Next generation ways to be late. Right. Good morning, everyone. I'm Stephen Willey one of the senior biotech analysts here at Stifel, and glad to have with us for the next presentation Mark Erlander, who is the CEO of Cardiff Oncology. He's going to be walking through some slides. There should be some time left at the end for Q&A. If anyone has a question, feel free to raise your hand. We'll get you acknowledged and hopefully your question answered. Mark, I'm going to turn it over to you. Thank you very much. All right. Thank you, Stephen. It's an absolute pleasure for us to be here at the Stifel Healthcare Conference. It's really a pleasure, as I said, for Cardiff Oncology to tell you guys what we're up to. I do have some forward-looking statements. Let's get into it. You know, at Cardiff Oncology, first-in-class PLK1 inhibitor for the first-line RAS mutated metastatic colorectal cancer. You know, why do I say that? If you look on the left side of this slide, it's because we have a molecule called onvansertib. It's a very selective PLK1 inhibitor. You may ask yourself, well, what is PLK1? PLK1 has actually been known for years to be a well-recognized target for cancer therapy. The issue in the past has been that previous programs by pharma have been fraught with toxicity. This is the first molecule that is well tolerated. And we believe the reason for that is because it's so specific for PLK1. PLK1 is an enzyme. It's the Achilles heel of tumors. It drives tumorogenesis, angiogenesis, DNA repair, survival. And it, this is the reason why we believe we're seeing such great activity on the right side of the slide. We've already reported a second line phase 2 trial, which was published in ASCO's flagship journal, JCO, last year. And also now today, I'm going to be talking to you about our first line trial and how we got there. You know, essentially, as on the bottom right, we met with the FDA a couple of years ago, and they recommended that we pivot our second line, clinical development path into first line. So why don't I get into it? Let's talk about onvansertib. I think just as a background, I think all of you know that colorectal cancer has a huge unmet need. Look down on the bottom left, 15% five year survival, and metastatic, really less than 12 month progression free survival. On the right hand side is really what's telling the story, the sad story. It was in 2004, so over 20 years ago, was the last targeted therapy for RAS mutated metastatic colorectal cancer. Now, what are we really talking about? On the right hand side of this slide, you can see a pie chart. Right away, you can see that in metastatic colorectal cancer, over 50% of the patients in metastatic colorectal cancer have a RAS mutation. On the left hand side, you can see where we are as far as targeting this patient population in, in actually is in second line. They're going after a very small subset of the RAS mutated tumors, which is the G12C. There is a huge opportunity here. Onvansertib targets, as I said, PLK1. PLK1, from a pathway point of view, intracellular pathway point of view, is downstream of RAS. It is able to be agnostic to any RAS mutation. That is the beauty of why we are being able to address the entire population. Now, just to sort of level set everybody, I'm going to really move now into our first line trial. Just to level set, what in the past has been the response rates that have been observed that then have led to approvals. You can see that we've highlighted in the light blue that really we're looking at about a 10-11% delta in response rates, is what we're really looking for, at least that, and that would be telling us that we're on the right path, for being able to have a successful registrational trial. Now, let's then talk about the trial that we are going to, I'm going to talk about today, which is really an ongoing trial and it's in first line. It's on the left hand side, you can see it's first line RAS mutated, unresectable. You can see it's also a randomized trial where you have a standard of care versus standard of care with two different dose levels of onvansertib. On the right hand side is really the dosing schedule. The patient's onvansertib is an oral drug. You take that orally and then every two weeks you get your standard of care infusions of the chemotherapy. Right away, I think what you're seeing here is that this trial, the CARDIF-004 trial, 110 patients, is all about selecting the dose. That is really the project optimist. This is part of what came out of our meeting with the FDA, our type C meeting back in 2023, where we are to identify a dose, select a dose, which we would then move into the subsequent registrational trial for both accelerated and full approval. On the bottom left, that is important. The endpoints are ORR, but also all the data you're going to see here is really assessed by blinded independent central review, or what we call BICR. That is important. It's really very non-biased as far as it's the highest level of sort of looking