Cardiff Oncology, Inc. ($CRDF)

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.