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

Greetings, and welcome to the Cardiff Oncology Clinical and Corporate Update Conference Call. [Operator Instructions] As a reminder, this conference is being recorded. I would now like to turn this conference over to your host, Mr. Tom Galassi of LifeSci Advisors. Thank you, sir. You may begin.

Thank you, operator, and thank you all for participating in today's call. Before we start, I would like to point out that the slides referenced by management on today's call will be broadcast on the webcast system. For those of you who have dialed in by phone, you can download the webcast slides from the Cardiff Oncology homepage. I'd also like to remind everyone listening that certain statements in this presentation are forward-looking within the meaning of the Private Litigation Reform Act of 1995 as is closed on the 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 10-K for the year ended December 31, 2021, and other periodic reports filed with the Securities and Exchange Commission. While the list of factors presented therein is considered representatives, 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 now like to introduce Dr. Mark Erlander, Chief Executive Officer of Cardiff Oncology. Mark?

Thank you, Tom, and welcome all of you to today's clinical and corporate update. Our focus today will be to provide the details of our clinical development strategy for onvansertib. Before doing that, I would like to briefly talk about the target of onvansertib, which is PLK1, and talk a little bit of why it is such an attractive target for cancer therapy. Many chemo agents damage a tumor's ability to replicate by targeting different phases of the cell cycle. Here showing irinotecan and taxanes. And targeting the cell cycle is effective because cancer cells highly prioritize gene replication and cell division in order to survive. The way they do this is to really hijack the innate survival mechanisms to evade cancer damage or chemotherapy damage. This includes the overexpression of PLK1, which is a master regulator of the genome integrity working across the different phases of the cell cycle. As you can see on Slide 6, in the S phase, by overexpressing PLK1, tumor cells can repair DNA that has been damaged by chemotherapies, such as irinotecan, thereby allowing cell replication to actually continue. At the G2/M checkpoint regulated by PLK1, the cell cycle is stopped if there is DNA damage because tumor cells express PLK1, they can escape this checkpoint and divide even if there is still DNA damage. This can also create new DNA mutations and further resistance to chemotherapies. A similar phenomenon is in the end phase where the overexpression of PLK1 can allow aberrant cell division. This is why there is a synergy between PLK1 inhibition and taxanes. Our drug, onvansertib, who structures -- pictured here on Slide 9, inhibits PLK1's functions at all of these phases of the cell cycle and therefore, prevents cancer cells from evading chemotherapies. An important point here is that PLK1 is not mutated in cancers, but is rather overexpressed. Therefore, inhibiting it can actually be an effective approach. Because of this, combining onvansertib with standard-of-care cancer agents provides opportunities for synergy with many cancer therapies across multiple indications. And to our knowledge, onvansertib is the only oral selective PLK1 inhibitor currently in clinical development. Throughout today's discussion of our clinical development strategy, we will repeatedly highlight how the data we have generated validated this thesis and guides our discussions for onvansertib's clinical path forward. Given the important roles played by PLK1, tolerability was a challenge for early generations of PLK1 inhibitors. However, onvansertib has a novel combination of efficacy and tolerability, which we believe comes from the properties identified here on Slide 10. Onvansertib is oral, it's a small molecule and has a 24-hour half-life. Because of these properties, onvansertib can be flexibly dosed to balance efficacy and tolerability. In addition, onvansertib is highly specific for PLK1 inhibition and has limited activity to PLK2 and 3, which are evolutionarily related and are also which are believed to have other activities such as tumor suppression. Given this understanding of PLK1 and our drug onvansertib, I'd like to turn to the details of our clinical development program. On Slide 11, you can see that over the next few years, we have 2 overarching goals for our clinical programs. First, we intend to validate the strong results of our ongoing Phase 1b/2 trial in metastatic CRC with an upcoming randomized trial. Second, we want to demonstrate clinical proof of concept in additional indications, balancing our desire to maximize the value of onvansertib with the need to allocate capital to program strategically and responsibly. On Slide 12 and 13, we list the topics we'll cover on this webcast. We will begin with a discussion of our lead indication for the second-line treatment of patients with RAS mutated metastatic colorectal cancer or metastatic CRC. We'll provide a summary of the new data from our ongoing Phase 1b/2 trial, and this is the first time that we'll be reporting data on the durability of those responses. Then we'll provide a detailed design of the next clinical trial we plan to conduct for metastatic CRC and explain how the trial design, we believe, positions us to accelerate and derisk our lead program. Afterwards, we will discuss the other trials. For our pancreatic cancer trial, we will present data on the first 8 patients enrolled. For our prostate cancer trial, we'll discuss a path forward now that enrollment is complete. Next, we'll provide the rationale and design of 2 investigator-initiated trials that are currently open for enrollment, 1 in triple-negative breast cancer and the other in small cell lung cancer. Finally, we will close with a review of our corporate outlook, including the impact of our plans on our expected cash runway and the anticipated catalysts