at data. The trial, like I said, is ongoing. On the far right, you can see there are 60 patients still on trial of 110. You are seeing a snapshot here. Here's really a snapshot of where the data looks as of the July 8 cutoff point and what we had reported out at our July 29, which was the last time we reported out data for this trial. You can see right away that we're looking at confirmed objective response rates, and where you're looking at the control is at 30%. Then you see a dose effect, 42% and then 49% with additional, adding onvansertib 20 and 30 mg. Also, what's really interesting to see is the second line, which is the confirmed ORR at six months. What that means is at a six month landmark, how many patients had a confirmed response? Interestingly, you can see in the control 22% or eight of the patients did, whereas a whopping 46% or more than double, were in the 30 mg. What does that mean? That means that you're seeing faster responses in the experimental arm than the control arm, telling you that this drug is working. Now, what about looking at it at a patient level? These are the classic waterfall plots. Those of you that are not familiar with that, it's really, if it's going down, that's good news. The tumor's shrinking. If it turns to a teal color, that means it's crossed, it's hit 30% shrinkage or greater, which means it's an, it is an objective response. If it goes all the way to the bottom and you see a black line, that means that that patient's, all of the tumor has disappeared. You can see right away that we are seeing in the, particularly in the 30 mg, a lot of minus hundreds. The ones that aren't black that are minus hundred means that the target lesions have disappeared, but not the non-target. If it's black, it's a complete response. All of the, all tumors disappear. Obviously we are very excited, and a lot of our investigators have been very excited about this trial because of these results. Another way to look at this data that I think is even more compelling is the, what some people call the spaghetti plot or the spider plot, depending on whether you like Italian food. What you can see here is that if you go from left to right on this slide, you'll see right away that what you're looking at is on the Y axis, you're looking at tumor shrinkage, right? If it turns that green blue, that means it's hit 30% shrinkage or greater. On the X axis, you're looking at time in months. What you can see right away is that in the control arm on the left, things kind of flatten out, whereas in the 20 and 30 mg, you can see, I think it is pretty obvious to see that you are seeing an increase in depth of response as you go, as you increase your dose of onvansertib on top of the standard of care. You know, a lot of times, and we also, by the way, it is a pleasure we have actually our Chief Medical Officer here today, Dr. Roger Sidhu, Roger Sidhu. After I speak, as long as I do not gobble up all the time, there will be time for Q&A and he can answer some of your, of those questions. He picked out a couple of the patients that, of the, of this, this journey of this trial. I'll just point out the one on the top left, a 47-year-old female, getting a 30 mg dose with FOLFIRI, achieved a complete response after six cycles, which means six months of treatment. Amazing. Bottom right, a 62-year-old male, also complete response, all tumor gone, went to curative surgery. Both of them are going to curative surgery. We have our fingers crossed, obviously, for these patients. This is really kind of what's, what we're seeing here. That is why the investigators have been so excited about this study. Now, a lot of you also pretty much know a lot about this kind of data. You're saying to yourself, okay, objective responses are great, but what really matters at the end of the day is durability. Durability, as you know, takes time, which means you have to wait. It's event driven. It's, and so this is something that, of course, can be frustrating when you're running a trial, but you just have to fasten your seat belt and wait for the data. What we're showing you here is really a very early peak at progression-free survival. And a very small number of patients are basically driving these curves at this point. All those little ticks that you're seeing on the three different curves are the patients just being censored. I think what we can say here right now, with this data cut, is it's encouraging. It's going in the right direction. The top line is the 30 mg, the bottom line is the control arm. Now we've also, and I'm not going to show it to you today because it's really a, I want to not get into all the details, but we also looked at some predictors of progression-free survival and overall survival that are well established in the literature. All I would say is that early tumor shrinkage and depth of response, these are, these are very well known metrics that are looked at early in trials to determine whether or not you actually are having an effect with your drug. The