Cardiff Oncology Inc Aktie

Ladies and gentlemen, thank you for standing by. Welcome to the Cardif Oncology ASCO Data Presentation Conference Call. [Operator Instructions]. Please be advised that today's conference is being recorded.

I would like now to turn the conference over to [ Han Ertman of Astra Partners]. Please go ahead.

Thank you, operator. During this conference call, the Cardiff management team will make forward-looking statements, including, without limitation, statements related to guidance, results and the timing of data readouts for inventive clinical trials. These forward-looking statements are based on the company's current expectations and inherently involve significant risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties.

Factors that could cause results to be different from these statements include factors the company describes in the section titled Risk Factors in its annual report on Form 10-K filed with the SEC for the year ended December 31, 2025. Part of oncology undertakes no duty or obligation to update any forward-looking statements as a result of new information, future events or changes in its expectations.

With that, I will turn the call over to Cardiff's President and Chief Executive Officer, Mani Mohindru.

Thank you, Hannah, and thank you all for joining this morning. Good morning. We are very excited to share the promising results from our CRDS004 Phase II study, first presented yesterday at ASCO by Dr. Heinz-Josef Lenz, who is fortunately also with us on our call today.

Today's discussion will go beyond the ASCO presentation with additional data, analysis and insights that further strengthen our confidence in envansitiv's potential in first-line remediated metastatic colorectal cancer. We will also discuss our plan to next steps for the program following a successful end of Phase II meeting with the FDA this quarter. I'm very pleased that we have with us today, not one, but hopefully, 2 world-renowned GI oncologists. Dr. Heinz Josef Lenz from USD and we're hoping that Dr. Joseph Trevena from Barcelona, Spain should also be joining us. Should his plane get there in time.

Their clinical perspective would be very critical in answering some of your questions. Denton the slide, the clinical positions and institutional lifilations can be seen on Slide #3. I hope the slides are online. Okay. Following today's presentation, our CFO, Josh Muntner, will also be with me during the Q&A session. Going to Slide 4.

Operator. And Hannah can you please make sure that the slides are online? so assuming that the slides are there, if not, we'll move to Slide 4, which is the transition slide. Before we get into Phase II data, let me quickly highlight the significant unmet need in first-line restated metastatic colorectal cancer and the opportunity we believe Onvansertib is uniquely positioned to address.

The slides should be up there. If they're not, I will move to Slide 5, which the slides should be on our website as well. Slide 5 provides a high-level interview of Onvansertib, our PLK1 inhibitor that has practice-changing potential in first-line RAS-mutated mCRC. Pollak Kinase 1 or PLK 1 is an important target that plays an important role in cell division and tumor sic survival. Our strong confidence in advantativs potential is built on 3 key pillars: first, strong efficacy. The 30-milligram dose of Onvansertib combined with full fury and bevacizumab, which I will refer to as Cyber demonstrated 30% improvement in objective response rate or ORR with median progression-free survival of PFS that has not been reached in the treatment arm as of the March 18 data cut.

Of note, the 004 trial is still ongoing, with patients being treated on different treatment arms. These data are aligned with our prior Phase Ib/II trial in second-line weenie patients. We will go through our Phase II data in more detail shortly. Second, the large commercial opportunity. First-line RAS-mutated MCRC represents an area of high unmet need with limited innovation over several years. There are no therapies approved specifically for band RAS-mutated MCRC, except for KRAS G12C subtype. Onvansertib, upLK1 inhibition has the potential to address MCRC all RAS mutations.

And number three, the clear registration pack. We recently completed a successful end of Phase II meeting with the FDA, where we aligned on the registrational path in first-line RAS-mutated mCRC. The Phase III trial, CRD5, is being designed to support both accelerated approval via ORR and durability and full approval via PFS.

Slide 6. The next slide shows why our data matter and the patients we aim to treat. Approximately 150,000 new patients are diagnosed with colon cancer in the United States each year, with 20% presented with metastatic disease. Of this MCRC population, approximately 50% have cancers with as mutations and only a small portion of these have TLC mutations with the option to be treated with a line specific inhibitors.

First line standard of care for most patients with RAS mutations have remained unchanged for 20 years that is chemotherapy backbone of Folfox older series or FOLFOX ER combined with Bats. Unfortunately, the median 5-year overall survival is still only 15% with median PFS of less than 12 months. Importantly, with no approved therapies available for PAD RAS-mutated MCRC, we believe Onvansertib has the potential to address a major unmet need and become a first-in-class treatment of these patients, if successful in Phase III.

Slide 7 shows data from 2 historic Phase III trials that define the current standard of care in draft mutated disease. Or in the 40% range with IFL plus BEV with PFS of 9.3 months versus 5.5 months with chemo alone. The TRI trial of wholefoxing rebar, a less tolerable regimen shows a 66% of RR in Ras-mutated subgroup and a PFS of 12 months with less than 3 months of improvement over chemo. These are some of the benchmarks the field has been working against and we believe CRDS004 Phase II data compares favorably to these established outcomes.

Next slide. With that context in mind, let's turn over to CRD4 results and the data that underpin our confidence in advances. I highlight the promising updated interim results from the Phase II trial that we presented by Dr. Lenz at ASCO yesterday, along with additional analysis and data not included in the ASCO presentation. All results are based on March 18, 2020 data cutoff.

Slide 9 shows the trial design of CRTS004, our dose-finding randomized controlled Phase II trial. Enrollment criteria required first-line MCRC with KRAS or NRAS mutation. Key exclusion criteria or BRAF V600 mutation, MSI-high or deficient mismatch repair tumors, resectable disease and prior bet treatment. The trial was designed to enroll 110 patients, the IIT population across 6 arms in equal randomization. The 6 arms tested 2 doses of onvansertib, 20 and 30-milligram combined with either 43 per or for Fox Bet the 2 standard-of-care regimens compared to each backbone alone as control. The goal of this trial was to determine a dose and regimen to bring forward into further development.

The primary endpoint is ORR, assessed by blinded independent central review or biker and secondary endpoints for duration of response and PFS.

Slide 10 shows the demographics and baseline characteristics that were largely balanced across all 6 arms for a trial of this size and this stage in development. Of note, the trial did enroll patients with liver mets and multi-organ involvement to patient populations with worse outcomes on the current standard of care.

Slide 11 shows the current status of the study as of the March 18, 2026 data cut off. Importantly, the trial is still ongoing with 13 of the 14 patients still in the study are from the Onvansertib plus standard of care chemo per arm. And 9 of these patients are Onvansertib plus 4 for Bev arm, the chemo combination, we intend to take forward in the Phase III trial.

Next slide, Slide 12, shows the primary endpoint of ORR. I just want to walk through it a little carefully given that it's a primary endpoint. As you can see on the right side of the slide, in the 30-milligram Onvansertib plus whole series Bev arm confirmed ORR by Picker was 72.2%, and the FCD bev control arm showed an ORR of 42.1%. That is very encouraging 30 percentage point improvement over standard of care in this randomized study.

In the middle, you can see that the 20-milligram arm showed an ORR of 44.4% and with some deeper responses versus the control arm, indicating some dose-dependent effect and confirming that 30-kilogram is the more active dose. This is also supported by PK exposure response analysis, data of which are not included here. The combined ORR for both 20 and 30 minimum value olives 58.3%. Importantly, 9 patients remain on treatment in the advances FOLFIRI Bev arm and only 1 patient in the full very best control arm, as shown by dark arrow heads. And the depth of response in the 30-milligram arm is also quite notable.

This waterfall plot analysis shows that the majority of patients achieving substantial tumor shrinkage, including several with near-complete or complete responses.

Moving on to the swimmer plots on Slide 13. This slide also tells an equally important story about durability. In the 30-milligram FOLFIRI BEV arm, 4 patients have been on treatment for more than 15 months as of March 18 data cut with 2 on greater than 18 months of treatment.

Slide 14, this pride a plot slide shows individual patient tumor burden trajectory. In the 30-milligram Onvansertib plus FOLFIRI Bev arm, the majority of patients showed sustained progressive tumor shrinkage over time. In our view, this promising profile is consistent with the therapy producing durable clinically meaningful benefit.

Next slide, Slide 15, shows progression-free survival, including Kaplan [indiscernible] for BFS. When comparing both advanced doses together plus 4 per bet against combined standard of care regimen, the hazard ratio by bigger analysis is 0.4 with a median PFS that has not been reached in the Onvansertib arm versus 11.04 months in the control arm.

The investigator-assessed hazard ratio is 0.5, with the median PFS, again, not reached in the invasive arm versus [ 10.97 ] months in the control arm. With sample sizes of approximately 36 to 37 patients per comparison, the directional signal is very encouraging and consistent across both assessment methods.

For a study of this size that is not powered for PFS, these are very promising trends.

Moving to Slide 16 and looking at the selected Phase III dose specifically, the 30-milligram on Onvansertib plus 4 Fred regimen. Median PFS has not been reached in the treatment arm and some patients continue to remain on treatment. Median PFS in the FOLFIRI Bev control arm was 18.8 9 months by bigger and 12.2 2 months by investigator assessment.

