Thank you everyone for continuing to join us here at Guggenheim's Second Annual Healthcare Innovation Conference. My name is Brad Canino, Senior Analyst here. Very happy to have on stage with us for the next Fireside Cardiff Oncology. We have Marc Erlander, the CEO, and Roger Sidhu, the CMO. Thank you so much for joining us. Thank you, Brad, and really appreciate not only you, but the whole Guggenheim group for inviting us to this great conference here in Boston. We are looking forward to having a nice chat, a nice fireside chat with you. Perfect. Let's kick off. If you could introduce the company and the clinical development work that you've accomplished to date at Cardiff. Oh, absolutely. I'll start out, and we're going to go back and forth a little bit, but it depends on the question, with Roger. Cardiff Oncology, it's a clinical-stage company based in San Diego, and our focus is the molecule onvansertib. And onvansertib is a very specific inhibitor of PLK1. And our main flagship program is in RAS-mutated metastatic colorectal cancer. That's really at a very high level. What we are, so I know you'll have other questions, but that's really the start of it. Okay. What are the priorities for the next year in the catalyst timeline that you described? Yeah, so just maybe back up a little bit. First of all, PLK1, I did not really talk about it too much, but our target is PLK1, and PLK1 is a serine/threonine kinase, and it is an enzyme that is overexpressed in tumors and across the board of many different cancers. Colorectal cancer is one where it is overexpressed. Really, the priority for us today is the CARD-004 trial that we are ongoing right now. We are in first line, RAS -mutated metastatic colorectal cancer. We did put out some really great data back on July 29 of this year. We are looking forward to putting out more data in the Q1 2026 timeframe, which will be more durability-related kind of data, PFS and duration of response. Really, that is our focus, being able to communicate that along with a regulatory update in Q1 of next year. Okay. Can we dive a bit into the mechanism then of PLK1 inhibition specifically for colorectal cancer? What do you think should be driving interest in the continued study of that space? Yeah, we're in a very unique situation because onvansertib, our drug we're developing, is very specific, as I've said, to PLK1. I think, you know, number one, really just to step back, there's no question that PLK1 is a great target for cancer therapy. This has been known for years. The big issue has been in previous PLK programs has been toxicity. That's because prior to onvansertib, the PLK inhibitors were really pan-inhibitors and had long half-lives and were not oral. That's exactly opposite of what onvansertib is. Onvansertib, it's an oral drug. It's highly specific, 5,000-fold greater specificity to PLK1 versus other PLKs. It has a relatively short half-life of 24 hours. That's really the framework. Let's talk specifically about colorectal cancer. Really, there's three different synergies going on, and that's why this trifecta is so important and why we think we're unique and have a real opportunity here for first-line patients. Number one is that we have synthetic lethality in the RAS -mutant background. Around 50% of patients that are newly diagnosed with metastatic colorectal cancer have a RAS mutation, and we have synthetic lethality by inhibiting PLK1 in that RAS -mutant background. Secondly, we have synergy with topoisomerase I inhibitors. The reason that's important is that FOLFIRI, which has got an irinotecan, which is a topo I inhibitor, we have synergy with the irinotecan. And then, you know, thirdly is really the synergy that we have with bevacizumab. This we actually discovered in our second-line trial, and this has been now published in ASCO's flagship journal, JCO, just last year, our clinical work as well as this newly discovered mechanism of action of synergy with BEV in our second-line trial. Okay. Can you expand upon that aspect? Because I think that's maybe one of the more interesting parts to what you've elucidated with the BEV combination. What was the main takeaway from that paper that was published in JCO? Yeah, that was really, quite frankly, a very exciting time of discovery. The takeaway there was that we had a second-line trial going, and we had this subset of patients that were doing extremely well. They had high response rates, 73%. We were trying to figure out, well, why is it there's this certain patient population that was doing so well? It turned out that these were the patients that had not been exposed to bevacizumab or BEV in their first line. This then led to a whole preclinical research into the underlying mechanism. We were able to show, and it was published in JCO, that onvansertib works in concert with BEV by, in essence, shutting down angiogenesis for tumors that are, in essence, as you know, tumors in general have become hypoxic because they grow faster than the blood vessels bringing nutrients and