Cardiff Oncology, Inc. ($CRDF)

Good day, and thank you for standing by. Welcome to the Cardiff Oncology Inc. Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Mani Mohindru, Interim CEO. Please go ahead, ma'am.

Thank you, operator. Good afternoon, everyone. My name is Mani Mohindru, and I'm the interim CEO of Cardiff Oncology. Thank you for joining today's webinar, where we plan to discuss the evolving treatment landscape in first-line RAS-mutated metastatic colorectal cancer or metastatic CRC. We will also discuss the recently shared clinical data for our novel, highly selective PLK1 inhibitor onvansertib and its potential to improve outcomes for metastatic colorectal cancer patients when combined with the standard of care therapy. March is a national colorectal cancer awareness month, decade to increasing understanding of the prevention, detection and treatment of colon and rectal cancers. According to the National Cancer Institute, more than 154,000 patients in the U.S. were diagnosed with collateral cancer in 2025 and nearly 53,000 died from the disease. Despite decades of research, first-line RAS-mutated metastatic CRC has seen limited progress, underscoring a significant unmet need. On that note, I'm very pleased to be joined by 2 globally recognized leaders in GI oncology, Dr. Heinz-Josef Lenz and Dr. Steve Kopetz. Dr. Lenz and Dr. Kopetz, thank you both for being here and for joining this discussion. Let me begin with a brief introduction of each of our speakers. Dr. Lenz is a university professor of Medicine, preventive medicine and cancer biology at the University of Southern California. He holds the J. Terrence Lanni Chair in Cancer Research, is the Deputy Director, Deputy Cancer Center Director and Core Director of the Brown Center for Cancer Drug Development. Dr. Lenz is a globally recognized leader in GI Oncology whose work has helped shape modern precision medicine. His contributions include establishing primary tumor location and gene expression subtypes as key predictive and prognostic markers now reflected in international guidelines as well as pioneering the use of next-gen sequencing in large Phase III trials. He played an important role in the development and approval of multiple therapies in colorectal cancer, such as cetuximab, regorafenib, TAS-102, nivolumab and ipilimumab and has authored more than 650 peer-reviewed publications. We are very pleased to have you here, Dr. Lenz.

Hello.