The hazard ratio by Bicker an investigator assessment are very similar at 0.55 and 0.57%, respectively. The slight discordance between Becker and investigator-assessed median BSS in the control arm, reflects the phenomenon seen in early stage or even some Phase III studies. In certain of our cases, investigator assessed and recorded progressive disease and sorry, investigators assessed and recorded progressive disease and discontinued these patients prior to their bigger confirmation.

Moving to Slide 17. The overall forest plot -- on this slide compares 30-milligram on vanity plus Pref versus 4 series bar control arms across various baseline characteristics as shown. The overall benefit consistently favors treatment arm across all subgroups. This is highly encouraging and indicates that the efficacy signal is not driven by any single patient characteristics.

Notably, benefit with Onvansertib plus FOLFIRI is seen even in difficult to treat subgroups, such as those with liver mets as well as multi-organ involvement.

Slide 18 shows forest plot for subgroup analysis for PFS. The PFS forest plot shows the same pattern as the ORR forest us. Hazard ratio favors the 30-milligram arm across all subgroups. Given the small patient numbers within individual subgroups, confidence intervals are appropriately wide, but the directional consistency across every subgroup strengthens our confidence in the overall signal and the meaningful clinical benefit of Onvansertib in this patient population.

Slide 19 highlights the safety profile of Onvansertib and shows that it is quite tolerable. Adding Onvansertib to FOLFIRI bev or FOLFOX bev does not introduce unexpected overlapping or new toxicities. The most common adverse events are consistent with the known profile of the background chemo and bet regimens.

Grade 3 or higher events are comparable across arms and no unusual or unexpected on vast specific safety signals have been identified. This safety profile is supportive of the Phase III program in the first-line setting and also highlights the differentiation of Onvansertib as a tolerable agent that can be potentially added to other synergistic chemo combination.

Moving to Slide 20 that shows FOLFOX combination data. Similar to what we had reported in January of 2026, I want to mention again that adding Onvansertib at either dose to the FOLFOX Best regimen did not produce very meaningful improvement in ORR or PFS versus 4 box beveralone, although we do see some improvement in a few patients. ORR in all FOLFOX arms range from 44% to 56% with no consistent dose response trend and no PFS benefit observed with the Onvansertib addition.

While this combination did not show much additive benefit, it is not completely unexpected, and I will address the scientific rationale for Onvansertib synergy with FFR versus Fort in the next couple of slides.

Moving to Slide 21. We have some data-driven mechanistic explanation and hypothesis as to why Onvansertib synergizes better with FOLFIRI and not FOLFOX. Both Onvansertib to PLK1 inhibition and irinotecan, the active component of holes, suppress HIF-1 alpha a critical driver of tumor vascularization and survival in the hypoxic tumor microenvironment. The result is a triple anti-antigenic effect, Onvansertib suppresses with an alpha arena the cancer presses F1 alpha and the best treatment block VEGF, which is vascular growth factor.

Additionally, unvested likely also inhibits PLK dependent DNA repair, downstream of irinotecan induced DNA damage, which highlights a second mechanism of synergy between Onvansertib and irinotecan. In contrast of Oxaliplatin in the backbone of Folfox does not suppress this 1 alpha and uses the DNA repair mechanism with limited PLK1 dependence or no meaningful role.

These mechanistic differences between irinotecan and oxaliplatin may explain the absence of synergy with FOLFOX and differential outcomes in the current study. But more importantly, CIDS004 is the second trial where we see synergy of the invasive with 4 per bets. Our prior Phase Ib/II trial was Onvansertib plus 4 pets in second-line in [ Bednife ] patients with KRAS-mutated NCRC, also showed improved clinical outcomes with the chemo regimen. -- reiterating our confidence in taking this regimen forward in the Phase III.

As shown on Slide 22, we believe that CRDS004 trial achieved all key goals and endpoints needed to move the program forward into a registrational trial. The primary goal of dose selection is complete. 30 milligrams of Onvansertib plus FOLFIRI is the dose and regimen we plan to advance into a Phase III trial after discussions with the FDA during our end of Phase II meeting. This dose and regimen demonstrated both superior efficacy and an acceptable safety profile.

The primary efficacy endpoint of ORR was met. 30 milligrams demonstrated compelling ORR of 72%, a 30 percentage point improvement over standard of care. The secondary endpoint is also quite favorable and promising. As of the March 18, 2026 data cut, median PFS has not been reached in the 30-milligram arm with 9 of 14 patients still on Onvansertib plus FOLFIRI bev treatment at the time of data cutoff.

The strong Phase II data support advancement of Onvansertib registrational development, and I will discuss our plans in the next slide.

Slide 24 shows the trial design of our proposed pivotal Phase III trial, CRDS004. CRD- sorry, CRDS005. CRDS-005 is designed as a global registrational Phase III study. While we will continue to refine some elements of the trial, Shown here is the design of a pivotal trial after feedback from the FDA at our end of Phase II meeting completed in the second quarter of 2026. EMA feedback is pending.

The trial as designed is a randomized controlled study with 1:1 randomization of patients to 30 milligrams of vanity plus whole very wet treatment versus 43rd treatment alone. Enrollment criteria are consistent with the CRDS004 trial, first-line NCRC, presence of KRAS or IndASmutation, no BRF600 mutations no MSI-high or deficient mismatch repair, unresectable tumors with no prior bev treatment.

The studies to all primary endpoints are ORR, which supports accelerated approval and PFS, which supports full approval. Secondary endpoints include duration of response and overall survival. The proposed sample size is approximately 640 patients powered at greater than 90% to detect differences in both ORR and PFS endpoint.

Moving to Slide 25. Let me close with a few points. Number one, there have been no meaningful therapeutic advances in first-line RAS-mutated MCRC over many years. The unmet need is large and the commercial opportunity is significant.

Number two, we now have a clinical trial outcomes from 2 studies, our prior Phase I/II study in second-line RAS-mutated mCRC and the current ongoing CRDS-004 randomized controlled Phase II trial in first-line RAS-mutated NCRC that both confirm that inventive synergizes with 4 series in bet naive patients. This is a reproducible and promising signal supported by scientific data and mechanistic rationale.

Number three, in the ongoing CRGS-004 trial, 30 milligrams Onvansertib with FOLFIRI bev shows an ORR of 72%, 30 percentage points over standard of care with a median PFS not yet reached in the treatment arm and patients on treatment beyond 15 to 18 months, and no meaningful safety signals have been observed.

Number four, we have FDA alignment on the Phase III design with a path to both accelerated and full approval if successful.

And number five, going forward, our focus remains single handedly on the execution of the pivotal program. Before opening the questions, I would like to -- I would like the call I would like to turn the call over to one of -- to both of our KOLs, but I'll start with Dr. Tabernero, first, but I would first like to thank him for joining this call shortly after landing in Spain. Dr. Tapiero will provide...

Thank you very much. Thank you. I'm sorry for being a little bit late by my flight from also in the land. Well, I think that the or lamps for sure can provide more uprate sites. All this data is just 1 day ago, and there was other interaction and pressure because -- actually the data was really very exciting during the session that had on Tuesday morning at Ascom.

Perhaps just to complement on what has been mentioned before on I completely agree that there are no new treatment options that we foresee for this difficult to treat population. And one may raise whether with a number of -- there are specific isospecific as inhibitors pan ainhbitors, Pan-RAS inhibitors. Actually, there is an opportunity for a compound like on uncertain.

And my answer is yes, basically because the data that we have seen at ASCO with a [indiscernible] RAS inhibitor for pediatric cancer, it's very exciting. And everyone is very happy about this situation for a difficult-to-treat population. But combinability of pandRAS inhibitor with conventional chemotherapy plus bevacizumab is something challenging, right? And in here, we have a compound that has demonstrated much very well with chemotherapy, especially with fire and results that have been presented are spectacular.

So I do fully support trying to evaluate the activity of 1 set combined with FOLFIRI in the first-line setting of this patient population with KRAS and NRAS mutations. And actually, I think the design that has been presented. It's really very good to demonstrate the proposed dual primary endpoints.

And honestly, I think that this trial would recruit very, very well. But happy to answer any specific questions that you may have.

Thank you. Thank you, Dr. Tabernero. Dr. Lenz, I'd love to hear your perspective as well and especially since you have experience treating patients with this drug.

Sure. Yes, I have been involved with the Onvansertib at the beginning. We did the first Phase I trial. And I was particularly excited about the incredible inhibition of PLK1 and interferon with really the major cycling pathways. You heard about the inpatients. It overcomes chemoresistant by really interfering with the cell cycle arrest and it has actually even modulator.

And then with the preclinical data showing the significant synergies notion because in ticket established trended D&A effect and Ocean or DNA Ada, it explains very well the differential in nutrition between Onvansertib and Ibanez and we saw very early on clinical secret of efficacy.

I think what weaning out that this drug is very well tautovated. It's 5 days of our medication out of the 2 big cycles and patient tolerated variable. So when I looked at the new data and we have the Phase Ib and the patient with no prior betadizumab treatment had 71%. That really was the basis to develop this randomized Phase II, which now really confirmed the significant synergism between FOLFIRI and [indiscernible] with no safety thickness.

