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

Good afternoon, and welcome to the Cardiff Oncology Data Presentation Webcast. [Operator Instructions]. Please be advised that this call is being recorded at the company's request, and a replay will be available on the company's website. I would now like to turn the call over to Tom Galassi of LifeSci Advisors. Please go ahead.

Thank you, operator, and thank you all for participating in today's conference call. Before we start, I'd like to point out that the slides referenced by management on today's call will be broadcast on the webcast system or for those of you who have dialed in by phone, you can download the webcast slides from the Cardiff Oncology homepage. I'd also like to remind all listening that certain statements in this presentation are forward-looking within the meaning of the Private Litigation Reform Act of 1995 as disclosed on the slide. There are a number of factors that could cause actual events to differ materially from those indicated by such forward-looking statements and investors should read the risk factors set forth on the Oncology's Form 10-K for the year ended December 31, 2020, and other periodic reports filed with the Securities and Exchange Commission. All the list of factors presented therein is considered representative, no such list should be considered to be a complete statement of all potential risks and uncertainties. Unlisted factors may present significant additional obstacles to the realization of forward-looking statements. Forward-looking statements included herein are made as of the date hereof, and Cardiff Oncology does not undertake any obligation to update publicly such statements to reflect subsequent events or circumstances. With that, I'd now like to introduce Dr. Mark Erlander, Chief Executive Officer of Cardiff Oncology. Mark?

Thank you, Tom, and welcome to today's webcast during which we'll announce new data from our ongoing Phase Ib/II trial evaluating onvansertib for the second-line treatment of KRAS-mutated metastatic colorectal cancer. These data are also summarized in a press release we issued at the start of this webcast, which can be found on the Investors section of our website now that the data embargo for the ASCO GI Symposium has lifted. Today's webcast will open with summary of the data we are releasing today as well as some additional context for the mCRC trial. Importantly, all the data we will discuss today reflect the data cutoff of December 3, 2021, used for our ASCO-GI poster, and then include follow-up data through today's webcast, which includes one additional initial partial response achieved in late December. Therefore, anyone interested in reviewing our data on their own should review what we will -- what we posted on the Cardiff Oncology website as this will reflect the most up-to-date data from the trial. After my comments, our Chief Medical Officer, Dr. Katherine Ruffner will review the data we are releasing today in detail. I will then close the webcast with some perspectives on next steps for Cardiff Oncology and our plans for onvansertib going forward. Here on Slide 4, you can see a high-level view of the objective response rate data from historical trials evaluating the standard of care therapies for metastatic colorectal cancer as well as a summary of each of our data releases through today. As the number of valuable patients has more than tripled, from 14 patients to 48 patients, our response rate is holding essentially steady and today shows 17 of the 48 evaluable patients across all doses achieving a partial response while on treatment. This 35% rate is about 3 to 7.5x greater than the response rates reported in similar patient populations treated with standard of care chemotherapy. Slide 5 shows similar data for median progression-free survival. Our median PFS is 9.4 months across all doses, which is the same as we released at our September 2021 KOL webinar. As you can see here, this compares favorably to what has been achieved in previous trials. We have not reached the median PFS for the recommended Phase II dose or RP2D cohort of patients. Dr. Ruffner will be providing significant additional context for today's data release later in the webcast. But I wanted to start with a snapshot of the data we are releasing today. In summary, we believe that the combination of onvansertib and standard of care chemotherapy may provide a more attractive second-line treatment option for this large patient population. On Slide 6 and the following few slides, I'll provide a high-level summary of the hypothesis underlying our clinical metastatic CRC program. A more in-depth presentation can be found on our website. We believe onvansertib's unique combination of efficacy and tolerability derived from properties identified on Slide 6. The drug is highly specific for PLK1 inhibition and has limited activity against PLK2 and 3, which are believed to have tumor-suppressor activity. In addition, as a small molecule with a 24-hour half-life, onvansertib can be flexibly dosed to balance efficacy and tolerability. Finally, given that PLK1 is overexpressed in a broad array of cancer types, we see many opportunities for broadening our clinical focus, and we will discuss our near-term targets later in this webcast. As a reminder, on Slide 7, our Phase Ib/II trial for metastatic colorectal cancer targets patients with a KRAS mutation. Unlike patients with KRAS wild-type who can benefit from newer agents such as the EGFR inhibitors, there is no targeted therapy available to the 43% of patients with a KRAS mutation. And on Slide 8, we show that once these patients progress to second-line therapy, their prognosis is poor with a 5-year survival rate of 10%. As we showed on an earlier slide, their historical response rates to standard of care therapy are in the range of 5% to 13%. And on Slide 9, when we look ahead to therapies in development, a common focus is on G12C inhibitors being developed for the treatment of metastatic CRC by Amgen and Mirati. However, these therapies are targeting only about 4% of the broader mCRC patient population. In conclusion, on Slide 11, we show a highly summarized view of why onvansertib has the potential to benefit all metastatic CRC patients who harbor a KRAS mutation, not just a small proportion with a G12C mutation. Specifically because PLK1 is active downstream of the RAS mutations that drive the proliferation of tumor cells, we believe that inhibiting PLK1 can then target any KRAS tumor subtype. Dr. Ruffner will present clinical data supporting this hypothesis. On the events page of our website, you'll find recent presentations that provide additional details on the two-pronged attack that onvansertib makes on metastatic CRC tumors. The functional synergy of combining the DNA-damaging agent with our PLK1 inhibitor is the underlying scientific rationale for our ongoing clinical trial for KRAS-mutated metastatic CRC. With that, I'll hand off the call to our Chief Medical Officer, Dr. Katherine Ruffner to review the details of a clinical trial and present the detailed data we are releasing today. Katherine?

