Cardiff Oncology, Inc. (CRDF) Earnings Call Transcript & Summary

Good afternoon, and welcome to the Cardiff Oncology Data Presentation Webinar. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Cardiff Oncology website following the conclusion of the event. Before we go further, I'd like to remind all listening that certain statements in this presentation are forward-looking within the meaning of the Private Litigation Reform Act of 1995 as disclosed in this slide. There are a number of factors that could cause actual events to differ materially from those indicated by such forward-looking statements, and investors should read the risk factors set forth in Cardiff Oncology's Form 8-K for the year-end December 31, 2020, and other periodic reports filed with the Securities and Exchange Commission. While the list of factors presented here is considered representative, no such list should be considered to be a complete statement of all potential risks and uncertainties. Unlisted factors may present significant additional obstacles to the realization of forward-looking statements. Forward-looking statements included herein are made as of the date hereof, and Cardiff Oncology does not undertake any obligation to update publicly such statements to reflect subsequent events or circumstances. With that, I'd like to introduce Dr. Mark Erlander, Chief Executive Officer of Cardiff Oncology. Mark?

Thank you, Sarah, and welcome, everyone, to today's KOL event. During the event, we will be announcing some exciting new data from our ongoing Phase Ib/II trial evaluating onvansertib in combination with FOLFIRI and bevacizumab with a second-line treatment of KRAS-mutated metastatic colorectal cancer. These data are also summarized in the press release issued earlier today and can be found on the Investors section of our website. We will be discussing the current treatment landscape and our data with 2 important thought leaders in the field of colorectal carcinoma. First, Dr. Afsaneh Barzi of the City of Hope Comprehensive Cancer Center will discuss the need for new therapeutic options for KRAS-mutant metastatic colorectal cancer. Afterwards, Dr. Heinz-Josef Lenz of the USC Norris Comprehensive Cancer Center and the principal investigator for this trial will present the updated data from the Phase Ib/II clinical trial. I will then return after the KOL presentation to provide additional Cardiff Oncology context on the data we are releasing today and our broader development program we are advancing at Cardiff Oncology. Finally, we will open the floor for questions that could be submitted in writing via the process described by Sarah a few moments ago. And now, I will hand things over to Cardiff Oncology's Chief Medical Officer, Dr. Katherine Ruffner, to introduce herself and our KOL presenters.

Thank you, Mark. For those of you who don't know me, I joined Cardiff as a Chief Medical Officer on July 6th of this year. Prior to coming on board here at Cardiff, I was the Vice President of Clinical Development at ALX Oncology, and also previously worked in clinical development at CTI BioPharma, Seagen, Medivation, Array BioPharma, Pfizer, Biogen Idec and Amgen. In my past roles, I contributed to the filing packages of multiple approved agents, as you can see on this slide. And one of the key factors that drove my decision to join Cardiff Oncology was the strength of the Company's clinical data. These data are even stronger with the update we're presenting today, and we look forward to discussing them with you and our key opinion leaders. Next slide, please. So, I'd now like to introduce our first key opinion leader, Dr. Afsaneh Barzi of the City of Hope Comprehensive Cancer Center. Dr. Barzi is a key clinical adviser to Cardiff Oncology and currently serves as an associate professor for GI Oncology at City of Hope and Clinical Director of the AccessHope Program at City of Hope. Her research and practice are focused on gastrointestinal malignancies with an emphasis on colorectal cancers, as well as the use of biomarkers for personalized care. We are very thankful that she is able to join us today. Dr. Barzi, please go ahead.