I think I'm very excited about the 62%. I'm very excited about the hazard ratio of PFS. And I think Dr. Taperneiro is completely correct. I think there are para-inhibitors, which show some interest in imply but the problem is really the toxicity limiting combining these Pavas inhibitors that any kind of chemotherapy or targeted agents. And this is one of the few trials, which actually showed that we can combine easily on [indiscernible] safety sickness and no toxicity and high efficacy.

So I think this is a very, very promising strategy, and I can only hope that this will go into a registration as soon as possible that we can apportion to really advance that field.

Thank you so much. Thanks so much for your perspective. Operator, we can now open the line for Q&A.

[Operator Instructions]. Our first question comes from Maurice Raycroft with Jefferies.

This is Amin on for Maury. Two from us. First, you've seen a clear ORR separation between the 20 and 30 man -- how should we think about the durability across the 2 doses? And are you seeing a meaningful PFS separation between the 2 doses?

And one question for Dr. Lenz and Dr. Tapernaro among patients with last inpatients, you think most slightly to benefit from adding online cert and to the supposed bone? And are there specific clinical features you're focused on for patients who can benefit the most from this drug?

Probably I'll take the first question, and then I'll let the 2 KOLs answer the second part. On the first question of 20 versus 30 milligram, if I understood correctly, the separation in ORR and how does it tie to durability? Is that right? Amin?

That's correct.

So yes, so the 20-milligram showed an ORR of around 44% and the 3-milligram approximately 72%. So we do see a dose trend, although the 44-milligram sounds closer to with standard of care. However, we do believe that 20-milligram is an active dose. We have internal data, which shows overlapping PK between the 2 doses and there is a dose response exposure response relationship as well.

Secondly, the PFS benefit that you see with 20-milligram also shows the hazard ratios between 20 and 30-milligram by investigator assessment also show a dose-dependent trend or an improvement. And this is not unusual. If you go back to the slide where I had shown initial addition of BEV on IFL and BEV on FOLFOX and irenotecan you can see that Ben did not add too much to the ORR but had significant improvement in PFS. So it may be these patients and the Knowles can talk to a bit more -- but we do believe a 20-milligram is an active dose, but certainly 30-milligram is a dose that provides the punch needed to take the pace I'll start with Dr. Lenz first and then go to Dr. Tapiero for the second part of the question.

So if I understand you, your question was really if it applies for all vast mutation. And if there are specific patients who benefit the most.

That's correct, yes.

So from our data, we do not see that certain mutations have less or more benefit. It seems to really like the par margin EBITDA affecting all the CMS mutation as well as the vast mutations. And the reason is very easy because we are not binding to a very specific VAS mutation, which limits the use and the development of allele-specific inhibitor it's a downstream event of the downstream signaling interfering with all major oncogenic pathways.

So we don't see a particular indication that some of the classes of the [indiscernible] mutations have differential benefit.

What was the second part.

I think that was it. That was it.

That's what it Okay. So I think this is a very unique target because it really interfered with the downstream ongoing activate in itaas and [indiscernible] and not depending on the binding affinity or characteristic of allele-specific or pan-banhibitors.

And Dr. Tabernero, if you have any specific opinions about what kind of patients with RAS mutations would benefit with a drug like Onvansertib?

So I fully conclude on your answer and Professor's line answer, right? So -- the important thing here is that the RAS signaling independently of the KRAS and Enamotations that the tumor of the patient fares. It's very constant, right? -- and the profound effect that it uses in the ER pathway is very similar. This has been very well documented in several people. I remember one publishing clinical cancer research where they look at what the outsource, look at what they call RAS signaling a score.

And they evaluated the different different cells and different in vivo models with different RAS and RAS mutations. And RAS signaling the score was very similar in terms of activation of the pathway, right? So I don't foresee that there are going to be differences in the profile of patients depending on the RAS mutation that the tumors were for the activity of Onvansertib.

Yes. And I wanted to follow up, you also mentioned a very important point. So we obviously look for KVANS and [indiscernible] mutation. But in a large study we published a couple of years ago in the landed showing the efficacy of cetuximab in wild type as because the K-bas mutation were excluded. And as Joseph mentioned, is there were wild-type patients who had activated oncogenic sickling in the vast pathway, which did not respond.

So I think the onvansertib also work in this patient population based on the activation downstream pathways. So there is certainly a very interesting aspects biologically, which would expand that to certain biotype patients if we can identify the activated pathways down between.

The next question will come from Marc Frahm with TD Cowen.

Maybe just on the -- to start on the trial design for the proposed Phase III that came out of the FDA meeting. Just you've mentioned the potential for accelerated approval on response rate. Can you maybe discuss when that analysis would be able to be taken within the trial -- do you need the full enrollment of the entire trial? Do you need a response rate on everyone? Or could you take that on a much smaller sample than the full 640 that you'll need ultimately for PFS and full to [indiscernible].

So without going into every detail of our discussions with the FDA, broadly, I will say that, yes, the FDA did give us guidance as to what could lead to ORR-based accelerated approval, 1 of which I will say was that they expect the trial to be fully enrolled and also to make sure there's no detrimental survival. So I will start with that. So while there is a path forward for accelerated approval with a certain number of patients and durability data we believe that the trial has to at least be fully enrolled by the time we take it to the FDA. Not fully read out yes, not fully readout definitely.

Yes. Yes. Okay. And then just on the data that you presented, can you maybe speak to the relative dose intensity that you're able to achieve with the chemotherapies in the different dosing arms? And is there any chance that some relative differences in tolerance of the chemo may be contributing at least some of the apparent treatment effect?

So let me begin by talking about safety first. The safety profile is very similar across both chemo regimens, FOLFOX and FOLFIRI. In terms of tolerability and if there were any kind of dose reductions or dose discontinuations of chemo, there are differentials in the irinotecan arm, we hardly saw any reduction in ore discontinuation in irinotecan. However, in Oxaliplatin or FOLFOX regimen, there were just continuations of the oxaliplatin regimen, but that is not unusual. That is similar to what has been reported in everyday practice. And I would let Dr. Lenz and Dr. Tabanaro comment on that as well, like do you actually discontinue oxaliplatin in fuel patients based on tolerability because that's what we saw in the study as well.

Yes. So usually, when you have an effective chemotherapy FOLFIRI, you don't have really a cumulative toxicities as you have with oxalate as you probably know that Folfox many of the investigators pools or stop the oxaliplatin in after 4 months of treatment because of the anticipated neurotoxicity. You have also a little bit more differential hematological tox with oxalate with more thrombocytopenia and particular anemia.

In the fulfill regimen, you see actually usually very well tolerated. And in our clinical trial, we did not really have significant holding of treatment or dose modification. So it's a very safe, very effective treatment regimen. And the reason I think FOLFIRI not only biologic agreed partner because you can actually treat Tilt progression with no cumulative toxicities over time.

Thank you, Dr. Lenz. Dr. Tabernero, do you want to add anything to it?

Yes. Well, if the truck has -- so premetal that does not have any interaction with none of the conference of for firm, and this is ratio, but also the first [indiscernible] and 38 local volume usually, the combinations are really very tolerable. And the advantage of 3 compared to Folfiri compared to Folfox, you can really treat patients until presides or an acceptable toxicity. Because usually, you don't have any kind of toxicity that mandates reducing or meeting the ironic and treatment on the midterm on the long-term basis.

As you know, with Oxaliplatin, although it's a very preferred chemotherapy backbone -- there are several aspects that limit the compliance and and dose intensity of oxaliplatin. But this is not only with this drug is with all experimental. And on top of that, actually, everyone knows that after 4 months of treatment because of the increasing sensitive polyneuropathy, oxalipatin has to be out, right?

So and this is the reason on top of the efficacy and safety data that fulfill it's a well-centered regimen and medical minable. Just to put you other examples, right? So -- also at ASCO, we have seen the data of another situation, and this is what we retapepulation in metastatic colorectal cancer and the data has been presented to this location is a combination of fulfilling for [indiscernible] metal population.

I want to make clear that is a different population. But importantly here is that the combination was very tolerable. -- and those patients could be treated for many, many months. And in this particular case, actually even results were slightly better than with [indiscernible]. So I do think that all these aspects fully support the full fee combination.

And maybe it's also interesting that particular in Europe and Asia for FOLFIRI ffer as a backbone is a preferred combination treatment. In the U.S., it's usually FOLFOX Bev, but with the data showing like the cardio study, the efficacy or was farms decisions, what we do because they're equally effective when you compare side by side, but if the combinations show significance in attrition, I don't think there is any issue to use that also in the U.S.

I agree with Professor Lenz. So at the end, physicians and patients, of course, -- the final preference for the Trion options is the activity and the safety, right? And I don't think that this trial is going to be ecruiting very rapidly.

Thank you, Dr. Lenz and Dr. Tapernaro. Operator, the next question.

And the next question is going to come from Andy Hsieh with William Blair.

So now we have full results, efficacy PFS median hazard ratio 004 study. And I'm curious for the Stevie,maybe just kind of an expansion from Mark's question earlier. In terms of PFS, I'm curious if you can kind of describe what level of risk reduction you expect from the 640 patient sample size.