Dr. Kopetz, he serves as the Professor and Deputy Chair in the Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center. He is also the Associate Vice President for Translational Integration and the program leader for genetics and gene regulation in the division of cancer medicine. He's a leader in translational oncology serving as principal investigator of the institutions gastrointestinal SPORE, co-leading the CCSG GI program and colorectal cancer Moonshot and helping drive rapid clinical translation through MD Anderson's traction platform. Dr. Kopetz has authored more than 400 peer-reviewed articles in leading scientific journals and his work has been instrumental in advancing new standards of care, particularly in patients with a BRAF-mutated colorectal cancer. Before I begin this discussion today, I would very quickly remind everyone of the top line data that we shared earlier this year. I will be sharing a few slides to recap our data and then begin our conversation with Dr. Lenz and Dr. Kopetz. So if I can have the slides on. I will be making forward-looking statements during the course of our discussion today. So I would advise everyone to look at our risk section as mentioned in our Form 10-K. Just to recap our study design, the study that we just announced top line data from, it is an ongoing Phase II study, which is a dose-finding study in RAS-mutated first-line metastatic colorectal cancer. The enrollment criteria are pretty straightforward, first-line patients with KRAS or NRAS mutations with unresectable disease, who have not been previously exposed to bevacizumab. It is a 110-patient study, which with 3 main randomization arm standard of control onvansertib, 20 milligram and 30 milligram, which are further randomized to based on the standard of care chemotherapy which includes FOLFIRI/bev or FOLFOX/bev, along with combinations of the 2 doses. On the right, we have how we administer onvansertib. Onvansertib is given on days 1 through 5 and then again from days 15 through 19 on a 28 -- in a 28-day cycle. The primary endpoints of the study were objective responses and the secondary endpoints were durability responses of duration of response and PFS. This is a busy slide. It is on our website, so you can take a look at the patient baseline characteristics across all treatment arms, pretty standard for what you would expect for a study like this. I do want to mention that we did include patients with liver disease and multi-multi-organ metastasis in this trial as well. These are our objective response rate data. Just to orient you to the slide, these are intent to treat analysis based on [ Becker ] independent review. The first panel refers to standard of care, which is a combination of patients -- all patients who were exposed to the 2 standard of care arms FOLFIRI/bev or FOLFOX/bev. The second one is FOLFIRI/bev standard of care alone and the next 2 panels are in combination with 2 doses of FOLFIRI, FOLFOX. As you can very quickly see that with the onvansertib 30-milligram arm in combination with FOLFIRI/bev, we do have a number of patients showing objective responses leading to an objective response -- overall objective response rate of 72.2%. Not only are there objective responses, but they are much more deeper when we look at the standard of care. So you have greater depth of responses as well as the number of responses that we got with our 30-milligram arm. The 20-milligram arm had only a very modest increase in the total number of responses. However, we did see the depth of responses like we saw in the 30-milligram arm. And the 2 standard of care arms that you see here behaved very similar to what has been historically reported, around 43% in 2 arms. So the next slide here shows you some durability measures that we have shared the top line durability mess that we have shared. Again, to orient you, this is the FOLFIRI/bev arm, the first column. The second column is 20 milligrams of onvansertib given with FOLFIRI/bev and the last column is 30-milligram onvansertib with FOLFIRI/bev. If you look at the median progression-free survival in the FOLFIRI/bev arm, it's approximately 11 months. similar to what has been reported in prior studies. However, we have not reached a median progression-free survival in either 20 or 30-milligram onvansertib arm. So this is a very promising sign that we believe that the drug is continuing to show benefit, not just at the objective response level but also durability. If you look at the PFS hazard ratios when compared to FOLFIRI/bev alone, again, you can see a dose-dependent improvement. You can see a hazard ratio of 0.56 in the 20-milligram arm and hazard ratio of 0.38 in the 30-milligram arm. Similarly, if you look at the PFS hazard ratio, when you look at the combined standard of care when we look at combined FOLFIRI/bev and FOLFOX arms, There, too, you see that in the 30-milligram arm, you have a hazard ratio of 0.37 which actually did reach statistical significance as well, p-value less than 0.05 even though the study was really not powered to show a difference in the PFS. And this is a landmark analysis of PFS rate at 6 months, which continues to show improvement over the standard of care and in a dose-dependent manner favoring the 30-milligram arm. So this is like the totality of the data. You cannot share efficacy data without tolerability. So this is a snapshot of our tolerability data as well. This is on our website in our corporate presentation. I will not go through all the details but the general impression is that we really don't see much additive toxicity on top of the chemo regimen. And most of these arms look very, very similar with maybe slight increase in some of the toxicities, but just numerically. Just to summarize again, I showed you the confirmed responses are going up to as high as 72% in the 30-milligram arm, almost a 30% improvement over FOLFIRI standard of care. We have not reached PFS in either the 20 or the 30-milligram of unmandated arm in combination with FOLFIRI, FOLFOX and the hazard ratios continue to look very promising whether we look at the combination of standard, whether we look versus the combined standard of care or with FOLFIRI. No added toxicities. So based on the totality of the data that I shared, we have chosen 30-milligram onvansertib as the dose to take forward in combination with FOLFIRI/bev in the registrational program which we are going to discuss with the FDA and finalize the plans there. I do want to mention that I did not share full detailed data of FOLFOX combination with onvansertib. But as we have previously stated, this combination did not demonstrate consistent benefit across the 2 dose levels. So we are not taking this forward at this time in the Phase III study. With that, I am going to end my presentation, so -- and move on to the discussion part of our webinar. Okay. Welcome again, Dr. Lenz and Dr. Scott -- I'm sorry, Dr. Kopetz. So let me begin by asking my first question, since we are talking about frontline patients, when you see a first -- when you see a patient who's been just recently diagnosed with metastatic colorectal disease, what therapeutic options do you generally discuss with patients based on either tumor diagnostics, age, multi-organ involvement and other factors. Just help us understand the various considerations you take into account while you plan management of such patients, especially given the heterogeneity of this disease. Maybe let me first start with Dr. Lenz and then I'll go to Dr. Kopetz.

So there is a lot of ongoing development in first line. I think what is very critical is really the molecular characterization of the colon cancer to really better understand and develop precision driven treatment decisions. What is absolutely necessary is that we know the KRAS, NRAS status, that we know the BRAF mutant status, that we know MSI high, that we know HER2 because for these, there are treatment strategies being developed. So we already know the MSI high very well with immune checkpoint inhibitors. The KRAS mutant have no really approved treatment in first line. There are trials going on combination with G12C inhibitors, which is only 3% of all rotations. So it's a very minority. The BRAF mutant, Scott can talk all about it with BREAKWATER showing incredible improvement of overall survival for this poor prognostic patient group and combine the morbid and onvansertib, cetuximab. And I think BREAKWATER was not only critical to understand how important targeted treatment is, but how important is to combine with chemo in first line. And I think this is just going back to the onvansertib study, so critical. I can only at [indiscernible] Cardiff to put that very quickly through with a passion development based on the data they had in the Phase I and the Phase II in second line moving into first line because targeted agents with chemo in first line will show the best outcome. And I think the data from the first-line study really being calculated actually that finding and actually validate the finding you saw in Phase II because the response rate also were over 70% and the PFS was 15 months. So this is very consistent when you look at it. So I think molecular catheterization will drive the decision in the past KRAS mutant that we adjust with a chemotherapy backbone, like FOLFOX or FOLFIRI or sometimes FOLFOX with bevacizumab. So I think this is kind of, I don't know, if Scott wants to add to it, but a lot of new trucks going into first line. We have heard all about bispecific antibodies, but we don't know what really will become positive or not. And I think not always the sexiest trial are the most successful. I think fashion development and data did drive the success. And I think this is adding up very nicely so far for the onvansertib.