Thank you, Dr. Ruffner, for the introduction, and thank you, everybody, for joining. In the next few minutes, we'll be discussing KRAS-mutated colorectal cancer, which remains an area of unmet need and a need for new therapeutic options. Next slide, please. The objective of this discussion is to discuss the clinical burden of the KRAS-mutated colorectal cancer, review ongoing areas of clinical development and their limitations, and finally, highlight the opportunity for onvansertib in KRAS-mutated CRC. Next slide. Now, mutated KRAS is a negative biomarker. What that means is it helps preventing given inappropriate treatment to patients with KRAS-mutated. Most biomarkers, if they're present, they're associated with benefit from a drug. An example is BRAF mutation in colorectal cancer is associated with treatment of -- with encorafenib in combination with other agents. However, presence of KRAS is not associated with benefit of any targeted drug that we know of today, at least in colorectal space, rather it is used to select the appropriate use of EGFR antibodies in this patient population. The graph on the right highlights the rationale for this with the EGF receptors on the cell surface interacting with the ligand and the interaction with the ligand activating the KRAS pathway, with the blocking of the cetuximab of the EGF receptor, the KRAS pathway will not be activated. And if KRAS is mutated, the red signal in the C panel, then there is no need for interaction with the EGF receptor and the pathway continues with the intracellular actions and oncogenesis. Next slide. Now, KRAS mutation is highly prevalent in colorectal cancer. If we think about 50,000 patients who are treated for metastatic disease per year in the US, and we think about the lifetime of these patients of 2 to 3 years, and we look at the biomarker in this patient population with 45% of this patient population carrying some form of KRAS mutation that highlights the importance of this mutation for this patient population. Next slide. Now, as I mentioned, there is no targeted therapy available for KRAS-mutated CRC in the colorectal space. And the treatment includes chemotherapy, either doublet or triplet chemotherapy in combination with bevacizumab in the first-line setting, and doublet chemotherapy with bevacizumab in the second-line setting, followed by Regorafenib/TAS-102 in the third and fourth-line setting. First-line therapy is usually the most effective and the longest duration of disease controlled for this disease. Second-line therapy remains effective, but less effective than first line. Next slide, please. KRAS mutation is also a negative prognostic indicator. What that means is beyond KRAS allowing us to choose the appropriate treatment for this patient population, its presence predicts a poorer survival for the patients. In a pooled analysis of German oncology trial, 1,200 patients were included with roughly a third of them having KRAS mutation. This pooled analysis showed that those who carry KRAS mutation as opposed to those with KRAS wild type are 40% higher likelihood of death with a significant p-value. Now, in a second meta-analysis of all of those patients who received bevacizumab containing regimen, similar results were identified. Out of 2,266 patients with 54% of them having KRAS wild type, KRAS wild type was associated with better survival with 35% lower likelihood of death as compared to KRAS mutation. The importance of this result is we need to develop drugs to target KRAS. And when we look at the results, we have to interpret the results with the caveat of this negative prognostic market in comparison to the KRAS wild type patients. Next slide, please. Now, as KRAS is very common and colorectal cancer is common, how come we don't have any drug that targets this pathway? While unfortunately, targeting KRAS has proven to be very challenging. Direct targeting of KRAS is really not feasible, because KRAS has a very high affinity for GTP, which is its activation mechanism. The only exception is G12C, which because of its conformational change allows for inhibition of G12C with direct inhibitors. And Amgen drug sotorasib has already an approval in the lung cancer space. Other efforts for KRAS inhibition, such as farnesyl transferase which gets larger with KRAS from the cell surface, has failed because of presence of redundant pathways. And most of the current effort is focused on downstream pathways such as MEK inhibition or combination of MEK, PI3K, AKT and other pathways. Next slide, please. Now, I mentioned that G12C is the only KRAS mutation that has a direct inhibitor. However, KRAS mutation in colorectal cancer is very heterogeneous and G12C is only a small population among the KRAS-mutated CRC. The 3 most common mutations are G12D, G12V and G13D. Next slide, please. Now even when we look at the G12C population among the colorectal cancer, and we compare them to non-small cell lung cancer population, we see a difference. In the sotorasib study, among the patients with non-small cell lung cancer, the response rate was 32%. Same mutation, G12C colorectal population response rate was 7%. So although it's the same mutation and it's the same drug, the colorectal cancer population stands out to be different. Next slide, please. While we may not know the reason behind the difference between colorectal and non-small cell lung cancer, a study by Amodio and colleagues highlights a potential mechanism for overcoming the resistant to G12C mechanism in colorectal cancer. In these graphs, in the PDX models, they looked at the effect of G12C inhibitor, AMG 