IDEAYA Biosciences, Inc. (IDYA) Earnings Call Transcript & Summary

Good morning, and welcome to the IDEAYA Biosciences Darovasertib Clinical Data and Regulatory Update Call. [Operator Instructions] As a reminder, this event is being recorded, and a replay will be made available on the IDEAYA website. I would now like to turn the call over to your host, Yujiro Hata, President and Chief Executive Officer. Please go ahead.

Thank you so much for the introduction. We're absolutely thrilled to welcome everyone to our Phase II clinical data update on the darovasertib and crizotinib combination and to walk-through the accelerated approval trial design and first-line metastatic uveal melanoma based on our successfully completed Type C meeting with the FDA. In addition, the company will also provide a clinical data update for darovasertib and neoadjuvant uveal melanoma. We will be making some forward-looking statements today. Please refer to our SEC filings as appropriate. To begin, I wanted to provide a special thank you to all our online participants and our KOL guest speakers. Today, we have a phenomenal lineup of international guest speakers that include Dr. Meredith McKean, the Director of melanoma and skin cancer research at Sarah Cannon Research Institute; Professor Anthony Joshua, the Head of the Department of Medical Oncology at the Kinghorn Cancer Center in Sydney, Australia; and Professor Mark Shackleton, the Director of Oncology at Alfred Health, Melbourne, Australia. Today's update is a culmination of over 5 years of innovative research and understanding of the fundamental biology of uveal melanoma and demonstrating IDEAYA's organizational commitment to advancing first-in-class therapies that address the highest unmet medical needs and cancer. Due to the mechanism of action of darovasertib as a PKC inhibitor, it has the opportunity to broadly impact the uveal melanoma. What makes uveal melanoma genetically unique is that over 95% of patients harbor an activating mutation of GNAQ, GNA11 or further upstream mutation that is believed to activate the PKC signaling pathway. Therefore, in the truest sense, the indication is the diagnostic. As demonstrated on the bottom left, darovasertib monotherapy drives complete regressions in our primary uveal melanoma in vivo model providing a scientific basis for a monotherapy clinical development focus in both the neoadjuvant and adjuvant uveal melanoma settings. Next, through our translational research efforts, we discovered specifically in the metastatic setting of the liver, a direct correlation between cMet pathway activation and disease progression in our darovasertib Phase I clinical trial, providing the scientific basis to pursue the darovasertib and crizotinib combination clinically in the metastatic setting. As noted earlier, we successfully completed our Type C meeting with the FDA, and I'm delighted to introduce Dr. Darrin Beaupre, our Chief Medical Officer, who will walk through the accelerated approval trial design and first-line metastatic uveal melanoma. Darrin, please take it away.

Thank you, Yujiro. And before we go directly into the trial design, what I'd like to do is make a few comments to set the stage for why we're so confident going into this study? And what you're going to hear from our key opinion leaders today. These are investigators who really lead the field in clinical research with respect to uveal melanoma. And from a high-level perspective, what you're going to hear today is in the metastatic uveal melanoma setting, the treatment with the darovasertib-crizotinib combination produces an unprecedented overall response rate in patients with both treatment naive as well as relapsed disease. And further, the progression-free survival you'll see today is more than double than what's been recorded previously with standard of care agents. And this is all delivered with a manageable safety profile with a low rate of discontinuations due to adverse events. Layered on top of that is what we've seen in the primary uveal melanoma setting, which is an impressive rate of tumor shrinkage in subjects treated with neoadjuvants either darovasertib or the combination, including crizotinib. And for the first time, you're going to see evidence of a patient who had a large uveal melanoma tumor who not only was able to save his eye from the treatment, but also was able to preserve his vision. So that sort of sets the stage for the registration trial, which is shown schematically here. Essentially, you are all aware that we had a discussion with the FDA at the end of March, mainly to discuss the trial design and key end points -- and the discussion really anchored on 2 key guidances. The first was project frontrunner. And of course, that's a guidance that's designed to bring exciting new therapies into earlier lines of treatment, which is very applicable here. Because we're talking about the treatment-naive setting, but also there's a guidance around accelerated approval. Again, the idea here would be to get exciting therapies to patients with significant unmet medical need. And I don't think anyone can argue that metastatic uveal melanoma doesn't have great unmet need. It certainly does. The trial design shown here is very similar to what we've described to you in the past. It's not very different. The subject population remains patients with metastatic uveal melanoma who are HLA-A2 negative. The treatment arms are either the darovasertib and crizotinib combination in the treatment arm versus the control arm, which is a choice of either checkpoint inhibitor therapy, which can come in the form of single agent checkpoint inhibitors or the combination of ipilimumab and nivolumab or for those patients who have a contraindication to immunotherapy, chemotherapy such as dacarbazine can be chosen. The randomization is in a 2:1 fashion. The design is a seamless Phase II/III type design, where approximately 230 patients will be enrolled in the Phase II component, an additional 120 patients will be enrolled to complete the Phase III. In the Phase II portion, there will be a small cohort of subjects that will be part of the dose optimization. And basically in the seamless design, this nested group of patients will actually be included in the registration portion of the study. As they go-forward, dose is chosen, patients will be continued to be enrolled towards the first co-primary endpoint of median progression-free survival. This will allow the potential for accelerated approval. And upon success, add to this first milestone, patients will continue to enroll to complete enrollment for the second co-primary endpoint of median overall survival to allow full approval of the combination. I would just remind people that this combination of darovasertib and crizotinib has fast-track designation. It's our hope. With this designation, it will allow us to continue the dialogue with the FDA in a seamless way throughout the conduct of the study to allow us to rapidly get this combination to patients. And so with that, this lays out the trial design with a few words about why we're so confident going into this study. But now it's time to really hear the details from the experts who treat patients with this disease. So now I'll hand it off to Dr. McKean from the Sarah Cannon Research Institute. Dr. McKean.

