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 National Colorectal Cancer Awareness Month dedicated 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 colorectal 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 two globally recognized leaders in GI oncology, Dr. Heinz-Josef Lenz and Dr. Scott 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 cancer center director and co-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're 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's 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 institution's 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 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. If I can have the slides on. I will be making forward-looking statement during the course of our discussion today. 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 three main randomization arms, standard of control onvansertib 20 mg and 30 mg, which are further randomized based on the standard of care chemotherapy, which includes FOLFIRI+ Bev or FOLFOX+ Bev, along with combinations of the two doses. On the right we have how we administer onvansertib. Onvansertib is given on days one through five, and then again from days 15 through 19 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-organ metastases in this trial as well. These are our objective response rate data. Just to orient you to this slide, these are intent to treat analysis based on BICR independent review. The first panel refers to standard of care, which is a combination of all patients who were exposed to the two standard of care arms, FOLFIRI+BEV or FOLFOX+bev. The second one is FOLFIRI+BEV standard of care alone. The next two panels are in combination with two doses of FOLFIRI, FOLFOX. As you can very quickly see that with the onvansertib 30 mg arm in combination with FOLFIRI+BEV, we do have a number of patients showing objective responses leading to an 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. You have greater depth of responses as well as the number of responses that we got with our 30 mg arm. The 20 mg 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 mg arm. The two standard of care arms that you see here behaved very similar to what has been historically reported, 40%, around 43% in two arms. The next slide here shows you some durability measures that we have shared, the top-line durability measures that we have shared. Again, to orient you, this is the FOLFIRI+BEV arm, the first column.
The second column is 20 mg of onvansertib given with FOLFIRI+BEV, and the last column is 30 mg 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 mg or 30 mg onvansertib arm. 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 know, you can see a hazard ratio of 0.56 in the 20 mg arm and a hazard ratio of 0.38 in the 30 mg arm.
Similarly, if you look at the PFS hazard ratio, when you look at a combined standard of care, when we look at combined FOLFIRI+BEV and FOLFOX arms, there too you see that in the 30 mg arm, you have a hazard ratio of 0.37, which actually did reach the 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. This is a landmark analysis of PFS rate at six months, which continues to show improvement over the standard of care and in a dose-dependent manner favoring the 30 mg arm. This is like the totality of the data. You cannot share efficacy data without tolerability. 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, you know, general impression is that we really don't see much additive toxicity on top of the chemo regimens. Most of these arms look very, very similar with maybe slight increase in some of the toxicities, but just numerically. Just to summarize again, you know, I showed you the confirmed responses going up to as high as 72% in the 30 mg arm, almost a 30% improvement over FOLFIRI standard of care. We have not reached PFS in either the 20 mg or the 30 mg of onvansertib arm in combination with FOLFIRI, FOLFOX, and the hazard ratios continue to look very promising, whether we look versus the combined standard of care or with FOLFIRI. No added toxicities.
Based on the totality of the data that I shared, we have chosen 30 mg 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 two 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 and move on to the discussion part of our webinar. Welcome again, Dr. Lenz and Dr. Kopetz. Let me begin by asking my first question.
You know, since we are talking about frontline patients, when you see a patient who's been just recently diagnosed with metastatic colorectal disease, what therapeutic options do you generally discuss with patients, you know, 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.
Sure.
Dr. Lenz.
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 and NRAS status, that we know the BRAF mutant status, that we know MSI-H, that we know HER2, because for these, there are treatment strategies being developed. We already know the MSI-H do very well with immune checkpoint inhibitors. The KRAS mutant have no really approved treatment in first-line. There are trials going on in combination with G12C inhibitors, which is only 3% of all mutations, 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 when combined chemo with encorafenib cetuximab. 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. I think this is just going back to the onvansertib study, so critical. I can only admire Cardiff to put that very quickly through with a rational 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.
I think the data from the first line study really recapitulates 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. This is very consistent when you look at it. I think molecular characterization will drive the decision. In the past, KRAS mutant were treated just with chemotherapy backbone like FOLFOX or FOLFIRI or sometimes FOLFIRI with bevacizumab. I think this is kind of. I don't know if Scott wants to add to it, but a lot of new drugs going into first line. We have heard all about the bispecific antibodies, but we don't know what really will become positive or not. I think not always the sexiest trial are the most successful.
I think rational development and data will drive the success, and I think this is adding up very nicely so far for the onvansertib.