Yes. Dr. Kopetz.

No, I'll just add to that nice summary that -- we take a step back while we're making advances in the small wedge of MSI and the small edge of BRAF and maybe HER2 in the future, G12C maybe in the future. We put those together, still such a small minority, right, 10%, 15% of patients that we really have something advances for, which means that the real wide open need for this. Now first line, I think to echo what Dr. Lenz said. First line is so critical, right, being able to get in the right treatment at the first setting is critical. It's critical because you need the activity of the cytotoxic to synergize with the biologic, with the targeted therapy here. What we know and have known for decades, unfortunately, is that the efficacy of cytotoxic in general really start to decline in later lines that the leverage that we get in first line, the activity that we get in this first-line setting really sets the stage for the patient's journey through other lines of therapy. And so -- that's where I really like the idea to say, well, let's bring the right biology forward for the right patients as soon as we can.

And maybe I can add something, Mani. So I think -- and Scott is completely correct, I think what -- the reason it drops in second and third line is the capacity of boomers to overcome resistance change what treatment you give or when we look at onvansertib cetuximab in second line, it is not very good. I mean, it is reasonable, but the full potential comes out in first line because the cytotoxic really prevents the escape mechanism on a molecular level. And I think this is a very important recognition that we need to move in this patient population and target agents into a first line for as many as we can.

Couldn't agree with the more. But selfishly, I heard a couple of things that you just mentioned in your prior comments, Dr. Lenz. You said rational drug design, and you said that we moved from second line to first line. So I do want to dig deeper there. And since you have been involved with this drug candidate since many years, maybe share some of that. Expand on that a little bit, where -- what did we see in the second line patients and how we think we rationally move and if you would agree with that, yes.

Yes. I mean, my history with onvansertib also way back before it was Cardiff, it was Trovagene, when Trovagene contacted us. We bought the first clinical trial FOLFIRI/bev combination because of significant synergies and preclinically with topo1 inhibitor with bevacizumab. So it made sense because -- and FOLFIRI/bev was at this time or is still considered often the second-line treatment in the U.S. after FOLFOX/bev. So we did that. And we established a dose, the 150 milligrams per square meter, which is now the 30 milligrams you move forward all the data was correct. And I think when we went to the second-line treatment in the Phase II part, we had 53 patients. It's not -- it's a really good Phase II, and it clearly showed that the overall had response rate of 20% to 30%, which is double what FOLFIRI/bev is , but it became clear when we looked at patients who didn't have bev before that response rate jumped to over 70% -- I think it was 76% or 77%.

73%, 74%, very similar. Yes. Yes.

And I remember the ovation response was, I think, 11 months. And I think the PFS was 15 months. So these were data which blew us away or me away. So of course, then discussion started. What is the biology behind it is previous bev converting resistance to this combination. And the decision was made based on many kind of biological data, which we published in JCO last year, not actually in 2024 is that to move into first line. And discussion is should we move with FOLFIRI/bev into first line because in the U.S., FOLFOX, onvansertib such an automatic reaction. That's not true in the rest of the world. In Europe and in Asia, FOLFIRI is often a preferred because you don't run into dose-limiting toxicity. And seeing now the data on the first-line study, there are extremely consistent and even more exciting now with high response rate, really deep responses. We don't even know the PFS yet. But when you look at the 12 months, PFS rate, it shows it's over 60%. So you will have a great PFS. So -- and -- the duration of response is not yet there. So it is really cool to see this data evolving really making very clear what the next step is to get this drug into a registration. So I have been a bit distracted from the beginning on. We're the first patient, and I'm seeing the last patient, but fit the first one. And clinically, you often don't know if they are on the -- take the pill or not because toxicity clinically is not in any way distinguishable from the control arm.

Yes. And if I may, go further? Because I think sometimes what's underappreciated is for something to be given in first line for a longer period of duration. You really need to have something that's tolerable, right? I mean we say from a drug development perspective, but we'll have to hear both your thoughts on whatever you experience with their own patients or seeing the data, even longer-term tox data, anything that you feel should be worth mentioning here or lack thereof of toxicity, yes?