Thank you, Mark. As a reminder, I'm going to start with Slide 13, it's showing you an overview of the Phase Ib/II trial design. In the trial, we are combining onvansertib with the FOLFIRI-bevacizumab regimen, which is widely used as standard of care for the second-line treatment of patients whose disease has relapsed or progressed following first-line treatment with oxaliplatin and chloropyrimidine. Patients receive the standard doses and schedule of FOLFIRI and bev on days 1 and 15 of a 28-day cycle and onvansertib orally once a day on days 1 through 5 and days 15 through 19 of each 28-day cycle. Patients are scanned and baseline in every 8 weeks on treatment for disease response assessment. Here on Slide 14, we're showing 3 of the efficacy endpoints for the Phase II portion of the trial. The primary efficacy endpoint is the objective response rate or ORR. Secondary endpoints include other measures of the disease response, including progression-free survival and duration of response. For one of the exploratory endpoints, we are evaluating the correlation between changes in the KRAS mutation burden in circulating tumor DNA and radiographic disease response. Slide 15 shows the proof-of-concept criteria for this trial, defined as an ORR of at least 20% and a median progression-free survival of at least 6 months. These both represent improvements over historical controls with standard of care, which has demonstrated ORRs of 5% to 13% and maybe in PFS of 5.7 months at the most. Slide 16 shows enrollment into individual dose cohorts and into the entire trial as well as the number of patients remaining on treatment as of the time of the December 3 data cut. A total of 50 patients have been treated with 18 patients in the Phase Ib portion, 6 at each dose level and 32 patients in the Phase II portion. The median age is consistent with the age distribution observed in CRC, colorectal carcinoma. There is a slight male preponderance also to be expected. Most patients have liver metastases and most patients had 2 or more organs involved with metastases. Finally, 2/3 of the patients have been previously exposed to bevacizumab. One of the drugs given on the trial is part of the standard of care FOLFIRI-bev regimen. Here on Slide 17, you will see a summary of the safety data from the trial, which indicate that the combination of onvansertib, FOLFIRI and bevacizumab has been well tolerated. The table shows the most frequently reported treatment-emergent adverse events, or TEAEs, in the Phase Ib/II trial regardless of cause. The numbers in the table represent the numbers of patients experiencing a given event, not the number of events. Each patient is only counted once for a given event and is counted at the highest severity observed for that patient. Neutropenia is the most commonly reported TEAE and over half of the events observed are grade 3/4. Recall that onvansertib is being given in combination with cytotoxic chemotherapy, which is also known to cause neutropenia. However, neutropenia and thrombocytopenia are both considered expected events in the onvansertib Investigator's Brochure and are consistent with the known mechanism of action for PLK1 inhibitors. Although it is part of standard FOLFIRI, the 5-FU bolus is thought to add only to the toxicity of the regimen, but not to the efficacy. Early in the Phase Ib portion of the trial based on feedback from our investigators, we amended the protocol to permit discontinuation of the 5-FU bolus from the treatment regimen if neutropenia of grade 2 or greater was observed. Discontinuation of the 5-FU bolus with or without use of growth factors has subsequently been shown to ameliorate the severity of neutropenia observed. The number of grade 4 events was low, with 11 events, total, occurring in 7 patients. Many of the other commonly reported TEAEs are consistent with the known toxicity profiles of the standard of care drugs such as nausea, vomiting, diarrhea, hypertension, et cetera. You'll note that of all 788 TEAEs reported to date, only 84 or approximately 11% were grade 3/4. Slide 18 is a review of the number of response evaluable patients in our data releases over the past year. Only a year ago, we were reporting on the first 14 patients enrolled on the Phase Ib part of the trial. Today, we are reviewing data from a population that's more than tripled. The 3 columns in light blue show the 3 different sets of data released around the ASCO-GI symposium, including the abstract for the September 16 cutoff, the poster with a December 3 cutoff and the data we are presenting here, which includes additional follow-up between December 3 and today. I should take a moment to explain the numbers in the light blue column. You'll recall that we have treated 50 patients total, with 18 in the Phase Ib and 32 in the Phase II. However, 2 patients in the Phase Ib did not complete a full 28-day cycle of treatment, so were not evaluable for disease response, which is why the number of patients here is 48 instead of 50. In addition, although there were 6 patients treated at the recommended Phase II dose on the Phase Ib and 32 patients treated at the RP2D in the Phase II, the total number of evaluable per protocol patients in this group is 35 instead of 38. The reason for this is that there were 3 patients across the Phase Ib and II who were assigned a 15 mg per meter squared, but were initially treated at 12 mg per meter squared. Thus, these 3 patients are not considered as part of the RP2 group, but are considered among the group of all doses. I'll speak more on these patients when we get to the swimmer plot. At 5:00 p.m. Eastern Time today, ASCO released abstracts that were submitted by companies in September of last year. The abstract for our metastatic colorectal carcinoma trial included a data cutoff date of September 16 and included data for 44 evaluable patients at all doses and 31 patients at the RP2D. The poster that Dr. Lenz will present this Saturday includes 4 additional patients in each cohort and has a data cutoff date of December 3. Slide 19 makes a very important point that I would like to take a moment