Great. Thank you so much. I'm excited to be here to present this data today. So today, we're disclosing the interim analysis of the first 63 patients treated with darovasertib and crizotinib at the expansion dose. You can see here the patient profile, the patients treated on the study. in addition to the patients treated on the frontline Tebentafusp study. You can see that the patient population treated on study has had a predominance of poor prognostic markers. So you can see the elevated LDH, which can indicate disease burden, the percentage of patients with a lesion measuring greater than 3 centimeters, it's been 66% in any-line, in addition to 60% in the frontline setting. And then patients have had a predominance of hepatic and extrahepatic disease. When you compare the frontline patients to the frontline tebentafusp patients, you can see here that the elevated LDH was seen at 50% versus 36% of the tebentafusp study. More patients with lesions greater than 3 centimeters compared to only 45% of patients on the frontline tebentafusp study. And then additionally, more patients with hepatic and extrahepatic lesions, 50% versus 44% in the tebentafusp study. Next slide. So starting now with looking at the AE profile. So you can see here that the combination of darovasertib and crizotinib has been very manageable. On the left, you see the summary indicating that no Grade 4 events have been reported, 1 Grade 5 that was felt most likely related to disease. And importantly, the SAE rate was 9%, and only 6% of patients discontinued study drug due to AEs, which is really indicating that the side effects were very manageable with supportive medications. You can see the summary on the right that most of the side effects were GI toxicity, diarrhea, nausea, vomiting, again, predominantly Grade 1 and Grade 2 that were easily managed. Other side effects there, edema, fatigue and rash. Next slide. So moving on to efficacy. Just excited to share here, very exciting frontline metastatic uveal melanoma clinical efficacy. You can see here in the waterfall plot that in the 20 patients in frontline metastatic uveal melanoma treated on the Phase II darovasertib and crizotinib expansion arm all but 1 patient had tumor shrinkage, and there was a confirmed overall response rate of 45% indicated with the plus sign below the patients with confirmed response. There was tumor shrinkage demonstrated in 95% of patients. This has really just been very exciting to see. And this efficacy supports registrational strategy in the frontline setting. Next slide. Looking at any-line metastatic uveal melanoma patients, you can continue to see just dramatic waterfall plot here with predominance of patients having tumor shrinkage and a number of patients achieving a partial response. The entire population of any-line metastatic uveal melanoma patients treated, you can see here with a 30% overall response rate and an 87% disease control rate. 92% of patients had tumor shrinkage. This clinical efficacy was seen in any-line metastatic uveal melanoma irrespective of HLA-A2 status, and in both hepatic and extrahepatic metastases. You can see here the light blue, were the first line patients, and the previously treated patients are the dark blue in this waterfall time. Next slide. Now when we look at hepatic only, so for metastatic uveal melanoma patients, the primary place of metastasis, the most common location that you see is in the liver, which is -- generally, it makes it so difficult to try to develop effective therapies for these patients. And the hepatic only cohort the 20 patients demonstrated here had a 35% overall response rate and 100% disease control. So every patient had tumor shrinkage treated with this combination. Next slide. So moving on to 2 patient examples. And this is just very consistent with the responses that we've seen in the patient profile on study. So the first patient on the left, so this was a frontline metastatic uveal melanoma patient. This is a 40-plus year old patient. This was an HLA-A2 positive patient that had metastasized after about 6 years from their initial diagnosis. This patient had large bulky tumors, as you can see in the picture on the left, in the liver and pelvis. This patient had an elevated LDH of 800. And after starting on treatment, the LDH normalized within 1 month. And you can see here, these large tumors have reduced by 49% and this patient remains on treatment for over 15 months. On the right, you see another example of the frontline patient treated on study. So this was another 40-plus-year-old patient. This was an HLA-A2 negative patient and metastasized after about a year, and this patient had many smaller liver lesions, but this patient was able to achieve a maximal target lesion reduction of 65%. And this patient also continues to have an ongoing response and remains on treatment at 10 months. Next slide. So moving on to PFS data. Exciting to share the swimmers plot here. So the last time this data was presented in September, the median PFS was about 5 months. Now with additional follow-up, we're seeing a median PFS of about 7 months. And when you look at that 20-patient hepatic only subset, the median PFS is now about 11 months. And this is just really unprecedented in the field and very exciting for our patients. Next slide. So looking at other clinical trials and assessments of therapies for patients in metastatic uveal melanoma. You can see here how darovasertib and crizotinib compares to other targeted therapies and immune therapies. So looking at the AE profile, seeing here on the left, Grade 3 or greater drug-related AE 33% darovasertib and crizotinib. This is compared to 50% -- nearly 50% or greater with any other regimen that's been assessed. You can see 46% for tebentafusp, 58% for ipi/nivo. When you look at the efficacy and the patients -- percentage of patients with tumor shrinkage, looking at 92% of darovasertib and crizotinib compared to ranges between 23% with cabozantinib, really no patients with crizotinib monotherapy having a response or tumor shrinkage and then ranges between 27% to 44% with the other therapies. So looking at overall response rate, so darovasertib and crizotinib, we're seeing for first-line, 45%, 30% for any-line. When you look at the cMET targeting agents of cabozantinib, crizotinib, 0%, there are no responses in patients. When you look at the combination of the targeted therapy with chemotherapy, so selumetinib and DTIC, 3% response rate. When you look at ipilimumab and nivolumab, a combination used in the clinic, overall response rate was 11.5%, and that's not been -- that was not confirmed on study -- not confirmed response. And tebentafusp was 4.7%. So we're just really seeing, like I said, an unprecedented efficacy signal and very tolerable safety profile. And then the data, thus far, looking at the median PFS as discussed that we're now seeing about 7 months PFS for the combination of darovasertib and crizotinib is really seen between 2 to 3 months with any other regimen assessed. Next slide. So when we look a little bit closer at the combination of ipi/nivo and compare the frontline patients, between the patients treated with darovasertib and crizotinib versus ipi/nivo, you can see that we're really seeing safer -- safety profile and a higher efficacy with this combination. So with ipi/nivo, like I said, the overall response rate, 11.5% and the confirmation was not required on the study compared to 45% with darovasertib and crizotinib. The median PFS about 3 months compared to about 7 months at this time. And this was taking into account just a patient population treated on darovasertib and crizotinib with a higher -- poor prognostic feature, a higher-risk disease population with a higher percentage of patients having an elevated LDH. And then importantly, looking at the safety profile, an SAE rate of 9% with darovasertib and crizotinib compared to 58% for patients treated on the ipi/nivo Phase II. Thank you. Next slide.