that fall within this runway. So now let's turn to our plans to accelerate our activities in metastatic CRC. The foundation for all of our plans in this area is the strong data from our ongoing Phase 1b/2 trial, so we'll begin with an update of that trial. Before I can go -- I go further, I'd like to explain that the data we are releasing today covers the first quarter of 48 evaluable patients from this trial. While the expansion cohort remains open to enrollment, the data from these patients are not sufficiently mature to draw meaningful conclusions at this time. As a reminder, on Slide 15, about half of metastatic colorectal cancer patients have a wild type or normal tumors and half present with a KRAS or NRAS mutation. For the patients with normal genetics, they can benefit from newer targeted therapies such as EGFR inhibitors in the first line of therapy. For patients with RAS-mutated tumors, there is no targeted therapy available in the first line. On Slide 16, we show you that these patients progress in second-line therapy, their prognosis is poor with a 5-year survival of 10% and historical response rates to standard care therapy in the range of 5% to 13% demonstrated in prior clinical trials. Slide 17 shows how onvansertib can bring a targeted therapy to this very challenging patient population by combining with current standard of care. And on Slide 18, looking at other therapies in development for the second line, RAS-mutated metastatic CRC population, a common focus is on the G12C inhibitors, the KRAS-G12C inhibitors being developed by Amgen and Mirati. However, these therapies can target only about 4% of the broader metastatic CRC patient population. And putting this another way on Slide 19, if you just consider those metastatic CRC patients with a KRAS or NRAS mutation, over 90% will not benefit from G12C inhibitors. So in conclusion, on Slide 20, we show onvansertib's 2 mechanism action, validated in preclinical models that led us to take on this challenge. First, because PLK1 is active downstream of the RAS mutation and drive the proliferation tumor cells. We believe that by inhibiting PLK1 onvansertib is synthetically lethal for any KRAS or RAS tumor type. Second, we have demonstrated the functional synergy of combining a DNA damaging agent such as FOLFIRI to use to treat second-line RAS mutated metastatic CRC tumors with our PLK1 inhibitor. Slide 21 gives you an overview of our Phase 1b/2 trial design. Patients in the trial are undergoing second-line treatment for metastatic CRC that has a KRAS mutation and the tumor is unresectable. In the trial, we are combining onvansertib with the FOLFIRI/bevacizumab regimen, which is widely used as standard of care in the second-line treatment of patients. Patients are scanned at baseline and every 8 weeks on treatment for disease response assessment. Fundamentally, this trial is designed to demonstrate a signal that onvansertib safely complements and improves the efficacy of standard of care. The 3 efficacy endpoints of the Phase 2 portion of trial is shown on Slide 22. The primary efficacy endpoint is the objective response rate or called ORR. Slide 23 shows the waterfall plot of the best radiographic response by patients as of July 25 of this year. As shown in the table, a number of PRs in both the all doses and the RP2D cohorts have not changed since our last data announcement, continuing to show a 34% and 35% ORR, respectively. Also in the table, you can see that the PR for patient 01-046, which has not yet confirmed in our last release did confirm on the patient's next scan. As I mentioned earlier, today's data release is the first time we have sufficiently matured data to report on the durability of responses. As you can see below in the table, for the 17 PRs in the all doses cohort, the median duration response was 11.7 months. And for the 13 PRs in the record Phase 2 dose of cohort, the median duration of response was 12.5 months. We and other investigators believe that these long durable responses suggest that this treatment is inhibiting the ability of the tumor to rapidly become resistant to therapy. This aligns with what we would expect given onvansertib's mechanism of action and PLK1's role in DNA damage repair. For context, in a recent Phase 2 trial for the combination of encorafenib plus cetuximab that led to an approval of metastatic CRC, the reported median duration response was 6.1 months. The median DOR that we are seeing from our trials recommended Phase 2 dose is more than double this. Slide 24 presents the swimmer plot as of the July 25 cutoff date. This gives you data on the time of study treatment, the timing of the disease response on treatment and the patient deposition or reasons for leaving the study. The number of patients who came off the study to pursue potentially curative metastasis directed therapy are indicated by the color teal triangles to the right of their respective lanes, and this number has increased from 5 in January to now 9 patients in today's data release. Slide 25 presents data on onvansertib's potential for efficacy across a number of different KRAS mutations. We show the distribution of KRAS mutations in the 48 valuable patients across all doses and the frequency of specific mutations in the patients on our trial generally follows the expected distribution from the literature with G12D and G12V being the most common. As the table shows, we see responses to therapy across different KRAS mutational variants, which clearly differentiates onvansertib from competing agents that exclusively target the KRAS-G12C variant. Slide 26 summarizes the ORR that we have observed and reported on a different time points in the last year, both for the entire study population and that for the RP2D subgroup again, calling attention to how our results compared to recent historical controls. The ORR reported today are the same as results shown in January. You can see in the graph that the response rate has been relatively consistent over time. This is about 3x to 7.5x greater than what has been achieved in previous trials