Maybe I'll just echo some of the things that Heinz mentioned on the toxicity, patients have tolerated it really well. And I think the experience that we've had with it has been encouraging to allow some continued dose dosing and that -- that I think especially is important when we can talk about this further. We think about the partner, the cytotoxic partner and how the ability to kind of keep that dosing intensity and the duration, which is so critical to get those type of results that Dr. Lenz mentioned as well. So certainly, the schedule, as you hear, is different than what other in other settings, right? So this is really an intermittent really following the biology, right? What is what is PLK1 doing? How do you get that therapeutic window? How do you combine with the mechanism of action of the cytotoxic therapy. So I think it really is a nice alignment of the drug development and the biology with the dosing regimen and the partner that we're seeing now.

And maybe -- go ahead, please, Dr. Lenz.

And Scott, and I know that with FOLFIRI, you can treat forever or I mean it's basically no accumulative toxicity. If you tolerate the first course, you will tolerate the next 100 to go. And patients are on for years with very little impact on quality of life. So that is a very good partner to have does not create any kind of overlapping toxicities or dose-limiting toxicities.

Yes. No, certainly, I know we have at least 1 patient who's been on this drug for a few years now. And coming back to Dr. Kopetz on the biology, you certainly have studied this drug very well like in nonclinical setting, trying to uncover the biology. So anything that you would like to share based on some of the translational and the preclinical studies that you've done that we would love to hear. We've shared some of the data and published but would be great, yes.

Yes. No, I think it -- so I think it is important to say where did this target come from, right? It came from an unbiased screen of vulnerability is unique to KRAS. And so that wearing my biologist hat as a scientist, I love the unbiased nature, right? It's not like I think I have an idea, and I'm going to target that like you'd start with a blank slate and let the biology declare itself to you, right? And so I think a good drug builds on a really strong foundation, and I think that's kind of an important component here. The other is that we recognized really the opportunities for combinations, right? And that while PLK1 plays a number of rules, it's role in kind of DNA damage repair is critical, right? And that is kind of a key component, and we've recognized looking at our preclinical models that there's synergy across a number of different agents. But the opportunity the recognition that topoisomerase I inhibitor in particular, we're uniquely sensitive to this. What is a topoisomerase inhibitor that's irinotecan? And so why is that? Well, without getting too deep into the weeds, what this topoisomerase inhibitors do is it creates these breaks in the DNA, these double-strand breaks that need a certain repair pathway, right? It turns out our body has a number of different pathways that get engaged depending on the type of DNA damage that occurs like we have a UV damage, for example, it's a different one. But this is the homologous recombination repair pathway for the efficient autos out there that gets triggered. And this PLK1 plays a critical role of getting recruited into these spaces, right? So it's really encouraging and rewarding as a physician scientist and we say, okay, we see these kind of strong signals with irinotecan preclinically and then to have the clinical data replicate and say, you know what, irinotecan really is the right partner, and that's kind of based on that biology that PLK1 plays a role in that. Oxaliplatin, 5-FU, very different nucleoside excision repair pathways, really no direct role for PLK1 in that mechanism. And so there's synergy through other mechanisms, perhaps -- but it really -- I think the biology is aligning with this clinical trial design to really think about the full Ferin bevacizumab partnering in the first-line setting.

Yes. I'm so glad that you bring this up because this just comes up a few times, why irinotecan, why topoisomerase I inhibitors and where do we go from now? And you also just sort of alluded to angiogenesis. We've also seen like why bev as well, right? Like -- so maybe you can opine on it a little bit further on the HIF-1 alpha aspect of it, like as well, so maybe yes.

Yes, absolutely. So we love it when a drug has 2 tricks up its fleet, right? And indeed, this is one of those. And so what we see is that when there is hypoxia, low oxygen levels in the tumor the tumors respond by upregulating a key inducible factor for hypoxia, HIF pox notable factor. HIF alpha, which is a key factor that starts a whole program that says we need to recruit more blood vessels, we need to bring in more oxygen into the tumor. And that's a critical part of how a tumor grows and progresses. Now it turns out that onvansertib directly reduces the HIF-1 levels pretty profoundly actually. So this is some nice synergy between the bevacizumab, which neutralizes VEGF, which is produced after a HIF signal. So you've got really 2 very potent ways to inhibit the neovascularization, this process of building new blood vessels to enable tumor growth.