Great. So thank you so much, Dr. McKean for that terrific walk-through for the data. And obviously, all your key involvement as an investigator on that study. Also, one of our key objectives for the data update that Dr. McKean just walked through. So the public -- our public investors and analysts also now have a very good understanding of the clinical data that the FDA observed while we had the discussion in March as it relates to getting endorsement on the first line accelerated approval trial design. For our next section on the darovasertib clinical data update and neoadjuvent uveal melanoma, it gives me great pleasure to introduce Professor Anthony Joshua, the Head of the Department of Medical Oncology at the Kinghorn Cancer Center in Sydney, Australia, who is also the lead investigator on our ongoing IST. With that, professor Joshua, please take it away.

Thank you very much, and thank you very much for having me. I am very excited to discuss this concept of neoadjuvant/adjuvant darovasertib and primary uveal melanoma and really to sort of demonstrate and discuss the paradigm that we're developing here. So as you can see in this slide, this is a Phase II study, which is currently being developed. And in this Phase II study, the patients will get both neoadjuvant therapy as well as adjuvant therapy. And you can see that there are 2 cohorts in this study. And the first cohort will be patients who have an A priority destination of unfortunately, having enucleation as determined by the treating ophthalmologist. And the second cohort will be those who had a determination for brachytherapy. They will both be treated with single-agent darovasertib to maximum benefit up to 6 months. before the primary local therapy is undertaken, be that surgery, enucleation cohort or brachytherapy. And the primary end point will sort of apply at that point being both safety and cohort 1 eye preservation to see how many eyes can avoid enucleation and cohort 2 decrease in the radiation dose from brachytherapy, which may have long-term visual consequences. That will then be followed by a period of adjuvant therapy with treatment with single-agent darovasertib for 6 months and then for routine follow-up to prevent what is really the devastating consequence of uveal melanoma, that is the development of metastases. So we haven't really had any proven adjuvant therapies in the clinic to date that have come with such rationale as darovasertib, so we're all very excited about the potential for this drug, not only to save eyes and save vision, but also to decrease the rate of metastases subsequently. So the trial will, as mentioned, cover those primary endpoints, but also the secondary endpoints being useful vision at 1 year. And as mentioned, what I'm particularly enthusiastic about is relapse-free survival both at the 1-year and at the 3-year time point, bearing in mind that most of the metastases occur at the 2-year time point. So certainly, we'll have enough time to understand the impact of the adjuvant component. So this trial -- this Phase II trial will have, in 1 study design, 3 important questions will be asked: one will be the ability to save the eyes by shrinking the tumor in situ, allowing the eye to avoid enucleation, the other being a brachytherapy cohort allowing decrease dose and finally, adjuvant therapy to save lives. So a very exciting protocol, which is going to be taken globally targeting Q2 2023. Next slide. But the rationale for this study design has really come from the experience, both my own and that of my colleague, Professor Shackleton, in treating patients on our ongoing IST with neoadjuvant and darovasertib. And you can see here that there are 2 cohorts presented here, which form the preliminary rationale for the Phase II study. First is our ongoing study patients who were destined for enucleation. And in that study, you can see here the tumor responses to date. Along the top, you can see how long the patients were treated for and then an equal 6 cohort trial still enrolling. And in the first 3 patients, they were required to stop treatment at 1 month as a safety measure to ensure there are no perioperative complications, which there were not. And subsequently, the protocol has now been expanded to what our treatment up to a maximum of 6 months similar to the soon-to-be-started Phase II study. And you can see here the excellent responses we've had to date in that study and the case study that Professor Shackleton will present shortly. There is also a small number of patients who have been treated with metastatic disease who have their ocular primaries in situ. And you can see the best ocular responses, as outlined on the right of that slide with tumor shrinkages ranging between 15% to near 100%. Next slide, please. And here, you can see very clearly, some of the shrinkages seen both by ocular ultrasound and by direct fundoscopy. So the first slide there on the far left, a 22% shrinkage after only 1 month of therapy, again, unprecedented really in the field that we haven't really had any agents that can shrink tumors in situ and be tolerable and allow eyeballs to be saved. And then going into the middle slide, we had a very nice 31% shrinkage after 1 month, and you can see those pictures there with the tumor shrinking from 12.48 millimeters down to 6.9 millimeters after only 1 month. And then in the final picture on the far right, very clearly visible on the bottom of that eye is this tumor, which is close to obstructing the optic disk and fovea, and you can see how nicely that shrinks away at month 2 and the vascular arcades being now visible on the back of the retina. So certainly, a very nice data to date and forms an excellent, both preclinical and now clinical rationale for a neoadjuvant and adjuvant paradigm to be developed with darovasertib in uveal melanoma. Next slide.

Great. Thank you so much, Professor Joshua, for that terrific walk-through on the neoadjuvant uveal melanoma and thank you also for your continued partnership with IDEAYA on the IST. I know the organization is extremely grateful for all of your contributions to the study. And we're very excited to see how the data continues to mature with more follow-up and more patients. Next, we're delighted to have Professor Mark Shackleton, the Director of Oncology at Alfred Health, Melbourne, Australia, provide a case study walk-through of this neoadjuvant uveal melanoma patient, which we believe is the first reported case of a patient spared enucleation through the systemic therapy. I know Professor Shackleton, we caught up a few days ago and personally, just at least I thought this was one of the most inspiring stories that I've heard in my career on the benefit patient received with therapy. So with that, really just gives me really pleasure to introduce you to walk-through your patient here.

