Kura Oncology Inc (KURA) 2023 Q3 法說會逐字稿

Good afternoon, ladies and gentlemen, and welcome to the Third Quarter 2023 Kura Oncology, Inc. Earnings Conference Call.

At this time, all lines are in listen-only mode. Following the presentation, we will conduct a question-and-answer session. (Operator Instructions) This call is being recorded on Thursday, November 2, 2023.

I would now like to turn over the call to Pete De Spain, Head of Investor Relations. Please go ahead.

Thank you, Lester. Good afternoon, and welcome to Kura Oncology's third quarter 2023 conference call.

Joining me on the call are Dr. Troy Wilson, our President and Chief Executive Officer; and Tom Doyle, our Senior Vice President of Finance and Accounting.

Before I turn the call over to Dr. Wilson, I'd like to remind you that today's call will include forward-looking statements based on current expectations. Such statements represent management's judgment as of today and may involve risks and uncertainties that could cause actual results to differ materially from expected results. Please refer to Kura's filings with the SEC, which are available from the SEC or on the Kura Oncology website for information concerning risk factors that could affect the company.

With that, I'll now turn the call over to Troy.

Thank you, Pete, and thank you all for joining us. Let's jump right in.

We believe our lead drug candidate, ziftomenib is well positioned for market leadership with multibillion-dollar global revenue potential in acute leukemias and beyond. Our conviction is supported by a growing body of clinical data as a monotherapy and more recently in combination with standards of care, a rapid pace of enrollment in our ongoing studies, driven by strong clinical data and robust enthusiasm among investigators and patients and a best-in-class safety and tolerability profile that we believe will enable ziftomenib to become a backbone of therapy across the continuum of care for AML patients. Ziftomenib is a once-daily oral drug candidate that targets the menin KMT2A protein-protein interaction and has potential to address all patients for whom the menin KMT2A pathway is a disease driver, representing up to 50% of patients with AML.

In our Phase I trial, ziftomenib demonstrated an impressive 35% CR rate and 45% overall response rate in 20 patients with NPM1-mutant AML treated at the recommended Phase II dose of 600 milligrams. Importantly, ziftomenib demonstrated a favorable safety profile and was well tolerated with no evidence of drug-induced QTc prolongation or myelosuppression, no patterns of toxicity and adverse events consistent with underlying disease. Building upon the strength of the data from our Phase I trial, we initiated a Phase II trial of ziftomenib in patients with NPM1 mutant relapsed or refractory AML earlier this year.

The registration-directed trial is expected to enroll a total of 85 patients in the United States and Europe. We continue to be encouraged by the pace of enrollment in the trial, which, in our view, speaks to the size of the NPM1 mutant patient population in the relapsed and refractory setting as well as ziftomenib's potentially meaningful advantages in safety profile and clinical activity relative to available therapies.

We expect to complete enrollment of all 85 patients in the Phase II registration-directed trial no later than mid-2024. Increasingly, our clinical investigators refer to ziftomenib as a potentially transformational therapy. We believe their enthusiasm reflects not only their experience with it as a monotherapy, but the tremendous potential benefit to patients that could be realized by advanced ziftomenib to earlier lines of therapy and combining it with standards of care.

Indeed, our vision for ziftomenib is that it can provide benefit to leukemia patients throughout the continuum of care, enabling deeper and more durable remissions in the frontline and relapsed/refractory populations in combination and is a potent monotherapy in the maintenance settings. Clearly, as ziftomenib can do that, it has potential to transform the treatment of AML and ultimately to transform the commercial market for anti-leukemic therapy. It is these transformations in the standards of care that have enabled meaningful advances for patients scenario such as CML, lymphoma and multiple myeloma with corresponding increases in market opportunity. Although AML has lagged behind these other areas due to the complexity, heterogeneity and aggressive nature of the disease, we believe ziftomenib may represent an inflection point for treatment of leukemia and potentially other diseases.

