial. But when that was spread across the three arms, it was a small number of patients. So what we've decided at this point is that, you know, it's really not our focus anymore. The focus is in first line in our trial, and so that's where we're really at with it. We don't really plan to talk any more about data about the Bev trial because it's just a small number of patients.
Yeah. Okay, got it. And I think you sort of have spoken to this, a little bit, but sort of the primary driving factor to sort of requesting that Type C meeting with the FDA, it sounded like it was sort of... You kind of worked backwards, looked at the second-line data, then went to preclinical models. I guess, how did that all ultimately come together?
Yeah, I mean, what happened was that we got the clinical data, and in the second line, we had these 73% response rate. We did go back into preclinical to understand the scientific underpinnings of that, which we've just talked about within the HIF-1α pathway. But I think that also when we went to the FDA, we knew that we had this huge signal in these bev-naïve patients in second line. They had, in essence, they had not received bev in first line, and when they came into our trial, when they were bev -naïve, this is the patients that had this huge response rate. When we went to the FDA initially, we proposed an accelerated approval program within second line.
The FDA looked at that and said, "You know, you could do that, but you could have a much bigger impact. Given your data, you have a much bigger impact in first line." Because in second line, it was really only about 30% of the RAS -mutated patients, whereas in first line, all patients are bev -naïve, and now you have 50% of all colorectal, metastatic colorectal cancer with the RAS -mutated that you'd be able to address. And so it was really their suggestion that then we came back with this plan, which then they agreed upon, which was really a plan for both accelerated and full approval in first line.
Yeah. I guess, sort of keeping with this theme of sort of the signal in bev-naïve patients, how confident are you that that's a real signal and not an artifact of, you know, just some post-hoc, you know, digging up?
We're very confident that it's real, and let me tell you why. There's really two major reasons why. First, clinically. So in the phase 1b/2 trial, in second-line, we actually did the phase 1b/2, and that was 48 patients, but then we did expand it with another additional expansion of patients. In that, which we've reported, it's all public, but in that, we actually, the clinical signal was coming from the bev-naïve patients once again. So that was really, to us, very telling, that we were seeing it yet again in an expansion cohort of the phase 2 trial. The second point is really all of the, the preclinical core. I mean, really, really being able to show that there is a scientific basis, there's really a reason why,
This was a novel finding. So I think those two things together make us very confident.
... Great. So, I want to talk a little bit about the first line randomized trial. Maybe first starting with sort of where you guys are at in terms of site activation and enrollment, and at this point, excuse me, your level of confidence that the trial will be in a position to generate some initial data, in 2024?
Yeah, we're very confident that we'll be able to report out in data from this trial in the mid-2024 timeframe. The reason I say that is, number one, it is an open-label trial, so we will be able to watch the trial as it goes. Secondly, as I mentioned to you, Pfizer Ignite is really doing the clinical operations of the trial, and we're working very closely with them, but this really, that we are really able to leverage their huge level of expertise in running clinical trials. So we do have a lot of confidence that we will be able to report out information mid-time next year. The trial itself is a U.S.-based trial. It will have 30 sites. We've already,
One site's already been activated, and many more are coming very soon. So it's moving very quickly. One thing to keep in mind here, too, is two things. Number one, treating physicians are very excited about this first-line because of the fact that the patients onvansertib will be added on to already existing standard care. So they're already going to get the best standard of care, and then we're going to add onvansertib on top of that in the arms that get onvansertib. So it's not like we are taking away something from the patients. Secondly, there are no other trials in RAS-mutated first-line. We have no competing trials. And that speaks huge volumes of why this is such a huge unmet need.
50% of metastatic colorectal cancer patients today have therapy that was around for a whole generation, 20 years.
So as we look towards that sort of mid-2024 readout, is what are your expectations, and I recognize it's still very much the early days of the trial. What are your expectations of what will be included, in that readout and what we will learn about onvansertib within the context of chemo/bev and first-line colorectal?
Yeah, there's two main objectives of that trial. First objective is really to confirm a dose. We have two doses in this trial, in the CRDF-004. It's a three-arm trial with two different doses of onvansertib with standard of care, and then standard care alone is the third arm. So the first thing that we will get out of this is we have two different doses, a 20 mg and a 30 mg, and we'll be able to identify that. The second objective is really to show randomized data showing what onvansertib's contribution is to standard of care because we will have it as a randomized trial. Those are the two things that really will be coming out of the information, be coming out of that trial, and the primary endpoint will be ORR.
As we think about ORR, I guess, in your view, what would you consider a positive outcome? What's the sort of absolute improvement in response rate over the control arm that you think would ultimately then translate to PFS and maybe long-term health?
Yeah, I mean, we've talked to several KOLs about this and what do they consider the absolute delta percent difference as being a clinically meaningful result. And when it comes down to what we've been hearing is about a 20% delta. So, and we know that, you know, today's standard of care for the chemos in first line, if you look at FOLFIRI, it's about 45% response rate, so you're looking at a delta 20 above that. But keep in mind that the... Really what we're looking for is that delta difference, and not some specific magical number of response rate.
Yeah. Well, maybe one last or a few last couple questions on the frontline CRC trial. You know, historically, you've looked at onvansertib in combination with FOLFIRI in the second-line setting. In the first-line, it's this dynamic of FOLFOX, of FOLFIRI.
Right.
So, you're sort of incorporating a new chemo backbone. I'm wondering if there's any reasons to think that the way onvansertib interacts with FOLFOX is maybe different, and I guess I'm thinking toward the sort of neutropenia that you saw with FOLFIRI. Is it similar? Is it worse? Is it better with FOLFOX? Yep.