Thanks very much Yujiro. It really is a great privilege to present this case, which is -- you're right -- it's really one of the most remarkable and satisfying cases I've been associated within my career, I would say. And it's certainly been a great opportunity to be partnering with Anthony and with your company. in the development of this combination, which I really genuinely believe is going to save eyes and save lives with ongoing clinical development given the nature of the data that we've seen so far, which is really quite something. So yes, to kind of put a human face, I guess, on the story. I'll talk about a patient of mine that I met just before Christmas time 2022, is a 70-year-old man. So he's actually already blind in the left eye as a consequence of many years' history of smoking and peripheral vascular disease and a previous diagnosis of the left retinal artery infarct, that is a blockage of one of the blood vessels in the left eye, which left him permanently and irreversibly blind on that side. But he was otherwise really quite well. He had the typical sort of medications that peripheral vascular disease patients are often on a statin, antihypertensive, and some low-dose aspirin, but generally very high functioning man living with his some family, grandchildren, et cetera, et cetera. And he presented in about October, November with really rapidly declining vision in his right eye. And therefore, overall, rapidly declining vision. And he was referred to one of my ophthalmological colleagues for evaluation. The ophthalmologist immediately identified a very large uveal melanoma in his right eye, dominantly obstructing vision. This is a really big tumor, 16.5 millimeters in its maximum height and 18 millimeters in its maximal basal diameter. And it was further compromising vision as a consequence of severe cataract that it was also causing. So my colleague at our eye and ear hospital here in Melbourne called me up and said, is there any way you can try one of your clever drugs to see if we can save this guy's eye, because otherwise, the only treatment for this tumor, which gives him any hope of cure is to completely remove the eye, which would render him permanently blind in both eyes. So I reached out to the team at IDEAYA and was really excited to get their support to treat this patient with combination of darovasertib and crizotinib with the goal being to avoid enucleation and therefore, preserve vision in this patient. And really, the response has been striking. At every month of review, he's exhibited impressive obvious tumor shrinkage. He has regular ophthalmological examinations once a month in addition to seeing me once every 2 to 4 weeks for treatment prescriptions and management of -- monitoring of toxicity. And he's currently on the fourth -- I think now it's actually the fifth month of treatment and remains on therapy doing very well. He's overall tolerated treatment very well. The main side effect has had has just been at a Grade 1 to 2 diarrhea, which we not uncommonly see with this combination managed with simple antidiarrheals. And he now doesn't need enucleation. Next slide. So as I said, the tumor has been monitored every month by the team at the eye and ear hospital and really quite strikingly only after the first month of treatment the tumor had already shrunk down by about 30%, even at that stage, potentially being treatable with the placement of plaque-based radiotherapy rather needing enucleation. So the response was really very rapid and quite dramatic and actually even more remarkable because I had to stop treatment for a couple of weeks over the Christmas period when he incidentally developed COVID and had some abnormal liver function tests associated with that, and I just have to shut up his targeted therapy. But he recovered from COVID, he settled down, his liver function tests are now fine on -- and then he was put back on to targeted therapy and really has had no major side effects that can be attributable to the combination apart from the diarrhea. And so every month of this guy gets examined, his tumor just shrinks down and down and down. He -- and the response has been so impressive that he has now planned to have plaque-based treatment. But really the ophthalmologists are keen for me just to keep treating him to see just how small we can get this thing, the idea being that the smaller it gets, the smaller the radiation dose that the retina of the eye is likely to be exposed to offer curative intent radiotherapy treatment. He has -- and he's actually gone on to have the cataract treated with intraocular lens replacement. And now has excellent vision in that eye. I mean, before he started, he