As first steps towards realizing this vision, we're evaluating ziftomenib combination studies, both in newly diagnosed and relapsed/refractory acute leukemia, including NPM1 mutant and KMT2A-rearranged AML. Our approach to combinations is to establish ziftomenib as a foundational therapy that can be combined safely with various commonly used regimens and then to prioritize those combinations that represent the largest unmet medical need and the greatest potential commercial value.

Combination approaches also offer the potential to mitigate differentiation syndrome, particularly in the KMT2A rearranged population as has been previously demonstrated in the development of IDH inhibitors in combination with azacitidine. We began dosing patients in the first of our combination studies, which we call KOMET-007 in the middle of this year. KOMET-007 is a Phase I dose escalation study designed to assess safety, tolerability and preliminary activity of ziftomenib in combination with either venetoclax and azacitidine in patients with relapsed/refractory NPM1 mutant and KMT2A rearranged AML or standard induction cytarabine daunorubicin chemotherapy, commonly known as 7+3 in NPM1 mutant and KMT2A rearranged patients in the frontline setting.

We're very pleased with the pace of enrollment in the KOMET-007 study, which currently includes patients with newly diagnosed and relapsed refractory NPM1 mutant and KMT2A rearranged AML across the United States. At this rate, we anticipate being in position to share preliminary data with sufficient follow-up from 20 patients in KOMET-007 in early Q1 2024. We expect the data set to include safety and tolerability from NPM1 mutant and KMT2A rearranged patients treated with ziftomenib in both settings. We're also working to initiate our KOMET-008 study of ziftomenib in combination with additional standards of care, including the FLT3 inhibitor gilteritinib as well as our post-transplant maintenance program for ziftomenib, both of which are expected to begin in the first quarter of 2024.

Meanwhile, we continue to make progress toward a next-generation menin inhibitor, which we intend to direct to additional as yet undisclosed indications of high clinical, commercial and strategic interest. As we continue to build the clinical data sets that we believe will support FDA registration and commercialization of ziftomenib, we recently enhanced our own commercial expertise with the addition of Brian Powl to our senior leadership team as our Chief Commercial Officer. Brian joined us over the summer with more than 20 years of experience in building commercial brands in hematology and oncology with expertise in patient-focused strategies across sales, marketing and market access for global biotech and pharmaceutical products. He's already making an impact in the organization as we continue to realize the significant potential of ziftomenib as well as our rapidly emerging farnesyl transferase inhibitor programs.

We continue to unlock the substantial therapeutic and commercial value of farnesyl transferase inhibition and believe this novel mechanism is uniquely positioned to augment clinical benefit in multiple large solid tumor indications. Last month, we presented positive results from our AIM-HN registration-directed trial of tipifarnib in patients with HRAS mutant head and neck squamous cell carcinoma. The results were featured during a late-breaking mini oral session at the European Society for Medical Oncology Congress in Madrid. Our AIM-HN data demonstrate that if one understands the proper biological context in which to use an FTI, it has the potential to drive meaningful clinical benefit for patients. We believe these data validate therapeutic value of farnesyl transferase inhibition as we look to advance beyond our initial strategy to target HRAS mutant tumors. With our AIM-HN data in hand, we continue to evaluate whether the combination of tipifarnib and alpelisib has potential to extend the clinical benefit observed in the AIM-HN trial to a broader set of HNSCC patients in our ongoing current HN study.

We continue to evaluate patients in the dose escalation study to inform selection of the optimal biologically active dose to the combination. Once we determine OBAD, we'll continue to evaluate whether the activity supports development and commercialization of the combination in HNSCC. One of the most important takeaways thus far from current HN is that tipifarnib demonstrates a favorable safety and tolerability profile at its full dose in combination with alpelisib. We believe this significantly derisks development of our next-generation farnesyl transferase inhibitor KO-2806, as we look forward to evaluating it in combination with other targeted therapies.