oxygen. We were showing that we were able to work in concert with BEV to shut down angiogenesis. This also, which was also a key part of this discovery, was the issuance by the USPTO of two new patents, specifically patient selection patents for CRC, which give the IP runway out to 2043. That was also very critical in this finding. Okay. Can you discuss the patient population specifically that you're focused on within colorectal cancer in terms of the baseline, the treatment line that you're focused on, and what the unmet need is that you see in that space? I'm going to turn it over to our Chief Medical Officer, Roger. Sure. I can take that one. Thanks, Brad. A couple of different ways of looking at the unmet need. Overall, colorectal cancer is the third most common diagnosed malignancy in the U.S. and also worldwide. When you think about metastatic disease or a disease that is advanced outside of the colon and rectum, the median progression-free survival for patients that have RAS -mutated MCRC is anywhere from 10-12 months. Also, overall, advanced colorectal cancer is on the rise, especially in patients that are younger, under age 50. The unmet need continues based on those criteria. We also look at what is available in terms of the treatment landscape. In the last 20 years, the only real targeted agent on top of chemotherapy that has been approved in this setting is bevacizumab. When you look at the number of treatment options, which are low, and the scope of the unmet need with the incidence that's increasing, and then the overall lethality of the disease, that really drives the unmet need that we're trying to address with onvansertib, which is, as Marc mentioned, targeting up to half of the overall metastatic colorectal cancer landscape. Yeah. Which line of therapy do you see onvansertib best positioned? At this point, we are targeting what's called first-line or previously untreated metastatic colorectal cancer. That gives us a well-defined patient population that hasn't had prior treatment. As Marc mentioned, from our second-line study, we learned that being naive to bevacizumab or sensitive to bevacizumab is actually synergistic with the MOA of onvansertib. In that setting, we're looking to advance the medicine in that setting in first-line, previously untreated disease. Got it. Yeah. You recently updated this year some randomized data in CRC, which I have to say is nice to see biotechs doing phase two randomized data sets. Thank you. We think so too. Can we dive into some of the details there that give you confidence? Because there was still a small sample size, but what gave you the confidence that what you're seeing is really a clinically material and meaningful benefit over the control arm that you had in that study? Yeah, that's a good question. There are a few ways we look at that. One is, as you pointed out, the structure of the trial. It is randomized. We're testing two different doses of onvansertib in combination with chemotherapy and bevacizumab, and we have active control. We're able to judge the contribution of components between the different arms, which we think is really important in a first-line setting. Secondly, in terms of the way that we look at the goals of the study, the goal of the study is really to do a couple of things. One is to select a dose to move forward into phase three. We have more confidence for a phase three study. We do that by, of course, looking at the totality of the data. The primary endpoint of the study is actually objective response rate, which is also judged by a central review. That helps to take some bias out of the assessment of response. Also, the study is being conducted in the U.S. We have nearly 50 sites in terms of the ongoing study. When we look at the actual data itself, we're really encouraged in three areas. One is just the actual delta or improvement in response rate and confirmed response rate that we're seeing for onvansertib. We actually saw a nice dose response that with increasing dose of onvansertib, we see increasing response with the combination. We think that when we look at the competitive landscape for what's been approved in the past, the improvements are very much in line or exceed what we've seen in previous studies. We've also been able to see the quality of the responses. They tend to happen early within the first couple of cycles of treatment. It is also leading over time with follow-up that we have reported in July with increasing depth of response compared to the control. Patients are getting down to, some patients are getting down to like 100% tumor shrinkage of their lesions. Some patients are getting down into complete response territory, which is happening with higher frequency with onvansertib. Lastly, but not least, is the safety profile. We're not seeing significant additive toxicity when we add onvansertib on top of standard of care chemotherapy. All of these things lead us to feel that we're going to have, although it's a small trial, you pointed out, it's data that we think