510 for tumor shrinkage. And they show that the drug by itself has a modest effect and so does cetuximab, basically a minimal effect. However, when the 2 agents are combined with each other, then you see a synergistic and significant effect. In other words, for colorectal cancer, combination therapy is needed, and that is the rationale behind an ongoing Phase III study that is looking at MRTX849, which is Mirati G12C inhibitor plus cetuximab in patients with G12C mutated colored cancer. This study is designed to be in the second-line setting and only dedicated to patients with G12C who never received any other G12C throughout their course of treatment. Next slide, please. Now, other therapeutic efforts for targeting KRAS includes cell therapy. A case report that was published in New England Journal of Medicine in 2016 highlighted the fact that cell therapy can actually provide a mechanism for appropriate treatment of a patient who had G12D mutation. This prompted further efforts and in a study that's going on at NCI, which is looking at administering peripheral leukocytes that are sensitized for G12D. But this study is only for patients who have certain HLA type. And this HLA type is unfortunately rare in the US population. It's very common in East Asia. Next slide. Now, we can go after the KRAS one-by-one and design a strategy to target each one of them differently or we can think about a strategy that would basically broadly cover all different kinds of KRAS mutation. SOS1 inhibitors are designed to affect all KRAS mutation. SOS is the mechanism for basically activating the KRAS and making it a GTP form and is currently being evaluated in solid tumors. If you look at the design of the trial, the trial that's looking at the colorectal cancer is, in fact, looking at the combination with Irinotecan, and that is all for the reason that single agent drugs are believed to not be adequate and effective enough in the colorectal population. Next slide, please. Now, I also mentioned that other efforts for KRAS pathway is to look at the downstream effects and MEK inhibitors are being explored in this space. Here is the data from trametinib that is looked at a single agent in multiple different tumor types, and the Graph C highlights the difference of colorectal cancer with other tumor types. Responses observed in patients with non-small cell lung cancer, in patients with pancreatic cancer, unfortunately, colorectal cancer patients have not achieved any response with MEK inhibitor trametinib. Next slide. Now, the challenge of MEK inhibitor, in this case, trametinib is their toxicity. These are very toxic drug. And although the most common toxicity of the drugs are skin reaction, diarrhea and fatigue, they are associated with significant organ toxicities, including ocular toxicities and cardiac toxicities that are very significant and severe. Next slide, please. The toxicity of MEK inhibitor is a class toxicity, and this is a different MEK inhibitor with similar toxicity profile. Next slide. Now, even MEK inhibitors by themselves are not adequate and looking at the combination, maybe a mechanism for allowing the colorectal cancer to see the benefit of these treatments. In this paper published in Cancer Cell in 2014 shows that the activation of CRAF may be a mechanism for lack of benefits from MEK inhibitors in KRAS-mutated tumors. Next slide. Now, so far, we reviewed the developments that are ongoing for KRAS-mutated colorectal cancer, and let's talk about onvansertib, which is a PLK1 inhibitor that is attributing or is contributing to the survival of the cell by facilitating the DNA repair. If you think about the topoisomerase inhibitors, such as irinotecan, they create a double-strand DNA break that then requires repair. PLK is recruited at the broken fork to promote the DNA repair and it facilitates the recruitment of RAD51 and BRCA1, both of which are homologous recombination repair mechanisms. Therefore, if PLK function is inhibited in this case with onvansertib, it breaks the potential for DNA repair and improves the chances for apoptosis and efficacy of irinotecan and in fact, efficacy in the space of colorectal cancer. Next slide. Beyond that, PLK collaborates with CRAF, which is a MEK/ERK-independent mechanism of KRAS and promotes the collaboration between PLK and CRAF, promotes the mitosis and tumor progression. Therefore, PLK inhibition via onvansertib shuts down the KRAS-activated CRAF and provides an additional mechanism for benefit in the KRAS-mutated population. Next slide, please. In conclusion, we discussed that drug development for KRAS-mutated cancer remains challenging. For colorectal cancer, especially challenging. And it looks like KRAS alone would not be adequate for colorectal cancer and combination therapy would be needed. We briefly discussed that onvansertib is a PLK1 inhibitor that impairs DNA repair and additionally impairs the KRAS downstream activity to CRAF. The combination of onvansertib and irinotecan is being tested in a second-line therapy. This provides a very rational approach, because irinotecan is a standard-of-care in the second-line therapy, and onvansertib you only adds to that therapy. More than 90 patients are treated with the combination of onvansertib and irinotecan, and the regimen remains safe with really 10% severe events. And response rate and duration of response in this population is very impressive and seen across most common KRAS subtypes that are observed in CRC. With this introduction, I'll pass on the microphone to Dr. Heinz-Josef Lenz to review the data with regards to the ongoing trial.