We also have a question for Dr. Lenz and Dr. Tapanaro terms of Spider plot we saw some dramatic reductions on the Onvansertib in around 6 from the FOLFIRI cohort. I'm curious if you can describe the nature of these patients. Do you see those dramatic reductions pretty common or it's kind of a rare occasion or and your PC phenomenon. I'm just curious about your thoughts on that.

And lastly for Mani, maybe just in terms of Nerviano what is the next step that we can expect regarding potential resolution or how to go forward.

So maybe -- thank you, Andy. I'll start with the third, first and poorest and then we can focus on the scientific discussion. So regarding Nerviano, as you know, we are in dispute, and we tried to resolve the dispute outside of court but reached a point where we felt that it was quicker and more expedited, it was important for us to get this resolved in a more expedited manner, and we sought legal intervention.

The dispute was related to obviously autoship or inventorship in our patents, which we believe are still not a patent based on the inventorship, and they -- we will continue to defend that. And regarding commercially reasonable efforts, we have made a lot of effort getting the program to this point and into Phase III.

So we will continue to defend our position, and we hope to reach a resolution very soon. We are open to resolution in and outside the core. So with that done, I will address the first question about the size, whether the size of the Phase III study can be reduced. It is too early and premature to comment on reduction in based on the current data. the CRDS 004 trial is still ongoing.

Median PFS hasn't been reached, but we have designed the study, the CRD5 study to ensure that we have a higher probability of success. The powering and all has been made with keeping that in mind that we power the study adequately for both accelerated and full approval with BFS. And I will let Dr. Tabernero, maybe start first. On the spider plot, the deeper spider plots that you see? Is it unusual? Is it -- do you see it with other therapies or not.

Thank you for the question. Actually, I think that the data with the forest plot is really amazing, right? I have to tell you and for that, actually, it's very good to to see new activity in terms of a towards [indiscernible] was also response rate that we have for -- even for the control arm, right, that is 42%. And this is not -- it's in the restructure.

So both 3D be from Ford Web usually, the response rate when it's independently reviewed by external radiologies is around 38%, 40%, right? And that the data that we have in the control arm really fits what is expected for the control on, right? But when you go to the experimental as, I think that the data that we have on overall rate for file, especially at the dose of most of 30 milligrams with overrespond rate confirmed 72%. This is amazing.

And it's not only that, but when you look at the the forest plot evaluating patient by patient, actually, you see that it's not only about the robust fund rate, but it's also about the patients that have disease control. So you can see that only one patient actually had a slight increase by 8% in the vision, right? All the others had any kind of tumor synchros, but again, the impressive 72% of response rate, it's really amazing for a combination of FOLFIRI in this setting, right?

So without any doubt, the addition of discremental rag on [indiscernible].

Dr. Lenz, would you comment on your perspective on the depth of responses on not.

So whoever as is a very smart person, and I think this is really a standout observation because usually, it takes 4 to 5 months to really have the full response and in many patients in this 1 particular one, it was very fast.

So I think there is a very unique dynamic. And when you look at the waterfall plot, patients had basically no detectable disease out of '18. So I think -- this rapid response as Dr. Tapanero mentioned, is very unique. The are there's basically not an innate resistance. And it seems the duration of response is very long. It almost looks like in monotherapy efficacy profile.

So I think we have -- I don't think we have a very good understanding who these patients are. We had in the Phase two, we look for the crediting the DNA with specific measurements of the mutations of the patient and the ones who had more than 90% within 4 weeks, and it was a very rapid decline in that one.

These patients did the best, but that was relatively a small patient population. But I think highlighting this significant dynamic and fast response of these patients.

Thank you, Dr. Lenz. And Andy, if I understood apologize we have misunderstood your question. So if you were trying to ask statistical assumptions that led to the design and the size of the study based on PFS movement. Again, without divulging all the details, we have been conservative in designing the study. So it's not as aggressive at 0.5 hazard ratio that have been reported in 2 we bend in and the prior Phase II to Phase III results, we have taken that into account while designing the size of the Phase III study. I hope that answers your question.

Yes, Yes, I was asking about the not about sample size, but about the risk reduction.

Yes, we have been conservative is what I can say in our assumptions. Operator, the next question, please.

And our next question is going to come from Albert Lo with Craig Hallum.

I think, Mani, you referenced it in your comments that the 20-milligram dose with Fuller bet is active. But could you share what the PFS and hazard ratio was for the specific dose arm?

Yes. So the median PFS hasn't been reached, but we did not share the details of it. I'm happy to share, but it is I don't have it at the top of my mind, but it is a little bit higher. The hazard ratio is higher than what has been reported with the 30-milligram arm with the investigator-assessed metric. And I don't have it at the top of my head, but it is directionally, if you look at the investigator assessment based analysis, it is directionally the hazard ratio is a little bit higher than what has been reported at the point, it's higher than 0.5 million. o

Phase 3-milligram is in [indiscernible] yes.

Yes. I was wondering what's the time line for potentially starting this Phase III trial? And could it begin while this license agreement dispute is still outstanding?

So pending funding, we expect to start the Phase III initiation related activities late this year, early next year. This litigation or this dispute is ongoing. And I don't think we -- it impacts any of our activities because -- for us, the license agreement is still active and the patterns are are. So from our perspective, it is business as usual.

And the next question is going to come from Christopher Lu with Lucid Capital Markets.

Congrats on the data. So 2 for me. I guess for the first question, have you guys done any kind of analysis to discern why there's such a stark difference in efficacy between the 20-milligram and 30 milligram, any additional analysis?

And then for the second question, quite a few patients in the 30-milligram arm were able to get 100% tumor aggression in the target tumor. Just wondering what kind of made those patients go off treatment?

So maybe I'll start on the 20 versus 30 milligrams. They do have overlapping -- so there is -- but there is a dose exposure versus response relationship there, both in terms of ORR and PFS. -- while there wasn't as much of a difference in the overall were definitely different. And as I said, with Avastin, you have seen a similar phenomenon where you don't see too much of an impact on ORR, but much more a benefit with BFS. So -- we similarly see that in '20 versus 30 milligrams. The trial is still ongoing.

We will continue to do more exposure-based analysis. But from our perspective, we have the right dose to take forward in the Phase III, and we also believe that 20-milligram dose is active, maybe not as high as 30-milligram dose. And remind me what was patient tumor reduction.

Yes. So on the second question, with the 30-milligram dose, you said that patients had very deep responses. There was a lot of reduction in target lesions. And they continue to be -- most of them continue to be on treatment for a long time. We will continue to assess and come up with the median PFS there. there were discontinuations leading due to various reasons, but very few to progress in disease. I can tell you that the 30-milligram arm, they were very few due to progressive disease.

There could be other reasons whether related to patient decisions. Actually, 5 patients went on curative surgery as well in the 30-milligram arm. The highest numbers of patients who went on curative surgery was with the 30-milligram arm. So hopefully, that answers your question.

That's a very important point because I think with higher efficacy with response rate over 70%, we will see more and more patients who will become eligible for cure resections -- and I think it's very important to know colon cancer is a very unique cancer. If you shrink it and you can resect it and removed with metastatic disease, these patients have a good chance of cure. That's not true for many other solid tumors.

In breast cancer, you can never here a metastatic disease. In colon cancer because of the biology, if you can remove these metastatic sites in really well-controlled metastatic cancer patients, you have a very good chance of cure. And these patients obviously depending when they had a really good pathological response and how much treatment they got may not continue or may not need further hope.

Thank you, Dr. Lenz. And yes, and hopefully, we'll be able to publish the full results of the study in the coming months where you can see, but I can tell you that, yes, the most number of teratosurgeries were in the 30-milligram on [indiscernible].

Next question, I think we're coming at the top of the hour Operator, do you have any more questions?

No, I am showing no further questions at this time. So I'd like to turn it back over to Mani for closing remarks.

Thank you, operator. Before I conclude, I would like to thank the patients and their families who place their trust in our clinical trials. Their participation makes this work possible and is just the foundation of the data we shared today. I also want to recognize our investigators, especially Dr. Lenz, our advisers, consultants, Dr. Tapernaro for stepping on to this call right after landing in Spain. Our investors and importantly, Cardiff's employees for their dedication and commitment.

We believe today's results represent an important step forward and further strengthen our confidence in the potential of envansitib enrapetated MCRC and beyond. While there is still work ahead, we remain focused on advancing this therapy for patients and creating value for stakeholders. Thank you for joining us today, and we look forward to updating you on our continued progress to the registrational trial. Thank you, everyone. Have a good day.

Thank you.

This concludes the conference call. Thank you for participating, and you may now disconnect.

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

Thank you, operator. Good afternoon, everyone. My name is Mani Mohindru, and I'm the interim CEO of Cardiff Oncology. Thank you for joining today's webinar, where we plan to discuss the evolving treatment landscape in first-line RAS-mutated metastatic colorectal cancer or metastatic CRC. We will also discuss the recently shared clinical data for our novel, highly selective PLK1 inhibitor onvansertib and its potential to improve outcomes for metastatic colorectal cancer patients when combined with the standard of care therapy.