and well above our proof-of-concept threshold. Slide 27 shows a Kaplan-Meier curve for progression-free survival to date. You can see that the median PFS is 9.3 months for patients across all doses. The 9.3 month median PFS represents a notable improvement in the length of PFS relative to standard of care. On Slide 28, you can see that the PFS we are reporting today is in line with prior data, also, although we are still following patients, the median PFS for RP2D is currently at 8.2 months. Here on Slide 29, you'll see a summary of the safety data from the trial, which we discussed in detail on our January call. The combination continues to be well tolerated with no new safety signals emerging. And on Slide 30, we show the patient demographics and characteristics for this trial. These are in line with what was observed for second line. One characteristic of interest is the number percentage -- a percentage of how many patients received prior bevacizumab versus those that did not have prior bevacizumab and first line. As shown, 15 patients or 30% did not receive bevacizumab or what I'll call bev prior to second-line therapy. As shown in Slide 31, bev is approved for both first and second line in combination with standard of care chemotherapy, including both FOLFOX and FOLFIRI. Pivotal Phase III trials have examined the question to second-line patients naive to bev show better efficacy than second-line patients with prior bev. As shown in Slide 32, in prior trials, median PFS was 6.7 months and 6.9 months, and overall survival was 12.5 and 13.9 months for prior bev versus bev naive, respectively. The conclusion from previous trials is that the median PFS and median OS are similar in second line and similar patient benefit in second line, regardless of whether patients were bev naive or had prior bev in first line. The ORR for bev naive patients is approximately 25% compared to a 5% to 13% for patients with prior bev. Keeping this data in mind, on Slide 33, we show a subgroup analysis from our trial. The ORR and the median PFS we see in our bev naive patients are unexpectedly high when compared to both our patients with prior bev as well as previous clinical trials. For bev naive patients, we observed an ORR of 69% and a median PFS of 13.5 months, which are well above historical benchmarks of 25% ORR and 6.9 months median PFS. As shown -- and shown on Slide 34, we asked the question of whether there is a specific patient characteristic or demographic that was causing this large increase in ORR. We analyze this by stratifying each patient characteristic into 2 groups: bev naive versus bev exposed at first line. Across all patient characteristics and demographics, there was a consistently higher ORR with values ranging from 50% to 80% in ORR in bev naive versus 14% to 31% bev-exposed patients. This indicated that there was not a particular patient characteristic or demographic that was the reason for the observed unexpectedly high ORR and median PFS. So how should we respond to this observation? We believe that this data may have been covered a clinically meaningful finding. And as shown on Slide 35, we have 2 hypothesis regarding the reason for the data we observed. One is that this is a statistical anomaly that is due to low numbers of patients. A second hypothesis is that there is synergy between bev and onvansertib in a bev naive setting. For the first hypothesis, we plan to address this finding within the design of our upcoming randomized metastatic CRC trials specifically stratifying for prior bev. For the second hypothesis, we are investigating this potential synergy in 2 ways. First, we are performing preclinical in vivo studies to assess synergy between bev and onvansertib. And secondly, we are examining both genomic and trial symptom analysis from bev naive versus bev exposed patients within our current Phase 1b/2 trial. Depending on what we learned from these analysis and studies, there may also be an opportunity to develop onvansertib as part of a first-line treatment regimen in RAS mutated metastatic CRC given that the response rate of FOLFIRI plus bev in the first-line setting is approximately 45% and the median PFS is 10.6 months. Shifting gears. Slide 36 summarizes data from 1 of the exploratory endpoints of our study measuring the mutant allele frequency or MAF in the patient's blood at baseline and at 28 days of treatment. What we've shown is that those patients who have achieved at least a 90% decrease in the KRAS MAF at day 28 have a substantially higher likelihood of achieving a PR or CR than to patients whose MAF does not decrease by at least 90%. This biomarker has the potential to provide early insights into disease response before the first post baseline scan. Slide 37 digs into this a little deeper into the MAF analysis and compares the ORR and the median PFS for the KRAS responders who showed a 90% integrated decrease in their MAF and KRAS nonresponders who did not achieve that same decrease. Here of the 45 patients who were evaluable for KRAS response, 49% of patients were determined to be KRAS responders who showed an ORR of about 64% versus 8.7% for the nonresponders and who showed a median PFS of 12.6 months versus 5.9 months for the nonresponders. Now I'd like to turn to the future clinical development plans we have for our metastatic CRC program and discuss the details of our next trough. We -- on Slide 39, we repeat the question at the core of our Phase 1b/2 trial in metastatic CRC, and that was, can we get a signal that onvansertib complements and improves the standard of care? Looking to the data we've just reviewed, we believe the trial has generated a clear signal in support of this hypothesis. So where do we go next? At our previous mCRC trial update in January of this year, we indicated that we were in the process of designing a randomized pivotal trial for metastatic CRC. As part of that effort, we evaluated a number of trial strategies for the next step in the program. The foundation for the design of the next trial comes from the insights we gained from the strong