No. That was very, very well put. And maybe I'll go back to Dr. Lenz you very eloquently laid out all the different ways of characterizing the disease and the kind of options they are did mention that while there are no approved agents for RAS other than the G12C targeting drug. I do want to say just sort of want you both to opine or just give your opinion. How do you take care of these patients, while there are no approved therapies, when these molecular diagnostics come out, you have patients who have RAS mutations, NRAS, KRAS, what's -- how do you manage them right now?

So it depends on the axes or presence of clinical trial standard of care would be usually a backbone chemo with bevacizumab and the backbone chemo could be FOLFOXIRI or a FOLFOX or FOLFIRI. In young patients where I want to be very aggressive, I would even triplet to have higher response rate. in the process of clinical trials, you may have clinical trial opportunity to include them in a trial, Phase II or Phase III with immunotherapy because immunotherapy tries to get into first line for MSS where the KRAS mutant not don't play a significant role, at least for now we don't know what's going to happen. So I always look, of course, for clinical trial involvement beyond a standard of care. But the standard of care would be a chemotherapy backbone with bevacizumab.

And what about you, Dr. Kopetz? Do you do anything different? Or it's pretty much?

That's the best we have. And if we look back now 15, 20 years, what would we do for our RAS mutated, that's kind of it, right? So I think just acknowledging that this is an area where we really have not had many advances, and it's kind of been a FOLFOX, FOLFIRI backbones with the bevacizumab. So lots of opportunities here to really break the mold and improve outcomes.

So...

Sorry, Mani. I'm sure there is discussion about what about the pan-RAS inhibitors because I'm sure the people who listen are aware of development of the pan-RAS inhibitors and we probably all are aware of the limitations of them, in particular, the toxicity. It's even very difficult to put that into the treatment for colorectal cancer, a single agent have extremely very little efficacy even where we targeted. And I think that is colon cancer where we have our big challenges, even we have the most targeted drugs, given alone, they do not do a lot. We need combination treatments. And I think this is a big benefit of the onvansertib. It's very targeted. It has synergism. Actually, it was clearly shown efficacy in second line with the big efficacy in naive move to first line and validating all the data we have seen. So -- and you already are in first line. So the only thing you have to do, do the registration that we have this drug in our clinical setting available.

No, this is great. So if I may sort of summarize some of the things that I heard both of you say that whatever you gave 20 years or so ago for these patients is still what you continue to sort of use for the management of these patients. And if there's a clinical trial available for this particular molecular characterize patients that you would opt for it even in frontline, right? Is that the correct way of characterizing the RAS mutant patient management at this time.

Pretty much. But I think it's very important, even we have made progress. And I think Scott pointed that out, absolutely importantly, our target agents we have in first line really address even in clinical trials, a subset or very few. And however you define it maybe 10%, maybe 12%, it is really the majority are still treated the same for the last I don't know how long, a long time. And I don't think it will change very quickly. So I think we need really, this is an unmet need, exactly what you said at the beginning, money. I think we need treatments for KRAS mutant in first line.

So okay. No, this is amazing. Even from every time I talk to the 2 of you, there's always a new learning. That's been very well put together from your perspective, just not the unmet need, but what's really out there as well. Maybe we go a little bit deeper as a company, as regulators, as investors, as patients, all of us are looking at metrics, like what are the right metrics to say that the drug is working or not. So maybe I just like the objective responses, PFS hazard ratios. So help us understand, like from your perspective, from a physician perspective, what do you think is clinically meaningful benefit for patients in frontline? What are you looking at? Is it the response rate? Is it the PFS? Just help us all understand that and then maybe contextualize to the kind of data I shared with onvansertib. I don't know who wants to go first, Dr. Kopetz can, yes.

No, happy to. So the...

I will come back to you Dr. Lenz as well. So...

I don't feel offended, okay.

So what we're looking for, I think, within the limitations, of course, small signal-seeking Phase IIs, clearly looking for evidence of regressions, response rates they tend to define activity, but the things that the regulators and as providers are looking for is ultimately the kind of progression-free survival. We tend to be a little better in estimating response rate in small studies than we are progression [indiscernible] but we're looking at all of the above. What really matters for getting a drug across the finish line is progression-free survival. That's the endpoint that regulators kind of around the world have settled on for first-line studies. And so that's certainly the most important component.

Sure. I can only add this. I think everyone wants to see too much shrinkage everyone. I think this is very important. The problem is we have seen with other drugs that there is too much shrinkage, but it doesn't last. And I think that is exactly what Scott was saying is that you need to have too much shrinkage, but you need to have that goes along with the PFS. Now I think colon cancer is a very unique disease. It has a very unique metastatic pattern mostly in the liver. We have a lot of oligometastatic disease. Too much shrinkage can make a big difference because if you are converting an unresectable metastatic colon cancer into resectable, you have a chance of cure. So response rate is more important for colon cancer than for other cancers, if this goes matching with the PFS. So I think we are talking about survival and professional fee survival but we have seen patients being unresectable, being converted and be cured. Colon cancer when it doesn't come back in 5 years, you're cured. You cannot say that to any cancer or rest cancer, you talk about survivors. In coronal cancer, we talk about cures. We talk about the shoulder in our survival curve. So that is a very important and the depth of response will correlate with the chance of getting curative resection. So I don't want -- I think Visa is very critical when it goes along with PFS. This is a home fun.

