IDEAYA Biosciences, Inc. ($IDYA)

Good morning, and welcome to the IDEAYA Biosciences webcast. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the IDEAYA Biosciences website following the conclusion of the event. I'd now like to turn the call over to your host, Yujiro Hata, Founder and Chief Executive Officer of IDEAYA Biosciences. Please go ahead, Yujiro.

Good morning. I'm Yujiro Hata, CEO of IDEAYA Biosciences, and I will be your host today. Please note, we'll be making forward-looking statements, and please refer to our SEC filings as appropriate. I welcome all of our online attendees and speakers to discuss the top line results from the OptimUM-02 study. I'm delighted to introduce our webcast participants, including Dr. Meredith McKean, a distinguished KOL and oncologist from Sarah Cannon Research Institute; alongside Chief Medical Officer, Darrin Beaupre; and Chief Financial Officer, Josh Bleharski. For today's agenda, Darrin, our CMO, will provide a brief introduction of darovasertib and the OptimUM-02 study design, followed by a summary of the top line results. Once the prepared remarks have concluded, we will open up the line for the analyst Q&A portion of the webcast, where Dr. McKean will also participate alongside IDEAYA management. Today's Phase II/III registrational trial results are an accumulation of over 5 years of clinical development activities, where our organization worked in close partnership with the U.S. FDA, patient community and leading clinical investigators globally. Importantly, the PKC and c-MET combination rationale was discovered by IDEAYA scientists, and we went from research bench discovery to dosing our first combination patient in the clinic in less than a year. The OptimUM-02 study represents the first frontline randomized registrational trial in HLA-A2-negative metastatic uveal melanoma, which we believe represents the majority of the mUM patient population. Next, this study is also the first randomized frontline registrational trial in mUM to utilize ipi/nivo in the control arm, which is the preferred investigator choice therapy in the U.S. versus PD-1 alone. Lastly, as Darrin, our CMO, will share, this is also the first time frontline randomized registrational trial in HLA-A2-negative mUM to demonstrate a statistically significant clinical benefit versus investigator choice therapy arm for both PFS and ORR highlighted with a p-value of less than 0.0001. With that, Darrin, please take it away.