was really -- it was more than legally blind with a prevision -- pretreatment vision score of 6/120. His posttreatment score after the cataract was replaced, is now 6/5, which is probably better than my eyesight. And he remains on treatment doing really, really well. The ultrasound examination shows really quite dramatic changes that you can see there on the right-hand side. The baseline image showed this really huge tumor causing substantial impingement of -- impairment of vision. And you can see that, that tumor is really on the repeat ultrasound 4 months later is substantially reduced by about 80% overall. So it's really an incredible response. Next slide. And this is just a fundoscopic demonstration of that with the pretreatment fundoscopic image on the left-hand side showing an obvious left tumor in that sort of right up a quadrant there of the funds. And then the most recent fundoscopic image taken a month or so ago shows that tumor is clearly obviously substantially diminished consistent with the overall improvement of his vision. So yes, so thanks for the opportunity to talk about that case, so I said it really is one of the most remarkable and satisfying cases that I've been associated with. And thanks to this therapy, this guy can now see and is likely to do so for a long time.

Well, thank you so much for that walk-through Professor Shackleton. Yes. And I think when you see this image, it's really pictures definitely can say a thousand words. And so I know for the team here, and I know when we saw this image, it was -- yes, this really was -- made a big impact, I know for us as well. And thank you so much for the opportunity to -- for everyone to hear the patient walk-through today. So I'm going to go ahead now and just proceed with the closing remarks section of the presentation today. Today marks an important day in IDEAYA's corporate history. As we achieved several major milestones for our lead clinical program, including an FDA-guided accelerated approval trial design and first-line metastatic uveal melanoma and a broad clinical efficacy update in both first-line MUM and a neoadjuvant uveal melanoma. Today, we believe we have demonstrated that darovasertib has the potential to be an important treatment for metastatic uveal melanoma with a compelling reported confirm over response rate by RECIST, disease control rate, meeting progression-free survival, including in the first-line metastatic setting. Next, we continue to see highly encouraging clinical efficacy from darovasertib in the neoadjuvant uveal melanoma setting, including a partial response for monotherapy and only 1 month of treatment in our first reported case of a systemic treatment sparing a patient of enucleation. This slide provides a summary of our broader clinical and commercial strategy for darovasertib in uveal melanoma. Based on darovasertib's unique mechanism of action, oral delivery, manageable AE profile and clear demonstrated ability to consistently shrink both primary and metastatic uveal melanoma tumors, we believe this agent has broad applicability across the patient journey, including in the neoadjuvant, adjuvant and first-line metastatic settings. Lastly, due to the high unmet medical need in both the primary and metastatic setting of uveal melanoma, we believe there are multiple first-line accelerator approval opportunities, which is unique for a solid tumor indication. We believe darovasertib is an ideal lead clinical program for IDEAYA based on the compelling clinical efficacy and manageable safety profile observed in a high unmet medical need indication. And the opportunity this program provides to pursue multiple first-line accelerated approval opportunities along the patient journey. In addition, as the treatment of uveal melanoma in the U.S., Australia and Europe occurs primarily in specialized treatment centers, it creates attractable commercial opportunity for a biotechnology company, such as IDEAYA. Darovasertib is followed by an emerging clinical and preclinical pipeline of potential first-in-class precision medicine oncology programs targeting large, solid tumor populations that will enable IDEAYA to build a world-class organization and diversified clinical pipeline. This exciting first-in-class pipeline includes MAT2A inhibitor of ID397 in Phase II, targeting MTAP deletion lung, gastric and bladder cancer. PARG inhibitor ID161 in Phase I, targeting HRD breast and ovarian cancer and preclinical stage poly theta Helicase and Werner Helicase programs, many of which were highlighted at this year's ACR. This now completes our prepared remarks. And operator, you may now open the line for the analyst Q&A portion of our webcast?