should be interpretable and informative and to over time continue to help de-risk a phase three trial. Got it. Maybe to expand on the depth of response you're seeing. Two-part. First, is it rare to see CRs in colorectal cancer? The second part of that is, can you talk a little bit about the anecdotes of who were those patients and what was the burden of disease that was shrunk by 100%? Yeah, great question. It is not common to see complete response with standard of care chemotherapy and bevacizumab in first-line patients with RAS -mutant MCRC. The fact that we are observing it with greater frequency, I think, speaks to two things. One is just the biology of the drug that we're seeing, multiple synergistic elements in the patient selection criteria. To further expand on your question, we looked at the patients who had the best responses on our trial, patients with onvansertib who had near disappearance of their lesions or complete responses. With both chemo backbones and both doses of onvansertib, we did observe that we had patients that had multiple target lesions. We had patients that had a peritoneum full of disease, like many different nodules, and we had patients with distant metastatic spread. Patients with not minor tumor disease burden that had really great responses with the drug. Our investigators are really excited about that in terms of the activity of the drug to date. Okay. Marc, you mentioned the differentiation of onvansertib being the most selective PLK1 inhibitor. Let's talk a little bit about the safety profile in the trial as well. What were you able to achieve in terms of dose intensity? What did you see in terms of discontinuations and adverse events leading to treatment interruptions and such? Sure. I can take that one. We reported in July that dose intensity was generally balanced and high across the different arms, anywhere from 85% to 90% in terms of actual versus planned doses of all components of treatment. With onvansertib-treated patients, we did not see any discontinuation of onvansertib for any onvansertib-related adverse events. The main adverse event that is expected based on the MOA is neutropenia. We did not see a significant increase in the incidence of hematologic adverse events when we added onvansertib to standard of care. We did not observe more complicated episodes like febrile neutropenia or any Grade 4 or any Grade 5 adverse events. We are delighted to see that patients are continuing on treatment for longer periods of time. We have patients now that have been on the study for 15 months. We've had patients on drug over a year. We are excited about what that might mean for durability down the road. Right. So what updated data do you expect to present in 1Q next year? Is that correct? And how do you think it should further support the profile of onvansertib? Sure. I think that one key aspect is the July update that we made is based on the Cardiff O4 trial, which is an ongoing study. Enrollment ended in the first quarter of the year. We had approximately six months of median follow-up at that update. As we discussed, the median PFS time in this disease setting is anywhere from 10-12 months. In the Q1 timeframe, we expect to be able to report data with a median follow-up time of at least a year on almost all patients. We think that based on the disease setting, that will be a more informative assessment, not only of the durability of response, but also PFS as Marc mentioned. Okay. What do you consider to be gating now to commence into a pivotal study in colorectal? There are a couple of elements. We have yet to meet with the FDA, so we look forward to interacting with them on the key design elements of phase three study. We think that in terms of what the O4 study was designed to do, which was to select a dose consistent with Project Optimus guidelines, we believe we've achieved that. We feel pretty good about the strength of that data. We're also excited to talk about the overall opportunity in RAS -mutated first-line MCRC with registrational design intent. Okay. I guess I know you haven't had the meeting yet, but what type of pivotal trial and regulatory pathways do you think might be available onvansertib in this particular treatment setting and with the data that you've demonstrated to date? Coming out of the Type C meeting that the company had in 2023, which was based on reviewing the second-line data, a discussion was had around what criteria could support approval in the first-line setting. What we are pursuing is an approach with a seamless single trial to be able to approach accelerated approval based on response consistent with Project Front Runner, but with full approval based on progression-free survival, also taking into account latest guidance from the FDA on measuring overall survival. We look forward to discussing the design of our trial with them. Okay. Do you see precedents in this space of similar trial designs that have made it through initial approvals? The most recent one, although not in our patient