March is a national colorectal cancer awareness month, decade to increasing understanding of the prevention, detection and treatment of colon and rectal cancers. According to the National Cancer Institute, more than 154,000 patients in the U.S. were diagnosed with collateral cancer in 2025 and nearly 53,000 died from the disease. Despite decades of research, first-line RAS-mutated metastatic CRC has seen limited progress, underscoring a significant unmet need. On that note, I'm very pleased to be joined by 2 globally recognized leaders in GI oncology, Dr. Heinz-Josef Lenz and Dr. Steve Kopetz. Dr. Lenz and Dr. Kopetz, thank you both for being here and for joining this discussion.

Let me begin with a brief introduction of each of our speakers. Dr. Lenz is a university professor of Medicine, preventive medicine and cancer biology at the University of Southern California. He holds the J. Terrence Lanni Chair in Cancer Research, is the Deputy Director, Deputy Cancer Center Director and Core Director of the Brown Center for Cancer Drug Development. Dr. Lenz is a globally recognized leader in GI Oncology whose work has helped shape modern precision medicine. His contributions include establishing primary tumor location and gene expression subtypes as key predictive and prognostic markers now reflected in international guidelines as well as pioneering the use of next-gen sequencing in large Phase III trials. He played an important role in the development and approval of multiple therapies in colorectal cancer, such as cetuximab, regorafenib, TAS-102, nivolumab and ipilimumab and has authored more than 650 peer-reviewed publications. We are very pleased to have you here, Dr. Lenz.

Hello.

Dr. Kopetz, he serves as the Professor and Deputy Chair in the Department of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center. He is also the Associate Vice President for Translational Integration and the program leader for genetics and gene regulation in the division of cancer medicine. He's a leader in translational oncology serving as principal investigator of the institutions gastrointestinal SPORE, co-leading the CCSG GI program and colorectal cancer Moonshot and helping drive rapid clinical translation through MD Anderson's traction platform. Dr. Kopetz has authored more than 400 peer-reviewed articles in leading scientific journals and his work has been instrumental in advancing new standards of care, particularly in patients with a BRAF-mutated colorectal cancer.

Before I begin this discussion today, I would very quickly remind everyone of the top line data that we shared earlier this year. I will be sharing a few slides to recap our data and then begin our conversation with Dr. Lenz and Dr. Kopetz. So if I can have the slides on. I will be making forward-looking statements during the course of our discussion today. So I would advise everyone to look at our risk section as mentioned in our Form 10-K.

Just to recap our study design, the study that we just announced top line data from, it is an ongoing Phase II study, which is a dose-finding study in RAS-mutated first-line metastatic colorectal cancer. The enrollment criteria are pretty straightforward, first-line patients with KRAS or NRAS mutations with unresectable disease, who have not been previously exposed to bevacizumab. It is a 110-patient study, which with 3 main randomization arm standard of control onvansertib, 20 milligram and 30 milligram, which are further randomized to based on the standard of care chemotherapy which includes FOLFIRI/bev or FOLFOX/bev, along with combinations of the 2 doses. On the right, we have how we administer onvansertib. Onvansertib is given on days 1 through 5 and then again from days 15 through 19 on a 28 -- in a 28-day cycle. The primary endpoints of the study were objective responses and the secondary endpoints were durability responses of duration of response and PFS.

This is a busy slide. It is on our website, so you can take a look at the patient baseline characteristics across all treatment arms, pretty standard for what you would expect for a study like this. I do want to mention that we did include patients with liver disease and multi-multi-organ metastasis in this trial as well. These are our objective response rate data. Just to orient you to the slide, these are intent to treat analysis based on [ Becker ] independent review. The first panel refers to standard of care, which is a combination of patients -- all patients who were exposed to the 2 standard of care arms FOLFIRI/bev or FOLFOX/bev. The second one is FOLFIRI/bev standard of care alone and the next 2 panels are in combination with 2 doses of FOLFIRI, FOLFOX. As you can very quickly see that with the onvansertib 30-milligram arm in combination with FOLFIRI/bev, we do have a number of patients showing objective responses leading to an objective response -- overall objective response rate of 72.2%. Not only are there objective responses, but they are much more deeper when we look at the standard of care. So you have greater depth of responses as well as the number of responses that we got with our 30-milligram arm. The 20-milligram arm had only a very modest increase in the total number of responses. However, we did see the depth of responses like we saw in the 30-milligram arm. And the 2 standard of care arms that you see here behaved very similar to what has been historically reported, around 43% in 2 arms.

So the next slide here shows you some durability measures that we have shared the top line durability mess that we have shared. Again, to orient you, this is the FOLFIRI/bev arm, the first column. The second column is 20 milligrams of onvansertib given with FOLFIRI/bev and the last column is 30-milligram onvansertib with FOLFIRI/bev. If you look at the median progression-free survival in the FOLFIRI/bev arm, it's approximately 11 months. similar to what has been reported in prior studies. However, we have not reached a median progression-free survival in either 20 or 30-milligram onvansertib arm. So this is a very promising sign that we believe that the drug is continuing to show benefit, not just at the objective response level but also durability.

If you look at the PFS hazard ratios when compared to FOLFIRI/bev alone, again, you can see a dose-dependent improvement. You can see a hazard ratio of 0.56 in the 20-milligram arm and hazard ratio of 0.38 in the 30-milligram arm. Similarly, if you look at the PFS hazard ratio, when you look at the combined standard of care when we look at combined FOLFIRI/bev and FOLFOX arms, There, too, you see that in the 30-milligram arm, you have a hazard ratio of 0.37 which actually did reach statistical significance as well, p-value less than 0.05 even though the study was really not powered to show a difference in the PFS. And this is a landmark analysis of PFS rate at 6 months, which continues to show improvement over the standard of care and in a dose-dependent manner favoring the 30-milligram arm. So this is like the totality of the data. You cannot share efficacy data without tolerability. So this is a snapshot of our tolerability data as well. This is on our website in our corporate presentation. I will not go through all the details but the general impression is that we really don't see much additive toxicity on top of the chemo regimen. And most of these arms look very, very similar with maybe slight increase in some of the toxicities, but just numerically.

Just to summarize again, I showed you the confirmed responses are going up to as high as 72% in the 30-milligram arm, almost a 30% improvement over FOLFIRI standard of care. We have not reached PFS in either the 20 or the 30-milligram of unmandated arm in combination with FOLFIRI, FOLFOX and the hazard ratios continue to look very promising whether we look at the combination of standard, whether we look versus the combined standard of care or with FOLFIRI. No added toxicities. So based on the totality of the data that I shared, we have chosen 30-milligram onvansertib as the dose to take forward in combination with FOLFIRI/bev in the registrational program which we are going to discuss with the FDA and finalize the plans there. I do want to mention that I did not share full detailed data of FOLFOX combination with onvansertib. But as we have previously stated, this combination did not demonstrate consistent benefit across the 2 dose levels. So we are not taking this forward at this time in the Phase III study.

With that, I am going to end my presentation, so -- and move on to the discussion part of our webinar.

Okay. Welcome again, Dr. Lenz and Dr. Scott -- I'm sorry, Dr. Kopetz. So let me begin by asking my first question, since we are talking about frontline patients, when you see a first -- when you see a patient who's been just recently diagnosed with metastatic colorectal disease, what therapeutic options do you generally discuss with patients based on either tumor diagnostics, age, multi-organ involvement and other factors. Just help us understand the various considerations you take into account while you plan management of such patients, especially given the heterogeneity of this disease. Maybe let me first start with Dr. Lenz and then I'll go to Dr. Kopetz.

So there is a lot of ongoing development in first line. I think what is very critical is really the molecular characterization of the colon cancer to really better understand and develop precision driven treatment decisions. What is absolutely necessary is that we know the KRAS, NRAS status, that we know the BRAF mutant status, that we know MSI high, that we know HER2 because for these, there are treatment strategies being developed. So we already know the MSI high very well with immune checkpoint inhibitors. The KRAS mutant have no really approved treatment in first line. There are trials going on combination with G12C inhibitors, which is only 3% of all rotations. So it's a very minority.

The BRAF mutant, Scott can talk all about it with BREAKWATER showing incredible improvement of overall survival for this poor prognostic patient group and combine the morbid and onvansertib, cetuximab. And I think BREAKWATER was not only critical to understand how important targeted treatment is, but how important is to combine with chemo in first line. And I think this is just going back to the onvansertib study, so critical. I can only at [indiscernible] Cardiff to put that very quickly through with a passion development based on the data they had in the Phase I and the Phase II in second line moving into first line because targeted agents with chemo in first line will show the best outcome. And I think the data from the first-line study really being calculated actually that finding and actually validate the finding you saw in Phase II because the response rate also were over 70% and the PFS was 15 months. So this is very consistent when you look at it.

So I think molecular catheterization will drive the decision in the past KRAS mutant that we adjust with a chemotherapy backbone, like FOLFOX or FOLFIRI or sometimes FOLFOX with bevacizumab. So I think this is kind of, I don't know, if Scott wants to add to it, but a lot of new trucks going into first line. We have heard all about bispecific antibodies, but we don't know what really will become positive or not. And I think not always the sexiest trial are the most successful. I think fashion development and data did drive the success. And I think this is adding up very nicely so far for the onvansertib.