Thank you, Yujiro. So let's start the discussion this morning with a little background around uveal melanoma. Next slide, please. Uveal melanoma is the most common ocular tumor of the adult eye. Although, fortunately, it remains relatively rare and is an aggressive form of cancer with a poor prognosis. In the United States, there are about 3,000 newly diagnosed cases per year and approximately 10,000 cases reported globally. Uveal melanoma comes in two forms, one that is HLA-A2 positive and the more common type, which is HLA-A2 negative. With respect to primary management of localized uveal melanoma, approximately 20% of patients will require enucleation for which the eye is removed. The remainder typically undergo either proton beam or plaque brachytherapy, which may create permanent vision loss. Unfortunately, about half of the patients diagnosed with this disease will develop metastases which is associated with a median overall survival of approximately 10 to 12 months and a 5-year survival rate of approximately 15% to 20%. There are limited treatment options available for patients with metastatic uveal melanoma. Liver-directed therapy is sometimes utilized, but most patients require some form of systemic therapy. For HLA-A2 positive subjects, there is one approved product known as KIMMTRAK. For HLA-A2 negative subjects, there are no approved therapies, although immune checkpoint inhibitors are often used off-label and have very limited clinical activity. Next slide, please. The important biology associated with this disease is noteworthy for the majority of uveal melanoma tumors harbor mutations in G-coupled protein receptors that are responsible for the constitutive activation of protein kinase C. This pathway drives uveal melanoma growth and survival and is the harbinger of the disease. Darovasertib is a potent and selective inhibitor of protein kinase C. It was found to have significant antitumor activity in preclinical models. In addition, overexpression of MET is often found in advanced uveal melanoma and is thought to play an important role in metastatic spread. It was determined in preclinical testing that the combination of darovasertib and crizotinib, a MET inhibitor, resulted in greater antitumor activity than either compound alone. This novel combination was therefore studied in Phase II in metastatic uveal melanoma subjects and was found to have a high response rate with an associated prolonged progression-free survival in treated subjects. This set the stage for the randomized Phase III trial, which we will discuss today. Next slide, please. OptimUM-02 is a randomized Phase II/III trial that completed enrollment in December of 2025. 313 HLA-A2 negative metastatic uveal melanoma subjects were randomized 2:1 to receive either darovasertib, 300 milligrams wise a day and crizotinib, 200 milligrams twice a day orally each day, versus standard of care therapy, which included either single-agent checkpoint inhibitors such as pembrolizumab, combined immunotherapy with ipilimumab and nivolumab or dacarbazine for those who would not tolerate immunotherapy.The primary endpoint was progression-free survival by blind independent central review for potential accelerated approval. And for Phase III overall survival was the key endpoint for a potential full approval. Secondary endpoints included progression-free survival by investigator overall response rate, duration of response, disease control rate, of course, safety and several quality of life questionnaires were included in. Next slide, please. The top line results from this study are presented here. With respect to the primary endpoint of progression-free survival, the darovasertib and crizotinib combination had a statistically significant improvement in median progression-free survival by blind independent central review of 6.9 months compared to 3.1 months in the investigator choice arm. The provided hazard ratio of -- this provided a hazard ratio of 0.42 with a 95% confidence interval of 0.3 to 0.59 with a p-value less than 0.0001, which equates to a 58% reduction in the risk of tumor progression in the treatment arm. Next slide, please. Also highly noteworthy was the overall response rate. Darovasertib, combined with crizotinib delivered an overall response rate of 37.1% compared to only 5.8% in the investigator choice arm with a p-value less than 0.0001. There are five complete remissions seen in the treatment arm none in the control arm. There was also a trend and improvement in overall survival. In terms of safety, both arms demonstrated a safety profile that was expected based on prior studies, and the full data of this trial will be presented at a future medical conference. Next slide, please. In conclusion, the darovasertib and crizotinib combination represents a novel emerging therapy growth subjects with metastatic uveal melanoma who have HLA-A2 negative disease and has shown a significant level of superiority relative to standard of care immunotherapy and is likely to represent a paradigm-shifting therapy in a disease that has high unmet medical need. With respect to darovasertib itself and the fact that it targets the driver of uveal melanoma protein kinase C, we believe darovasertib either as a single agent or in combination with crizotinib has the potential to have a major impact across the entire uveal melanoma patient journey. And we have several trials either underway or being initiated to uncover the promising activity of this agent. In the neoadjuvant setting, darovasertib is being tested in primary uveal melanoma with very important endpoints that include both I and Vision preservation. Post primary local therapy, darovasertib combined with crizotinib will be tested in the adjuvant setting in subjects that are high risk for metastases to determine whether this combination can reduce both local in distant relapse. And lastly, of course, in the metastatic setting, the OptimUM-02 trial has provided evidence of promising activity of darovasertib and crizotinib in HLA-A2 negative disease but it's also being tested in the OptimUM-01 study in subjects to our HLA-A2 positive. Upon completion of these trials, we believe darovasertib will become a backbone therapy for all phases of uveal melanoma and will improve the lives of subjects that have to live with this life-threatening disease. I'll remind folks today that darovasertib is a breakthrough therapy drug designated by the FDA. And today is the first study where it's shown a really significant impact on patients with uveal melanoma and we have several trials underway with more to come. So with this, I conclude my remarks, and I'll pass it back to you, Yujiro.

Thank you so much, Darrin. This now concludes the prepared remarks. And operator, let's now please transition to the analyst Q&A portion of the webcast. We please ask the analyst keep to question. We will also ask the operator status reach the 30-minute mark. Operator, you may now proceed to the first question.

So our first question comes from Anupam Rama at JPMorgan.

Just a quick question. In the full medical conference presentation, will you be quantifying the overall survival separation? Or is this really a wait until the full analysis type of scenario? And if the KOLs on line, just based on this data as well as the early-stage clinical experience, where do you see the combination fitting into both HLA negative and positive patients.

Yes. And upon the OS question, we will not be specifically at the upcoming medical conference. So as we noted, we have observed an early trend, which is encouraging. There's been about roughly 10 months of follow-up. So to see that early separation, we're quite encouraged. And as you know, we did report a robust survival result back in the fall at the Society of Melanoma Research. With that, Dr. McKean, if you're on the line.