Yes-
Yeah.
Dr. Kopetz.
No, I'll just add to that nice summary that, you know, we take a step back while we're making advances in the small wedge of MSI-H and the small wedge of BRAF and, you know, and maybe HER2 in the future and G12C maybe in the future. We put those together, still such a small minority, right? 10%, 50% of patients that we really have 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? Getting 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 cytotoxics in general really start to decline in later lines. That, you know, 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. 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.
Maybe I can add something, Mani. I think, and Scott is completely correct, I think what the reason it drops in second and third line is the capacity of tumors to overcome resistance change what treatment you give. Or when we look at encorafenib 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 part really prevents the escape mechanism on a molecular level. I think this is a very important recognition that we need to move this patient population and target agents into a first line for as many as we can.
You know, couldn't agree with you more, but selfishly, you know, 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, you know, we moved from second line to first line. I do want to dig deeper there, and since you have been involved with this drug candidate since many years, you know, 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 moved, and if you would agree with that, yeah.
I mean, my history with onvansertib goes all the way back before it was Cardiff. It was Trovagene. When Trovagene contacted us, we wrote the first clinical trial FOLFIRI+BEV combination because of significance in actually some preclinical with TOP1 inhibitor with bevacizumab. It made sense because FOLFIRI+BEV was at this time, or is still considered often the second-line treatment in the U.S. after FOLFOX+BEV. We did that, and we established the dose, the 50 mg per square meter, which is now the 30 mg you move forward. All the data was correct. When we went to the second-line treatment in the phase II part, we had 53 patients.
It's a really good phase II, and it clearly showed that we overall had response rate of 20%-30%, which is double what FOLFIRI+ BEV is. 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. Yeah.
Yeah.
Yeah.
I remember the duration response was, I think, 11 months, and I think the PFS was 15 months. These were data which blew us away or me away. Of course, discussion started, what is the biology behind it? Is previous BEV converting resistance to this combination? The decision was made based on many kind of biological data, which we published in JCO last year, actually in 2024, is that to move into first line. Discussion is should we move it FOLFIRI+ BEV into first line because in the U.S. FOLFOX and Avastin is such an automatic reaction. That's not true in the rest of the world. You know, in Europe and in Asia, FOLFIRI is often preferred because you don't run into dose limiting toxicity.
Seeing now the data on the first line study, they 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-month PFS rate, it shows it's over 60%. You will have a great PFS. And the duration of response is not yet there. It is really cool to see this data evolving, really making very clear what the next step is to get this drug into registration. I have been with this drug from the beginning on with the first patient, and I'm not saying the last patient, but certainly the first one. Clinically, you often don't know if they are on, take the pill or not because toxicity clinically is not in any way distinguishable from the control arm.
Yes. If I may, you know, 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 it from drug development perspective, but would love to hear both your thoughts on whatever you experience with your own patients or seeing the data, you know, even longer-term tox data, anything that you feel, you know, should be worth mentioning here or lack thereof of toxicity. Yeah.
Yeah. Maybe I'll just echo some of the things that Heinz mentioned on the toxicity. You know, my patients have tolerated it really well. I think the experience that we've had with it has been encouraging to allow some continued dosing. That I think especially is important when we can talk about this further, we think about the partner, the cytotoxic partner, and how you know 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 and as well. You know, certainly the schedule as you hear it you know is different than what other in other settings, right?
This is really an intermittent, really following the biology, right? What is PLK1 doing? How do you get that therapeutic window? How do you combine with the mechanism of action of the cytotoxic therapy? You know, I think it really is a nice alignment of, you know, the drug development and the biology with the dosing regimen and the partner that we're seeing now.
And maybe-
And-
Go ahead, please, Dr. Lenz.
Scott and I know that with FOLFIRI, you can treat forever or I mean, it's basically no cumulative toxicity. If you tolerate the first course, you will tolerate the next hundred or so. Patients are on for years with very little impact on quality of life. That is a very good partner to have. Let's not create any kind of overlapping toxicities or dose-limiting toxicities.
Yes. No, certainly. I know we have at least one patient who's been on this drug for a few years now. Coming back to Dr. Kopetz, on the biology, you know, you certainly have studied this drug very well, like in non-clinical setting, you know, trying to uncover the biology. 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, you know. We've shared some of the data and published, but it would be great.
Sure.
Yeah.