to call attention to, and Mark actually touched on this earlier. In this presentation, we have included additional response data reported on the 16 patients that were ongoing as of December 3. One additional partial response was reported based on a scan obtained on December 27 after the December 3 cutoff date. Therefore, the 35% ORR we are reporting on today's webcast is the most current ORR for the trial and is slightly higher than the ORR than you will see on the poster that will be presented on Saturday morning at ASCO-GI. Those interested in reviewing our data on their own can refer to the slide deck posted on our website. Slide 20 highlights several efficacy events from most recent -- from the most recent data readout from the trial that are noteworthy, along with the objective response rate observed. First, a patient has achieved a confirmed complete response while on therapy. This patient's measurable disease at baseline consisted of 2 target liver lesions with the sum of longest diameter of 41 millimeters. This patient showed a partial response at the first post baseline scan after 8 weeks on therapy, and the partial response subsequently confirmed at 16 weeks. The target lesions became unmeasurable at 24 weeks and remain unmeasurable -- undetectable, is actually the better word, at 32 weeks for a confirmed complete response. We are very excited to see this outcome. The second favorable outcome to highlight is the opportunity for 5 patients across all doses to proceed the potentially curative metastasis-directed therapy, including surgery or microwave ablation. Two of these 5 patients were determined to be candidates for this potentially curative treatment, even though they had not yet achieved a partial response, but instead had stable disease. Although these patients have become off study to go for these procedures and were censored for duration of response and progression-free survival, we consider these very positive outcomes as these procedures are potentially curative for these patients. Lastly, as I mentioned earlier, the most recent partial response on the trial occurred in a patient at the time of the 32-week or roughly 8-month scan after 3 earlier scans showing stable disease. This is the longest on-treatment time point at which we have seen an initial PR. All of these events are noteworthy in the second-line setting for patients with KRAS-mutated metastatic colorectal carcinoma. Slide 21 shows the waterfall plot from the December 3 data used in the ASCO-GI poster. I'd like to point out the patient who had stable disease as of December 3, indicated by the arrow shown, but who has subsequently achieved a partial response. As you can see from the legend, the red bars represent a best response of progressive disease, yellow bars represent stable disease, teal bars represent a best response to partial response and the confirmed complete response is represented by dark blue bar. The circles above the PR and CR patients indicate confirmed results. So these are responses that have been confirmed and the asterisks along the x-axis indicate which patients were treated at the recommended Phase II dose. The table here on the right reiterates the objective response rate at both all doses and at the RP2D and shows that over 2/3 of the patients treated experienced some reduction in their tumor burden. Also of note is the disease control rate consisting of CR, PR or FD of 92%. There are a total of 4 patients, including the brand-new partial response from December 27, who have not yet had their responses confirmed, and I'll provide further details on the next slide. Slide 22 shows data on the 4 patients indicated by numbers 1 through 4 whose initial partial responses have not been confirmed. Number 1 is patient 01046 who had a first PR in December 27. The confirmatory scan will occur in February as restaging scans are performed every 8 weeks on this trial. Number 2 is patient 04038, whose initial partial response documented at week 8, regressed to stable disease at week 16 and 24, at which point the patient was determined to be a suitable candidate for potentially curative metastasis-directed therapy and became 1 of the 5 patients discontinuing the trial to have this procedure. Number 3 is 02028, whose PR at week 24 regressed to stable disease at week 32, but who remains on trial and thus may experience a subsequent PR and confirmation. Number 4 is patient 02004 who had a PR at 24 weeks, but discontinued prior to the confirmatory scan as a result of hepatitis B infection, which was considered unrelated to study treatment. Slide 23 shows the spider plot for all 48 evaluable patients. The minus 30% threshold for PR and the plus 20% threshold for PD, progressive disease, are marked with dotted horizontal lines. And the minus 100% threshold for complete response overlaps the x-axis. The patients with the best response of PD are shown in red, stable disease in yellow, partial or complete responses are shown in teal. This is a bit busy. So on the next slide, I'll show you the same data broken out into 2 plots. Slide 24 shows the patients broken out into either PR plus CR on the left or stable disease on the right. We've actually removed the 4 patients whose best response with progressive disease who are visible on the prior slide. What these plots show particularly for the PR, CR patients is a fairly steady decrease in measurable tumor burden over time that continues to deepen on treatment. And for the stable disease patients, you can see some [ fairly long ] duration of stable disease, which corresponds to progression-free survival. And you can see patients who remain early in treatment whose measurable disease continues to decrease and who may well achieve a PR, CR, as patient 01046 has indicated here by the arrow. Slide 25 shows the swimmer plot as of the ASCO December 3 cutoff date with an additional note pointing out the patient who had an initial PR on December 27. The plot shows all patients broken out by the individual dose levels on the Phase Ib and the patients treated on the Phase II at the RP2D of 15 mg per meter squared. This