Yeah, we have extensively looked at that in preclinical models, and we don't see any issues from a safety point of view. What we do see is we do see very robust synergy with the FOLFOX backbone, when onvansertib is added to it in preclinical models of KRAS-mutated CRC. So what we've decided to do in this trial that we're talking about, the CRDF-004, with the two different doses, is we wanted to add into that trial, build into that, the both backbones, the FOLFIRI and the FOLFOX, like you mentioned. And the reason for that is because that de-risks the registrational trial that's next, which will also be looking at both backbones. And because we realize that patients get FOLFOX, and they get,
or they get FOLFIRI, they're both approved for first line, they're both approved for second line, for that matter. So I think that what we've seen so far is we have not seen any kind of safety flags. We've not seen any issues with combining with FOLFOX with our preclinical models.
Maybe actually going back to the mid-2024 readout, you know, we talked about what a positive outcome would be there in terms of response rate. Do you think you'll be able to pick a dose at that point, and maybe, you know, shut an arm down and sort of accelerate, you know, consolidate the trial into two arms, and take just by taking one dose forward?
Well, I mean, we'll have to see how that goes, you know? But I think, you know, with, with the dosing, it's not a, it's not a statistical test. It's more of a numerical. You look at it, you look at the PKs, as well. But, you know, we think that we should be able to have enough data, in that mid 2024 to be able to go back to the FDA and say, "Here is our dose." And so that, from our point of view, the dose really is confirmation, is the gate to the registrational trial. So we wanna move that as quickly as possible, to the FDA.
So in these last five minutes or so here, maybe we could shift gears and talk about some of your efforts outside of colorectal for onvansertib, and start with pancreatic cancer. You recently disclosed,
Right.
... a little bit more data,
Mm-hmm.
Back in September. When you look at that early data set, what do you see as the most compelling evidence that, you know, adding onvansertib onto, again, a chemo backbone is providing additive benefit?
Yeah, I think, you know, there's really two major reasons. First, with our trial in second line, we were combining it with, in essence, a full FOLFIRI backbone. And our PFS data that we have seen so far is median PFS is around 5 months. Now, for second line, it's really what you see is 3 months. So we're really a lot above that mark of 3 months. And also, when you look at first line, with the gemcitabine trials, the median PFS is 5.5 months. So we're not too far off from that of our first-line median PFS. So I'd say that was number one. That was really data that allowed us to propel ourselves to a first line.
The second thing was actually, we also have seen robust responses as well. We reported a 19%. We continued to monitor them, and we just reported out, a couple of weeks ago in our 10-Q company call, that we had four PRs, and now a second one just got confirmed. So that was also important. I'd say a third reason actually is also important, was that we are in parallel, conducting a investigator-initiated trial out of Oregon Health & Science University. And there, they had a really novel approach where they were doing, in essence, pancreatic patients would come in, and then they would give onvansertib for 10 days, and they would have a tissue biopsy before the 10 days and right after the 10 days.
And then ask the question: What happened with onvansertib as a single agent? And two patients have gone through that so far, and one of them had dramatic decrease in the proliferative index, Ki-67, in the blood. The patient had also significant decrease in CA 19-9. So we know that right away, that in pancreatic cancer, onvansertib, as a single agent, is able to affect the major indices of, in essence, a response. And so that was a third leg to the stool that really propelled us into a first-line approach to pancreatic cancer.
Yeah, I want to ask about the first-line strategy, but maybe first, you mentioned that we're now at two out of the four responses,
Yeah.
Confirmed. Wondering if the other two have had subsequent follow-ups, subsequent scans, anything you could say there?
It was only a couple weeks ago when we reported out the other one. So we're still awaiting the scans. These two patients, actually, have already been on 8 months, both of them. So they're doing well, as patients, because as you know, a median PFS for second line is three months. So, yeah, we're still awaiting the scans, but I would also say that these patients both have done very well so far.
On the first-line PDAC strategy, maybe you could talk through that. I'm wondering if there's opportunity, and maybe this is a big ask, to you know, run a smaller, randomized trial to again, sort of avoid this ambiguity of single-arm combination. What do we make of it? Is there a signal there versus something more definitive where you have a control arm to reference?
Yeah, I mean, what we're proposing right now is a first line in the addition of onvansertib to the standard care of gemcitabine. But we would like to have, initially, some patients go in as a single arm, but depending on the signal, we are then going to make it into a randomized trial, where we'd have the standard of care versus standard of care plus onvansertib.
So maybe in these last two minutes, we could then touch on small cell lung cancer, another sort of early data set you,
Right.
... reported back in September. Again, what are some key takeaways there? What's the next steps for that program?
Yeah, that program was an exciting program and it's still ongoing. Obviously, it's an investigator-initiated trial, where actually we're looking at onvansertib as a monotherapy. And that was based on some very strong preclinical data. And so far, what's been reported out is the first seven patients. These are refractory patients, so really very sick patients. And we are showing that one of the first seven patients had a huge response. They had a confirmed PR of 50% reduction through the single agent of onvansertib. The plan, though, really going forward, that this is great to see the single-agent activity, but going forward, our placement of onvansertib is going to be in second line, in combination, with paclitaxel.
Paclitaxel is a second-line approved, and we do have preclinical models now, PDX models, in small cell that show really significant effects of the combination, of onvansertib with paclitaxel.
In these last 20 seconds, sort of, I guess, a housekeeping. You know, as we think about the mid-2024 initial readout for the first-line trial, how should we think about that in the context of sort of your cash runway?
Cash runway is into 2025. We have, we do have enough runway to be able to see these, this readout in the randomized trial. So, we feel very confident with, you know, basically our cash runway and being able to see the results.
Perfect. Well, with that, out of time, I want to thank Mark, first time and thoughts, and thank everybody for tuning in. Take care and enjoy the rest of the day.
All right. Thank you. Thank you, Joe.