So to that end, I didn't share the data today because this was matched to be a discussion, and we have put out publicly some anecdotes from patients and you guys are available -- you are obviously previewed that information as well that we've had patients on our trials that have gone to a curative surgery. An underappreciated fact, we're a small company, but I do want to say that what you're seeing, we've actually shown it even in this small study, right? Would you agree or not and have a couple things to say there. We've debated. We've taken a hit on the PFS because obviously, it counts as an event, but these patients have benefit and hopefully they are cured. It will be amazing as a drug developer to know that, that happens. That's what we work for.

No, I have no doubt I have seen it. And I think with response over 70%, hopefully, you will do more and more patients leading to a curative resectability.

Yes. response rate, depth of response, PFS, [indiscernible] PFS hasn't been reached. We continue to follow these patients. So we are pretty excited about it, and we certainly want to engage the regulators to make sure we get it as fast as possible into a registrational trial. Yes. So maybe again, I do want to make sure that this is not just about us. but also as a last topic from my side before I open for questions, is anything else you're seeing that you feel are promising for RAS-mutated metastatic colon cancer in frontline. Anything that listeners on this call should also pay attention to.

Yes. I mean I think as Dr. Lenz mentioned the kind of pan-RAS inhibitors just don't look like they're going to have a role in colorectal cancer. It breaks my heart to say that. seeing all the great things happening in pancreas, but it's just -- it's not in the cards for colorectal due to the kind of the adaptive resistance that colorectal is so well known for. We are certainly know that G12C, as Dr. Lenz mentioned, is a small wedge 2% to 3%, and we look forward to seeing what that looks like. It's useful to note that they decided to use FOLFIRI as a backbone for their study. based on the data that they saw as well. So I think that's kind of a useful point from at least the NN perspective. The difficulty is that there's just not -- once we get past the if we take the pan brass off the table, even if we get in the future, perhaps maybe the G12D allele specifics may make their way forward. But again, these are -- we're cutting off little small wedges of the population. And colorectal cancer and KRAS in particular, tends not to be driven by any one particular there's a lot of RAS mutations and in 13 and 61 and 146 that is a much broader repertoire. And so really thinking about how do we attack the biology that's broad I think is important. And maybe we can make some headway in 1 or 2 of the allele specific space in parallel. But I don't think those are mutually exclusive by any stretch in imagination.

So I wanted to mention a little bit on the development. And one of the promising new developments are the antibody conjugates. And what do the antibody conjugates have as a payload -- but topo 1 inhibitor, okay? What are the data with antibody conjugate staff, increasing the response rate in refractory setting. You can only assume that these ADCs will move into earlier lines of treatment and they're all desperate looking for ways to increase efficacy. So it would be absolutely logical to think about and onvansertib in KRAS mutant. And so I think there are big opportunities in the future. Independent of the FOLFIRI/bev, this has to go anyway. But I think this is not the end of the development, maybe only the beginning. And we published a paper a couple of years in on showing also the PLK1 signaling is associated with immune cell signaling and immune cell trafficking. So I think this is not even explored. So I think there may be very unique opportunities to further explore. So if Scott has a lot of time. We can do that in his models. He has done so much work already. So what I'm saying is there is a lot of still exciting projects to evaluate and to look forward to potentially further increase the ongoing activities you already see.

You pretty much read my mind because that's where I was going with ADCs, what that's exactly the point. What do ADCs have their topoisomerase inhibitors. And to that effect, I know I'm bringing something else. We are working at least in the company on the reclinical side to show the synergies there, and I'm just putting a plug out for the company, we are presenting some preclinical data, albeit in breast cancer, but with the topoisomerase I inhibitor tag to an ADC. But that just tells you that, yes, we have much more than for free to combine even as the newer therapies emerge there is a room for the benefit to be expanded with onvansertib and plus the tolerability. That's what I've been saying consistently. Sometimes it's -- you have good agents, but it's harder to put them together. At least that's my perspective. I don't know if you would agree with that as well or not, yes.

Absolutely.

Yes. Okay. I think there are people we have waiting on the line, our analysts waiting on the line to have the questions being answered by the 2 experts that we have here. So operator, may I request you to open the line for Q&A, please?

