Good afternoon, everyone, and welcome back to Oppenheimer's 36th Annual Healthcare Conference. I am delighted to welcome Mani Mohindru, the Chief Executive Officer of Cardiff Oncology, to take us through the story. Mani, welcome, and look forward to hearing the latest on Cardiff. I'll hand it over.
Thank you. Thank you, Jeff. Good morning from the sunny San Diego area, and good afternoon to people on the East Coast and wherever else you are. I would like to begin by first thanking the Oppenheimer team, to give us the opportunity to be here and talk about our company, give you a little bit of an overview of what Cardiff is, and the kind of opportunity that our lead program onvansertib presents. Okay. I just want to make sure I have the pointer on. Moving on, I will be making forward-looking statements, so just putting it out there during the course of this presentation. I want to just give you a broad overview of the value proposition we present in a high-value oncology market.
Our lead program is a very highly selective PLK1 inhibitor, which has blockbuster potential in first-line RAS mutated metastatic colorectal cancer, a disease area with very high unmet need and not much happening for the past several decades, couple decades at least. This is our molecule onvansertib. It is an oral, highly selective PLK1 inhibitors, and I say this because prior attempts at targeting this molecule haven't been successful, given the lack of selectivity, which resulted in toxicity. We believe our molecule is highly selective, as you can see from our tox profile in the subsequent slides. What is this? A PLK1 is an enzyme that is a key signaling target, which impacts tumor cell division, a DNA repair mechanism.
It is also involved in angiogenesis, which is required for these cancer cells to grow and survive. Targeting this can potentially impact cancer growth in multiple ways. Hopefully, in the next few slides, I will show what we believe is a strong efficacy signal in first-line RAS mutated metastatic colorectal cancer patients in the two studies that we've done. Importantly, in our intent-to-treat analysis, recently, you know, we released some data. The trial is still ongoing from our phase II study. We have shown a confirmed overall response rate of 72% with the higher dose of onvansertib when combined with FOLFIRI and bevacizumab arm, which represents approximately 30% improvement with the FOLFIRI/bev standard of care arm, which is pretty compelling in our view.
You know, we have shared some metrics of durability of response, where median progression-free survival has yet not reached in the onvansertib arm, but we have that for the standard of care arm, very similar to what has been reported favorably. We have favorable dose-dependent trends, and PFS hazard ratios for the two doses that we studied in this Phase II study that's still ongoing, in combination with FOLFIRI/bev, which is one of the standard of care in this setting. We believe, you know, we have practice-changing potential in onvansertib, especially in underserved populations like frontline RAS-mutated mCRC. Not just there, we, hopefully, will be able to expand the utility of this drug candidate beyond in other RAS-mutated cancers or RAS-driven cancers, such as chronic myelomonocytic leukemia.
We have some data from our investigator-initiated study, where it was studied in monotherapy. I'll have a slide that shares the top line from there. In the near term, we think we are getting to finalizing a path to registration in frontline RAS-mutated mCRC, having a belief that, you know, 30 milligram onvansertib in combination with FOLFIRI, bev should be the one that we want to take forward in the registrational study, and we will be finalizing that very soon after meeting with the regulators, the US FDA, and provide you with a feedback and full plan within this first half of this year.
Before I go further, I just want to give you a sense of the colorectal cancer market, and especially in the RAS-mutated, you know, setting. You know, this is the third most common cancer type worldwide, approximately 150,000 new cases each year, with deaths that actually the latest numbers go beyond 55,000, you know, expected deaths in 2027. It's a little bit even higher than this. Very, very bad outcomes, you know, for patients with metastatic colorectal cancer. The five-year survival continues to be very poor, 15%, with less than 12 months of median PFS. If you look at the standard of care in first line, it has pretty much remained the same, you know, combination of chemo with bevacizumab and anti-VEGF.