results we just reviewed. We then focused on designing a trial that would meet the 4 clinical and corporate objectives that you see here on Slide 40. First, we want to generate statistically significant randomized data that demonstrates the contribution onvansertib makes to patients' outcomes when combined with standard of care. Second, we wanted to confirm our dosing strategy in light of the feedback we and others have received from the FDA's Project Optimus initiative for optimal dosing. Third, we wanted to generate robust efficacy, safety and dose confirmation data that could position us to pursue an accelerated approval for onvansertib if such an option is supported by the clinical trial results. And fourth, we wanted to achieve these goals rapidly and entirely within the funding we already have on our balance sheet so that we operate with maximum efficiency. By focusing on these goals we created a trial design that you will see in the next few slides. I am pleased to say that we believe the next trial satisfies all of these goals, positions us to accelerate and derisk our lead program in a capital-efficient manner. For the rest of this presentation, I will refer to this next trial as the ONSEMBLE trial. A name we designed or assigned to reflect both the O-N of onvansertib and its mechanism of action, combined hormonously with the standard of care to improve patient outcomes. The design of the ONSEMBLE trial is shown on Slide 41. As we say in the title, the ONSEMBLE trial will be in a randomized, open-label Phase 2 trial that has the power to demonstrate a statistically significant and clinically meaningful difference between the standard of care plus onvansertib versus standard of care alone. Like our ongoing Phase 1b/2 trial, we will enroll patients with metastatic colorectal cancer that is unresectable and who are entering their second line of treatment. Given onvansertib's mechanism of action, which acts downstream of RAS, ONSEMBLE will include patients with both KRAS and NRAS mutations. Together, these patients account for approximately 52% of second-line metastatic CRC patients. we expect to enroll 150 patients in the trial who will be randomized into 3 arms on a 1:1:1 basis. These arms include a control arm in which patients receive standard of care FOLFIRI plus bevacizumab. And 1 of the 2 treatment arms -- and 1 of the 2 treatment arms in which onvansertib was added to standard of care. One important aspect of the ONSEMBLE trial is based on the statistical analysis of the 48 patients in the earlier Phase 1b/2 trial, we have decided to evaluate flat doses of onvansertib rather than a dose calibrated by the patient's body surface area. Patients in the treatment arms will be randomly assigned to receive either 20- or a 30-milligram dose of onvansertib along with standard of care. We believe this dosing approach achieves multiple benefits. First, we selected the 20- and 30-milligram flat doses for the ONSEMBLE trial because they are in line with the 2 most common doses administered in the ongoing Phase 1b/2 trial. For an average patient, for example, the 30-milligram flat dose equates to the recommended Phase 2 dose of 15 mg per meter square. Second, by examining efficacy and safety of the 30-milligram RP2D dose and a lower 20-milligram dose, we can confirm our dosing strategy given the FDA's focus due the Project Optimus initiative on identifying the dose that maximizes not only the efficacy of the drug, but its safety and tolerability as well. Third, using a flat dose in each treatment arm reflects the typical approach of a commercial dosing protocol for an oral therapy. The dosing schedule of the treatment arms is identical to the schedule in our ongoing Phase 1b/2 trial, as you can see on this slide. Slide 42 shows the endpoints of the ONSEMBLE trial. The primary endpoint is objective response rate, including independent assessment for complete and partial responses, with secondary endpoints of median PFS, disease control rate, duration of response and overall survival. Given the strength of the data from the Phase 1b/2 trial in the cohort of patients who achieved a 90% or greater reduction in circling tumor DNA after 1 month of treatment, we have prespecified all the endpoints above to be examined for the patients in the ONSEMBLE trial who achieve a similar reduction in circling tumor DNA. Slide 43 presents some additional details about the design and the statistical powering of the ONSEMBLE trial. The design we have discussed on the prior slides will generate data that maximizes the chance of identifying a therapeutic contribution of onvansertib in several ways. First, the control group will be exclusively include the standard of the care, allowing for a robust comparison to the experimental arms, which includes standard of care plus 1 of 2 doses of onvansertib. We believe that this approach is both efficient and cost-effective. Secondly, with 50 patients in each arm and 150 patients overall, the data collected in this trial will be statistically meaningful. We size the trial to have an 80% power to detect a meaningful difference in ORR, our primary endpoint between each experimental arm versus control. In addition, the design makes optimal use of the significance level or alpha. Each dose of onvansertib will be compared to control at an alpha level of 0.045 compared to historical ORRs of 10%, this translates to demonstrating an ORR of at least 24% for either dose of onvansertib. Our design will also include a stratification within the randomization for bev-naive patients versus prior bev, thereby having equal proportion numbers of naive versus prior bev within each arm of the study. This will enable us to test in a randomized trial, our observation of a much greater ORR and median PFS and bev naive patients from the Phase 1b/2 trial. Finally, our key secondary endpoint PFS will have the ability to pool the 100 patients in the 2 onvansertib arms to increase the power of the PFS analysis. If the 2 doses of onvansertib reached statistical significance, the alpha level for the PFS analysis will be