[Operator Instructions] Our first question is going to come from the line of Maury Raycroft with Jefferies.

I'll ask a general one, just to get the doctor's perspective, now we should think about durability results we've seen so far from onvansertib compared to standard of care and other assets in development for fine colorectal cancer. So let me jump in, Scott can jump in and Mani can jump in any time. So the duration of response was in the Phase II almost 12 months. That is extremely long. So -- and this is a second-line treatment. So -- and the PFS was 15 months. So this really speaks out for the potential ration of activity that there is not an immediate mechanism of resistance evolving under the treatment where you combine FOLFIRI/bev and onvansertib. And the data from the first line seem to confirm that the response rate is the same. We have not reached the PFS and we have no reiteration of response. We just know that professionals be survive over 1 year was over 50%. So we know it's more than 12 months. So it is all going into the same data which we had generated before really supporting the long duration of response and that there is not a very high active mechanism resistance, which we see with other treatments. So -- but Scott, you can add anything that I missed.

Yes. Maybe just one thing to mention is that when we're stress testing the data and just taking a look at it. One is like how did the control arm perform, right? And that was right around 11 months. So that's kind of expected, right? That's important. And then is there a dose response that was seen. And just like with the response rate, we saw a dose response trends against small numbers, but this is how I look at it is like, oh, I see the PFS dose response as well. So with the caveats it's early days, but hazard ratio for PFS that's under 0.5 is very kind of encouraging given all those other components. So it is hard to cross compare, but I will say there's not a ton out there that we've got Phase II data in this population for. So they really -- even if I even if we had a larger data set to compare to, there really is nothing that is out there to explore against.

Got it. Really helpful. And maybe just one follow-up on just how you think about gating factors for choosing curative resection and what proportion of patients reaching curative intense surgery bar and a pivotal study would be clinically meaningful in a RAS mutant colorectal cancer population.

So I don't think there are data to refer to. But I tell you the resectability and [indiscernible] is a very soft end point because it depends on patients selected. Are there oligometastatic disease or they have liver, lung and bone lesions that will never be convertible? So it depends really on the patient selection. But we know the higher the response rate in this patient population the higher is receptibility of version to a curative resection. If you can resect 10% to 20% for curate recession, it would be amazing. Now we know when it's liver limited disease up to 30% can convert it. So it can get very complicated. But the effect when you really convert a non-resectable evaluated by a multidisciplinary tumor board in any kind of clinical trial, it is a significant success. So I think this data should be captured and really will play a supporting role because I think for colon cancer resectability means so much more than for other metastatic epithelial cancers.

Before we go to the next question, again, I sort of want to refer some of the people who are listening here to the slides that we have on our website, Dr. Lenz, you mentioned that liver is a hard one, but we do have at least one patient that I'm aware of who had nontarget lesions in liver and still end on curative surgery after being treated with onvansertib. So I just sort of wanted to put it out there, yes.

Our next question will come from the line of Marc Frahm with TD Cowen.

Maybe for the physicians, I mean I completely appreciate your sentiment on the GLCs only being a small sliver of RAS-positive disease. But yes, as you mentioned, there are few other mutant selective inhibitors coming for different portions of RAS positive. Just if we take that G12C example as maybe as a predictor of what will happen with this other mutant selective inhibitors. Can you maybe put the data in the context that Cardiff is generating in the context of the G12C data and how it might fit in for that growing percentage that will never become 100%. But is a potentially growing percentage options who may have a selective RAF inhibitor?

We don't have a lot of first-line data to compare here with that. The Amgen study is running for G12C, work for G12C. The G12D were we're optimist by nature. We're hopeful that those will provide some benefit as well. But that's 10%, right? So -- and that's -- or less there. So it really is -- will be -- won't really get to that next level. Do you start to think about -- like you said, it won't go to 100%, but not even sure that we're going to get to like 25% of the KRASs that will be able to be covered here with these allele-specific ones, just given the difficulties here. And are you going to develop a drug for a [indiscernible] 146 mutation. No, right? I mean this is kind of diminishing return. So yes, I guess kind of I don't have a great answer to your question just because we don't have a lot of that data to really make a head-to-head comparison.

So let me also jump in [indiscernible] Scott. We almost have a green not always, but, okay. So I think -- the truthy question is, will you have a G12C inhibitor mutation? Do you use a G12C inhibitor with chemo or you use onvansertib? In addition to the argument, it's only 3%. And I think biology right now is on onvansertib side or because you have the direct interaction with the topo I, you have the direct interaction with the bevacizumab and we don't have similar data for the CPFC inhibitors or at least preclinically or clinically. So even in this case, I'm not sure what will that be. That would be very interesting to really show and demonstrate. But as mentioned and Scott is right, this will be a very low subset and the toxicity profile is also in favor for onvansertib. So I'm not sure even for these patients, what would be the best treatment in the future depending on what data we will generate.