I think it is important to say, where did this target come from, right? It came from an unbiased screen of vulnerabilities unique to KRAS. You know, wearing my biologist hat and as a scientist, I love the unbiased nature, right? It's not that like, I think I have an idea and I'm gonna target that. Like you'd start with a blank slate and let the biology declare itself to you, right? I think, you know, a good drug builds on a really strong foundation, and I think that's kind of an important component here. You know, the other is that we recognized really the opportunities for combinations, right?
That while PLK1 plays a number of roles, its role in kind of DNA damage repair is critical, right? That is kind of a key component. We've recognized looking at our preclinical models that there's synergy across a number of different agents, the opportunity and the recognition that topoisomerase I inhibitors in particular were uniquely, you know, uniquely sensitive to this. What is a topoisomerase inhibitor? That's irinotecan, right? 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-stranded breaks that need a certain repair pathway, right? Turns out our body has a number of different pathways that get engaged depending on the type of DNA damage that occurs.
Like if you have a UV damage, for example, it's a different one. This is the homologous recombination repair pathway for the aficionados out there that gets triggered. This PLK1 plays a critical role of getting recruited into these spaces, right? It's really encouraging and rewarding as a physician scientist when we say, "Okay, we see these kind of strong signals with irinotecan preclinically." 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. Nucleotide excision repair pathway. Really no direct role for PLK1 in that mechanism. There's synergy through other mechanisms perhaps. It really, I think the biology is aligning with this clinical trial design to really think about the, you know, the FOLFIRI and bevacizumab partnering in a first-line setting.
Yes. You know, I’m so glad that you bring this up because this just comes up a few times, you know, why irinotecan, why topoisomerase one inhibitors, and where do we go from now? You also just sort of alluded to angiogenesis. You know, 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. Maybe. Yeah.
Yeah. No, absolutely. We love it when a drug has two tricks up its sleeve, right? Indeed this is one of those. 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, Hypoxia-Inducible Factor. HIF alpha, which is a key factor that then starts a whole program that says we need to recruit more blood vessels, we need to bring in more oxygen into the tumor. 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.
This is some nice synergy between the bevacizumab, which neutralizes VEGF, which is produced after a HIF signal. You've got really two very potent ways to inhibit, y ou know, the neovascularization, this process of building new blood vessels to enable tumor growth.
No, thank you. That was very well put. Maybe I'll go back to Dr. Lenz. You know, you very eloquently laid out all the different ways of characterizing the disease and the kind of options there are. You did mention that, you know, while there are no approved agents for RAS other than the G12C targeting drug, you know, I do want to say, you know, 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? You know, when you, when these molecular diagnostics come out, you have patients who have RAS mutations, NRAS, KRAS, how do you manage them right now?
Depends in the absence or presence of clinical trials. Standard of care would be usually a backbone chemo with bevacizumab on, and the backbone chemo could be a FOLFOX or a FOLFIRI. In young patients where I want to be very aggressive, I use even a triplet to have higher response rate. In the presence 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 don't play a significant role, at least for now. We don't know what's going to happen. I always look, of course, for clinical trial involvement, beyond a standard of care. The standard of care would be chemotherapy backbone with bevacizumab.
What about you, Dr. Kopetz? Do you do anything different or it's pretty much?
That's the best we have. You know, if we look back now 15, 20 years, what would we do for a RAS mutated? That's kind of it, right?
Exactly.
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. Lots of opportunities here to really break the mold and improve outcomes.
I'm sure.
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, particularly 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 very 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. 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 effect efficacy in FOLFIRI-naive, move to first-line and validating all the data we have seen. You already are in first-line. The only thing you have to do the registration that we have this drug in our clinical setting available.
No. This is great. You know, 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. If there's a clinical trial available for this particular molecularly characterized patients that you would opt for it even in front line. Right? Is that a correct way of characterizing the RAS mutant patient management at this time?
It's pretty much.
Yeah.
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. 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. I don't think it will change very quickly. I think we need really, this is an unmet need, exactly what you said at the beginning, Mani. I think we need treatments for KRAS mutant in first line.
Okay. No. This is amazing. You know, even for me, every time I talk to the two of you, there is always a new learning. That's been very well put together, you know, from your perspective, just not the unmet need, but what's really out there as well. You know, maybe we go a little bit deeper, you know, 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? Maybe, you know, I just showed, like, the objective responses, PFS, hazard ratios.