equal to 0.1, which is considered reasonable for a Phase 2 trial. The analysis of PFS will reach statistical significance if at least 1 dose of onvansertib has a median PFS of at least 8.4 months as compared to historical median PFS of less than 6 months. The median PFS was 9.3 months in our single-arm onvansertib study. In summary, for all these reasons, we believe the design of the ONSEMBLE trial maximizes the likelihood of generating statistically meaningful data in a minimum amount of time for a minimum cost. Before concluding my remarks on the design of the ONSEMBLE trial, I'd like to take a few words about our interactions with the FDA as we move to the design process. Our process for determining the final design of the ONSEMBLE trial did consider the following: detailed feedback provided by the FDA during our end of Phase 1b meeting. Secondly, additional interactions that we subsequently had with the FDA. Also our discussions with trial investigators and our Scientific Advisory Board. And finally, recent feedback from the FDA regarding the designs of other clinical trials relating to dose confirmation requirements of the Project Optimus initiative. The ONSEMBLE trial protocol was submitted to the FDA in June of this year. And in August, the agency provided us with detailed comments on the protocol, all of which we found acceptable. Currently, we are conducting all the necessary activities to activate in the fourth quarter of this year. Finally, on Slide 44, you can see our expectations of the timing of the trial's top line readout. We have been conducting activation activities as we completed our dialogue with the FDA. And once the ONSEMBLE sites are open for enrollment, we intend to stop enrollment in the expansion cohort of the Phase 1b/2 trial. Our forecast for enrollment shows we expect to release top line data from the trial in the second half of 2024. We believe these data have the potential to create substantial value for the reasons shown on the slide, and I'll comment further on 2 of them. Regarding the potential for accelerated approval. We -- when we received Fast Track designation, the FDA acknowledged that the metastatic CRC was a serious condition and that our preliminary data from the Phase 1b indicated onvansertib has the potential to address this unmet medical need. The possibility of accelerated approval will be based upon the design and endpoints of the ONSEMBLE trial and importantly, having trial data that demonstrates onvansertib's clinical benefits. Finally, we believe the ONSEMBLE trial has the potential to signal the broader opportunity for onvansertib combinations and other indications. And next, we'll discuss some of our ongoing and new programs outside of metastatic CRC. We'll start with our program in metastatic pancreatic ductal adenocarcinoma or called metastatic PDAC. Slide 46 shows the enrollment criteria for the ongoing Phase 2 open-label PDAC trial. Patients must have progressed on first-line treatment with gemcitabine plus Abraxane and received second-line treatment with onvansertib in combination with standard of care as shown on this slide. The trial is expected to enroll approximately 45 patients at 6 clinical trial sites across the U.S. Like our metastatic CRC trial, the main objective of this trial is to get a signal that onvansertib complements and improves the standard of care. As shown in Slide 47, the primary endpoint of the trial is the objective response rate and the secondary endpoints are duration of response and overall survival. We will also be exploring biomarkers that may indicate sensitivity or resistance in a combination therapy. Slide 48 shows a significant unmet need for second-line PDAC patients. The historical ORR for this patient population is approximately 8% and the historical median PFS is 3.1 months. The early data shows -- is shown here. 8 patients have been dosed, and there are 5 that have had their first scan so that means 5 evaluable at this time. 4 of the 5 evaluable patients have achieved disease control and remain on treatment through the data cutoff date, with 1 patient achieving a partial response. 2 of the patients are now reaching 8 months of stable disease, which is encouraging given the median PFS is 3.1 months, and the overall survival is 6 months in standard of care -- with standard of care. We look forward to the continued advancement of this trial and expect to report additional data in mid-2023. I'll now turn to our ongoing clinical program in metastatic castrate-resistant prostate cancer. On Slide 51, we highlighted some important new data from the poster we presented at AACR General Meeting in April of this year, showing that both the disease control rate and the median progression-free survival increased with increasing dose density of onvansertib. As we show on Slide 52, this trial has now completed its enrollment, and we've learned some important clinical filings from the data. For example, unlike our other clinical trials that combine onvansertib with cytotoxic agents known to cause myelosuppression, this trial combines with agents that do not have such overlapping toxicities. Therefore, we were able to show that onvansertib generated negligible myelosuppression. However, after discussing the results of this trial with KOLs and other advisers and considering the evolving landscape in castrate-resistant prostate cancer, we've decided that we will not independently fund any future CRPC clinical activities. This decision allows us to prioritize and focus our resources on our other clinical programs. Next, I'll talk to you about how we are leveraging collaborations with leading academic institutions to evaluate onvansertib in additional indications through investigator-initiated trials. This allows us to take a capital-efficient approach as we assess onvansertib's broad therapeutic potential. I'll begin by discussing in investigator-initiated trial evaluating onvansertib plus paclitaxel in triple-negative breast cancer or TNBC. As you can see from the graph, preclinical studies have shown robust in vivo synergy of this