population, would be Pfizer's study of encorafenib, a BRAF V600E inhibitor in combination with cetuximab and FOLFOX compared to chemotherapy. The BREAKWATER study is what it was kind of referred to, was able to achieve each of those elements with accelerated approval based on response rate at an interim point with full approval, I believe, has occurred or will occur soon based on meeting statistically significant differences in progression-free survival. Again, that's not exactly apples to apples in our patient population or with the MOA, but is a regulatory precedent for this setting. Got it. And then the control arm expectation of that setting in terms of durability measures, DOR, PFS, what do you think about as the benchmark for what needs to be beaten in that setting? We're looking to employ standard of care chemotherapy that we've studied, FOLFIRI and FOLFOX with bevacizumab in this setting. When you look at kind of some of the key benchmarks for PFS, what's been published from large studies is PFS times that are in the 12-month range. We look to hopefully show some improvement over that. In terms of what would be clinically meaningful in that setting, KOLs have been telling us that anywhere from two to four months could be a meaningful improvement in that clinical setting. Although we have a small trial, we think that we're going to be able to show what onvansertib is adding to chemotherapy and the standard of care with a more informative data set in the Q1 timeframe. Okay. Maybe to Marc, how do you size the sales opportunity for onvansertib in this particular CRC setting? Yeah, I mean, this is a huge indication, obviously. First-line metastatic colorectal cancer, what I can say is that it's multi-billion dollar really size. And it's really a huge opportunity for Cardiff Oncology, but also really with these patients not having anything for the last 20 years, this is such a great opportunity to be able to bring something new to the first-line setting. Yeah, from a commercial point of view, it's huge. Yeah. And then what degree of competitive intensity do you see in this setting in terms of clinical stage? We are the only company developing a drug to really address 50% of that first-line population, which is those patients who have a RAS mutation. There are other programs, but really ours is very encompassing. We are the only ones that's really going after this targeted population that is really underserved as well as has the most aggressive tumors in CRC. Okay. Maybe if you can talk a little bit too about the current state, the balance sheet, Marc, and the runway that it brings you through in terms of key catalysts. Right. I mean, as of our Q3, September 30, we had a little over $60 million in cash. That really brings us out into a runway into Q1 of 2027. And so we will basically have a year of funding after we put out our Q1 2026 update of CARD-004. Got it. For onvansertib, how do you think about potential business development and what scope of strategic deal could make sense for the asset? Is there a timeline to think about when that is best to maximize value? Yeah, I mean, I can't get into the specifics there as far as BD, but I would say to you that because it's such a huge market and such an opportunity, we do have a lot of interest across the board. We have a lot of different companies watching us quite closely. They obviously are very interested in our Q1 2026 update, where we'll be showing, we're looking to show durability. I think that overall, it's something that we are watched very closely and we'll just have to stay tuned. Okay. Maybe last one for me, if there is more access to capital, are there other areas or settings in which you think onvansertib could play a role in terms of the treatment paradigm? I mean, I can take this and then Roger could also answer it. I mean, clearly we are onvansertib, it goes across a multitude of different tumor types and has activity. We obviously have put our resources into our flagship program in CRC. Maybe Roger, you want to talk a little bit about some of the other areas that we're looking at? Sure. I think that we have a preclinical rationale in potentially an EGFR rechallenge in metastatic colorectal cancer when adding onvansertib to EGFR. And there is a strong kind of preclinical data set to support that. We also have seen data presented at ASCO in triple -negative breast cancer with onvansertib in combination with paclitaxel. There are multiple responses observed at a slightly higher dose. That is an interesting avenue to pursue. I think that as Marc mentioned at the beginning, we have a unique preclinical synergy with irinotecan-based treatments. That also opens up interesting development opportunities potentially with ADCs like Enhertu in multiple different indication types. We are looking forward to talking a little bit more about those in the future. Okay. Great. We are out of time. Marc, Roger, thank you so much for joining us. Really appreciate it. I appreciate it. Thank you. Thanks everyone for listening.