Help us understand, like, you know, from your perspective, from a physician perspective, what do you think is clinically meaningful benefit for patients in front line? You know, what are you looking at? Is it the response rate? Is it the PFS? Just, you know, help us all understand that and then maybe contextualize to the kind of data I shared, you know, with onvansertib. I don't know who wants to go first.
Sure.
Dr. Kopetz can.
Yeah.
Yes.
No, happy to.
I will come back to you, Dr. Lenz, as well.
I don't feel offended. Okay?
No. It's so, you know, so what are we looking for? I think, you know, within the limitations, of course, small signal-seeking phase IIs, clearly looking for, you know, evidence of regressions, response rates. They tend to define activity, but, you know, the things that the regulators and as providers we're looking for is ultimately the kind of progression-free survival. We tend to be a little better at estimating response rate in small studies than we are progression-free survival, but we're looking at all 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. That's certainly the most important component.
I can only echo this. I think everyone wants to see tumor shrinkage. I think this is very important. The problem is we have seen with other drugs that there is tumor shrinkage, but it doesn't last. I think that is exactly what Scott was saying, is that you need to have tumor shrinkage, but you need to have that goes along with the PFS. 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. Tumor shrinkage can make a big difference because if you are converting an unresectable metastatic colon cancer into resectable, you have a chance of cure. Response rate is more important for colon cancer than for other cancers if this goes matching with the PFS.
I think we are talking about survival and progression-free survival, but we have seen patients being unresectable, being converted and be cured. You know, colon cancer, when it doesn't come back in five years, you're cured. You cannot say that to any other cancer. Breast cancer, you talk about survivors. In colon cancer, we talk about cures. We talk about the shoulder in our survival curve. That is a very important, and the depth of response will correlate with the chance of getting curative resection. I think response is very critical when it goes along with PFS. This is a home run.
You know, to that end, I didn't share the data today because this was meant to be a discussion, and we have put out publicly, you know, some anecdotes from patients, and you are obviously privy to that information as well, that we've had patients on our trials that have gone to a curative surgery. You know, an underappreciated fact, you know, we're a small company, but I do want to say that, you know, what you're saying, we've actually shown it even in this small study, right? Would you agree or not and, you know, have a couple things to say there? You know, we've debated, you know, 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.
You know, it'll 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 rate over 70%, hopefully you will do more and more patients leading to a curative resectability.
Yes. You know, response rate, depth of response, PFS, median PFS hasn't been reached. We continue to follow these patients. 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. Yeah. Maybe, you know, again, I do wanna make sure that this is not just about us, but also, you know, as a last topic from my side before I open for questions, is anything else you're seeing that you feel is promising for RAS mutated CRC, metastatic colorectal cancer in frontline? You know, anything that listeners on this call should also pay attention to.
Yeah. I mean, I think as Dr. Lenz mentioned, the kind of pan-RAS inhibitors just don't look like they're gonna 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 adaptive resistance that colorectal is so well known for. We certainly know that G12C, as Dr. Lenz mentioned, is, you know, a small wedge, 2%-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.
I think that's kind of a useful point from at least the Amgen perspective. The difficulty is that there's just not once we get past the, if we take the pan-RAS off the table, you know, even if we get, you know, in the future, perhaps maybe the G12D allele specifics may make their way forward. But again, these are, you know, we're cutting off little small wedges of the population. Colorectal cancer and KRAS in particular tends not to be driven by any one particular allele. There's a lot of RAS mutations in codon 13 and codon 61 and codon 146 that is, you know, a much broader repertoire. You know, really thinking about how do we attack the biology that's broad, I think is important.
You know, maybe we can make some headway in, you know, one or two of the allele-specific space, in parallel. I don't think those are mutually exclusive by any stretch of the imagination.
I wanted to mention a little bit on the development and, you know, one of the more promising new developments are the antibody conjugates. What do the antibody conjugates have as a payload? A topoisomerase inhibitor. Okay. What are the data showing with antibody conjugates path 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 desperately looking for ways to increase efficacy. It would be absolutely logical to think about an onvansertib in KRAS mutant. Also I think there are unique opportunities in the future, independent of the FOLFIRI path, this has to go anyway. I think this is not the end of the development, maybe only the beginning.