good news, I'm not showing you this data here, but the good news is that we are seeing very active and stat sig on early tumor shrinkage in the experimental and 30 mg in particular versus the control, as well as depth of response. You can see that on the, on the spider plot, the increase in depth of response with the 30 mg versus the control. The other thing that I talked about when I first started this conversation with you all was, was safety. This has been an issue with PLK1 inhibitors in the past, as I have mentioned to you. The on-target toxicity for a PLK1 inhibitor is really the bone marrow, but in essence, and specifically neutropenia, and white blood cell decreases as well as lymphocyte decrease. The one that really people look at is that neutrophil or neutropenia. You can see that I have highlighted or we have highlighted that. If your eyes go across that, the control versus the 20 and the 30, and you look at grade three or higher, you can see that they are the same. We're really not seeing any incremental increase in safety with this agent, with onvansertib. This is really very reassuring to the investigators in this trial. This is consistent with what we saw in our second line trial. Where are we going? What's our roadmap? We met with the FDA back in June of 2023 with a type C meeting. From there, there was agreed upon and laid out, in essence, a path in first line. On the left hand side is a trial I've been talking to you about, which is still ongoing, which is really selecting a dose. I think for those of you that are seeing this data are thinking, well, it looks like it's the 30 mg. You're right. That's what we're going with. We will be meeting with the FDA soon. The 005 is really this registrational trial that we have already agreed upon at a high level with the FDA as being a seamless one trial for both accelerated and full approval. Accelerated would be, of course, that response rate with the duration of response. For full approval, you need PFS with showing lack of any detriment to overall survival. Let us take a step back and say, how did we get here? How did we get there? Why are we seeing this kind of activity with onvansertib? Is there an underlying story? How did Cardiff Oncology move into the first line? Why did the FDA recommend we do move into the first line based on second line? Let me take you through a little bit of the journey, because I think it really tells you the story of how we got to where we are today. That really started with when we did our first trial in colorectal and RAS mutated in second line. We had an unexpected finding, which I'm going to show you in a second, with a subset of patients did extremely well. That was really this trial. This was a second line trial, RAS, KRAS mutated, unresectable, same dosing schedule, five days on, nine days off, oral drug, and then ORR being the objective, the primary, was endpoint. What we did not know when we got into this trial was that patients who came into our trial in second line came in two flavors. They either got Avastin, which is also Bevacizumab or BEV for short, or they didn't. That turned out to be a big deal. What that big deal is, is showing you right here on this waterfall plot. On the left hand side, pretty much every patient, you know, the vast majority had all tumor shrinkage with a 73% response rate. On the right hand side, you saw patients who had had prior BEV exposure and you're not seeing this kind of activity. In a BEV naive patient, you're seeing this really huge response. Not only that, but that then also equated into a much longer PFS, 15 months versus about eight months. Almost a doubling. That was really our finding. At the end of the day, the question was why? What was going on? Was there an underpinning molecular mechanism that could explain the clinical finding? Because that's very important, that you try to understand that. And we think we have. We started very simply. We looked at, in essence, preclinical models that were RAS mutated. Some of you are familiar with this. You basically grow a human tumor on the hind leg of a mouse and kind of see how, whether it grows or shrinks by giving them the treatment. You can see right away that we, because we were very intrigued about the BEV story. Why in a BEV naive patient? We gave these mice BEV and onvansertib as a combination, and of course, single agent as well. Right away in the curved Y axis, that's tumor growth. X axis is days. You see right away that the combination has a greater effect. We thought, why don't we check out a couple more? We did, got the same result. We called up the CRO and said, hey guys, before you sacrifice these animals, can you do a gross dissection of the tumors and take a photo of them and send it to us? They did. What you see right away is that in the control, those are large tumors and they're quite bloody. They're very vascular. Take your eyes all the way to the bottom and you see much smaller tumors, but what's different is they're pale. They've lost pretty