With the success of targeted therapies such as KRAS inhibitors, tyrosine kinase inhibitors and EGFR inhibitors, there's now considerable focus on the development of companion therapeutics that have potential to drive enhanced antitumor activity and address mechanisms of innate and adaptive resistance. Last month, we presented exciting preclinical data at the triple meeting, supporting our rationale to combine KO-2806 with adagrasib in KRASG12C-mutated non-small cell lung cancer and with cabozantinib in clear cell renal cell carcinoma. A week later, we announced the first patient was dosed in the FIT-001 Phase I dose escalation trial of KO-2806. Concurrent with the dose escalation as a monotherapy in the FIT-001 trial, we also plan to evaluate KO-2806 in dose escalation combination cohorts with adagrasib and cabozantinib.

Earlier today, we announced a clinical collaboration and supply agreement with Mirati Therapeutics to evaluate the combination of KO-2806 and adagrasib in patients with KRASG12C-mutated non-small cell lung cancer. Under the terms of the agreement, Kura will sponsor the Phase I study and Mirati will supply us with adagrasib for the study. This collaboration highlights the potential to address the urgent need for more durable and effective treatment options for patients with cancers driven by the KRASG12C-mutant oncogene. We look forward to collaborating with Mirati an established leader in targeted oncology.

We expect to begin dosing KO-2806 in combination with adagrasib in KRASG12C-mutated non-small cell lung cancer and in combination with cabozantinib in clear cell renal cell carcinoma by the middle of 2024. If successful, we believe KO-2806 could become an ideal combination partner for multiple targeted therapies in large solid tumor indications. We look forward to sharing our continued progress in the months ahead.

With that, I'll now turn the call over to Tom for a discussion of our financial results.

Thank you, Troy, and good afternoon, everyone. I'm happy to provide a brief overview of our financial results for the third quarter of 2023.

Research and development expenses for the third quarter of 2023 were $29.3 million compared to $25 million for the third quarter of 2022. The increase in R&D expenses was primarily due to the increase in clinical trial costs related to our ziftomenib and KO-2806 programs. General and administrative expenses for the third quarter of 2023 were $13.1 million compared to $11.6 million for the third quarter of 2022. Net loss for the third quarter of 2023 was $38.6 million compared to a net loss of $35.5 million for the third quarter of 2022. This includes non-cash share-based compensation expense of $7.1 million compared to $6.4 million for the same period of 2022.

As of September 30, 2023, we had cash, cash equivalents and short-term investments of $452.6 million compared to $438 million as of December 31, 2022. We believe that our cash, cash equivalents and short-term investments will be sufficient to fund our current operating plan to mid-2026. Today, we are filing a shelf registration statement and corresponding prospectus supplement for an at-the-market facility for our common stock. We are refreshing our shelf, which was set to expire next month, along with an ATM in order to maintain good corporate housekeeping.

With that, I'll now turn the call back over to Troy.

Thank you, Tom. Before we jump into the question-and-answer session, let me lay out our anticipated milestones for the remainder of this year and next year.

For ziftomenib, we report preliminary clinical data from 20 patients in the KOMET-007 trial in combination with ven/aza, or 7+3 early in the first quarter of 2024. We dosed the first patients in the KOMET-008 trial in combination with additional standards of care, including the FLT3 inhibitor gilteritinib in the first quarter of 2024, initiate the post-transplant maintenance program in the first quarter of 2024 and complete enrollment of 85 patients in KOMET-001 registration-directed trial in NPM1 mutant AML by mid-2024. For tipifarnib, determine the optimum biologically active dose in combination with alpelisib and determine next steps for the program by mid-2024. And for KO-2806, dosed the first patients in the FIT-001 dose escalation trial in combination with adagrasib in KRASG12C mutated non-small cell lung cancer and with cabozantinib in clear cell renal cell carcinoma by mid-2024.

With that, Lester, we're now ready for questions.

Thank you. Ladies and gentlemen, we will now begin the question-and-answer session. (Operator Instructions) Your first question comes from Jason Zemansky from Bank of America.

Regarding the upcoming KOMET-007 update, what do you think investors should be looking for from the data? What's necessary before the community can start to feel confident about the potential for combinations and what are we looking for in safety and efficacy? And then a follow-up, if I may.