Yes, sure. So it sounded like the question was where do we see this in practice for both potentially HLA positive and negative patients?

That's correct.

Okay. Yes. I mean I think the -- this data, obviously, the randomized trial was for patients that were HLA-A02:01 negative, however, the data that we've presented before at ESMO in 2023 and then ESMO in 2024 included patients with both HLA-A02:01 positive negative and we saw similar response rates. And so I think the excitement here is certainly that we've never had a systemic therapy with this HLA response rate for these patients. to be able to feel like we really have the opportunity to see improvement in their disease from time of onset of medication. And so I think there's really kind of limitless possibilities of where we could use this medication for patients with metastatic uveal melanoma.

Our next question comes from Maurice Raycroft at Jefferies.

Congrats on the update. And I'll follow up on the overall survival topic. So Yujiro, you've talked about a potential interim OS readout in first half '27. Could that time line change based on what you're seeing in the current data? And then also for Dr. McKean, if you could just talk more about how these data could influence your use in the frontline HLA-positive patients? And are the PFS and response rate data sufficient? Or is there something specific on OS you'd want to see there?

Darrin, do you want to take the interim OS?

Yes. So the interim OS is planned for midyear, of course, next year. But there'll be opportunities as we get into the filing to discuss with the FDA the progress of the trial and the data itself. So it will be evolving, but the plan is for the interim. But if an earlier look with the FDA makes sense because at this stage, we have such a very positive study here without an ability to cross patients over. So it really just depends on the maturity of the data to be quite honest.

I can jump in. So obviously, this is just a huge day for patients with metastatic uveal melanoma. For patients that are HLA-A02:01 negative, the only systemic therapy option we've had was Ipi/Nivo, right? And you can see how well that performed and really what we been able to offer patients. So I think, Daro/Crizo is going to be an exciting option for those patients. For patients that are HLA-A02:01 positive tebi there's still some questions about maybe the long-term benefit with the overall survival that was seen in the clinical trial but the response rates are single digit, right? So when patients come in with large volume disease, extra hepatic metastases, you still just have not had good options for those patients. And so I think this really is exciting for all patients with metastatic uveal melanoma to be able to have an agent like I said, that shows such a significant response rate, allow stability of disease and potentially shrinking the disease to be able to get the next line of therapy.

Our next question comes from Tyler Van Buren at TD Calin.

Congrats on the data and the great execution of the study. So the 7-month median PFS clearly hit a bar and is consistent with what you guys have shown in the past. But just wanted to focus on the 0.42 hazard ratio for a bit. That's clearly an incredibly impressive PFS hazard ratio by any standard. So can you elaborate just on the significance of that magnitude benefit in the context of the data that's been reported in the uveal melanoma population historically as well as the fact that Ipi/Nivo was included in the control arm.

Yes. Dr. McKean, do you want to maybe discuss the hazard ratio and kind of your view as a clinician? And as we noted in the beginning, I think the usage of Ipi/Nivo on the control arm, this is the first front-line randomized study where that was incorporated. So your comments here would be helpful.

Yes. I think there's going to be a lot of discussion in the field that as the way the trial is designed, as investigators, we have the opportunity to give patients Ipi/Nivo. The only other combination systemic therapy option. And you saw the results here and it -- and that's really what we've felt for our patients. The only other data that's available has been retrospect to single institution data sets, and there's obviously a lot of selection bias in which patients you're able to give Ipi/Nivo to versus potential liver-directed therapies as the only treatment options. And so I think this is an important data set for the field as well because this is the most data that we have treated with Ipi/Nivo. And we've known that the response rates in uveal melanoma is far worse than anything we've seen in any of the other subtypes, cutaneous, mucosal or [ acrlintigious ]. So I think that -- I think there's going to be a lot of discussion in the field about how ipi actually performed in a randomized trial because that fits with what we see and feel for our patients and having had kind of the lack of any other systemic therapies for these patients. And then as far as the PFS and objective response rate, that really help with what we've seen for the number of patients treated on the Phase I, Phase II data. So I think pleased to see that, that was similar and what was expected from the patients we've treated before.

Our next question comes from Yigal Nochomovitz at Citi.