Thank you, Dr. Barzi. I believe I'm going to introduce Dr. Lenz for us. So, I'd like to now introduce our second key opinion leader, Dr. Heinz-Josef Lenz of the USC Norris Comprehensive Cancer Center and the current Principal Investigator for the Colorectal Carcinoma Trial. As you can see here, Dr. Lenz is also the Associate Director for Clinical Research and Co-leader of the GI Cancers Program at the University of Southern California Norris Comprehensive Cancer Center, as well as a Professor of Medicine and Preventive Medicine, Section Head of Gastrointestinal Oncology in the Division of Medical Oncology, and Co-Director of the Colorectal Center at the Keck School of Medicine of the University of Southern California. We are very pleased that he is joining us here today. Dr. Lenz, please go ahead.

So, thank you very much, Dr. Barzi and Dr. Ruffner, for setting the stage that I have now the opportunity to really share with you our clinical data on the Phase I -- Phase II combination of FOLFIRI, bevacizumab and onvansertib. Next slide. You heard very elegantly presented from Dr. Barzi, the mechanism of action and the importance of Polokinase-1 downstream of KRAS mutations and that this downstream effect is not dependent on specific KRAS mutation, but all KRAS mutations. Based on preclinical models, it was clear that there was in synthetic lethality studies that inhibition of PLkinase-1, you have significant synergism with chemotherapeutic agents such as irinotecan and bevacizumab. Now, the irinotecan makes a lot of sense because it leads to DNA strand breakage and you need DNA repair, which is closely linked to the activity of PLK1. Bevacizumab, we don't know for sure what the interaction between angiogenic pathways and DNA repair is, but we have seen in other clinical studies and molecular characterization that PLK1 is directly also linked to immune pathways and tumor microenvironmental changes, which would, of course, include angiogenesis. So, here in the study, you clearly see the synergistic effect of onvansertib and irinotecan on the left and with 5-FU on the right, as well as data which are not shown this angiogenesis. Next one. So, the clinical trial design, which was based on preclinical and early clinical studies, we decided that patients who failed FOLFOX bevacizumab were treated with irinotecan, 5-FU and bevacizumab, the treatment regimen you see in the schedule that onvansertib was given already the first 5 days. The primary endpoint of the Phase Ib was the safety, particularly the characterization of the dose-limiting toxicity. And in the Phase II part, the primary endpoint was objective response rate. We also included secondary endpoints which show progression-free survival as well as to better understand can we measure the KRAS mutation allele frequency in liquid biopsy as a potential marker for efficacy. The key eligibility criteria are shown below, which are usually standard for second-line treatments. Next one. You can see here in the table that in the Phase Ib, the 3 dose levels were done with 18 and 27 patients were involved in the Phase II study. You can see in the lower one, the ones who are still ongoing being treated. The characteristic you can see on the left-hand side showing the median age was 58, about 50-50 male and female; the majority had an ECOG of 0; a third where right sided; the rest were left side or rectum. The most common site of metastasis was liver, including with other metastatic sites. You can see 70% have more than 2 metastatic organs involved and 2-thirds had prior treatment with bevacizumab. Next one. You see here the safety and toxicity profile of the 45 patients, including the 27 in Phase II and the 18 in the Phase I part. You can see overall very well tolerated. 8 patients out of the 45 had Grade4 adverse events, predominantly, as you can see, neutropenia, neutropenic fever with one patient. Of course, decreased WBC is also neutropenia. But the other most common side effect, you can recognize is fatigue, which is well established for this treatment, including the onvansertib. Now, we had a lot of discussion because the FDA required us to use the standard approved FOLFIRI regimen, which includes the 5-FU bolus. And we all are aware of the 5-FU bolus toxicity, which is particular nausea, vomiting, diarrhea and bone marrow suppression. We were forced to include that as a standard-of-care, but our dose modification be allowed if there was Grade3 neutropenia or Grade3 toxicity that 5-FU bolus was discontinued after the event. With that in place, only 2 out of 16 patients who continue to have neutropenia after the 5-FU bolus was eliminated. So, we think that most of the side effects regarding neutropenia were related to the chemotherapeutic regimen. Next one. You can see here the overview about the efficacy data. When we look at all doses, the 12, the 15 and the 18 milligram doses