So in terms of what investors should expect, so 007 is a Phase I dose escalation study, as I indicated. We are evaluating ziftomenib in combination with ven/aza, in the relapsed setting and with 7+3 in the frontline setting. Importantly, we're evaluating KMT2A and NPM1 mutant patients separately in separate cohorts. So there are 6 patients per cohort. So think of it as 4 cohorts and 6 patients each, that's 24 patients at a 200-milligram dose. And then as we dose escalate 24 patients at 424 patients at 600.

In terms of what to look for, whether it's our data or anyone else's data, I think you start with safety and tolerability, ability to combine drug-drug interactions, do you have to discontinue doses, do you have to dose reduce. And then ultimately, of course, there will be activity, although, of course, in combination. I think, Jason, we feel confident based on the monotherapy data that we've shared thus far from the 001 study. If you recall, we had among 20 patients with NPM1 mutant AML, we had a 35% CR rate with full count recovery.

Thus, we have no QTc prolongation, we have no drug-induced myelosuppression, we have no predicted adverse drug-drug interactions, we're once daily, we're not a sensitive CYP3A4 substrate, all of those considerations will become important as you look to combine with these standards of care. This will be a preliminary look. We wanted to get it out there so that investors could assess safety, tolerability, ability to combine and importantly, ability to mitigate DS. That was a question that we were getting a lot as to why do you see a difference between KMT2A and NPM1.

And we feel confident, Jason, that in early Q1, when we shared the data with you, among those 20 patients, we'll be able to answer investors' questions. We will, of course, hopefully, continue dose escalation and look to reach a recommended Phase II dose in each of those 2 settings to then help inform the design of ultimate registration-enabling Phase II/III studies, but one step at a time.

Got it. And then in terms of the opportunities here, how do you prioritize 7+3 versus ven/aza, the frontline versus maintenance? And I guess, among those 2, is 1 better able to kind of give you a glimpse into how a combination with FLT3 would look?

Yeah. So two good questions there. Let me take them kind of in order. If you look simply at the commercial opportunity, venetoclax combinations and maintenance probably stand the tallest. Again, given some baseline assumptions, probably more detail than we have time for right here. But ultimately, what we'd like to do and I think it will be important, we look toward doing this eventually with someone, right, through some sort of partnership with a strategic partner, you really want to be able to position ziftomenib in every combination setting. Why do I say that?

You referenced specifically FLT3. FLT3 is half the NPM1 mutant combination. You now have quizartinib approved in the front line, you have gilteritinib approved in the relapsed refractory setting, that's half of NPM1 is 15% of AML in the preclinical models that we and Syndax have both enabled through publications, that combination is curative in a preclinical setting. So if you add an all-oral regimen that could drive that kind of clinical activity, that would be pretty impressive.

I think, Jason, what we'd like to do, and you see us doing it. We are laying the foundation for what I think is the broadest and potentially most value-creating menin inhibitor franchise in AML, and that's going to be frontline, that's going to be relapsed, that's going to be maintenance. Then you also heard us reference additional undisclosed indications that we're thinking about directing our next-gen menin inhibitor to, we'll speak more to that. We pick our spots carefully. But there, again, our goal is to have not just a best-in-class menin inhibitor, but truly a best-in-class franchise throughout the continuum of care.

Thank you. Your next question comes from Peter Lawson from Barclays.

Troy, just to follow-up on the KOMET-007. Beyond safety and differentiation or lack of differentiation benefit, what are the kind of the response rate bars or durability bars you kind of want to hit there as well?

Let me give you a caveat, and then I'll kind of give you the numbers to think of. So the caveat is the numbers that excite you are come from either retrospective analysis or Phase III studies, right? And there's always kind of an emotional desire to compare those numbers to a Phase I dose escalation study. We all do that at our apparel, right? I just want to give that important caveats. I think one of the things we do is very, very credible drug development, and let's just put that out there.