You know, with the choice of chemo is FOLFOX, FOLFIRI, predominantly the doublet chemo, with some patients who have very good ECOG status, they or younger patients can also get a triplet FOLFIRINOX. This really hasn't changed. The other point that I want to make is there isn't any drug truly approved for RAS mutated mCRC at all. This continues to be for the entire population of these patients. Putting into context, what is the proportion of patients who have RAS mutations in mCRC, NRAS and KRAS? You know, approximately 150,000 patients diagnosed, around 20% present with metastatic disease, and almost half of these patients have RAS mutations.
You know, while there is some development happening in allele-specific or mutation-specific inhibitors, a large proportion of these patients really don't have any approved therapies or any therapies that we know in development. This slide just gives you puts things into perspective. What is the competitive landscape in RAS-mutated frontline? I've heard this message enough. This continues to be the standard of care for the past couple decades. We believe onvansertib is the only program that is specifically designed for the entire RAS-mutated population. There are some specific mutation-specific compounds that are being studied. For non-MSI-high, and all of these are non-MSI-high because MSI-high population, which is a very small fragment of these patient populations, are being treated by PD-1.
In non-MSI-high, people are now looking at either the PD-1 VEGF bispecifics with chemo or PD-1 with chemo and Bev to see if they can provide benefit based on some promising data from very small studies coming out of China. Moving over to our program, onvansertib, we believe its mechanism, the way the drug acts, lends itself very well into KRAS-mutated metastatic colorectal cancer. Our first attempt to look at the benefit of this drug was in second line, where we started that study based on two known mechanisms, you know, the synthetic lethality in RAS mutant background, because these patients, or these tumors with RAS-mutated cancer are hypersensitive to PLK one inhibition.
Secondly, you know, there is known synergy with chemo, you know, because onvansertib or PLK1 inhibitor can actually enhance chemo-induced damage done to these DNA damage in the setting. By inhibiting PLK, you really shut down some of the repair mechanisms that the cancer cells take to escape chemo. This is what our first trial in metastatic colorectal cancer looked like. It was a phase Ib/II study, where we studied onvansertib in combination with FOLFIRI Bev, which is the regimen used predominantly in the U.S. in this setting. Second-line patients were enrolled with KRAS mutant disease, all of whom had unresectable disease.
It was around a 68%, 68-patient study, with the primary endpoint being ORR by RECIST and secondary endpoints looking at durability by duration of response or progression-free survival. The drug, study drug, onvansertib, is dosed on days one through five, and then again from dose 50, days 15 through 19 in a 28-day cycle, along with the chemo and bev regimen. This slide just gives the high-level ORR data that we saw from this prior study in second-line bev-naïve patient, second-line patients. Two things I want to highlight. This is a post-hoc analysis, but what we found was patients in the second line who had not previously been exposed to bev or treated with Avastin with chemo showed the most benefit, and this is here.
In this particular subset of patients, we saw an overall response rate of 73%, and the median duration of response, that was 13%. On the other hand, the typical second-line population that had seen bev in the first line, or the so-called bev-exposed patient population, we did not see as robust a response, with only 16% overall response rate and median duration of response being eight point nine months, which is very comparable to what has been previously reported in other studies. Importantly, when we looked at the bev-naive patients and compared them to patients who had been previously exposed to bev, we found that the median progression-free survival was quite markedly improved, 15 months versus 7.8 in patients who were previously exposed to bev in first line.
This was very compelling data that led us to actually not just, you know, focus on the combination with chemo, but also to figure out that there was something going on in combination with bev, or bevacizumab, in patients who had previously not seen bev. Then again, we did some preclinical work in-house, and what we found that in addition to the synthetic lethality in RAS mutant background, as well as synergy with chemo, there was also synergy of onvansertib, our PLK1 inhibitor, with bevacizumab, and had. This was related to the anti-angiogenic effects of onvansertib. We wanted to take it forward, you know, the lessons learned from our first metastatic colorectal cancer study, and that led to actually our current study that is ongoing, the phase II study.