combination in an in vivo model of TNBC. These data as well as other preclinical studies with the rationale for this investigator-initiated trial. On Slide 55, the TNBC trial, which will be conducted at the Dana-Farber Cancer Institute is a single-arm Phase 1b/2 trial of onvansertib in combination with paclitaxel in patients with unresectable locally advanced or metastatic TNBC. This trial is currently open for enrollment. In Phase 1b, approximately 14 to 16 patients will be treated with different doses of onvansertib in combination with a fixed dose of paclitaxel to determine the maximum tolerable dose and the RP2D of onvansertib. In Phase 2, approximately 34 patients will be treated with the selected onvansertib recommended Phase 2 dose in combination with paclitaxel. The primary endpoint of Phase 2 of this trial is ORR with PFS included as a secondary endpoint. Preliminary data from this trial are expected in Q4 2023 or Q1 2024. Next, I'll discuss a second investigator-initiated trial and this one in small cell lung cancer. On Slide 58, you can see that onvansertib shows robust single-agent antitumor activity in patient-derived xenograft models of small cell lung cancer, and this activity is in both platinum-sensitive and platinum-resistant tumors. This preclinical data was the rationale for the monotherapy single-arm trial in small cell lung cancer. The small cell lung cancer trial, which will be conducted as a single-arm 2-stage Phase 2 of onvansertib monotherapy in patients with relapsed small cell lung cancer is now open for enrollment. The trial is designed to enroll 15 patients in Stage 1 with the study proceeding to Stage 2 if 2 or more Stage 1 patients achieved an objective response. Stage 2 is designed to enroll an additional 20 patients. The primary endpoint of the trial is ORR, while key secondary endpoints include PFS and overall survival. Preliminary data from the trial are expected in Q2 or Q3 2023. Slide 60 shows our current pipeline of development programs for onvansertib. Regarding the ovarian cancer program, we have not made any decisions about a future trial in this indication, and we will provide additional details when available. As we conclude today's webcast, I would like to leave you -- leave you with some important context about the commercial opportunity available to onvansertib. On Slide 61, you can see some examples of cancer therapies that target oncogenic alterations to attack cancer cells. These targets, however, by definition, address patient populations that are narrow -- in 2 examples, RAS1 and RET, the company is developing these therapies publicly disclosed their views on the size of the eligible patient population in the United States that could benefit from such treatment. For RAS1, the estimate was approximately 3,000 U.S. patients per year. And for RET, the estimate was approximately 5,000 U.S. patients per year. I would like to contrast this with another group of cancer therapies, ones that do not target a specific oncogenic alteration, these therapeutic targets include our own target, PLK1, as well as PARP, CDK4/6, which is inhibited by palocycli PD-1 and PD-L1, the key targets for cancer immunotherapy and VEGF, which is targeted by bevacizumab. Because these targets are not defined by a specific oncogenic mutation, they typically address a much broader patient population. For example, on the left side, you see the KRAS-G12C inhibitors. Earlier in this presentation, we showed you how these therapies only address a small subset of total RAS oncogenic mutations in metastatic CRC whereas inhibiting PLK1 potentially allows onvansertib to address all KRAS and NRAS mutations in metastatic CRC. As a result, the eligible metastatic CRC population in the U.S. that we believe onvansertib can address is approximately 23,000 patients, much larger than many of the oncogenic alteration targets. And when we add our additional clinical programs, it reinforces the large opportunity onvansertib can address through the clinical development programs we have discussed today. On Slide 62, we show the expected timing for readouts from each of the programs I discussed today. In mid-2023, we expect to have more mature data from our PDAC program and a first look at data from the small cell lung cancer investigator-initiated trial. In late 2023 and early 2024, we expect to have a first look at data from the TNBC investigator-initiated trial. Finally, as I said earlier, we expect to have top line data from the ONSEMBLE metastatic CRC trial in the second half of 2024. As we work towards these milestones, we are doing so in a robust financial position. We had $122 million in cash as of June 30, 2022, and recently, our cash burn rate has been approximately $9 million per quarter. Looking ahead, based on our projections for the cost and timing of the trials I discussed today, our current cash will fund our operations beyond all of the anticipated data readouts I just mentioned into 2025. As I said at the beginning, we have 2 clear goals for our onvansertib development program. And on Slide 65, you can see our strategy for executing against these goals. Our strategy for the first goal is to leverage both strong efficacy data and learnings from the Phase 1b/2 trial to execute a randomized trial that has been designed to be efficient, confirms our optimal dose, stratifies for bevacizumab and set up a potential opportunity for accelerated approval. Our strategy for the second goal is to explore other indications. Onvansertib targets PLK1, which is a pleiotropic -- which is pleiotropic in its key roles within the cell cycle. And because of this, onvansertib is synergistic with many approved standard of care therapies, which we believe speaks to its broad potential. We hope the material I have reviewed conveys our optimism about the clinical programs we are running and the significant commercial opportunity for onvansertib. We look forward to providing additional updates on our progress toward these goals. With that, I thank you once more for your attention today, and we will now take some questions.