Yes. Dr. Kopetz.

No, I'll just add to that nice summary that -- we take a step back while we're making advances in the small wedge of MSI and the small edge of BRAF and maybe HER2 in the future, G12C maybe in the future. We put those together, still such a small minority, right, 10%, 15% of patients that we really have something advances for, which means that the real wide open need for this.

Now first line, I think to echo what Dr. Lenz said. First line is so critical, right, being able to get in the right treatment at the first setting is critical. It's critical because you need the activity of the cytotoxic to synergize with the biologic, with the targeted therapy here. What we know and have known for decades, unfortunately, is that the efficacy of cytotoxic in general really start to decline in later lines that the leverage that we get in first line, the activity that we get in this first-line setting really sets the stage for the patient's journey through other lines of therapy. And so -- that's where I really like the idea to say, well, let's bring the right biology forward for the right patients as soon as we can.

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

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

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

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

And I remember the ovation response was, I think, 11 months. And I think the PFS was 15 months. So these were data which blew us away or me away. So of course, then discussion started. What is the biology behind it is previous bev converting resistance to this combination. And the decision was made based on many kind of biological data, which we published in JCO last year, not actually in 2024 is that to move into first line. And discussion is should we move with FOLFIRI/bev into first line because in the U.S., FOLFOX, onvansertib such an automatic reaction. That's not true in the rest of the world.

In Europe and in Asia, FOLFIRI is often a preferred because you don't run into dose-limiting toxicity. And seeing now the data on the first-line study, there are extremely consistent and even more exciting now with high response rate, really deep responses. We don't even know the PFS yet. But when you look at the 12 months, PFS rate, it shows it's over 60%. So you will have a great PFS. So -- and -- the duration of response is not yet there. So it is really cool to see this data evolving really making very clear what the next step is to get this drug into a registration. So I have been a bit distracted from the beginning on. We're the first patient, and I'm seeing the last patient, but fit the first one. And clinically, you often don't know if they are on the -- take the pill or not because toxicity clinically is not in any way distinguishable from the control arm.

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

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

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

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

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

Yes. No, I think it -- so I think it is important to say where did this target come from, right? It came from an unbiased screen of vulnerability is unique to KRAS. And so that wearing my biologist hat as a scientist, I love the unbiased nature, right? It's not like I think I have an idea, and I'm going to target that like you'd start with a blank slate and let the biology declare itself to you, right? And so I think a good drug builds on a really strong foundation, and I think that's kind of an important component here. The other is that we recognized really the opportunities for combinations, right? And that while PLK1 plays a number of rules, it's role in kind of DNA damage repair is critical, right? And that is kind of a key component, and we've recognized looking at our preclinical models that there's synergy across a number of different agents. But the opportunity the recognition that topoisomerase I inhibitor in particular, we're uniquely sensitive to this.

What is a topoisomerase inhibitor that's irinotecan? And so why is that? Well, without getting too deep into the weeds, what this topoisomerase inhibitors do is it creates these breaks in the DNA, these double-strand breaks that need a certain repair pathway, right? It turns out our body has a number of different pathways that get engaged depending on the type of DNA damage that occurs like we have a UV damage, for example, it's a different one. But this is the homologous recombination repair pathway for the efficient autos out there that gets triggered. And this PLK1 plays a critical role of getting recruited into these spaces, right? So it's really encouraging and rewarding as a physician scientist and we say, okay, we see these kind of strong signals with irinotecan preclinically and then to have the clinical data replicate and say, you know what, irinotecan really is the right partner, and that's kind of based on that biology that PLK1 plays a role in that.

Oxaliplatin, 5-FU, very different nucleoside excision repair pathways, really no direct role for PLK1 in that mechanism. And so there's synergy through other mechanisms, perhaps -- but it really -- I think the biology is aligning with this clinical trial design to really think about the full Ferin bevacizumab partnering in the first-line setting.

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

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

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

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

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

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

So...

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

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

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

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

No, happy to. So the...

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

I don't feel offended, okay.

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

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

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

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

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

Yes. I mean I think as Dr. Lenz mentioned the kind of pan-RAS inhibitors just don't look like they're going to have a role in colorectal cancer. It breaks my heart to say that. seeing all the great things happening in pancreas, but it's just -- it's not in the cards for colorectal due to the kind of the adaptive resistance that colorectal is so well known for. We are certainly know that G12C, as Dr. Lenz mentioned, is a small wedge 2% to 3%, and we look forward to seeing what that looks like. It's useful to note that they decided to use FOLFIRI as a backbone for their study. based on the data that they saw as well. So I think that's kind of a useful point from at least the NN perspective. The difficulty is that there's just not -- once we get past the if we take the pan brass off the table, even if we get in the future, perhaps maybe the G12D allele specifics may make their way forward. But again, these are -- we're cutting off little small wedges of the population.

And colorectal cancer and KRAS in particular, tends not to be driven by any one particular there's a lot of RAS mutations and in 13 and 61 and 146 that is a much broader repertoire. And so really thinking about how do we attack the biology that's broad I think is important. And maybe we can make some headway in 1 or 2 of the allele specific space in parallel. But I don't think those are mutually exclusive by any stretch in imagination.

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

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

Absolutely.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

And if I may jump in. I know this is a question that we often face. We did show in our analysis when we combine both FOLFOX and FOLFIRI in our current data set in the frontline setting, whether you look at objective responses, whether you look at the limited PFS and durability data that we've shared, it seems to be quite superior, at least as the data are evolving whether we look at it from a FOLFOX regimen perspective, all FOLFIRI. And from what I hear, you guys are data-driven. So if that works, then that's what it is. But yes, I do Don't want to take everybody else's time. We are running out of time. So please operate next question.

Can we have the next question, please?

Okay. So since I don't hear anything from the operator I just thought about it when we were talking about G12C and 3%, 5%, whatever it is, maybe help us end the session by giving us a sense of how large are the -- how large is this RAS-mutant population, pan-RAS, whatever you think, whether they are KRAS, NRAS, G12D, like together, if you look at it. Is it 50% of your patients? Like what is it? Like just help us understand that as well. Who wants to go first? Yes.

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

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

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

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

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

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

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

Yes. KRAS [indiscernible], yes.

That's important.

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

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

Likewise. Yes.

Yes.

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

Bye guys.

Bye.

Welcome to the Cardiff Oncology Onvansertib Data Update Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to turn the conference over to Candice Masse of Astr Partners. Please go ahead.

Thank you, operator. This is Mani Mohindru from Cardiff. Given the technical difficulties, I'm going to take over. Joining the call today with me from the Cardiff Oncology team will be me, myself, the Interim CEO. In addition, I'm joined with my Chief Medical Officer, Dr. Roger Sidhu; our Chief Scientific Officer, Dr. Tod Smeal; and our newly promoted Chief Accounting Officer, Ms. Brigitte Lindsay, and will also be available during the Q&A session.

During this conference call, we will be making forward-looking statements, including, without limitation, statements related to guidance, results and the timing of data readouts for onvansertib clinical studies. These forward-looking statements are based on the company's current expectations and inherently involve significant risks and uncertainties. Our actual results and the timing of the events could differ materially from those anticipated in such forward-looking statements as a result of these risks and uncertainties.

Factors that could cause results to be different from these statements include factors that the company described in the section titled Risk Factors in its annual report on Form 10-K filed with the SEC for the year ended December 31, 2024. Cardiff Oncology undertakes no duty or obligation to update any forward-looking statements as a result of new information, future events or changes in its expectations.

With that, I am going to take over the conference call and proceed further with my prepared remarks. Once again, good morning to all, and I would like to thank you for joining our conference call.

Before we begin, I want to take a brief moment to introduce myself. As you may have read in our press releases, I've been appointed Interim Chief Executive Officer by the Cardiff Board of Directors. Since 2021, I have had the honor of serving on Cardiff's Board, where I have become intimately familiar with the company's development programs for onvansertib.

In addition to serving on Cardiff's Board, I have significant experience at both the operational and executive levels. I've been a biotech company founder, CEO, CFO and Board member. I'm a scientist by training with a Ph.D from Northwestern. And prior to my roles at biotech companies, I served as an equity research analyst on the Wall Street covering the sector -- biotech sector. You can read more details about my background in today's release.

Today, Cardiff issued two press releases that can be found on our website. The first one announces a management transition aimed at positioning the company optimally for late-stage development to fully leverage the value we believe onvansertib represents. The second announcement provides an update on onvansertib's very promising Phase II data from our ongoing clinical trial in first-line RAS-mutated metastatic colorectal or mCRC patients.

I'll begin today's call with a discussion of the management transition first. Given that our management and financial needs have evolved, Cardiff's Board decided that this was the appropriate time to transition the company's leadership to ensure it is best positioned to fully leverage the opportunity that onvansertib represents.

This reflects a forward-looking business decision to position Cardiff for its next phase of growth as we look to finalize and execute on our registrational plans, starting with our program in first-line RAS-mutated CRC patients. This population represents about 50% of all of metastatic CRC patient population with a significant need for new and improved therapies.