We published a paper, oh, God, a couple of years ago in Oncogene showing also the PLK1 signaling is associated with immune cell signaling and immune cell trafficking. I think this is not even explored. I think there may be very unique opportunities to further explore. If Scott has a lot of time, he can do that in his models. He has done so much work already. 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 know, you pretty much read my mind because that's where I was going with ADCs. You know, that's exactly the point. What do ADCs have? They are topoisomerase I inhibitors. You know, to that effect, I know I'm bringing something else, we are working at least in the company on the preclinical side to show the synergies there, you know, 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 tagged to an ADC. But that just tells you that, yes, we have much more than FOLFIRI, bev, to combine.
You know, even as the newer therapies emerge, there is a room for the benefit to be expanded with onvansertib, and plus the tolerability, you know. That's what I've been seeing consistently. You know, 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'd agree with that as well or not. Yeah.
Absolutely.
I think there are people we have waiting on the line, our analysts waiting on the line to have their questions being answered by the two experts that we have here. Operator, may I request you to open the line for Q&A, please?
Sure. As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. We ask that you please limit yourself to one question, one follow-up. One moment for our first question. Our first question is gonna come from the line of Maury Raycroft with Jefferies. Your line is open. Please go ahead.
Hi. Thanks for hosting this event and for taking my question. I'll ask a general one just to get the doctor's perspective. I always think about durability results we've seen so far from onvansertib compared to standard of care and other assets in development for frontline colorectal cancer.
Let me jump in.
Sure. Yeah.
If Scott can jump in, and Mani can jump in any time. The duration of response was in the phase II almost 12 months. That is extremely long. This is a second-line treatment. The PFS was 15 months. This really speaks to the potential duration of activity, that there is not an immediate mechanism for resistance evolving under the treatment where you combine FOLFIRI, bev, and onvansertib. 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 not reached duration of response. We just know that the progression-free survival over one year was over 50%, so we know it's more than 12 months.
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 of resistance which we see with other treatments. Scott, you can add anything what I missed.
Yeah. Maybe just one thing to mention is that, you know, when we're stress-testing the data and just taking a look at it, one is, like, how did the control arm perform, right? That was right around 11 months, so that's kind of expected, right? That's important. Then, you know, is there a dose response that was seen? Just like with the response rate, we saw a dose response trends. Again, small numbers, but, you know, this is how I look at it as like, "Oh, I see the PFS dose response as well." With the caveats of its early days, but the, you know, a PFS or a hazard ratio for PFS that's, you know, under 0.5 is very kind of encouraging given all those other components.
It is hard to cross-compare, but I will say, you know, there's not a ton out there that we've got phase II data in this population for. There really, even if we had a larger data set to compare to, there really is nothing out there to explore against.
Got it. Really helpful. Maybe just one follow-up on just how you think about guiding factors for choosing curative resection and what proportion of patients reaching curative intent surgery in a pivotal study would be clinically meaningful in a RAS mutant colorectal cancer population?
I don't think there are data to refer to, but I tell you the resectability and curative resections is a very soft endpoint because it depends how patient is selected, you know? Are there oligometastatic disease, or they have liver, lung, and bone lesions that will never be convertible. It depends really on the patient selection. We know the higher the response rate in this patient population, the higher is the resectability or conversion to a curative resection. If you can resect 10%-20% for curative resection, 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. 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.
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.
Got it. That's helpful. Thanks for taking my questions.
Sure.
Thank you. One moment, sir.
You know, before we go to the next question, you know, again, I sort of want to refer some of the people who are listening here to the slides that we have on our website. You know, Dr. Lenz, you mentioned that, you know, liver is a hard one, but we do have at least one patient that I'm aware of who had non-target lesions in liver and still went on curative surgery after being treated with onvansertib. So I just sort of wanted to put it out there. Yeah. Yes, please go ahead. Open the line for next question, operator.
One moment. Our next question will come from the line of Marc Frahm with TD Cowen. Your line is open. Please go ahead.
Hi. Thanks for taking my questions and thanks for hosting the session to the Cardiff team. Maybe for the physicians, I mean, completely appreciate your sentiment on the G12Cs only being a small sliver of RAS positive disease. Yeah, as you mentioned, there are a 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 these other mutant selective inhibitors, can you maybe put the data in the context that Cardiff is generating in the context of that G12C data and how it might fit in for that growing percentage. That will never become 100%, but is a potentially growing percentage of patients who may have a selective RAS inhibitor.