For Dr. McKean, I'm wondering if you could comment a little bit on how you see the potential in the other settings that IDEAYA's running studies in adjuvant and neoadjuvant given that we now have a very favorable data in the metastatic setting in HLA-A2 negative.

Yes. I mean, the field has really been waiting for an effective systemic therapy to be able to move these therapies forward. There's been some data presented for the neoadjuvant setting for patients potentially life changing to be able to save their eye, not have to undergo enucleation try to preserve vision. So I think there's certainly a lot of enthusiasm in the ophthalmology community about how else we can use this medication and the data presented thus far, I think most recently, in Rio earlier this year, really demonstrating it using the higher response rate to try to offer patients more options for local disease control and then the adjuvant setting is really exciting because we've had fantastic prognostic tools, whether that's gene expression profiling or chromosomal analysis to identify exactly which patients we know are high risk. So at the time of diagnosis, we can tell patients, unfortunately, you have 50% likelihood of recurrence, but we haven't had effective therapies to then offer in the adjuvant setting. So I think there's a lot of excitement in the field about the other uses and potential situations for the monotherapy in combination.

Thank you Dr. McKean. Darrin, anything else you'd add about neoadjuvant or adjuvant?

Well, it's funny, a few comments. I was just thinking about the prior comment, too, in terms of where we sit in the metastatic setting. When you review all the historical data, no matter what you look at, you end up at a response rate of 5% to 10% and the PFS of 3 months over and over and over. And now we're finally breaking away from that, which is great for patients. And as Meredith pointed out, I think in the neoadjuvant setting, we have shown we've been able -- with darovasertib as a single agent able to save 60% of eyes for patients who would otherwise require enucleation and then for those with plaque brachytherapy being able to reduce radiation dose, improve vision while on treatment and have a predictive tool that suggests that down the road, their vision will be better for those who get plaque brachytherapy, great. But I think what everyone is really, really looking forward to is the adjuvant trial as well simply because there's a potential to save lives. Patients who are at high risk, as Meredith pointed out, with high-risk genetic features, Class II, monosomy 3, those are the folks that tend to have the highest risk of relapse, if you could reduce that rate or push out the time to metastases, that would be incredible. And when you look at that curve that we presented, the progression-free survival curve, again, separation throughout the entire journey of that curve, the separation is real. It's big. And you would have to think that, that would translate in a benefit to benefit in the adjuvant setting. And so that's why we're really excited to get that trial going as well.

Yes. Maybe just only other add is with this kind of data just gives us continued further confidence in that adjuvant opportunity. So I think with that, we'll move on to the next question.

Our next question comes from Michael Yee at UBS.

Great. Thank you for the question. Thank you for the comments on adjuvant. In HLA-A2 positive, can you remind us, Yujiro, will you be able to have a good package to -- of data to help file in your filing to address that with the potential also for compendia listing and when the doctors consider using that there in positives if you have compendia listing? And second question is in this study that you are reporting today, do you expect that duration of treatment is expected to be much longer than 7 months and the doctors continue to treat well past progression?

Yes. Maybe, Mike, I'll take the latter part first. So I would say, typically, in the past, we've seen patients getting treated beyond progression roughly about 3 months. So -- and I think that's been consistent with what we've seen through this study, including the single-arm studies. In terms of HLA-A2 positive, very significant focus for us. So we do have a strategy both in terms of our efforts to get it on the label as well as vis-a-vis compendia. Darrin, anything else you'd highlight on this one and HLA-A2 positive, I don't know a signal.

I know I just saw the 01 trial is continuing to mature. We have around 100 patients dosed that are HLA-A2 positive Again, we presented data at ESMO in 2023 to show that really, we don't see any difference between the 2 with respect to the kind of benefit that patients with HLA-A2 negative disease received the positives get that as well, best that we can tell thus far. So we're very enthusiastic about bringing that data forward and working with NCCN type panel as well as the FDA in order to make sure that patients have access to this kind of therapy because as shown in the randomized trial, it's making a big difference.

Yes, Mike, I think here also, we do have a very aggressive publication strategy for both HLA-A2 negative and positive. So you're going to start seeing quite a bit of data coming from us on that front for both fronts.

Our next question comes from Li Watsek at Cantor Fitzgerald.