Before proceeding further, I do want to take a moment to thank both Mark and Jamie for their dedication and many contributions to Cardiff through the years. Their efforts led to the progress of onvansertib from early stage to Phase II development, positioning it well for further advancement into late-stage clinical program.

I do want to emphasize one very important point. This transition is by no means related to any issues with onvansertib's colorectal cancer program. In fact, this transition is a direct result of the promising data we are seeing with onvansertib. The CRDF-004 program remains fully on track and continues to demonstrate promising clinical benefit as well as safety data in cancers such as RAS-mutated mCRC, as we reported today.

I've been intimately aware of Cardiff's pipeline and operations over the past several years as a Board member. In my interim CEO role, I'm surrounded by experienced operational, scientific and clinical development teams. Hence, we do not anticipate any operational interruptions during this transition. We will continue to lead this program forward and also explore the potential for indication expansion driven by evidence.

We remain extremely excited about the potential of onvansertib and its promise to be a paradigm-shifting therapy for patients with RAS-mutated metastatic CRC.

I will now spend some time on the updated promising Phase II data we reported today. Just as a reminder, onvansertib is a highly specific oral PLK1 inhibitor, currently in mid-stage clinical development for RAS-mutated metastatic CRC. It is being evaluated in multiple other cancers through investigator-initiated studies.

Recently, very promising single-agent activity data showed hematological responses in chronic myelomonocytic leukemia or CMML. These encouraging data were presented at the American Society of Hematology's Annual Meeting in December of 2025.

Today's data update is centered around CRDF-004 trial, a company-sponsored Phase II dose-finding study evaluating onvansertib in combination with first-line standard-of-care regimens in patients with colorectal cancer harboring the RAS mutations. Patients were randomized to receive either 20 milligram or 30 milligram of onvansertib in combination with either of the 2 standard-of-care regimens, that is FOLFIRI plus bevacizumab or FOLFOX plus bev or were given the standard-of-care therapy alone.

The trial was designed to identify the lowest effective dose and to assess the safety, efficacy and PK of our drug candidate in combination with FOLFIRI/bev or FOLFOX/bev in the first-line setting.

In an intent-to-treat analysis, our updated data showed dose-dependent benefits across multiple efficacy measures, especially in patients who got onvansertib plus FOLFIRI/bev versus patients who either got FOLFIRI or FOLFOX-based standard-of-care regimens alone. A similar dose-dependent and consistent clinical benefit has not been observed thus far with onvansertib in combination with the FOLFOX/bev regimen.

I also want to highlight that today's onvansertib, FOLFIRI/bev top line data are actually aligned with positive results from a prior second-line mCRC Phase II trial in bev-naive patients, where the chemo backbone was also FOLFIRI as well.

Just want to remind that these results have been published in the Journal of Clinical Oncology and in fact, were the basis of our decision in consultation with the FDA to move onvansertib to the first-line setting.

As you can see in the table included in today's press release, the onvansertib 30-milligram dose, when combined with FOLFIRI/bev, provided a much higher confirmed overall objective response rate of 72.2% versus 43.2% seen with FOLFOX, FOLFIRI standard-of-care regimens combined or 42.1% seen with FOLFIRI plus bev standard-of-care regimen alone.

Additionally, median PFS has yet not been reached in either of the onvansertib FOLFIRI arms, which indicates extended benefit. In contrast, the standard-of-care regimens had a median PFS of about 11 months, which aligns with published data from other studies. Of note, the 30-milligram onvansertib arm achieved statistical significance for PFS versus the standard of care despite the relatively small number of patients.

These findings highlight both improved tumor responses and enhanced durability with the addition of onvansertib on top of standard-of-care regimen of FOLFIRI/bev. Further, the PFS hazard ratio was 0.37 when comparing 30-milligram onvansertib plus FOLFIRI/bev arm to the combined standard-of-care arms. This also achieved statistical significance, suggesting a notable reduction in the risk of disease progression.

To be clear, this dose selection trial was not powered to assess the difference in the secondary endpoints of PFS or duration of response, and yet we saw consistent dose-dependent responses in the measures of durability with a higher dose of 30 milligram, given with FOLFIRI plus bev.

The other important point here is that we expect our registrational study to also compare the onvansertib plus FOLFIRI regimen to the combined standard-of-care arms when measuring efficacy.

The safety and tolerability of onvansertib, when added to standard-of-care, remains favorable and similar to what we have reported previously. No unexpected toxicities or additive AEs were reported. Grade 3 or higher AEs were infrequent, with neutropenia being one of the most common treatment-emerging AEs across onvansertib combinations as well as the standard-of-care arms alone.

Together, we believe these data tell a very compelling and consistent story of onvansertib's practice-changing potential. Based on the totality of the data thus far, we have selected the 30-milligram dose of onvansertib in combination with FOLFIRI/bev regimen to bring forward in a registrational study in patients with RAS-mutated metastatic CRC in the frontline setting. Cardiff expects to initiate a registrational program later this year.

The study protocol will likely include comparison of onvansertib plus FOLFIRI/bev to both standard-of-care regimens, i.e., FOLFIRI/bEv and FOLFOX/bev in a prospective manner. This, of course, is subject to confirmation following the review of our study designed by FDA per usual guidelines. We expect to disclose details of the study design after our discussion with the regulatory authorities.

Looking ahead, we expect to provide a more mature clinical data set from the CRDF-004 study before the end of first half of 2026, either at a medical meeting or a similar event. At that time, we also anticipate that we would have received feedback from FDA on our registration plan in metastatic colorectal cancer.

It's a very exciting time for Cardiff as we make this transition to late-stage development. I'm especially grateful for the opportunity to help guide the final stage of development for this potentially practice-changing drug candidate. I look forward to working closely with the outstanding team at Cardiff in realizing the full therapeutic potential and value of onvansertib.

I also look forward to continuing the dialogue with you, our investor base, as we take steps towards our goal of regulatory clearance with an eye towards commercialization.

And before we open the Q&A session, I would like to thank all employees and consultants of Cardiff, who continue to work tirelessly to advance onvansertib further in clinical development. But most importantly, I would like to thank all the patients, who have participated in our current and past clinical trials and contributed immensely to the advancement of our drug candidate.

With that, we will begin the Q&A portion of the call, where I will be joined by our CMO, Roger; CSO, Tod; and our Chief Accounting Officer, Brigitte. Lisa, you can open the call for questions.

[Operator Instructions] The first question that we have for today will be coming from the line of Marc Frahm of TD Cowen.

Welcome aboard, Mani. Maybe just to start off with, I know the focus is very much on the FOLFIRI combination since that's the one that you plan to move forward. But maybe if you can just kind of address what trends or signals of efficacy may have also been seen within the FOLFOX subset of patients?

And then looking forward to the Phase III, can you maybe speak to some of the preliminary powering assumptions you have there in terms of how large the trial may need to be, maybe some of the rationale for using both chemo backbones in the control arm versus maybe making a slightly simpler trial design by just focusing on FOLFIRI on both arms?

Sure. Nice to meet you, Mark, as well. Let me address what happened in the FOLFOX arm and why we haven't included that data in the release.

We did see activity with FOLFOX in combination with onvansertib as well. However, the results were not as robust or consistent across all the different measures of efficacy. And specifically in PFS, which is one of the durability measures, we didn't quite see the consistency and the robustness that we saw with the FOLFIRI arm. So we're definitely taking all of the trial results into consideration.

And the trial is still ongoing, by the way. So we will continue to get some more mature data. We believe FOLFIRI is the right regimen to take forward with onvansertib in the frontline setting for our next trial.

And now to address your question about the Phase III trial design, I know you asked a bunch of things. I am not in a position to comment on the size of the trial right now because we would need to work with the agency, taking into account the robustness of the data in doing the powering assessment, and that would lead to the final or the total size of the trial. So stay tuned for that.

But your question about making a simplified FOLFIRI plus onvansertib versus FOLFIRI alone or standard of care, I think I can tell you that most physicians want to see how did your drug do in combination with chemo versus standard of care. I think most people would like to see how did it perform not only versus FOLFIRI, but also FOLFOX because both of these regimens are used in frontline.

And given the robustness of the data, despite small end, I do want to make it clear, we are able to show that onvansertib when combined with FOLFIRI/bev, is better -- appears to be better than both FOLFOX and FOLFIRI-based standard-of-care regimen. So it makes sense to go with them. It is a more aggressive design, something I know that some of the regulators prefer.

And certainly, I think physicians' decision-making would become much more easier if we are able to replicate the results of our Phase II study in a bigger registrational trial.

And our next question will come from the line of Maurice Raycroft of Jefferies.

Congrats on the update. Maybe just one on -- just we're not seeing a meaningful difference in response rate between the 20 mg dose and the standard of care yet. The PFS hazard ratio is 0.56. How do you explain the notable improvement in durability despite the similar response rates?

I think that's an excellent question, Maurice. Nice to meet you. If you study the literature or talk to the KOLs, especially in this disease setting in frontline, the focus is on durability. It's great to see ORR, but there are limitations in the study. It's a small study, and it's a subgroup of the total onvansertib arm. It's FOLFIRI plus onvansertib 20 milligram.