much all their vascularization. That was a huge hint and clue for us that something was going on. Onvansertib was working in concert with BEV to shut down angiogenesis in these tumors. How are they doing that? It's really, hypoxia is a well-known hallmark of cancer. On the left-hand side is a cartoon. We all know that tumor cells grow faster and outpace the ability for those tumors to receive vascularization, which means nutrients and oxygen. When that happens, you get hypoxia. Most of the time, tumor cells would just die, but tumor cells adapt. They adapt by turning on this HIF-1 alpha pathway, which is a whole new set of genes that allows them to have not only do they put out VEGF, which is basically a growth factor to attract blood vessels, but also survival, proliferation. It is a whole set of over 200 genes that are turned on. What we knew, of course, was BEV, you know, neutralizes VEGF A. This has been known for years. What we did not know was that onvansertib shuts down HIF-1 alpha, shuts down the ability for these tumor cells to adapt. This really then led, and I won't go into all the science, there's a whole, this thing's all been published, but it led to, really, we were very excited that the JCO, ASCO's flagship journal, published this last year, not only the clinical data I showed you, but also this translational work. Even more importantly, because this was a new discovery and really identifying a patient population that had not been known before, that is a BEV naive patient population. We have now, already two patents have been issued by the USPTO, which give us runway into at least 2043 in colorectal cancer. Very exciting, finding that led to increasing IP runway. With that, I'm honing in on the end here, guys. Let's talk about the coming catalysts. One side note, Pfizer has an investment in us. They gave a $15 million equity investment several years ago. Also, that whole trial that I was showing you the data on, and 004, the first line, that was actually run by Pfizer at night, to their standards. We paid them in cash, no strings attached. The Pfizer equity investment really also is really, and you see on the left-hand side, the only string we have there is that before we publicly disclose data, we have to show it to them two days in advance. Really not a big string. That is really, we are very, we really enjoy our relationship with Pfizer. They are on our scientific advisory board. We bounce off some of our ideas with them. It has been a great relationship. With that, we have CAF, out to into Q1 2027. As of our last Q, we had $60, $61 million in cash. I think with that, I've got another 10 minutes left. I've also got my, our Chief Medical Officer, Dr. Roger Sidhu here, would love to take any questions, as well. Thank you for your attention. That was great, Mark. Yeah. Yeah. Question in the room? Yes. Hey. How are you doing Max? Doing well. Do you think we'll have median PFS in the readout early next year? Roger, do you want to talk about that? He wants to know if we are going to have median PFS then we have. What we believe we will have is that given that the trial and the enrollment, if you want an urgent buy update with the follow-up time of about six months, they expect that in the Q1 timeframe, we would have at least a year's follow-up on those. Oh, hold on. Why don't we do that again? Because this is going to be recorded. The question really was, will we have median PFS in our readout in Q1 of 2026? Now you've got a microphone, so that will be recorded. Sure. What we reported in July was based on data from a cut where we had a median follow-up time of about six months on all the patients. In the first quarter next year, we expect to have a median follow-up time of approximately 12 months on all the patients. Whether we reach a median or not will be event-driven, but we feel that that data cut should be much more informative given the median PFS time and the disease state. Any other, any other burning questions? Yeah. Can you talk a little bit about what the framework of the disclosure will look like? Is this going to be a medical conference presentation? Are you just going to host this as kind of a company-sponsored? It's going to be a, it's going to be a company-sponsored. [crosstalk] At this point. It gives us the greatest flexibility, as far as, you know, data release. It gives us really the opportunity to give investors a much closer, you know, better look at it in a sense that we do not have to wait, you know, months and months because of a medical meeting. With respect to the data that you showed us back in July, I think there was a little bit of a differential between those patients who had a confirmed response and then the overall response rate itself. What proportion of that delta was just driven by the fact that you still had patients on therapy who had just yet to see a second confirmatory scan? Right. I mean, maybe you can talk about that. Yeah, it is a good point. At that data cutoff, we had approximately 60 patients