for evaluable patients, the partially response in second line was 38%. When we look at the recommended Phase II dose, which is 15 milligrams per square meter, the response rate remains very high at 42%. The ones which are not included, which were not response available are either ongoing or 2 patients stopped and did not get the first CT scan prior to the first cycle of treatment. Next one. You can see here the swimmer plots, looking at the duration of response, and you can clearly see that we see efficacy in ongoing treatment in actually all dose levels. You can see in the Phase II, this, of course, has started later in the study. So, you can see that all these patients, except with the red dot at the end had progression of disease. We had initially had the data cutoff of July 2nd, 6 confirmed and 6 unconfirmed, but we just updated it today showing that 10 were confirmed and 2 unconfirmed partial response rate. 2 patients actually went off who had potentially -- actually had curative surgery. Next one. This is the efficacy profile at the recommended Phase II dose level of 15 milligrams per square meter. You can see that 19 of 22 patients were available for efficacy, 8% achieved a partial response. 7 of them were confirmed and 1 is unconfirmed as of September 8th. You can also see that the duration of the response where patients are still ongoing be treated, the longest is now over 20 -- 220 days. So, we don't only see efficacy in form of response, but also promising duration of response, but this is still very early on. Next one. When we look at the median progression-free survival, we have not reached it. It looks like when we use all patients, it seems to be about 9.4 months. So, the PFS is not reached for the 15 milligrams per square meter based on the median follow-up, but it seems to be a very promising PFS of over 9 months looking at all evaluable patients, including Phase I and Phase II studies. And these are 32 patients. Next one. When we look at the waterfall plots, you can see that the distribution of the partial responders and stable disease in all doses as well as in the recommended Phase II dose, the 15 milligram per square meter are very interesting and showing promising efficacy. Interestingly, we see the PRs at all dose levels even at the 12 milligrams. We have actually confirmed 4 additional partial responders since July 2nd with a new update of September 8th. Next one. As mentioned, one of the secondary endpoints was to measure the KRAS mutant allele frequency in the liquid biopsy. And you can see here in the figure, the decrease percent of change from via to start to undertreatment dosing. The first was pre-dose and the second was day 1 of cycle 2 to 9. And you can clearly appreciate that the more the mutant allele frequency decreases, the more likely you have a partial response. In fact, when you had more than 90% decrease in the mutant allele frequency after the first cycle, you had a response rate of 92%. So it is very promising to develop potential monitoring biomarkers in liquid biopsy to monitor not only response, but potentially also identifying recurrent or resistant clones. Next one. As we would expect on the mechanism of action of PLK1, we see the responders in all KRAS mutations. It's not selective to the well now described G12C or the kind of rising target of G12V. We see it in all the different KRAS mutation because it's a downstream effect of activated KRAS. Next one. So in conclusion, I hope I could convince you that the combination of onvansertib and FOLFIRI/Bev is well tolerated. Only 10% of reported treatment-related events by Grade 3 and 4, which we think most of them are actually related to the chemotherapeutic protocol. Of the 32 patients in Phase I and II, which were evaluable efficacy, we saw 38% of partial response. And we saw that in further follow-up, 10 were confirmed and 2 are unconfirmed as of September 9. So we have confirmed PRs 10 out of 32 patients. Of the 19 patients at the recommended Phase II level, 42% partial response. And we have now also 7 confirmed PRs in this group and 1 unconfirmed, which would do the confirmed partial response rate at 37%. The median progression fee survival across Phase I and II is 9.4 months. As I told you, in the Phase II, it's not reached. We have some interesting biomarkers looking at the KRAS mutant allele frequency measuring in liquid biopsy showing a significant decrease and the first cycle indicates a higher likelihood of response to treatment. So we are thinking that we have a very interesting novel combination for KRAS mutant, particularly in second line with response rate well above 30% with confirmed partial response rate, which, as you probably know much better than I, is a very promising efficacy profile with a very well-tolerated chemotherapy regimen. And I think that was my last slide, and I give it back to Dr. Ruffner.