Great. That's super helpful, especially the last comment. And then maybe just thinking broadly, with the backbone of FOLFIRI given the preference of some physicians, particularly in the U.S., useful FOLFOX. Just can you speak to kind of what ultimately needs to be shown in a Phase III to not just kind of convert practices that are using FOLFIRI but also those that might be using FOLFOX?

Oncologist, vote with their feet. If there is efficacy that go for it, it doesn't matter what it is, okay? As long you show superior efficacy, they will do what it takes to reach that. So I'm not worried that the American oncologists will not choose FOLFIRI/bev. I think for has a lot of benefits with no agreement toxicities. And whenever we have an effective treatment, we will choose that. So I don't know how you think, Scott, but I don't worry about it. The reason FOLFOX Avastin is often used even in my clinic is because all clinical trials subsequent are tiered to FOLFOX/bev failures, okay? So when you have a certain mutation, you want to make sure the patient can go on, you need to do FOLFOX Avastin. Okay, otherwise you miss out. So I think all these arguments will go out of the window when you have an effective truck. There is no discussion anymore. So I'm not void at all. I don't know if you are Scott...

No, it's not -- I mean, FOLFOX backbone can't be used by patients who had adjuvant FOLFOX, right, or have neuropathy or other things, right? So there's a proportion of patients aren't eligible for FOLFOX. You really don't have that problem with FOLFIRI, right? It's -- if you're really -- if your approval is limited to a certain backbone, right? You'd much rather that backbone be FOLFIRI, then it would be full FOLFOX because you're going to get a lot of population out of that. So I think that's an important recognition to complement what in just said.

And if I may jump in. I know this is a question that we often face. We did show in our analysis when we combine both FOLFOX and FOLFIRI in our current data set in the frontline setting, whether you look at objective responses, whether you look at the limited PFS and durability data that we've shared, it seems to be quite superior, at least as the data are evolving whether we look at it from a FOLFOX regimen perspective, all FOLFIRI. And from what I hear, you guys are data-driven. So if that works, then that's what it is. But yes, I do Don't want to take everybody else's time. We are running out of time. So please operate next question. Can we have the next question, please? Okay. So since I don't hear anything from the operator I just thought about it when we were talking about G12C and 3%, 5%, whatever it is, maybe help us end the session by giving us a sense of how large are the -- how large is this RAS-mutant population, pan-RAS, whatever you think, whether they are KRAS, NRAS, G12D, like together, if you look at it. Is it 50% of your patients? Like what is it? Like just help us understand that as well. Who wants to go first? Yes.

I don't want to go first every time. Scott?

No, no. I did make sure I was going back and forth, but...

Yes. So yes, you're spot on it. 50% is kind of a good rough rule of thumb. So that includes KRAS as well as NRAS mutations, right? We don't see as many NRAS in long or pancreas, but it's a significant number there within kind of colorectal cancer. And so collectively, we can think about this as about half of the population there as well that the targetable -- potentially targetable subset, as we mentioned, is kind of a fraction, maybe collectively 15%, right? It would be kind of an estimate if we kind of look at what's coming there. So there's a huge group of patients and unmet need for sure.

Yes. By targetable, you mean targetable by RAS specific...

The allele-specific, right? That were there before. So the if we see in G12Cs and the Ds there?

Yes. Yes. And on onvansertib, of course, it doesn't matter what the munition is given the mechanism of syntaculatality with RAS mutations in general.

Right. Works in KRAS and NRAS, right? So...

Yes. KRAS [indiscernible], yes.

That's important.

Yes, we did -- our control that we're discussing did obviously have patients with [indiscernible] included all of them. Yes. Well, I don't see any further questions online, and I think we've come at the -- like right on time. So I would first like to really thank the 2 of you, you for engaging me, not just today, but even in the past, as we've been having sessions on our advisory board and other discussions, because you guys are the ones who actually treat the patients and help us conduct these trials. So thank you very much for coming today on this webinar, Dr. Kopetz, Dr. Lenz and for making the time to speak to me despite your very busy clinical responsibilities, and I certainly want to thank all the patients who have participated in current trial and our past trials and have truly contributed immensely to our learning of how to start using this drug in this disease. So thank you again. It's been a pleasure, yes.

I would never say no to Scott when he participates. So it was fun to talk to him and to you. So thank you very much for inviting us.

Likewise. Yes.

Yes.

And with that, we can end the call. Thank you, everyone online.

Bye guys.

Bye.