That being said, the bar for those standards of care, that kind of what you would expect in the front line in 7+3, you're looking at, depending on the literature reference, a 70% to 90% CR/CRH trade. In ven/aza in the relapse setting, you're looking at roughly a 40% to 60% CR/CRH rate. So that's kind of the way to think about it. Our goals, of course, are safety, tolerability, are there drug-drug interactions that require changes in dose or interruptions. Of course, combinability, ability to mitigate DS and then, of course, efficacy. We'll be looking at that as well.

I'll just highlight for you and this is why I took pains to explain to Jason's question, it's 24 patients at 200 milligrams. So we're going to share 20 patients' worth of data. But the goal, of course should be let's get a robust data set of up to 72 patients across the cohorts to help inform our recommended Phase II dose for each of those 2 regimens. But I hope that a, gives you the numbers and b, gives you the appropriate context in which to think about them.

And then just on 2806 and that cabozantinib combination, just like kind of where you're thinking about driving that? Would that be a partnership as well like you did for the KRAS or would that potentially be an IST?

Yeah. So just to be clear, because you have a couple of things in your question. So let's start with the clinical collaboration between Mirati and Kura. Mirati is supplying at-aggressive to us. They've of course had input on the protocol. They have all of the appropriate safety reviews and whatnot. We're not yet formally co-developing that combination together, right? This is early days. It's an exploratory study. They're supplying it under a supply agreement.

With cabozantinib, our expectation is that given that we'll be in the labeled indication and cabozantinib is fairly widely used, we'll be going into a second-line setting that will largely be covered by insurance, thus not an immediate need for a clinical collaboration and supply agreement or even any other agreement. Cabozantinib is well understood. And if you, again, look at the preclinical data that was published at the Triple Meeting, very, very impressive activity in a second-line setting and in particular, even after patients have progressed on 1 TKI, the combination of a second TKI plus 2806 really drives meaningful benefit.

And again, a lot of the things that we've learned about FTIs over the years, they have anti-angiogenic properties. They have other reasons that make that combination really pretty slick. And so we'll look forward to getting into that combination again, approximately middle of next year.

Your next question comes from Roger Song from Jefferies.

A couple from us. Maybe still focusing on the combo, given that will be the most upcoming data readouts you will have. Maybe just to drill down some of the details, Troy, if you can, for those 20 patients, how balanced we should see for the first time versus the relapsed/refractory and NPM1 versus KMT2A understanding you have 2 cohorts by the dosing, but how balanced within the dose, we will be able to look at it. And then also just confirm that 20-patient or will be from the 200-milligram, but not a 600-milligram. That's my first question.

Sure. Yeah, Roger. So let me take your second question first. So we're starting the dosing at 200 milligrams. Obviously, I don't want to -- there is an intention to escalate all 4 cohorts. I don't want to speak to exactly sort of what you'll see yet. But what I can tell you with respect to your first question is we have KMT2A and NPM1 as 6 patient each separate cohorts for each of the 2 regimens. I can tell you this. They're all enrolling well. There's strong activity for each of the 4 of those cohorts.

We anticipate that the data set when you see it in early Q1 next year will be well-balanced in terms of NPM1 and KMT2A, both frontline and relapsed. So again, an early data set, but we think an important data set in terms of addressing this question of, can we mitigate differentiation syndrome. And it's just a credit to our team and we talk a lot about being highly encouraged. We started dosing this study in July.

We're already at a point where if we can guide to giving you data in early Q1 '24, our team is just crushing it on the operational execution. And we'll of course continue to dose escalate as appropriate. That's why I want to be careful how we answer the question on exactly what dose level. When we share the data, we think it will address these questions around safety, tolerability, combinability, ability to mitigate DS, et cetera. We'll, of course, look then to providing a subsequent update that will continue to flush-out that picture.