which was supported obviously by data from our phase Ib/II and, you know, preclinical research showing the combination effect on anti-angiogenesis. Before I actually discuss the data, I do want to sort of level set what the current first-line treatment options are for patients and what kind of data exists as of this time. These are data from the phase III studies. None of them had prospectively been designed to study RAS-mutated, you know, mCRC, they were patients who had been enrolled who had RAS-mutated status. In the first, row, you see when bevacizumab was first added to chemo regimens, you know, having added an anti-angiogenic chemo regimen to either wild-type or mutated mCRC patients, you found that even though chemo.
even though bev didn't add much on the ORR side, it did improve PFS in this difficult-to-treat patient population. Also, you know, even in the entire patient group, including wild type at mutations, again, the ORR benefit of bev was modest. It did improve PFS, and that's why it became the current standard of care. There's another study where this bevacizumab was studied in context with the triplet, and here again, you know, it did improve both ORR modestly, but did provide benefit on the PFS side. With that, I will go into the phase II design, the study that was conducted by us and is still ongoing, where we randomized 110 patients in the frontline CRC setting after discussion with the FDA.
We enrolled patients who had both KRAS and NRAS mutations, so all inclusive of RAS mutations, had unresectable metastatic disease, and obviously, since they are frontline patients, they had not seen bev previously. Our endpoints were ORR, a primary endpoint of overall response rate, second secondary endpoints of durability or duration of response PFS. Patients were actually randomized to six different arms. The intent was to see standard of care alone versus two different doses of onvansertib, to be given with either of the two current standard of care regimens. The drug was dosed as previously on days one-five, and then again, days 15-19 of a 28-day cycle with these chemo and bev regimens. This slide just captures the baseline demographics. Nothing unusual here, very typical of what you would see in this patient population.
One other thing I wanted to point out was we did have patients who had liver mets as well. These are patients with, like, much more aggressive disease and poor outcomes. We did include patients, you know, who had liver mets, which is a difficult-to-treat patient population. These are some of the top-line data that we had shared previously, end of January. Want to just go through this again. This is in frontline, where onvansertib was given with FOLFIRI, two different doses of onvansertib, 20 and 30 milligram.
When we looked at the 20 and 30 milligram given with FOLFIRI bev and compared it to standard of care, either the combined standard of care or the standard of care of FOLFIRI bev, what we saw was that we, again, like what we had seen in our second-line study, we got over 70% of objective responses. These are confirmed ORRs, so 72.2% of the patients in the onvansertib 30 milligram with FOLFIRI and bev had a response, versus, if you look at the combined standard of care of 43.2% ORR or FOLFIRI bev standard of care of 42.1. While the response in the 20 milligram arm was not as robust as the 30 milligram, in addition to ORR, what we did find that onvansertib actually, patients who had onvansertib had deeper responses.
The depth of responses was much more than when you look at the two standard of cares, either combined or individually. These depth of responses actually translate to durability of responses in this setting. This slide actually shares some data talking about durability, which was also shared late January this year. Again, to orient you, two different doses of onvansertib combined with FOLFIRI bev, around 18 patients per arm, and here it's being compared with FOLFIRI bev standard of care. The median progression-free survival was reached with FOLFIRI bev, which is around 11 months. The two onvansertib arms, the 20 and 30 milligram, have yet not reached median PFS, and we are continuing to follow these patients as the study is still ongoing.
Importantly, if you look at the hazard ratios, the PFS hazard ratios, they show pretty good, you know, trends of durable and deeper responses in these patients exposed to onvansertib versus FOLFIRI alone. Hazard ratios are a reflection of, you know, risk reduction by the treatment arm when compared to the comparator arm, in which case this is FOLFIRI-bev. We compared the PFS hazard ratios, not just with FOLFIRI-bev, but also with combined standard of care. This is important because, you know, patients currently get both FOLFIRI and FOLFOX in the frontline setting, and we really wanted to make sure is onvansertib adding benefit on top of FOLFIRI versus the combined standard of care.