So yes. And actually, I'll turn it over to Dr. Erlander.

All right. Thank you. Hello again, everyone, and I'd like to start by thanking Dr. Barzi for that thorough review of the field of advanced CRC and the current clinical needs for new therapies in KRAS-mutated metastatic colorectal cancer. I also would like to thank Dr. Lenz for providing the update on the data from our ongoing trial of bevacizumab for second line treatment with KRAS-mutated metastatic CRC. So next slide. I'll begin my remarks with some additional cartooncology perspective on the presentation so far. Next slide. As you've just heard from the experts, it is well known that there is a significant need for new treatment options for metastatic CRC patients in second line setting, given that the response rates range from 5% to 13% within previous randomized trials. Please keep in mind that this is the historical response rates for all patients with advanced disease regardless of whether the patient has a tumor harboring a wild-type or mutated KRAS. As you've heard from Dr. Barzi, patients with KRAS-mutated disease have an even worse prognosis or outcome, and KRAS-mutated disease makes up about half of the cases of CRC. So it represents a significant patient population with a poor prognosis and a substantial need for better treatment options. Next slide. As we look back at our last data release for this trial in April of this year, the efficacy data we are reporting today remains consistent even as the number of evaluable patients has grown from 18 to 32 patients. We believe the -- that almost doubling our end value while seeing a response rate hold essentially steady at a value that is about 3 to 7.5 times greater than response rates reported in similar patient populations treated with standard of care chemotherapy, substantially increases the weight of the evidence supporting on onvansertib's anticancer activity and clinical benefit. Additionally, the trial has continued to enroll very well, and we have a number of patients who are doing well on treatment, but have not yet reached the first time point for restaging radiographic scan. As I alluded earlier, the data we have seen across all dose levels is exciting. However, what may be even more important is that this is the first time we have had enough patients to separately report out the response rate for those patients receiving the recommended Phase II dose of 15 mg per meter squared. We are very encouraged to observe a response rate of 42%. That is 8 initial PRs within 19 patients evaluable as of the data cutoff. And importantly, that 7 of those 8 PR subsequently confirmed, suggesting there are durable responses. One point I'd like to emphasize here is that because the swimmer plots in the data presented by Dr. Lenz were as of July 2, these swimmer plots show 3 and 5 unconfirmed partial responses. Since July 2, we continue to monitor those 5 patients with unconfirmed responses and saw 4 out of 5 subsequently confirmed after the July 2 date, leading to a total of 7 confirmed responses. The fifth patient had a second scan demonstrating stable disease, but remains on treatment so may convert to a confirmed PR in a substant scan. The reason we selected the July 2 as our data cutoff was to facilitate the presentation of additional data from the trial in conjunction with a medical meeting in early 2022, which is the next anticipated catalyst for our CRC program. Based on our current interactions with the FDA, where we explored a number of potential regulatory paths forward for onvansertib, we know that more mature safety and efficacy data from this trial will be a critical factor in our discussions with the agency regarding the best and most efficient path forward for onvansertib. In summary, the data we presented today compare quite favorably with the projected response rates of 5% to 13% reported in trials used in historical controls. We believe these data will indicate the combination of onvansertib and standard-of-care chemotherapy agents, which has been demonstrated in preclinical models to be synergistic, may provide a more active second-line pivot option for this large patient population. Next slide. Stepping back a bit, I'd like to take a moment to talk about PLK1, the enzyme which onvansertib inhibits, which is the basis for a broader opportunity we see for our drug candidate. It's becoming increasingly clear for mounting scientific literature that functional PLK1 is integral for tumor growth and survival. Specifically, functional PLK1 is necessary as the tumor cell progresses through the cell cycle from the S Phase to G2 phase, the G2 Phase to M Phase and M Phase, which is the period of cell division itself. Because PLK1 is involved in multiple phases of the cell cycle, tumors are vulnerable to PLK1 in addition by onvansertib, we believe PLK1 can be thought of as an Achilles heel for tumors. So now how can this knowledge of PLK1's function in the cell cycle be leveraged clinically? For instance, the fundamental scientific rationale for combining full period with onvansertib in our current metastatic CRC trial was the observation that our irinotecan, which is the area of porphyry is synergistic upon onvansertib in preclinical models. So how does this mechanism work? Our irinotecan causes DNA to break specifically double-stranded breaks, which are the most deleterious for the viability to sell. The way tumor cells are able to recover from double-stranded DNA breaks is to have a functional PLK1. The PKL1 facilitates the repair of the DNA, so that the tumor cells will continue to divide and multiply. So with both the presence of both irinotecan, which causes the deleterious DNA breakage and onvansertib, which inhibits PLK from facilitating repair of the DNA, the outcome is tumor cell death. Importantly, what this dual attack strategy, how it works, it's not a single agent exerting deleterious effects, but rather the functional synergy of combining a DNA damaging agent with a PLK1 inhibitor that regrants DNA repair, both are necessary. Additionally, by inhibiting PLK1, we are targeting multiple phases of the cell cycle and thereby exploiting multiple tumor vulnerabilities throughout this cycle. So not only can onvansertib inhibit DNA repair in the SDG phase of the cell cycle, but onvansertib can also inhibit the ability of copay to move the tumor cell from a G2 phase as well as the ability to hit a PLK1 driving cell division or also known as mitosis. In summary, we believe the promise of PLK1 inhibitor can be leveraged by not only using onvansertib in combination with different cancer drugs with different mechanisms of action, but also targeting many different cancer types. And whereas both prior PLK1 inhibitors failed to achieve clinical success due in part to tolerability issues, onvansertib, as you've heard today, is well tolerated in our clinical trial results today. Next slide, please. The science of PLK1 highlights onvansertib's potential as a platform molecule. On this slide, you can see our 3 Phase II trials that are currently enrolling in KRAS-mutated metastatic colorectal carcinoma or metastatic CRC, metastatic pancreatic ductal adenocarcinoma or metastatic PDAC, and metastatic castrate-resistant prostate cancer or metastatic CRPC. Across these trials, we are leveraging knowledge from preclinical experiments, which have demonstrated synergistic effect of the combination of onvansertib and irinotecan for both KRAS-mutated metastatic CRC and PDAC and onvansertib and abiraterone for metastatic CRPC. However, as shown on the column on the left, the potential opportunity spans numerous cancer types. One new possible development area for onvansertib has been getting a lot of attention as of late is the potential synergy with PARP inhibitors, which like irinotecan also damaged DNA. We have been exploring a number of possible indications in preclinical models, such as the combination of onvansertib with a PARP inhibitor in ovarian cancer within a PARP-resistant setting, yielding compelling data that you can review in our corporate slide deck on our website. On the right side of this table, we show that where onvansertib combined with microtubular targeting agents, which also disrupt by mitosis. While the promising data on tolerability and efficacy from our metastatic CRC program and other trials, there are important 4 steps in the clinical development of onvansertib. We see onvansertib as a platform molecule that may synergize with a range of existing anticancer agents. Looking forward, we will continue to take a data-driven approach and selectively pursue indications and drug combinations where we believe onvansertib can generate value for shareholders, and most importantly, provide new treatment options for patients. As I conclude, I'll leave you with 3 thoughts. First, we believe that the data we've shared today demonstrate that onvansertib can provide meaningful improvement in the treatment outcome of a large patient population that has limited treatment options. Secondly, as a well-tolerated PLK1 inhibitor, onvansertib could be evaluated in a number of other malignancy areas of combinations, either by Cardiff alone or in partnership with other companies we see the opportunity increasing the antitumor activity of existing therapies. Finally, we expect to release more mature data early in 2022, representing an important and near-term catalysts. These are exciting times for Cardiff Oncology. And with our strong cash position, we have the ability to execute on our existing clinical programs and to explore the full potential of onvansertib. At this point, I will turn it back over to Sarah, our moderator to start the Q&A. Thank you.