Sure. Yeah, I agree. It's pretty rapid enrollment. And then so I don't want to lose sight of your pivotal monotherapy data, the study for NPM1. So I think that's the first time you guide you will close the enrollment by midyear. Just curious any statistical plan you have disclosed to us in terms of maybe any interim analysis or the non-hypothesis? What is the minimum follow-up to have the final readout? And since you are guiding the enrollment completion, any guidance around the timing of the readout.

Sure, Roger. So there's again a few questions in there. So this is the first time we've really put it on our milestone slide, drawing a line as far as completion of enrollment of an 85 patient study no later than the middle of next year. I'll note that one of our principal competitors is expecting to enroll its NPM1 cohort now sometime between Q1 and Q2 of next year, a 64-patient study. So we're clearly, I think, neck and neck and closing ground. The reason we picked 85 patients was driven by safety and tolerability. That always has to be paramount. That's why we are doing 007 the way we're doing it.

That's really what the FDA wants to see, even in these devastating diseases. So 85 patients plus the experience we have in NPM1 from the Phase I study, we think gives us approximately 100 patients. That should meet the agency's expectation as far as safety and tolerability. We have not disclosed a statistical plan or the no-hypothesis. I can tell you, we are being very conservative. We are, I think, quite encouraged by the 35% CR rate with full count recovery in the Phase Ib that we saw. But we're giving the trial every opportunity to be successful, and we're taking advantage of every opportunity we can to pull the time lines forward. So I think it's important to put that out there.

As far as disclosure of data, that was the last of your questions, let's get to that maybe a little further along. We want to make sure we've got really clear visibility into the end of enrollment. And as you know, you need enrollment, you need follow-up, you need data cleaning. And ideally, your data release coincides with the scientific or medical meeting. We want all those stars to align. We're working on it. We'll give you an update when it's appropriate. I think I've answered all your questions, Roger, but tell me if I missed anything.

No, that's great.

Your next question comes from Li Watsek from Cantor Fitzgerald.

Just wondering, a, if you can just comment on the combo data from your competitor released from (inaudible) this morning. And then since you had some initial experience with your own combo, I understand it's not really apples-to-apples. But just from the safety perspective, how do you see a trend relative to your competition?

A lot of drug development is sort of pattern recognition and learning from the past. And if we go to other areas where people are developing targeted therapies, safety, tolerability, drug-drug interactions, ability to combine or what's sine everybody, right? We've seen this in the KRAS field, ability or not to combine with checkpoint inhibitors. We've seen it in combining with inhibitors of the RAS pathway in the PI3 kinase pathway. That's why we're so excited about 2806 and adagrasib. Here is no different.

I think, Li, some of the critical questions are going to be what are the drug-related AEs that you see both as a monotherapy and in combination. Are you seeing high rates of neutropenia, thrombocytopenia, febrile neutropenia, that's what we're seeing. You would, of course, expect activity, the standard of care gives you activity, right? But what you're really looking for is are there going to be challenges that are going to be posed in being able to either administer the standard of care or really optimize it.

I'll just go back to what do you already know about zifto. We've given you a very robust data set at the 600-milligram dose that I believe, despite the data from the handful of competitors here at ASH, really shows that we have a best-in-class menin inhibitor from the perspective of safety and tolerability. That's going to have 2 important considerations lead.

One is the challenges that limit the duration of exposure in combo is one of the things you want to focus on. And the other, of course, is the maintenance setting, right? You want to have the most benign compound there. So that's what we, as sort of players in the field are looking at as we look forward to the ASH presentations. And I would say we're looking forward to sharing our early clinical data with you. It's early, but we're encouraged by enrollment and looking forward to sharing it in Q1.

And then maybe just a follow-up on your own combo data in Q1. I'm just curious, is there any reason to expect different responses in NPM1 versus KMT2A.