But the focus for this patient population is really trying to see whether you are able to have durable benefit, which also includes, by the way, stable disease, which is reflected in PFS. So from our view, what we see is that the higher dose does much better than the lower dose in terms of ORR.

But definitely, we see a bigger benefit in PFS. We do see benefit in both arms, but the bigger benefit -- and I don't think this is unusual in this particular disease setting. That's why the focus is on ORR, but higher -- bigger, bigger emphasis on trying to see the durability. If you can keep patients on a combination regimen for a longer time, stable diseases become effective as well.

Got it. That's helpful perspective. And your analysis combines BICR and investigator-assessed data. Can you share insights on the stand-alone results for BICR and for the investigator assessed separately on this call? Or is this something that you'll share more details on later in the first half?

Again, a very astute observation. Yes, the limitation is small numbers, and this trial is still ongoing. So the number of events, if you take either BICR or investigator alone, would become very small. So to make the data more meaningful, we had to combine, and that's what we've disclosed.

I cannot predict what we'll be able to share how many events later, but we will continue to collect the event-based data. And if BICR presents enough opportunity to do that, we'll present those updated results.

And our next question will come from the line of Ted Tenthoff of Piper.

Congratulations on the new position and on really stellar data. So again, congrats on the data, that's really exciting. I'm trying to think a little bit broader here and wondering whether with this strong data set, it makes sense to entertain partnerships even potentially overseas to help pay for the Phase III trial and/or to broaden development beyond the initial indication, as you were sort of mentioning in your prepared remarks.

Excellent question, something that we continue to work on. I think up until this point, we had single agent -- sorry, single-arm data that was published. But with this study, we are well positioned to start both strategic discussions and some of which have already been started by the previous leadership, and we will continue to work on that.

Yes, absolutely. I think the potential of this drug is, even in CRC, pretty broad, but beyond is even bigger. So certainly something that would certainly be well served by bringing a partnership in place. Working for that, yes.

Makes sense. Great. Looking forward to more details in the data presentation later this year.

And the next question will be coming from the line of Andy Hsieh of William Blair.

Mani, I look forward to working with you. So in terms of baseline characteristics, and that's important in terms of contextualizing what you're seeing comparing [ cross-arms ], maybe, Roger, I'm curious if you can share your view on some of the baseline characteristic differences.

Obviously, that's an [ effect ] of the small end. But some, I guess, I would interpret as favoring the control arm and some are favoring the experimental arm. So maybe just kind of overall, what you see in the baseline characteristics and how that could potentially impact the cross-arm comparison?

So I'll let take -- Roger take over, but we have shared obviously the baseline characteristics previously. So you should have that data as well, and it's probably on the website as well in our presentation out there, but I'll let Roger give his views on the baseline characteristics.

Yes, randomization has already been completed in the first quarter last year, and we have already shared the baseline characteristics. We are seeing consistent benefit for the 30-milligram FOLFIRI combination across key subgroups, which contributes to the robustness of the data moving forward, and we look forward to sharing more, as mentioned, in an upcoming medical meeting or such interaction.

Yes. But at least based on our preliminary assessment, and Roger, you could correct me if it's wrong; like we really didn't see anything jump out that could have skewed the results one way or the other.

We haven't seen any significant outlier outcomes that could skew the data in terms of interpreting the objective response data we've shared or the PFS data that we today.

And the two standard-of-care regimens, the FOLFIRI standard of care and the FOLFOX standard of care arm, actually behaved very similarly to what has been previously reported, which gives us confidence in the overall data.

Got it. And I guess one of the things that were striking from the -- from last year's release was kind of the dose and depth of response. And I'm curious if you can maybe kind of characterize what you've seen with longer follow-up. Is that depth of response with higher -- with the 30-milligram versus standard of care or 20? Was that also -- was that trend also preserved?

Yes. So we'll certainly share a lot more details around the data in an upcoming event, but I'll Roger let chime in as well. But I think the depth of response gets captured in durability to a certain extent. I think it's the combination of depth of response, stability, which is captured in durability measures of PFS and beyond, but I'll let Roger to add his perspective as well.

Yes. To address your question, we continue to see impressive depth of response, in particular, with the 30-milligram dose in combination with FOLFIRI in a dose-dependent manner.

And the next question will be coming from the line of Albert Lowe of Craig-Hallum.

A few questions about the data. First, I was wondering, did you see any pronounced dose-dependent effects from onvansertib in the FOLFOX combination arms?

So what we did say that we did see activity of the drug in the FOLFOX combination arm, but there weren't consistent trends across all efficacy measurements with the FOLFOX combination.

Okay. I see. I was wondering if you could share perhaps how many more patients remain on trial and perhaps what guided the decision around taking the data cut here versus given the PFS data some more time to mature?

I cannot go into the specifics of how many patients are on the trial at this time. But I think we were at a critical point where we had seen efficacy with a certain dose. So we believe that we have the dose we want to take forward, we have the regimen. And with the transition, we thought this was appropriate time to provide the Street some updated data and more details to come as we continue to work on collecting the maturing data and to present later at a medical meeting or an analyst event.

I see. Maybe one last question. Just to clarify, at the time of the next update that's coming here in the first half, do you expect to have already had the meeting with the FDA to potentially share the finalized trial details?

That is the plan that we can get all the data together and have at least some discussion or have some connection with the regulators within this half.

Next question will be coming from the line of Kevin DeGeeter from Ladenburg.

Just one for me. Thanks for including the PFS rate at 6 months, particularly in what's pretty small cohorts, they're numerically quite similar. So is it reasonable to conclude a lot of the PFS benefit kind of captured in the hazard ratio? There's really kind of separation of the curves kind of beyond 6 months? Or is there something that's kind of more nuanced that we should be considering when trying to parse out sort of depth of response based on what was disclosed today?

Thank you. That's an excellent question as well. I think what we wanted to share was a few different things, but in a nuanced way. The 6-month PFS is a little bit early, but it's an important landmark to see if the drug's benefit is in the right direction.

You can see actually within that analysis that there is a dose response there as well. You don't expect too many differences between the control and the test arms, but there's certainly trend towards improvement with onvansertib and that too in a dose-dependent manner, which gives us in the confidence of these data. These are small ends. So we have to look at the data every which way.

And curves are definitely when we are ready to share with you, you can see like based on the hazard ratio, the curves are much more separated with the FOLFIRI arm, and we've not disclosed the FOLFOX hazard ratios. But we feel quite comfortable and not just with FOLFIRI alone arm, but even looking at the standard-of-care regimens combined arm. the 6-month landmark analysis is just to get more confident about what we are looking at dose trends and the right direction in the efficacy setting.

And the next question will be coming from the line of Christopher Liu of Lucid Capital Markets.

It's good to speak to you again, Dr. on the data so far. Maybe a question about efficacy and then a question about tolerability. For the question about efficacy, what's kind of the median time to response that we see in the 30-milligram arm? And are we continuing to see some deepening of responses as time goes on, including now? And then for the tolerability question, what was the dose discontinuation rate looking like?

So you have asked quite specific details. Unfortunately, I will not be able to provide full data on the depth of response over time. But I think the way from our perspective to look at the data is to look at PFS hazard ratio and the totality there because in this patient population, stable disease matters as well.

We do believe, and we've shared this with you previously that the depth of response is certainly much better with onvansertib combinations, but we should not take stable disease patients lightly, and I think that's important to be captured.

And remind me what your second question was, sorry?

No worries. I was just wondering what the treatment discontinuation might have looked like in 30 milligrams...

I would say stay tuned for the full data set, but nothing very -- there were differences in treatment discontinuations, I can tell you, between different arms. But stay tuned for that, so we can share the reasons of discontinuations as well in the next data cut. There were differences between FOLFOX and FOLFI, let me put it this way, which obviously is reflected in the data, but we'll give the full details at a later time.

And our last question today will come from the line of John Vandermosten of Zacks.

I think that Pfizer had the right of first look for the data from the trial. Did they -- was there any response from them or any sign of interest from them at all that you've seen?

This is too early to comment on that. Certainly, Pfizer has -- we have shared the data, and we will continue to share for that with them and others. But too early to say anything beyond this at this point in time.

Okay. And since you're looking for a new executive team, will you be focused at all on deal experience or commercialization experience? It might be too soon for that, but perhaps it's never too early. What are some of the features you're looking for in the full-time CEO?

Yes. I think certainly, not just the CEO, we are increasing and expanding our clinical team as well and bringing people in with a focus towards taking the drug to late-stage development, regulatory interactions and commercialization as well.

So all of these things. And not just in metastatic CRC, but as I mentioned in my prepared remarks, even looking beyond that because we are seeing signals of activity, clinical benefit in other indications. So certainly, we'll keep all that in mind as we build not just the leadership team, but the company at large.

This does conclude today's Q&A session. I would like to turn the call back over to Mani Mohindru, Interim Chief Executive Officer. Please go ahead.

Thank you, Lisa. We're incredibly excited about the potential opportunities with onvansertib and look forward to keeping you updated as we advance this program. Thank you again, everyone, for joining us this morning, and please reach out for any additional questions. Thank you.

This does conclude today's program. Thank you so much for joining. You may now disconnect.