We don't have a lot of first-line data, right, to compare here with that. You know, the Amgen study is running for G12C. There's Merck for G12C. The G12Ds, you know, we're optimists by nature. We're hopeful that those will provide some benefit as well. You know, that's 10% or less there, right? It really won't get to that next level.
You know, you start to think about, like you said, it won't get to 100%, but not even sure that we're gonna get to like, you know, 25% of the KRASs that will be able to be covered here with these allele-specific ones, just given the difficulties here. You know, are you going to develop a drug for a, you know, a codon 146 mutation? No, right? I mean, this is kind of a diminishing return. Yeah, I guess kind of 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.
Let me also jump in. I go first, get clear with Scott. We almost always agree, not always, but okay. I think the choosing question is when you have a G12C inhibitor or mutation, do you use a G12C inhibitor with chemo or you do use onvansertib. In addition to the argument, it's only 3%, or. 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 G12C inhibitors, or at least preclinically or clinically. Even in this case, I'm not sure what will the winner be, you know. That would be very interesting to really show and demonstrate.
As mentioned, and Scott is right, this will be a very low subset, and the toxicity profile is also in favor for onvansertib. 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. Maybe just thinking broadly, you know, with that backbone of FOLFIRI, given the preference of some physicians, particularly in the U.S., to use 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?
Oncologists vote with their feet. If there is efficacy, they go for it. It doesn't matter what it is, okay? As long as you show superior efficacy, they will do what it takes to reach that. I'm not worried that the American oncologist will not choose FOLFIRI+BEV. I think, FOLFIRI has a lot of benefits with no accumulative toxicities. And whenever we have effective treatment, we will choose that. 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? 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.
I think all these arguments will go out of the window when you have an effective drug. There is no discussion anymore, so I'm not worried at all. I don't know if you are, Scott.
No, it's not. I mean, you know, FOLFOX backbone can't be used by patients who've had adjuvant FOLFOX, right? Or have neuropathy or other things, right? There's a proportion of patients who just aren't eligible for FOLFOX. You really don't have that problem with FOLFIRI, right? You know, if your approval is limited to a certain backbone, right? You'd much rather that backbone be FOLFIRI than it be FOLFOX, 'cause you're gonna get a larger population out of that. I think that's an important recognition, you know, to complement what Heinz just said.
If I may jump in, I know this is a question that we often face. You know, 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, you know, 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 or FOLFIRI. From what I hear, you know, you guys are data-driven, so if that works, then that's what it is. Yes, I don't wanna take everybody else's time. We are running out of time, please, operator, next question. Can we have the next question, please? Okay.
Since I don't hear anything from the operator, you know, I just thought about it when we were talking about G12C and 3%, 5%, whatever it is. Maybe help us end this session by giving us a sense of how large is this RAS mutant population, you know, pan-RAS, whatever you think. You know, 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?
Okay.
Yeah.
I don't want to go first every time. Scott?
No, you didn't. I did make sure I was going back and forth, but-
Okay.
Yes, you're spot on it. As you know, 50% is kind of a good rough rule of thumb. That includes KRAS as well as NRAS mutations, right? We don't see as many NRAS in lung or pancreas, but it's a significant number, you know, there within kind of colorectal cancer. Collectively, we can think about this as about half of the population there as well. You know, of which, 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. There's, you know, a huge group of patients and a big unmet need for sure.
Yes. By targetable, you mean targetable by RAS-specific-
The allele-specific, right?
Specific inhibitors.
To the questions that were there before.
Yes. Yes.
If we say the G12Cs and the Ds, there.
Yes. Yes, onvansertib, you know, of course, it doesn't matter what the mutation is, given the mechanism of synthetic lethality with RAS mutations in general.
Right. Works in KRAS and NRAS, right?
Yes. KRAS and it.
That's-
Yeah
...important.
Yes. Our current trial that we're discussing did obviously have patients with the inclusion criteria included all of them. Yes. Well, I don't see any further questions online, and I think we've come right on time. You know, I would firstly like to really thank the two of 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. 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.
I certainly want to thank all the patients who have participated in our current trial and our past trials and have truly co-contributed immensely to our learning of how to start using this drug in this disease. Thank you again. It's been a pleasure. Yeah.
I would never say no to Scott when he participates. It was fun to talk to him and to you. Thank you very much for inviting us.
Likewise. Yes.
Yeah.
Thanks so much.
Thank you.
Okay.
With that, we can end the call. Thank you everyone online.
Thank you so much. Bye, guys.
Bye.