Wanted to my congrats as well, a great outcome. I guess for patients who progress, can you talk about subsequent therapies used in the trial. I'm curious if you're different [ in ] actually negative versus positive patients in our observation. And then related to that, for Dr. McKean, can you comment on your approach to sequencing once daro is approved just across the HLA status?

Sure. Darrin, do you want to take the first one? And then Dr. McKean.

Yes. With respect to sequencing, probably we've had Meredith take that because the sequencing that occurred in this trial would be no different than you sequence a patient with standard therapy. Maybe you can Meredith speak to now in the context of the daro/crizo combination coming on scene, what your vision is of how therapies will be sort of sequenced in the future?

Yes. I mean I think to -- on study, patients could treat on progression, but you weren't able to do any local therapies, which we know is very important for these patients in their disease control. And so I foresee there's -- there will be a lot of -- and we've seen other data and uveal of looking at combination approaches with liver-directed therapies. And so I have a patient on compassionate use that has now been on, Daro/crizo 3 years because we did 90 to the on progressing liver lesion. -- then we're going to see a lot more of that now that we're going to have flexibility to be able to treat the patients in front of us using all the tools that we have. So I think there's probably been a lot more kind of combination approaches. I think there's going to be patients that were previously ineligible to even receive liver-directed therapies. But then I think there's still probably a lot to be learned about sequencing with immune therapy. But I think at the end of the day, daro/crizo is the highest response rate, the best progression-free survival that we've seen. And so I think there's going to be a priority to make sure every patient receives this treatment and then how best can we reintroduce this later like other targeted therapies. And renewed response rate again? Or can we -- but I think there's going to be a lot of combination approaches likely with trying to do liver-directed or other local therapies to try to keep patients on this as long as possible.

Just to add on what Meredith is saying there, too, I think just understanding the biology and protein kinase C and trying to stay on the driver and thinking about the patient journey that these studies all read out the way this one did, we'd be looking at the -- in the primary uveal melanoma setting, trying to get on the target with darovasertib and helping the patients save their life, their vision, also potentially maybe preventing metastases even in a neoadjuvant setting, although the current trial is not really designed to show that. And then ultimately, after their primary therapy for those high-risk subjects, you still want to stay on the disease on the driver and then you'd be able to continue to do that in the adjuvant setting. And then perhaps down the road if the patient were to get their 1 year's worth of therapy and discontinue and then further down, develop metastases that again, you'd want to be on the driver. And then again, as Meredith pointed out, as you're thinking about combinations, you're thinking about strategies that are liver directed. It seemed to me that you'd always want to be on the driver, which is protein kinase C, have that shut down and try to take care of the rest. So I can see a therapy like this, just like any other targeted therapy like your GFR inhibitors were people talking about keeping on keeping folks on for as long as possible. You may see a similar thing here because it just seems like this disease really needs that pathway to begin and to thrive. And so being on top of that is going to be important.

Thank you, Darrin. Next question?

Our next question comes from Charles Zhu at LifeSci Capital.

First of all, congratulations on the data, and thanks for taking our questions. Can you talk perhaps a little bit about subsequent therapies that your OptimUM-02 trial patients may be taking whether they're [ posterocrzo ] or post control arm and any potential impact to longer-term OS there? And maybe also related to that, I recall there was a dynamic where you had the option at some point to upsize the trial for OS. Is that still an option for you at this point? And do you even need if you could clarify that? Congrats again.

Yes, so, I know for the therapy sequence some of that was covered. But Dr. McKean, anything additional there. And then maybe just on the second question. We do still have additional time to ultimately make that decision, Charles. But Darrin, any comment there. I mean based on the data we've seen and even on the early trend in OS, I think we're in really good shape. But, Darrin, do you want to make?

I would just say we're very comfortable with where I was sitting right now. But we do have an option. That's the nice part of how the protocol was designed -- but like I said, I think we're going to be watching the maturity of the data over the next -- as we are in the process of filing. And so we'll monitor that situation, but we're sitting in a really great shape. I mean you just look at the data, you look at the separation of the curves, you look at the response rate. You look at the continuity of the data that we have now relative to what we've presented at SMR and it's very, very consistent, which is beautiful. I mean, a lot of times you see data when you go from Phase II to Phase III, you may see some detriment to the efficacy outcomes. We haven't really seen much of that at all. Safety profile, very much similar. Really, the SMR data tells it all. And you know what the OS looks like for the SMR data that looked exciting. And so far, all the parameters that we've been following seem to be following in the same direction. So we're very, very bullish on the opportunity to get this across the finish line with full approval.