gives you some idea of the time on study treatment, the timing of the disease response on treatment and the patient disposition or reasons for leaving the study. The 3 patients who were assigned to 15 mg per meter squared who initially received 12 mg per meter squared are marked with asterisks on the left of their respective lanes. The 5 patients who came off study to pursue potentially curative metastasis-directed therapy are indicated by teal triangles to the right of their lanes. The table on the right summarizes the timing for all responses observed, partial and complete to date. Over half of the observed responses have not been detected until week 16 or later, with 6 of the 17 responses first occurring at week 24 or 32. Thus, persistent stable disease on onvansertib does not necessarily mean a partial or complete response cannot be achieved and equates with continued progression-free survival. Slide 26 returns to a point Mark made earlier in the webcast regarding onvansertib's potential for efficacy across a number of different KRAS mutations. Here, we show the distribution of KRAS mutations in the 48 evaluable patients across all doses in the table on the right. The frequency of specific mutations in the patients on our trial generally follows the expected distribution from the literature with G12D and G12V being the most common. As a reminder, while a KRAS mutation is required for admission to the trial, specific mutations are not required or excluded, although the protocol does stipulate that the mutations must be in exons 2, 3 or 4. As the table shows, we see responses to therapy across different KRAS mutational variants. This clearly differentiates onvansertib's specifically -- from agents specifically targeting G12C, which accounts for only about 8% of the KRAS mutations in metastatic colorectal carcinoma patients. Slide 27 summarizes the objective response rate that we have observed and reported on a different time point in the last year, both for the entire study population and for the RP2D subgroup. Again, calling attention to how our results compare to recent historical controls. These numbers will continue to evolve, and the current results should be considered interim. But today is our first release of data that includes at least one post-baseline scan for all patients enrolled under the original protocol. The protocol has subsequently been amended to add another 40 to 50 patients at the RP2D for a total of approximately 100 patients in the study, and I'll provide more details on this in a few slides. You can see in the graph that the response rate has been relatively consistent over time. Our ORR is between 3 and 7.5x greater than that, which has been achieved in previous trials and is well above our proof-of-concept threshold. Slide 28 shows the Kaplan-Meier curve of our median progression-free survival to date. As Mark mentioned in his presentation, you can see that the median PFS remains 9.4 months for all patients across all doses, consistent with our September 2021 data release and is not yet reached for patients in the RP2D cohort. The 9.4-month median PFS represents a 65% increase in the length of PFS relative to standard of care and is a notable improvement. Slide 29 summarizes data from one of our exploratory endpoints. Our research and development group has been measuring the mutant allele frequency or MAF in patients' blood at baseline after 28 days on treatment and at various time points thereafter. Once we've learned what the specific KRAS mutation is that a parent patient's tumor has, we perform droplet digital PCR specific for that patient's mutation on circulating tumor DNA. What we've shown is that those patients who have had at least a 90% decrease in the circulating KRAS MAF at day 28, have a substantially higher likelihood of achieving a partial or complete response, than do patients whose MAF does not decrease by at least 90%. As you can see from the p-values at the bottom of the figure, the difference between both the PR/CR group and the stable disease group and between the PR/CR group and the progressive disease group are both statistically significant. This biomarker has the potential to provide early insights into disease response before the post baseline -- before the first post baseline scan. I'd now like to turn to the future plans we have for our NCRC program on Slide 30. As I mentioned previously, we have amended our Phase Ib/II protocol to expand the Phase II population by 40 to 50 patients. Our reasons for this are to obtain additional safety data, additional PK data and to generate ORR data with a relatively tight confidence interval and to continue evaluating the KRAS, MAF biomarker. The amendment also serves to keep sites active and excited ahead of the initiation of our pivotal trial. The amended trial is again open for enrollment, and we've already started treating additional patients. For my final slide, #31, I'll discuss the catalysts that we are anticipating in 2022. In mid-2022, we expect to have another data release from the mCRC trial as we continue to generate more data, both from our original cohort of 48 evaluable patients, which will continue to mature and from the entire cohort of the Phase Ib/II patients, which will include patients enrolled under the recent amendment. We are also in the process of finalizing the design for the pivotal trial in second-line KRAS-mutated mCRC. For now, we can say that we will be aggressively pursuing a regulatory path that follows the strength of our data. We are currently planning a randomized Phase III trial that will support full approval and may allow the opportunity to pursue accelerated approval from an interim analysis. We also expect further updates in 2022 from our pancreatic and prostate cancer Phase II trials. Lastly, we are looking to expand the onvansertib pipeline to include ovarian cancer, breast cancer and/or medulloblastoma trials, which may be done as Cardiff-sponsored trials or in partnership with another company or as investigator-initiated trials. That concludes my presentation. So now I'll turn things back to Mark.