We were actually convinced that this activity that we see is real, and in the case of combined standard of care comparison with a 30-milligram arm, we were even able to reach statistical significance with p-value less than 0.05. These are some other landmark data. You know, if PFS at six months, PFS rate at six months, again, you see a dose-dependent benefit, you know, with the onvansertib added to FOLFIRI. Both looking at ORR as well as PFS, we do see dose-dependent improvements. Here, you know, just a few anecdotes. There were a couple of patients on the 30-milligram arm who actually went on to curative surgery as well.
Side effects, I think one of the most differentiated features we have with onvansertib, and this is from the July data cut, because we have not shared the latest data cut, but it's very similar. It's completely unremarkable. You really can't tell the difference of once onvansertib is added to any of these different, you know, side effect profiles that you see with the regular chemo. I know this is a busy slide, but you can take a look. Nothing remarkable here at all to report. No additive toxicities. This just summarize what I've already shown, the benefit of 72% with 30 milligram combined with FOLFIRI on the ORR side, and median PFS continues to remain promising. We will follow it.
Hazard ratios show that the drug indeed looks quite, you know, the efficacy is robust, reaching even statistical significance when we compare it to the current standard of care. Based on these data, we believe 30 milligram is the best dose to take forward. No significant toxicity here. This slide actually is a repeat of a previous slide, but with added onvansertib data, so you can compare what is currently available to the patients and how, While acknowledging it was a small study, but we believe that the data through multiple measures, the totality of the data at ORR, PFS, hazard ratios, shows that the drug indeed appears to have significant clinical benefit versus the standard of care.
You can look at it like, you know, our standard of care arms behaved very similarly to what has been previously reported. This is just to, you know, give some rationale why we believe our drug is acting. You know, this is also supported by some of our internal work, where, you know, it is already known, like FOLFIRI, it is a topoisomerase. irinotecan is a topoisomerase 1 inhibitor, lowers HIF-1 alpha level, and provides some anti-angiogenic benefit. Similarly, if you inhibit PLK1 with our drug, it also lowers it HIF-1 alpha, providing another shot of anti-angiogenic response, and in combination with bev, all three, like three punches to inhibit angiogenesis and have a beneficial effect in these patients.
This study, sort of, reiterated what we had seen in second line, and that's why we are very optimistic that we should be able to replicate some of these findings in the next registrational trial that we are very excited to put in place. Before I talk about the registrational trial, we hope to give more detailed data later this year. We are also in the midst of planning our discussions with the regulators. Hopefully, within first half of 2026, we should be able to share more data and provide regulatory feedback of next steps. As of now, this is sort of how we are thinking about our phase III design, taking 30 milligram onvansertib forward with FOLFIRI-bev and going after both standard of cares.
Of course, this needs to be finalized with the regulators. This is a little bit more detailed representation of what we believe at this time our phase III could look like, and we'll get the final blessings from the FDA, hopefully, the next few months. First-line CRC patients with both KRAS and RAS mutations, acceptable, unresectable metastatic disease, we will see if we can even have a potential for Accelerated Approval or full approval all built into the same study. These are our endpoints of ORR and PFS to all primary endpoints with more measures of durability included in the secondary endpoints. We hope to go after the current standard of care based on investigator's choice.
This will be a global study, so we should be able to enroll this study fairly well. Of course, all this is pending FDA discussions that we also hope to have very soon. Just a very quick word, you know, Pfizer has been an amazing CRO partner, which has been executing the trial for us. The study was conducted with Pfizer acting as our CRO partner as part of the Breakthrough Growth Initiative that was put in place a couple of years ago with Pfizer. They had also made a $15 million investment.
However, Cardiff, at this time, retains full rights to the program with you know, we do have some obligations to show some data in a timely manner to them, but we still retain full ownership and control of the program. Beyond metastatic CRC, we also feel, since I said that this drug has very limited toxicity, can be combined well with chemo, has effects on DNA repair mechanisms, so it has the potential to be combined with other chemo regimens as well. We are, as part of our Investigator-Initiated Studies, are looking into multiple programs. One specific one I want to highlight is CMML, where we have seen single-agent activity. This is an Investigator-Initiated Study being conducted at Mayo Clinic, Rochester. We have seen single-agent activity.