So again, let's go back to the standards of care. You would expect, in general, the KMT2A patients to not respond as well. But depending on what regimen you look at, what line of therapy, it's pretty close. It's ven/aza, I believe, for NPM1 is in the mid-40s. KMT2A is kind of in the low 40s. You can't drive a truck between them. But in general, the KMT2A patients probably do a little worse as you look across different regimens. I do want to be carefully again that it is though as tempting as it is, we want to just be careful whether we're looking at our data or at our competitors' data, you want to make sure you have enough patient experience before you try to draw any kind of conclusions on activity because you're looking also at duration at MRD, I mean there's a whole lot of factors here. Our goal is to keep patients on therapy months or even years. And that's going to be driven by safety and tolerability. It is going to be maintaining clinical activity, but safety and tolerability is really going to be paramount. And it will be an interesting next 2 or 3 months here.

Your next question comes from Justin Zelin from BTIG.

This is Mukherjee on for Justin. On the topic of the combination study with zifto, you've elaborated on the efficacy bar that one would want to look for. But could you just give a bit more color on the safety bar that one would be looking for, at least in the context of the various cytopenias, knowing that myelosuppression is very much characteristic of agents in the frontline in the relapsed refractory setting. And I have a follow-up question.

Sure Jeet. So yeah, I mean, what you worry about, of course, and I think you've correctly called it out. Cytopenias are not uncommon in the frontline setting. You do see not insignificant myelosuppression with ven/aza. So to the extent that you have an AE profile, a drug-related AE profile that runs the risk of compounding that, what you run the risk of is, are you going to need to dose reduce, are you going to need to discontinue, are you going to require continuous monitoring, whether it's QT or various cytopenias. That's what you're looking for.

The biggest risk, and the thing that gets the combinations of any flavor in trouble is when the toxicity profiles are overlapping. In a Phase I study, just to put it simply, you're looking to show a combo safety profile that's at least no worse than the standard of care, right? It's rare that you do better because you're not mitigating the toxicities, but you're not looking for a lot of additive toxicity. That's where you can create issues.

So the other thing is you're potentially looking to improve upon the backbone as you have additional experience with your agent and other agents in terms of how to combine, right, can you take certain things away, can you do dose optimization, but that's later on down the line. For these early combo studies, it's really about what's the safety of the backbone and then what's the safety of your agent plus the backbone.

Jeet, since you asked the question, I want to just call something out. And it's a credit, I think, to our team. The way our study is designed, we begin patients on the standard of care on day 1. We dosed them for 7 days and then we start zifto on day 8. There's really 3 reasons for doing that. Number 1, you get a safety baseline on the standard of care. So that helps you deconvolute any talks that you see in the combination.

Secondly, of course, it allows you time to genotype. And then third, it helps to debulk the patient further mitigating the risk of differentiation syndrome. I don't want to speak to what others are doing, but we found that approach to be very successful, and it's something that we're implementing kind of across the board. Starting with these 2 combinations and as you hear in 008, we're going to roll out to some additional combinations, most notably gilteritinib.

Got it. That makes perfect sense. And just a second question I had. Turning to the FTI program. Could you just share your thinking and strategy a bit more broadly around this program? What would you be looking for from a safety and efficacy perspective to justify moving, tipi forward as a monotherapy or the alpelisib combo?

You're asking specifically about tipi or about 2806. I just want to make sure I answer the question. You asked tipi and head and neck.

Yeah. Perspective on both programs would be helpful.

Okay. So with head and neck, I mean -- and this was one of the takeaways from the [AMJ] data that was presented by Dr. Ho in the mini oral session at ESMO. You have at best in the second line with standard of care and 20% response rate. The third line is 5%. Tipi as a monotherapy is driving sort of meaningful activity with very -- and it has a favorable safety and tolerability profile. What we know is, tipi is not active as a monotherapy in the PIK3CA setting. Alpelisib is reported to drive only stable disease. Clearly, if you can drive responses with reasonable durability and you have an acceptable safety and tolerability profile, then you start to look at it.

The bigger question, and let me come to 2806 is, as you're hearing, this is a busy quarter. I think subsequent quarters may be equally busy. We have a number of investments in zifto. You've heard relapsed setting, frontline settings, we're going to start into maintenance. You're hearing us now push forward with 2806 in both non-small cell lung and renal cell carcinoma. I'm interested if there's an opportunity with 2806 in pancreatic cancer, RAS-driven pancreatic. I think that's a huge unmet need and a huge opportunity in a rapidly evolving space.