Thank you, Katherine. On Slide 32, we show our current onvansertib pipeline and the programs we have in development. Metastatic CRC is our lead program, but we are exploring a number of other opportunities both on our own and with partners. On Slide 33 shows how onvansertib is a platform molecule that can synergistically combine with DNA-damaging agents, microtubule-targeting agents and epigenetic agents. We believe these combinations will improve the efficacy of a range of cancer therapies. Slide 34 shows our leadership team. Last week, we announced that Tod Smeal joined us as Chief Scientific Officer; and Chuck Monahan joined us as Senior Vice President of Regulatory Affairs. We welcome their addition to the team because now we have a scientific, clinical, regulatory and business leadership we need to maximize the potential of onvansertib here at Cardiff Oncology. Looking ahead, Cardiff Oncology is well funded with $134 million in cash as of September 30, 2021, plus an additional $15 million in proceeds raised from the Pfizer investment and relationship we announced in November. This provides funding to the next several catalysts Katherine discussed earlier. We are excited for what lies ahead and we'll assure to keep everyone updated along the way. With that, I thank you once more for your attention today, and we'll now take some questions.

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

Maybe the first one for me. I'm wondering if maybe you could discuss the level of interaction and feedback you've received from the FDA around that registrational trial and what the size of such a trial could look like and what would actually determine whether an interim analysis could potentially support an accelerated filing? And I have a follow-up there.