[Operator Instructions] And with that, our first question comes from Anupam Rama at JPMorgan.

2 quick questions for me. 1 for the company and 1 for the KOLs on the line. For the company, just -- based on the totality of the data that you have to date for the Phase II/III frontline MUM study, what's that power to show on PFS? And what are you assuming that investigators choice shows. And then for the KOLs, I know that the Phase II/III front is being studied in frontline MUM, but if available, would you consider using the darovasertib and crizotinib combination in your more refractory-prevalence population, given the all-comers data that we've seen to date.

Sure. Thanks, Anupam, and I appreciate the question. Dr. McKean, do you want to maybe first start with just answering the question on the pretreated MUM and darovasertib and crizotinib combo.

Sure. Absolutely. I mean, I think there would definitely be excitement to obviously, I think what we're demonstrating is trying to have as many opportunities and settings to try to use this treatment as possible and I think there's going to be a lot of excitement for the frontline setting and trying to treat patients as soon as possible with this combination. But yes, there's definitely excitement in the treatment refractory setting as well.

Great. Thank you, Dr. McKean. Darrin, do you want to take the question on the powering on the PFS? I know we haven't specifically noted the powering, but you could probably go backwards with the appropriate numbers.

Yes. without getting into tremendous details and looking at the TEBE study where the control arm had a 16-month median overall survival and you looked at the graphic that was shown today about what standard of care delivers in terms of median progression-free survival of around 3 months. So those are good sort of starting points for us to look at and the trial was designed around those types of metrics. And so we have designed the study with the FDA in such a way that we can show superiority to compare to numbers like that.

The next question comes from Maury Raycroft at Jefferies.

I'll add my congrats. Wondering, just based on the clinical experience so far, can you talk about enrollment expectations and time lines for the registrational study and for picking or confirming the go-forward dose, how long do you think you will need to do that? And what you do an interim analysis around that decision?

Sure. I'll start, and then I'll pass it to Darrin. In terms of the enrollment cadence, Maury, we've, to date, have enrolled very quickly. So even with the limited number of sites in the U.S., roughly 10 sites, we've been able to enroll at even 15 patients a month. The registrational study will be a much broader effort in the U.S. as well as globally including across Europe. So we'll give an update on that. We anticipate as we got this launched, but that's been our historical experience. In terms of the other questions there, maybe Darrin, do you want to comment?

Yes, just a few things. One is the fact that we're including the ipilimumab and nivolumab combination in the control arm, obviously ought to help enrollment as well. It's a very commonly used regimen in the U.S. So that's the first thing and towards rapid enrollment, we're excited about that. Not only that, we're excited about the opportunity of just showing once and for all that this combination is the king in the uveal melanoma space. And this will be one of those studies that allow us to make that claim because there'll be no other treatments that people can point at. That's the first thing. Second thing, with respect to the dose optimization, that's what's so beautiful about the design that we have, this is a seamless design that allows us to look at 2 cohorts of patients. I have to say that we're -- based on the data set that we have, not only from single-agent darovasertib, but the combination of darovasertib with crizotinib as darovasertib doses from anywhere from 100 to 300 milligrams, we're fairly convinced that the 300 milligram -- 200-milligram dose combination is the go-forward dose. However, we acknowledge that the sample size is not large, and so we want to bolster that with a larger end. And so in part of the registration trial, the 300, 200 dose will be compared to the 200, 200 dose in a seamless way, while the control arm is continuing to enroll and then using a pick the winter-type design, we'll go forward with the optimal dose, and we'll do so in a way that really shouldn't really afford much of an effect on the time line once ever. It is embedded within the registration portion of the study, which is what's so great about this. And then, of course, we have the Phase II tied into the Phase III in a seamless way as well. So it's really a nifty design, and the FDA was very supportive of what we proposed.