Dr. McKean, anything else you'd add on the sequencing?

Yes. I mean the reality -- the unfortunate reality of these patients that were treated on trial in HLA-A02:01 negative is a at the time of progression, right, if you were lucky enough to be on the treatment arm, you could receive Ipi/Nivo, otherwise, it's just liver-directed therapies. And so for patients that had disease outside of the liver, you didn't really have any other options. And so you're really it's kind of local palliative radiation and in the liver, it's Y90 ablation or perfusion therapy. So there just really aren't -- this isn't like another cancer where you can just keep pulling up your next line chemo. -- like there just aren't good options for these patients, whether they progress -- once they progress on daro/crizo or if they're on the control arm. It's really just local therapies.

Our next question comes from Paul Jeng at Guggenheim.

And let me -- my congrats on the results today. I wanted to ask about the relative dose intensity that was maintained for the regimen and to what degree there were any dose interruptions or reductions to manage adverse events either for daro and crizo. And then a quick follow-up question, just on the OS. So based on your stock feedback, how important is that OS data in driving uptake for daro in the HLA negative patients? Are there any physicians who may wait for those results before prescribing? Or is that more important as you think about potential utilization in the HLA positive segment?

Maybe for the first piece, Paul, we'll need to sort of stick to the disclosure. Obviously, I know we've got Dr. McKean on as well. I know there's also just sensitivity. We do have, hopefully, an important upcoming presentation at a major medical conference, we'll hear further detail. But I think we can say at a high level, the safety profile, including things such as discontinuation rates dose intensity was very consistent with what we've reported in the past. And I would say also enriching to historical data on Ipi/Nivo. In terms of the other item here, I don't know, Darrin, do you want to take that?

Well, as you know, the overall survival data is still maturing and we'll be going to the FDA to talk about using the surrogate endpoint, progression-free survival, overall response rate, et cetera. The data from both what we've seen from by BICR and investigator assessment of the outcomes. And if this gets approved, it's going to be used as the OS data matures. And I don't know if Meredith, if you want to pile on top of that, but I can't imagine once this gets approved, I think you're going to probably have another very important tool in your tool belt to use for these patients.

Yes, absolutely. And I think the question in regards to the HLA-A02:01 positive patients maybe is just we -- the Phase I/II study enrolled patients early on regardless of HLA status, right? So like Darrin said, there's a large number. I think it sounds like 100 patients that are HLA-A02:01 positive that were treated. It's, I think, more data to come in that space. But as a treating provider we would generally -- the way it works is really just try to point to the data available and say, this is why this is an option that we'd like to pursue for the patient. And so that's looking at showing the data, hopefully, if it's added into the NCCN guidance at some point that will be helpful and just trying to demonstrate to the insurance companies why these patients even for HLA-A02:01 positive, don't have a lot of options. So I think that's where as much data as we can put out there, it would be helpful.

Our next question comes from Silvan Tuerkcan at Citizens JMP.

This is Josh on for Silvan. Congrats on the great data. You provided that 2 half '26 guidance on the time line to filing. Maybe if you can just discuss some of the gating factors to that filing, will it be on a rolling basis and maybe discuss the potential for expedited review.

Yes. So Darrin, do you want to take on?

Yes. We'll be working with the FDA in order to talk about how to most expeditiously get this filing completed. So those are on the table for sure. Now that we have the data in hand or we're going to have those discussions.

Yes. And I think on the expedited piece, we will be evaluating options around our tour as well.

Yes. We have -- remember, we have Fast Track, and we have breakthrough, we have Fast Track. We have orphan. We have just about every designation you can think of. So I think they're going to be very open to talking to us about that.

Our next question comes from Graig Suvannavejh at Mizuho.