Katherine, do you want to talk about that?

Yes. No, we are still in the process of developing that pivotal trial. And I can tell you that all we can say at this point is that it will be randomized, it will be for full approval, and it will include a potential avenue for accelerated approval based on an interim.

Okay. And that interim would potentially be based on what endpoint? Or what are you thinking there?

I can't actually speak to that right now in the absence of our further communication with the agency.

Okay. Got it. And if I could ask a follow-up. I'm wondering now with a pretty sizable cohort, if you could break out at a very high level whether you're seeing any distinct differences in activity in patients with prior bev exposure and those who maybe were bevacizumab-naive?

Yes, I think...

Go ahead. Thank you.

Yes. Go ahead, Katherine. What do you -- I mean we know what Katherine already said about the fact that about 2/3 of the patients have received prior bev. We have not broken out the breakdown on PR, SD and PD at this point. Although, as you know, we reported that earlier, and there was no sort of correlation.

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

Great. The first question is on the biomarker that was presented later in the presentation today. Can you just how you see that potentially being used in clinical trial development or even on the market?

Katherine, do you want to start that one? I can follow up after that if there's more.

Yes. You'll recall that we were looking at these changes in mutant allele frequency at day 28. And the patients don't get scans until 4 weeks later. So we are looking at this assay as a potential way to give us an indication of whether a patient may eventually obtain a radiographic response. You may be familiar with the molecular diagnostics around CML. We're in the BCR/ABL, transcripts are followed for disease response. And we're thinking that this KRAS mutant allele frequency may eventually have a use similar to the testing of the BCR/ABL.

Yes. And the only thing I would add is that it's exploratory endpoint right now, and we will continue to evaluate it as we go forward, and we'll probably be talking more about how we may use that in the future.

Sounds great. And then maybe a follow-up question on safety. It's great to see in the presentation that most of the safety issues I think were of grade 1 or 2. I guess could you talk more about safety in terms of focusing on the serious adverse events and if any of those seem to be related to drugs?

I can tell you that the number of SAEs on this trial so far has been low. It's either 16 or 17. So when you consider that these are patients with advanced disease, it's not surprising and that are receiving cytotoxic therapy. And very few, if any, have been considered related to onvansertib.

Our next question comes from the line of Marc Frahm with Cowen.

Sorry about that before. I got disconnected the most inopportune time. I apologize also if I repeat a question that I missed while I was dialing back in. Just on the safety side, can you maybe provide a little bit more details on just how the neutropenia differs before and after the 5-FU bolus is being used in terms of the frequency of it kind of in those different visits? And then I have a follow-up.

Yes. What we've noticed, and of course, sometimes elimination of the 5-FU bolus is not the only dose modification that's made. Sometimes the sites also decrease the irinotecan dose or decrease the 5-FU dose. Sometimes they add growth factors, sometimes they don't. But what we can say is that for patients who exhibited or who demonstrated grade 4 neutropenia early on in treatment, meaning within the first 1 to 2 cycles, once the 5-FU bolus was decreased, the grade 4 neutropenia did not occur.

Okay. That's helpful. And then maybe just from a more holistic perspective of the tolerability. Can you just provide a review of the rates of discontinuation that you are seeing, the rates of kind of dose adjustments that are needed in kind of through the course of the trial?

I can't comment on the rates of dose adjustments. I just -- I can't comment on that at this point. But we are seeing -- people are coming off trial for a variety of reasons. And the swimmer plot shows that. Not only do we have the 5 patients that came off to pursue the potentially curative therapy, we have had some patients come off for what is being called chemotherapy fatigue. And that is -- we're thinking is the fatigue that we also noticed in the safety table, but is coming largely from irinotecan, because irinotecan is known to cause fatigue or asthenia. And of course, with the Phase Ib/II -- Ib portion of the trial, we weren't allowing breaks, treatment breaks of longer than 2 weeks on trial. If the patient needed more than 2 weeks off treatment, they had to come off therapy. That is no longer true on the amended trial. So we expect to see some differences in patients coming off treatment for reasons other than progressive disease or to go to potentially curative therapy.

That's very helpful. And then you kind of...