still on trial. We still had, most of the patients had at least two scans, which is a very early time point to have a confirmed response. You would have to have a response on your first scan and confirmed on the very next scan. I think it reflects just when that data point was, that data cut was taken. The response rates will, you know, most likely move around as we increase the scan frequency and increase the response maturity. Okay. As you think about the phase three trial design, I mean, this is, it looks like it's going to be done under the auspice of the project front runner mandate, right? Where you can kind of incorporate an accelerated in a confirmatory trial into the same entity. How are you thinking about just in terms of powering that trial, sizing that trial? What kind of percent fraction of patients do you think you may need to look at once you unblind that response rate analysis that could serve as the, as the interim? I guess whether or not at that point you think you would have a mature enough look at survival to also be able to show that to FDA to give them greater confidence that an ORR could serve as the basis of an accelerated? Yeah, great questions. We are actively, you know, looking at different trial designs based on our maturing data. I think that when we look at the latest regulatory example, it would come from the Breakwater study, which is obviously not a PLK1 inhibitor. It's a BRAF inhibitor, which is a different treatment setting. but, from what was publicly available, we're trying to emulate, a single seamless phase three trial, where a response-based endpoint could serve as the basis for approval on, ideally a smaller fraction of patients than the overall, enrolled population, and being able to achieve a, a full approval on PFS. We look forward to, you know, discussing, you know, such a design, with the, with the agency. How are you just thinking about colorectal frontline specifically from a competitive perspective? I know that there's not a whole lot that's going on there. you know, we follow Incyte. I think they just nominated a PD1 TGF beta R2 bispecific to go into frontline. But outside of that, there's really not a whole lot happening. Just would be curious as to, you know, how you're thinking about the space, how you're thinking about where and how the KRAS inhibitors might show up in this patient population. And then just given the fact that the mechanism here appears to be just more kind of synergistic with the HIF-1 alpha part of the story, do you actually think about generating data in a patient population agnostic to KRAS mutational status? Yeah, great questions. I think [crosstalk]. In terms of the competitive landscape, you know, we are seeing more activity in the recent timeframe and projected to occur than the last two or three years. To your point, the, you know, KRAS G12C inhibitors are moving forward, in the first line treatment, in previously untreated mCRC for obviously a narrow sliver of the overall RAS mutant population, about 4%. In the wild type population, you know, we're seeing bispecifics like the EGFR MET to move forward, which isn't exactly in our patient population. It's in the RAS wild type population. And we are seeing more activity around the PD1 VEGF programs. Pfizer just announced one that's planned to start soon. And we've seen, BMS and, and some have also signaled that they may be starting programs in the near future. So what we're very focused on is, the rationale for our program and our clinical data, is very strong. We think that, A, we have the only PLK1 inhibitor. We have multiple synergistic reasons to be in, in first line RAS mutant mCRC, synergy with RAS mutation, synergy with bevacizumab, as you mentioned in the HIF-1 alpha pathway, and also with the chemotherapy agents in terms of their mechanisms for DNA damaging. We are very excited about the response rate data, the depth of response data we are showing. We are excited to, you know, try to shift this program into first line. You talked about the patients who, I guess from an anecdotal perspective, were able to, I think post CR they were recommended for curative surgery. How are those patients that are then recommended to go to surgery, how are they treated in the context of a Kaplan-Meier analysis? Are they a sensor mark or do they continue out on the tail of that curve? In general, what's done is that if a patient leaves the trial for another cancer therapy, which surgery would be, they're counted as an intercurrent event and then censored at the time that they leave the trial. Although it's a very good outcome for a patient, ideally, if they're able to achieve a curative surgery, we're no longer able to capture response-based information for those patients, but we would endeavor to try to capture survival data, but that may be challenging. Patients leave trial to pursue surgery. Okay. Are there any other questions? Really appreciate it. Yeah, great. Thanks for the time. Thank you, guys. Thank you. Thank you, everybody.