Data from this was presented at ASH of 2023 in December. you know, a very bad disease with no approved drugs in relapsed refractory, with very bad prognosis, so, and an orphan designation. wanted to sort of share as we think about prioritizing our program beyond metastatic colorectal cancer. What to look forward to? We have a very busy year ahead of us. Within the first half, we'll be sharing more detailed data from our phase II study that is ongoing, and also our registrational feedback as well as, you know, our discussions with the FDA and our full phase III trial design. our second half would be spent, you know, putting our phase III plans into action.
We will also continue to look at other indications for potentially taking onvansertib forward, you know, with signals coming from some of these ongoing IITs. I would like to end by just giving a very brief snapshot of our cash position. We just reported our earnings yesterday, $58.3 million in cash equivalents. That will be sufficient to take us into the Q1 of 2027. With that, I will end here. How are we doing with time, Jeff?
We've got a few. I think we've got four minutes, so time for just a couple of questions. Obviously, a big data update recently, with year-end results yesterday in terms of cash. Just in terms of that one Q-27, runway estimate, what are the assumptions in there? Does that include the potential start of the trial or just trial prep?
Yes. The current cash guidance does not include any significant investment into the phase III study. This is, you know, of course, we have our ongoing study and other activities in the company, but does not include any significant investment there.
Okay. I know when you reported the data just a couple of weeks ago now, I know I was in your offices a day or two later. I guess there's some head-scratching around the objective response rate versus the hazard ratios on the PFS. Obviously, you haven't reached medium PFS in at least one of the arms yet. As we think about this from a time perspective versus hazard ratios, where do you think you need to be in terms of additional PFS benefit over the FOLFIRI or FOLFOX+ bev arm to provide a clinically meaningful benefit versus a statistical benefit? What does that number look like in your mind to drive, both from a regulatory perspective as well as a clinician perspective, interest in this?
begin by saying that, you know, you have to look at the data in totality. You know, looking at the objective response rates, you know, this was an intent-to-treat analysis, so we counted every patient who got enrolled. Looking at the ORR, we have reported confirmed ORRs. The benefit in durability as measured by both PFS, hazard ratios, duration of response, which we haven't reported, but also, you know, like looking at the depth of responses that we see.
Mm-hmm.
Also the dose-dependent manner of looking at the efficacy benefits. If you look at the totality of the data, this being a small study, wasn't designed, didn't have the statistical power to look at every metric of clinical benefit individually. We believe based on the totality of the data, you know, looking at this robust response rate with depth of responses, combining it with the hazard ratio that we have in hand right now, it is pretty compelling to have discussions with the FDA. We really don't need to wait for the full PFS data to mature in the treatment arms. Yes, we have not reached median PFS in both the 20 milligram onvansertib or 30 milligram onvansertib arm, but our control arm behaves the way it is behaving.
We will obviously continue to monitor PFS, but to have regulatory discussions based on the totality of the data, and we really haven't shared, you know, exposure-response relationship. You know, there is dose-response relationship. We have a lot of data that hopefully we should be able to share, you know, in the next few months, that we feel like, you know, we're ready to convince the regulators that we really do see clinically meaningful benefit. I also say this, having discussions with both US and ex-US, European KOLs.
You know, they've some of them have looked at these complete data very carefully, and they believe that the small study, while not powered for everything, has shown us enough data to suggest that it shows the potential for having meaningful clinical benefit and is ready to be taken into phase III. So I do want to mention that. Yeah, so that's why we are going, while we continue to gather PFS data and report as soon as we believe we are ready to report.
Okay, wonderful. Well, I think we are up on time. Thank you very much for the presentation. I hope you have some very productive discussions with investors this afternoon. Operator, you can take us clear.
Thank you, Jeff, I am joined by my team of CSO, CMO, and Chief Accounting Officer today, it's been productive so far. Thank you. Thanks for the invitation. Bye.