[Operator Instructions] Our first question comes from the line of Joe Catanzaro with Piper Sandler.

Sorry about that. Apologies. Maybe I'll just jump right into it, Mark. First question, if you could maybe elaborate a little bit around the discussion with the FDA as it relates to the potential for this trial to support potential accelerated filing? And what exactly would the trial need to demonstrate? And then perhaps relatedly, is it your expectations that the top line readout in the second half of 2024 would include relatively mature PFS data? And I have a follow-up or 2.

Okay. Yes. I mean, as I said in the script, I mean, we obviously have met with the FDA they really -- as you know, they don't really tell you what is going to be accelerated approval data. They always say, let's wait and see what your data looks like. So there's -- so from that point of view, we've structured the design such to be robust from a statistical point of view, but I think, of course, it comes down to the data. The other question is the mature PFS. Yes, we have designed as such that we should have a -- what should I should say, a reasonably good view of PFS at that time point.

Okay. Got it. And then I'm trying to guess better understand this difference in patients with prior bev exposure and those without. I'm wondering if you have a sense of at least in the U.S., why patients are not receiving bevacizumab in the first-line setting and the ease of enrolling and finding such patients and what that may mean for the ONSEMBLE study?

I mean we've looked at some databases that show that about 25% to 30% of patients don't get bev in first line across the country. That's what we've been seeing. And -- but they don't really discuss reasons why in these reports. It's more observational. But I think, obviously, that's something we'll keep an eye on.

Okay. Got it. And I'm wondering if the ONSEMBLE analysis plan includes for looking at ORR and PFS in a prospective manner in patients with prior bev and without prior bev.

Well, I mean -- Joe, are you talking about the randomized trial? I mean that, of course, would be prospective. But is that what you're talking about? Or maybe I misunderstood the question.

Yes. If the stat plan includes to sort of look at that difference between bev naive and bev experienced.

Yes, absolutely. It's all prespecified.

Okay. And then if I could just squeeze one last one and quickly. So I know we've talked about the delivery of 5-FU and the bolus and that being challenging within the Phase 1b/2. I'm wondering what the delivery of 5-FU would be in ONSEMBLE and whether there are any sort of protocols in place to mitigate and manage neutropenia?

Let me turn that over to Vicki, she's -- knows a lot about this.

Yes, Joe, in the ONSEMBLE trial, patients in the control arm will be administered with the full complement of the regimen, including the 5-FU bolus. However, there is stipulation within the protocol that should a patient have a grade 2 or greater neutropenia they -- the clinicians based on their experience and institutional guidance will have the opportunity to adjust or remove the 5-FU bolus from future cycles. In the 2 onvansertib investigational arms, the patients will not be administered the 5-FU bolus. They will receive the 5-FU infusion and the other components of the regimen, but the FDA has allowed us to eliminate the 5-FU bolus from the start of this trial in the 2 onvansertib arms.

Our next question comes from the line of Divya Rao with Cowen.

This is Divya on for Mark. Just a couple from us. So the first thing is, does the FDA want to see at least a strong trend on PFS at the primary or analysis to file? Or like where do you need to show something?

Or show what? I didn't hear the last part.

Do you need to show statistical significance? Or is just the strong trend enough in order to file?

That really -- we have not -- that's not something they usually -- they don't talk about. So I mean, I think what they want to see is that we'll present the data to them, and at that point, we can discuss it.

Okay. And then just in your conversations with the FDA, is the filing just based upon ORR? Or will they potentially ask for other end points you seeing? And if so, what level of separation do you think you need to achieve with the ORR other than the 24% that you saw?

Yes. I mean I think like I said in the script, I mean our primary objective -- our primary endpoint is ORR. And our key secondary endpoint is PFS, and we have alpha spend for obviously the ORR and also PFS.

Okay. And then just the last question. How long is based on your experience with the Phase 2 expansion cohort, do you think that the Phase III enrollment will take?

Well, I mean, I can -- I'll pass that to Vicki. She can discuss a little bit about the timing of the trial, but we're assuming that we would be starting in January of this next year.

So we're in the process of activating sites. We anticipate having approximately 40 clinical trial sites across the United States participating in this Phase 2 randomized trial. And certainly, it's always hard to predict how quickly enrollment will go, but there's definitely a lot of enthusiasm for this trial.

Our next question comes from the line of Andy Hsieh with William Blair.

Great. Thanks, Vicki and Mark, for the additional color on your plans. So I have a couple. So the first 1 has to do with the dosing, and I'm just curious about any sort of previous data that allowed you to kind of transition from a kind of body surface area base dosing to a fixed dosing, any sort of PK data to support that. And you obviously cited the Project Optimus as 1 of the reasons to do that. So I'm just curious about any sort of discussions regarding the transition to the fixed dose with the FDA. That's question #1.

Yes. I mean, Andy, great. Thanks for the question. So yes, we did have PK data from our Phase 1b, part of the Phase 1b/2 trial. And so we were able to really look at that. And that allowed us to do a lot of PK analysis and simulations and really be able to present in our protocol, our randomized protocol. The reason why we went with those 2 flat doses. But really, the -- and basically, the 12 mg per meter squared and 15 mg per meter square they were using, they -- when you look at the data, they are equivalent to the 20 and 30 mg flat doses.

Got it. Got it. Okay. Great. So the second question has to do with the 5 to 9 patients that you mentioned, who had a response that's sufficient to transition for a potential curative surgery. I am also curious about FDA's view on those patients since they are pretty rare in the relapsed CRC setting. And I'm also curious if the ONSEMBLE study is looking at these events as well.