I'm sorry, you're breaking up a little bit. I didn't catch all of that.

[indiscernible] on the [ phase ] [indiscernible], can you give a little more details on the design that you -- I recognize it's early and you're still working with regulators, but just kind of the early thoughts on trial design there in terms of size, PFS versus response rate as primary endpoints, things like that?

Yes. It is very much a work in progress. And I can tell you that it will be randomized, and we will design it with input from the regulators to obtain full approval, but potentially with an opportunity to obtain accelerated approval at an interim.

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

Congratulations on really the consistency of data. So I have kind of 2 historical perspective question. So one is really on the curative therapy. I think previous KOL calls, they basically commented on this is just something that they don't see very often. So I'm just curious if there's like any sort of historical studies on -- in the second-line setting, what percentage of patients typically are eligible for curative therapy like surgery or radio ablation. And the other question, which is kind of related is also about the disease control rate. So I just want to get a perspective on how significant is kind of the 90-plus percent disease control rate in this setting? And then the third question is I'm curious about if you look at the PFS for patients treated with the recommended Phase II dose. Is that pretty consistent with the overall population? Or how would you kind of characterize the duration?

Sure. Okay. Hopefully, I've remembered all of them. With the first one, I'm not aware of any published data on how frequently patients can go to metastasis resection in second line. So we're reliant on what we hear from investigators who have actually been treating these patients. And yes, it's my understanding that it doesn't frequently happen, which is why we're so encouraged by these 5 patients that we've seen. And your second question, I'm sorry, I have forgotten that.

So it has to do with the disease control rate. So it's basically kind of help us understand the significance of the 90-plus percent disease control rate.

Yes. That is all going to boil out in the progression-free survival. And progression-free survival does include patients with stable disease. So that's where the objective response rate is not telling us the whole story really. But we need further follow-up to see just how long these stable diseases are going to go or if some of them are going to cross into partial responses. And of course, would continue to contribute to the progression-free survival. And then with regard to the progression-free survival at the RP2D, we are just too early to even -- we need additional follow-up and additional scans on those patients before we can really comment on what's happening with the RP2D. And you'll recall that there are 35 of the 50 patients are at the considered RP2D population. So when you think about how big a chunk of the total population we have so far, and it's actually 35 out of 48, then you get a better idea that we certainly don't expect anything to change between the 2, but we definitely need more follow-up.

The only thing I could add to that -- Andy, the only thing I could add to that is that the original pivotal trial that was [indiscernible] of FOLFIRI plus bev, the original pivotal trial, the SD plus PR was equal 68%.

Nice. Okay.

That's very helpful. Okay. And Mark, since your arm, I'm just curious about the logistics. So you're adding 50 patients. So is it true from a timing standpoint that you will be concurrently enrolling the additional patients from the amendment and also, at the same time, kind of starting the pivotal preparation? So just kind of help us understand the timing of these 2 events.

I think I'll pass that to Katherine. She can take that question.

Yes. Certainly, the pivotal, as we mentioned, we're in the process of designing and pulling the timeline together. But we're certainly well aware and we don't want to be in a position of competing with ourselves on 2 different trials. So that takes -- we'll take that -- we have taken that into consideration during our design. The other thing I should mention is that the pivotal will not just be in the United States. It will be in other countries where we have good reason to believe that we could enroll well and that would give us good data.

Our next question comes from the line of Yuan Zhi with B. Riley Securities.

Congratulations on the new data. I have a couple of questions, if I may. So first, just curious, has FDA provided any input on your expansion that you are going to have about 100 patients in the RP2D cohort group?

I can tell you that the protocol has been submitted to the FDA. The amended protocol has been submitted.

Okay. That's helpful. And then the next question is between now and the initiation of your Phase III trial, how will the incremental update of your Phase II trial part, the data part guide your Phase III design?

Well, we are gathering additional PK and safety data. So it will guide us with respect to that. But beyond that, the pivotal is a separate development stream.

Okay. Got it. And the last question, maybe piggyback on the historical PFS. So I believe you gave a range of the PFS, which was between the 4.5 months to 5.7 months. And for the 5.7 months, I believe it's from the original trial where you have bucket of all comers. I'm just curious for -- can you kind of characterize for patients with KRAS mutation, how will their PFS compare to the overall group?

That is not published to my knowledge, and that is something that we are working on, looking for if it's available at all.

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

Thank you.