[Operator Instructions] The first question comes from Marc Frahm at Cowen.

And congrats on the data update today. And maybe just there's the one patient still out there outstanding to be confirmed in the 15-milligram group. Can you just discuss that patient? Are they still on therapy, still being followed or have they discontinued? And then beyond on the safety side, I think there were a few more cases of Grade 3 plus neutropenia. Can the company speak to what they're seeing on an overall basis now that the 5-FU bolus has been removed and really within that 15 milligram cohort that's going forward and then, maybe the physicians can put that into context to what they see with standard of care FOLFIRI/bev without the 5-FU bolus?

Yes. I think I go first to Katherine and then -- I think then to Dr. Lenz, it sounds like.

Yes. I can speak to the one patient who did not achieve a confirmed PR. That patient is ongoing and he had a stable disease at the second scan. So he had a PR at the first scan, a stable disease at the second scan, still on treatment, still getting scanned. So there is definitely opportunity for this patient to experience a confirmed partial response. With regard to the safety, I don't know if we could go back to Slide 30 maybe, you can touch on that Slide 30, go back to 30. This is 35, 32 there, we go, okay. So what you can see here, and keep in mind that what's in the table on the left are treatment emergent adverse events, so they are not necessarily treatment related. These are all adverse events that were -- are taken from all adverse events observed on the treatment. And yes, you can see -- and the other thing to keep in mind is that the table includes each patient. So it doesn't necessarily reflect the total number of events. But if a single patient had several grades of neutropenia, but the worst rate that they had was a Grade 3, then they're only counted here once for the Grade 3. So you can see there were 8 patients that had a Grade 3 highest severity of neutropenia and 5 patients that had a Grade 4 severity of neutropenia. So yes, we have seen that. And of course, it's not unusual with FOLFIRI. The other thing to remember is down here in the third bullet, just looking at the 18 patients that were treated in the dose escalation, which, of course, includes 6 patients that were treated at the RP2D, of the 16 patients who went beyond who stayed on beyond the first cycle of drug, all of them had that 5-FU bolus discontinued. So it's happening very frequently on this trial with the results being good management. Frankly, it's addressing the issue of the neutropenia. And as you can see from the efficacy, it does not appear to be impacting the efficacy.

I don't know -- if Dr. Lenz, do you want to comment more on that...

So I think the expected toxicity with the 5-FU bolus containing [indiscernible] is Grade 3 to 4 is about 30% to 40%. I think we are always fighting. In our standard of care, we even don't use 5-FU bolus in most centers because it does only add toxicity, but not efficacy. So after 5-FU bolus was out, the frequency of neutropenia is what we see also with FOLFIRI without 5-FU bolus. So not more. So we don't have any suggestion that onvansertib is really responsible for any dose-limiting neutropenia.

Further questions, Mark. The next question comes from Joe Catanzaro from Piper.

And congrats on the nice data. I just wanted to understand a little bit better the misallocation of a couple of patients who are supposed to receive 15 mg but were sent to the 12 mg dose and whether those patients were allowed to step up to 15 mg after you realize that knowing that 15 mg is a safe and tolerated dose. And I have a quick follow-up after that.

Yes, I think -- I don't know, Katherine, why don't you start and then maybe Dr. Lenz can follow up on that one.

Yes. Of those patients, and it was one on the dose escalation and 2 on the Phase II portion of the study were treated initially with 12 mgs per meter square. So they were assigned 2 15, but they were treated initially with 12. Now, 2 of those patients did go ahead and dose escalate to 15. One of them actually de-escalated, went from 12 down to 6. And then I believe, and Dr. Lenz can speak to this, came off trial. So, we did -- 2 of the 3 did go on to get 15 mgs per meter squared. But because they were not treated per protocol, that is why we subtract them from the patients who got the recommended Phase II dose. So, instead of seeing 22 patients, you see 19 patients, which is -- just has those 3 patients removed.

Yes. So, it's actually -- it's obviously patients which are treated at 12 instead of 15 were USC patients, because we had preprinted orders and for some logistic issues that was not increased to 15. As Katherine mentioned, 2 of them increased to 15 with no problems, and they continue on it. And one had multiple neutropenia. He's one of the patients who had repeated neutropenia despite 5-FU bolus. So, we had to go down a bit onvansertib anyway. So, I think they are valuable patients, but according to the protocol, we have to remove them to evaluate the efficacy at the recommended Phase II that level. But it was a logistic failure -- mistake, not something intentionally done, because we were worried about anything. It was just an order issue.