The FDA has not commented specifically on that specific data at this point. But I think that, obviously, the investigators in the trial, we are very encouraged about that -- those particular patients. The -- I apologize. Your second question, Andy, I'm sorry. I was thinking about your first.

It's on the ONSEMBLE trial as well.

Yes. And then in the ONSEMBLE trial, we would also continue to -- this would continue to accrue. Now 1 thing that we will do, of course, is follow these. We have more ability to follow all these patients in the ONSEMBLE trial.

Okay. Great. And then maybe lastly, as you kind of think about concluding your expansion cohort patients. Obviously, that single arm. So patients will get the drug versus the randomized portion where patients could potentially get just the standard of care without onvansertib. I'm just curious about any sort of strategy to ensure proper enrollment for the randomized study? Or you're thinking about this in a sequential way so you basically finishing enrollment of the expansion studies and then you transition that into the randomized portion.

Yes. Our plan would be to discontinue the expansion when we start the randomized trial. So we would not want to have competing trials. So that's our plan.

Our next question comes from the line of Joel Beatty with Baird.

The first one is on the new ONSEMBLE trial. Can you just for the powering assumptions, what is assumed for the response in the control arm?

In the control arm, we estimated because pivotal trials previously ranged from 5% to 13%, we picked 10%.

That's helpful. And then let's see. Meanwhile, over the next couple of years, while these clinical trials are going on. Can you describe the extent of the preclinical work and what you'll be focusing on there?

Well, as I mentioned in the script, of course, we're very intrigued by this finding with bev. And so we are -- we'll be looking at preclinically at different models, and we'll be pursuing that quite actively given the data that we've seen so far clinically.

[Operator Instructions] Our next question comes from the line of Yuan Zhi with B. Riley.

Thank you for the update here. Maybe first, since this Onsemble trial will be an open-label trial, will you have an interim readout or have an interim analysis for futility?

At the moment, we are not planning on an interim at the moment.

Yes. Got it. And then maybe a follow-up on the assumption that Andy mentioned -- or Joe mentioned, the assumption you have talked about the assumption related to ORR. Just want to clarify what was your assumption related to PFS for this Phase 2 trial?

6 months. I mean the previous random -- our pivotal trials in second line over the last 15 years have been very consistent, ranging from 4.5 to 5.7 months. So we pick 6 months.

Yes. Got it. And one last one from us. Since this will be a second line sighting, do you expect the enrolled patient would have become resistant to KRAS-targeted therapy such as those from Amgen or Mirati?

Yes, I don't think so because those -- they are targeting second line and greater and larger numbers, greater lines. And we're focused on second line, so we're getting patients only from first line.

Our next question comes from the line of Robert Burns with H.C. Wainright.

Mark, congrats on the plan for the ONSEMBLE trial. And you've presented a well to update here. So a lot to digest. I've got several questions for you. So I'm not sure if I missed it in your prepared remarks, but would you expect any meaningful differences in the efficacy for the flat 20-milligram and 30-milligram onvansertib doses based on the results for the 12 mg per m square and 15 mg per m square results in the Phase 1/2?

Yes, that's a good question, Robert. I mean if you look at the data, the -- we have 3 doses, but 12 mgs and 15 mg per meter square or the equivalent of 20 and 30. When you do look at the 12 mg from use care, we do have activity there. So we just -- but we only have 6 patients in the 12 mg or what would be the 20. So the answer is we look -- you're looking at the data, yes, we will have activity there. But quite frankly, it's only 6 patients. And so that's why we're doing this.

Okay. So my next question. So you stated earlier that 65% to 70% -- 75% of frontline and colorectal patients in the U.S. receive bevacizumab. And that's based on past literature and databases. Now do you see that holding up while you enroll in the -- while you enroll the onsemble patients? Or is there a reasonable possibility that you see a lower percentage of bevacizumab naive patients in the ONSEMBLE trial?

Well, I mean, we don't know per se, but I would say that we do have pretty recent data of our own in the last 2 years, showing that we're at about a 70%, 30%. So just based on 7 sites across the country, which represent both academic and community-based hospitals.

Okay. Two more questions for me, if I may. So it appears that the bevacizumab-naive population is meaningfully contributing to the efficacy seen in the Phase 1/2. So I was just curious what the 95% confidence intervals were for the objective response rate and the MPFS in the bevacizumab exposed population from the Phase 1/2 trial, if you have that data?

Yes, I don't think we have that. We did not put that in the actual slide deck. But -- so I'd have to go back and look at that. I don't have that on my tip of my tongue here.

Okay. Last question for me then. Is there a scenario where you could potentially try to pursue accelerated approval for second-line KRAS mutant bevacizumab-naive colorectal cancer patients based on the ONSEMBLE trial, if the ITT-based analysis does not ultimately meet that stats?

Yes. I mean I think all things are going to be possible. And I think what we need to do is we're just excited to get this trial going, and we obviously are very intrigued by this finding with bev naive patients. But I think we just have to get things going, and we'll see what the data looks like.

Ladies and gentlemen, we have reached the end of today's question-and-answer session. This concludes today's conference. You may disconnect your lines at this time. Thank you for your participation and enjoy the rest of your day.