One other question I was going to ask, if I might, for the hepatic-only strategy. If you can talk about that. And if you can stratify for this population in your registrational study, and how this could factor in commercially maybe considering competition and with or without NCCN guidelines or compendia listing updates?

Sure. I'll take the commercial piece. Darrin, do you want to take the first part?

Well, listen, I think the reason why we kind of highlighted the hepatic-only patient population is for 2 reasons. Number 1 is, obviously, if you don't have disease beyond the liver, perhaps your disease isn't as advanced as patients that have metastases in multiple organs. And remember, when you're comparing our results across the board to other therapies, ipi/nivo single-agent checkpoint inhibitors, the TEBE study, what frequently happens is in these trials for just by chance perhaps the patient populations in those studies tend to have lower LDH, lower tumor burden. As Dr. McKean pointed out, these patient populations aren't as heavily burdened with disease. And so therefore, not only is the data that we're showing today quite impressive, but if you think about it in the context of we're not really comparing apples-to-apples. In fact, what we're comparing it to with other therapies is a patient population that perhaps would be doing better in any case yet there's still a dramatic difference. That's one thing to keep a note. And so by looking at these patients with hepatic-only disease, if you think about them as sort of a surge for maybe perhaps patients whose disease isn't quite as advanced, again, you see a very, very impressive median progression-free survival of 11 months, which may bode well for us in the registration trial if we have a patient population like we saw in the TEBE study, our results may be even more remarkable. The second part of this is, there's a lot of talk around the liver-directed therapies. They're used very frequently, of course. And so what our data shows that compared to the liver-directed therapies that are reported, the progression-free survival in that patient population for the treatment of darovasertib and crizotinib, clearly looks very, very nice relative to what a liver-directed therapy can provide in terms of progression-free survival. So those are the -- so the input is to show the data. But in terms of the registration trial, there'll be no really emphasis on selecting out that patient population because we feel like we can help all patients irrespective of if they have disease beyond the liver or not. Does that answer your question, I hope?

That's very helpful.

Yes. Thanks for that, Darrin. Maybe just to add on the commercial piece, Maury, as you know, our perspective here is we'll be pursuing first-line accelerated approval in HLA-A2 negative and at least we anticipate that we have the opportunity to be the first potential approval there. But as you know, we're not forgetting about the HLA-A2 positive based on our data. We see activity irrespective of HLA status. And I think the hepatic only potentially could be a really nice opportunity there when you think about A2 positive. So as we know, there is a drug approved there. We're basically at a point here if that data continues where PFS is approaching a year, right? So it's a situation where the PFS is basically exceeding historical median OS, which is quite a remarkable result in metastatic uveal melanoma. And we also know in the first-line setting, if you look at the TEBE data, both the treatment arm, the comparator arm our study, that about 50% of the patients have hepatic-only disease. So you can imagine even in the HLA-A2 positive as we noted around our Compendia strategy, if you're making a decision with our agent versus another and if that type of PFS continues, I think that's a -- will be quite attractive. So I think that's how we're thinking about it, Maury, from a commercial perspective and also how the value of that hepatic-only could continue as we continue to advance this program.

The next question comes from Ashik Mubarak at Citibank.

This is Ashik on for Yigal Nochomovitz from Citi. And really great to see this data, congratulations. I wanted to ask a couple on neoadjuvant. Starting with, I think the case study that you shared was very compelling. And I'm just wondering for the neoadjuvant setting, the IST data you shared, it looked like some of the best responders came with the combination of darovasertib and crizotinib, it looks like your company-sponsored study that you're getting up and running will be with the monotherapy. So I'm wondering if you can kind of comment and remind us on why you were going forward with the monotherapy strategy and what you think crizotinib may or may not add in the neoadjuvant or primary uveal melanoma setting?

Sure. So I think the first part of that, Ashik, is really around the mechanistic rationale, which I covered in the beginning of the presentation in terms of the MOA, and with that, Mike, if you're on, Mike White, our Chief Scientific Officer, maybe, Mike, you could answer that one?

Yes. Thanks for that question. Clearly, in the primary setting, as Yujiro noted, the genetics really defines the mechanism of action. We have no evidence that we require a MET receptor inhibitor in that setting. The monotherapy is working great preclinically. The MOA is very consistent with what our investigators are seeing clinically, and that's usually the case when you get your MOA correct. The MET receptor is coming into play in the metastatic setting because of that bypass mechanism and that's where we think it's important to have the combination.