The other thing we've got to do is be good fiduciaries and say how can we be as disciplined on the investment side as we are on the scientific and clinical side, and that's the calculus we go through on a pretty regular basis. So we're going to get everything we can out of head and neck and then we're going to fold that into where do we make these investments? Where are we going to drive the greatest amount of value for patients, for employees and for our shareholders. And that's how we'll do it.

Your next question comes from Phil Nadeau from TD Cowen.

A quick question from us on the updated enrollment time lines. When do you think you have clarity to really say when the moment in the pivotal trial is going to complete? Do you think that's likely early next year or will we know it is complete once it's completed?

I think Phil, so today, we put down in our milestone slide for the first time. It's no later than mid-2024. Based on what we're hearing from the competition, guiding that they'll complete enrollment Q1, Q2, I think even that, let's hit that. We're super competitive, right? We're maybe a few weeks apart or maybe a couple of months at the most, we're going to do everything we can to drive enrollment. We've resisted the urge, given that we continue to say we're highly encouraged. We've resisted the urge to pull those milestones in until it's really a data complete. So I would say to you, don't anticipate us to move any milestones on enrollment of our NPM1 pivotal. I think we're very much to do as well as that, if not better. And I would say just stay tuned.

Your next question comes from Brad Canino from Stifel.

Troy, I just want to pull back and ask a question about the menin class in general. I think the street view is that KMT2Ar is the more sensitive population to men inhibition, which might just be because the name of the alteration is more similar. But nevertheless, some struggle with investing in this class because the best efficacy is then expected in the smaller patient population. But as I was reflecting on all of the menin data sets this afternoon from J&J, from Syndax and of course, your own, the common trend is to actually see more responses in NPM1. And I want to know where do you stand with your synthesis of the data across the class? Should we on the Street actually recalibrate and expect the best efficacy to be confirmed in the larger NPM1 population?

It's actually not a question I've heard before. And I think it is worthwhile to set expectations. So we have to be careful what we're talking about here, right? The registrational endpoints for the relapsed/refractory setting are CR/CRH, for the frontline setting, they will be CR, for the maintenance setting, they will be survival. Other companies, and we got to wrap abstracts out our reporting ORRs in one case, even including stable disease, MLSS, CRIs, those are all measures of clinical activity, and those are important. But I think the registrational endpoints are, at least at this stage are what's important. Can you drive the CR/CRH and in the frontline, can you drive the CR.

The reason I frame it that way is that can be a little confounded by are you getting full count recovery, are patients going on to (technical difficulty). So that's why CRC is also worth looking at. We probably wouldn't go beyond CRC. And at this point, I think although again, emotionally, intuitively, it makes sense that KMT2A should be more sensitive. In reality, we're seeing activity pretty robust activity in both populations across the class. And I think that's only going to improve in combination.

What we're really hoping in combination to do is, can we drive deeper responses, can we eliminate extramedullary disease and minimal residual disease, can we drive length in the time to recurrence and drive better survival. And I'll go back to something I said a couple of -- as an answer to a couple of calls ago, that's going to come down to who has the ability to keep menin pressure on in the presence of combo and then ultimately in the maintenance setting as a monotherapy without having to jump through a lot of hoops. That's what we've seen with every targeted therapy. There's no reason to believe menin is any different. I think zifto has to stand pretty tall when you look at it that way.

(Operator Instructions) There are no further questions at this time. Dr. Troy, please proceed with your closing remarks.

Thank you, Lester, and thank you all once again for joining our call today. We'll be participating in the Stifel Healthcare Conference and the Jefferies London Healthcare Conference in a couple of weeks. We look forward to seeing many of you there. In the meantime, if you have any additional questions, please feel free to contact Pete, Tom or me. Thank you, and have a good evening, everyone.

Ladies and gentlemen, this concludes today's conference. Thank you for participating. You may now disconnect.