Okay. Got it. That makes sense. I appreciate the commentary there. And if I could just ask a quick follow-up. I recognize that Phase II cohort needs to complete and the data need to mature. But let's presume that the data mature favorably and consistent with what we've seen to date for the Company and maybe for the KOL as well, what do you see as the potential next steps in development here?

Yes, I think -- yes, go ahead, Katherine.

I was going to say, this trial, the Trovagene TROV-054 trial is now fully enrolled. So, the originally envisioned trial has completely enrolled. The first thing we are doing is actually amending this trial to add more patients treated at the recommended Phase II dose, which will give us more safety data, more efficacy data. So, that's the first step we're taking.

So, from the clinical point of view and Afsaneh jump in any time is I think these are very, very promising data. To have response rate over 30% in second line is extremely rare because we expect about 10% to 15%. So I think, of course, what I would like to see is a randomized potential registration trial, then with the amendment more data are kind of further supporting the promising early results, that would be absolutely the next step from a clinical development point of view. The Company can comment on how they will do it, but that is the logical next step with data like this.

I absolutely agree with you, Dr. Lenz. The expansion of the Phase II is the only thing I can comment on, but I agree with your assessment that a pivotal randomized trial makes a lot of sense.

The next question comes from Naureen Quibria from Maxim.

Mark and team, congrats on the great data. So, I guess the first question is really -- I was wondering, is there anything notable about the patients that achieved the partial responses such as -- do most of them have liver mets or they don't, or what have you observed?

Yes, go ahead, Katherine. Yes.

I was going to defer to Dr. Lenz since he's actually treated these patients and has a more holistic view of the patient. Do you have any comments?

It's a very good question, because we are asking us the same question. Nothing actually pops out right now. Obviously, we are interested in the biomarkers, which Mark is responsible for. But clinical features seem not to be right now distinguishing the ones who do -- who develop a PR versus not. I think what is maybe not as clear that we have some patients on for almost a year with no accumulative toxicity. So that's very important for clinical development, too. With oxaliplatin, you cannot do it, you will run into problems. But with this drug for a long time, no issues, not an issue. So, I think I was actually -- I would turn the question around. I already talked to Mark and Vicki and the whole team, because we have very few progresses as best response, so I was interested in the ones who were progressed, and we don't have a really good understanding. This is, of course, of high interest for everyone involved in this trial, what actually facilitates progression of disease because with high response rate so far, we have not identified any predictive biomarker or predictive clinical feature.

Got it. Sorry. Mark, did you have something else?

Well, I was just going to say, I think what we're doing is this is a continuing effort here at Cardiff where we are looking at circulating tumor DNA, next-gen sequencing at baseline, as well as that end of study, if a patient does finally progress, getting a sample at that point to see -- to determine what did change. So, we're really -- we're in the beginnings of really trying to understand this. But we are putting a lot of effort into this area.

Right. Yes, that's helpful. So, I have something sort of similar along those lines. I saw there's a certain percentage of patient populations that are bevacizumab-naive, right. So I was just curious, do you have any insight? Or do you think that those that are bev-naive that may have an impact on the outcome or durability of the response at all?

That I can speak to. I've got this in front of me here. So, of those patients that achieved a partial response, 6 of them had had prior bevacizumab. So, that's 50% of patients at all doses with a PR that achieved a partial response. If you look just at the recommended Phase II dose, there were 3 patients that had received prior bevacizumab. So, it does not appear to be predictive at all, whether patients had prior bevacizumab or not.

Okay. That's helpful. If I may ask 1 more question. So, there's a competing drug in the KRAS space, that Mirati -- that's evaluating right, their drug in 2 different indications, colorectal as well as non-small cell lung cancer. And within non-small cell lung cancer, they're looking at dual -- co-mutation, right, with STK11 as well as a specific GRAS -- KRAS mutation, sorry, and that STK11 also exists in CRC, colorectal cancer. So, I was wondering if you have any patients with the 2 mutations, or if you have any thoughts on evaluating that as well?

We are gathering that information, because we are looking at a number of other mutations in addition to KRAS. And just to comment, Dr. Lenz did have to drop off at the top of the hour.

I was just going to make one other comment, Sarah, about the question about the clinical development. I think one of the things that where we are right now and where we are with the FDA, all paths are still a possible at this point or open. We will be obviously getting more mature data in the early 2022. So I think that as the data matures and -- but as we sit here today, we have all options available and possible from accelerated approval to full approval as ways of discussions with the FDA.

Thank you, Mark. This concludes today's question-and-answer session. Any questions that were not addressed, please reach out to the Company directly at [email protected]. Thanks, everyone, very much for your time today. And this concludes today's call. You may unmute your line.