And I think just last piece, Ashik, I'll just mention, I think our view is we just need additional treatment duration on mono. As you saw, we already had an early PR at 1 month. We also have in the metastatic setting, in half a month by PET well over, was a 60% tumor reduction and others, we're already at 20% in that 1- to 2-month range. So that other patient, again, was that month forward.

Got it. That's very helpful and very clear. Let me ask 1 more then on potential duration of treatment within the neoadjuvant setting. It looks like the design is set up for 6 months neoadjuvant followed by 6 months adjuvant. Does that -- is there potential for patients to be treated beyond that period in a more maintenance like setting? Or is that not part of the potential regimen?

Yes. Darrin, do you want to take that?

I would say that's a really great point, and that's something that we've been discussing. I mean, just like with the darovasertib in the neoadjuvant setting, as a single agent, we have to start somewhere, right? And the place to start is monotherapy darovasertib presumably, it's going to -- it's by itself is really well, well tolerated, and that's when you start thinking about how long can I give this treatment. And so the original study is designed to do a 6-month neoadjuvant portion with definitive local therapy, followed by 6 months in the adjuvant setting. But suffice it to say that we're thinking hard about that, especially, as was pointed out by our -- the opinion leaders here on the call today, I mean metastases is the biggest problem that can happen several years down the road and you have to ask yourself, why do I want to stop -- if I know a patient has a 50% chance of metastases, why do I want to stop the therapy at all in the adjuvant setting if it's well tolerated. I think those are great questions for us to ask, and that's what we're asking ourselves now, but I think we need to have a data set to begin with. And so that's where we're starting, but that's probably not where we're going to end, but we haven't decided exactly at what point and how exactly we're going to do that. But suffice it to say, it wouldn't be crazy to think that there wouldn't be a longer duration of therapy at some point down the road, but we just are ready to cross that. We want to build some data to make some decisions on.

Yes. I think just the only other piece I would add there is we know that darovasertib monotherapy can be tolerated for a very long period of time. So going back maybe some time in history here, but from our Phase I darovasertib monotherapy, we had a confirmed complete response, actually a patient in Paris that was on therapy for over 5 years as a monotherapy completely tolerated throughout the whole period. We had also hold another set of patients that were confirmed PRs that remain on therapy for over 2.5 years. And all those patients as well were able to have long-term tolerability. So we do know from that perspective, from -- at least from an AE perspective, the possibility is also there.

The next question comes from Charles Zhou at Guggenheim.

And congratulations again on the strong updates across the board. Maybe my first one, going back now to the metastatic setting. On the swimlanes, there were a handful of patients who are being treated beyond progressive disease. Can you talk about some of those mechanics and how a real-world duration of therapy may ultimately compare to a numerical progression-free survival?

Yes, sure. So yes, I mean, I think if you look at the swimlane plot, I think folks could look at it and sort of determine that. But our clinical experience is that patients are continuing to get treated beyond progression. In some cases, it's been 6 months or more, some it's been a bit less. But if you sort of eyeball it, it's we think it's roughly about 3 months beyond progression. We know with TEBE, patients are also getting treated beyond progression for quite a long period of time. So Charles, I think at this point, that's sort of a rough estimation, but at least practice today, what we've seen on the trial our patients are getting treated beyond progression roughly in that range of about 3 months.

Great. And then maybe my second question now on to the primary uveal melanoma setting. Not sure if I missed this one, but I was wondering if you could clarify 1 thing. Just given the strength of your data so far, as well as the amount of safety data you have from the metastatic setting, at your Phase II neoadjuvant study supported registration? And if not, how much additional data from that study would you need before you approach the FDA for guidance on registrational development.

Darrin, do you want to take that?

Yes. I mean in that study, we have 40 patients in each arm. I think as the data accrues, I think we can have discussions with the FDA. As you know, there are things that they may want to see as part of the evaluation process in order to make the study registration enabled. And so it's hard to have those discussions with the FDA without any data. So I think our first objective is to get those first 10, 20 patients and start seeing the kind of information that we're presenting today and then start having those discussions on what the key parameters are and likely there will be some expansion of what we have in each 1 of those cohorts but that's to be determined. And again, it depends on the magnitude of effect, right? If we do the first 10 patients and all of them say they're -- we saved the eyes in the first 10 patients, that's a different discussion than if you maybe save the 1 out of 10. So it's kind of a work in progress, but we obviously have to have data to have an intelligent discussion with the FDA. So that's our first objective.

The next question comes from Gregory Renza at RBC.

Great. And let me add my congratulations as well on the great updates today. And maybe just a quick one for me. Perhaps just circling back on the inclusion of ipi/nivo and the comparator arm, certainly helpful to hear your thoughts on the potential impact on speed. Just wanted to gather your views on how that would impact target ORR, maybe PFS as well as potential powering assumptions. And maybe for the docs, just curious on thoughts on how ipi/nivo could perform in HLA negative patients only perhaps in part to all comers and HLA positives.