My congrats to the IDEAYA team on great data. I did want to ask just about the adverse event profile. I think the syncope and hypotension were something that I had not been appreciative of before. I'm just wondering if there is a mechanistic rationale? Is it more maybe crizotinib driven? If you -- just any color on that? And maybe for Dr. McKean, the KOL, thoughts on uptake. Does that, in any way, the safety tolerability impact how you think about uptake? And is there an immediate impact to KIMMTRAK in the HLA-positive setting?

Yes. So Graig, maybe I'll take the first part. So the hypertension syncope is exactly consistent with what's been reported in the past, including at SMR and ESMO. So that's been known and reported for the last several years. Darrin, Dr. McKean for the second question.

Well, I can say, at least mechanistically, I mean, we think it's likely more darovasertib and there has been some studies that implied that it may have maybe secondary to the effect of inhibition of protein kinase C and its effect on smooth muscle cells. So -- but again, manageable, not different than what we've seen before none. And again, the things there that we do typically is we ask patients to maintain their hydration. We stopped their blood pressure medicine. We make sure that they're not running around right after they get their dose. And you can speak to the management of this and the outcomes. But I think in general, this is -- if you know and you expect it, it can be managed quite easily. But Meredith, I'll let you take that.

Yes. I think hopefully, this is -- this is data that will be kind of illustrating more as we publish the Phase I/II data. Because I think like Darrin said, we learned a lot, right, holding patients, having patients hold their blood pressure medications once we got through the food effect just seeing the significant importance of patients being able to take the medication with food, high protein breakfast. And then I think some of it, too, with crizotinib can add some edema. And so just recognizing that early for patients and even short -- these medications have short half-lives. So for patients, any of the side effects, you're able to say, okay, hold the CRS for 3 days and then restart, right? And patients feel immediate relief. So I think there's a lot of ways that we've learned to try to help navigate these medications and really find how -- with supportive medications, how to help patients be able to stay on treatment.

Our next question comes from Gregory Renza at Truist.

Great. And congratulations, Yujiro, and the team for really nice outcome today. Yujiro, maybe just on the OS expectations. I just wanted to ask if you could perhaps remind us of maybe some of the internal assumption is around the differentiation between the daro/crizo combo and the control arm. If the Phase III OS data are to trend shorter than 24 months previously observed maybe just a comment on what range would you view as consistent with respect to a positive outcome? And then secondly, let me throw in a strategic question, Yujiro. Now that you're staring at a potential filing and a transition to commercial, how do these data maybe impact your view of the Idea pipeline? Does it reshape how you would prioritize and establish focus as you build out the portfolio?

Thanks for the question, Greg. So in terms of less, I think the good news here is the response rate, the PFS, the data we observed has been very consistent from what we've reported at the Society Melanoma Research with a more limited data set to now a large randomized Phase III study. So I think that's the good news. And Greg, as you know, the OS that we reported at society Melanoma Research, just as a reminder, with over 21 months. So our hope here is we showed consistency in response rate as well as PFS, and I do think that bodes well for the OS portion. I would say on the control arm, as we've seen, the vast majority here is Ipi/Nivo. And I think, Greg, I know there was a lot of topic on what the PFS would come out at. And as you know we consistently were noting the published data, in particular, the Pilots paper, right, where that PFS came in exactly what we're reporting essentially 3.1 months versus 3 months. And also, just as a reminder, if you go to that paper, I believe the OS that was reported was about 12.5 months. So I think that all sets up nicely, and I do think that past publication, we've been putting to did come in exactly as our study reported out. Then lastly, as it relates to our larger portfolio, Greg, look, we think darovasertib is just the start for the company. We're tremendously enthusiastic about the progress on DLL3, MTAP, A67, as well as others. And we believe with darovasertib, now hopefully transitioning towards commercialization phase. The tremendous progress and we think we have one of the deepest portfolios in precision medicine oncology. What you're going to see as an organization is to drive forward to build that next leading precision medicine oncology. And that's exactly our vision, and this is exactly what we're moving towards.

So this hits the 30-minute mark on Q&A and all the time we have. I'll turn it back to you, Yujiro, for quick closing remarks.

Great. Tara, thank you for that. This now concludes the prepared remarks and as well as analyst Q&A portion of the webcast. So thank you, everyone, for participating on the webcast event today. And operator, you may now close the line.

Great. Thanks, Yujiro. So this concludes today's event. You may now disconnect.