IDEAYA Biosciences, Inc. (IDYA) Earnings Call Transcript

Good morning, and welcome to the IDEAYA Biosciences Investor 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.

This is Yujiro Hata, Founder and CEO of IDEAYA Biosciences, and I'll be the host today for the Darovasertib Clinical Program Update [ in ] Neoadjuvant Uveal Melanoma. Please note, we will be making forward-looking statements today, and please refer to our SEC filings as appropriate. I wanted to first begin by welcoming all of our listeners, analysts and guest speakers to today's event. Our speakers today will be Dr. Carol Shields, the Chief of Ocular Oncology at the Wills Eye Hospital at Thomas Jefferson University and Dr. Darrin Beaupre, the Chief Medical Officer of IDEAYA Biosciences. For today's agenda, I'll provide a brief market introduction of pre-metastatic uveal melanoma, then Dr. Darrin Beaupre will provide a walk-through of the registrational trial design feedback in neoadjuvant uveal melanoma from the recent FDA Type C meeting. Next, Dr. Carol Shields will provide a comprehensive Phase II clinical data update of darovasertib and the neoadjuvant uveal melanoma setting, including a summary, patient-baseline characteristics, safety and clinical efficacy. I will then provide closing remarks, and then we will finish with the analyst Q&A portion, the webcast. The pre-metastatic uveal melanoma market can be summarized by 3 key points: First, this is an indication that is an extraordinarily high unmet medical need with currently no FDA-approved systemic therapies in either the neoadjuvant or adjuvant settings. Second, we believe the pre-metastatic uveal melanoma market is substantially higher than the metastatic uveal melanoma with an annual incidence of approximately 12,000 patients across North America, Europe and Australia. Finally, third, we believe the total addressable uveal melanoma prevalence is multiples of annual incidents, partly driven by approximately 30% of small ocular tumors that are currently managed with wait-and-see as they have no existing treatment options. We believe darovasertib treatment has the potential to be applicable to all uveal melanoma patients in the neoadjuvant setting. I will now introduce Dr. Darrin Beaupre, who will walk through the regulatory feedback on the darovasertib neoadjuvant uveal melanoma registrational trial design from our recent FDA Type C meeting. Darrin, please take it away.

Thank you, Yujiro. On this slide, we display the potential for darovasertib to impact the entire patient journey of subjects with both localized and disseminated uveal melanoma. We have clinical trials either open or planned that address all facets of the disease. Beginning in the metastatic setting, we are currently executing a randomized Phase II/III trial in HLA-A2-Negative uveal melanoma patients, comparing the darovasertib and crizotinib combination versus standard of care such as immunotherapy. Key endpoints for this trial include progression-free survival and overall survival. In addition, in HLA-A2-Positive subjects, we're continuing to evaluate the efficacy of this combination in our ongoing Phase II trial, IDE196-001. With respect to subjects with primary uveal melanoma, we are evaluating the activity of darovasertib as a single agent in the neoadjuvant setting and study IDE196-009, with tumor reduction, enucleation prevention, vision preservation and radiation reduction as key endpoints. Further information about longer-term plans in this setting will be addressed in the next 2 slides. Due to the fact that darovasertib inhibits a key driver pathway in this disease, we also believe we have the opportunity to prevent metastases by treating subjects in the adjuvant setting. Therefore, in summary, darovasertib in early clinical testing has been found to have a significant impact in uveal melanoma patients and we are constructing a development plan that will address all aspects of this disease. Next slide, please. Transitioning to the darovasertib uveal melanoma registrational trial design update, the following are highlights based on regulatory guidance from the recent FDA Type C meeting. First, eye preservation rate and time to vision loss are acceptable primary endpoints for enucleation and plaque brachytherapy uveal melanoma patients treated in a randomized Phase III setting. Importantly, the FDA briefing book outlined an objective to exceed a lower bound of 10% eye preservation rate with a 95% confidence interval. Next, no detriment to Event-Free-Survival was an acceptable secondary endpoint. Discussions are ongoing with the FDA to include overall response as a potential surrogate and composite endpoint to support earlier approval scenarios. In fact, at the meeting, a preliminary primary uveal melanoma response criteria was proposed, the response criteria was supported by preliminary correlations between degree of response with eye sparing and visual preservation. These aspects were discussed, and further validation of response criteria and imaging modalities utilized to assess response will be provided to the FDA as requested. The registrational study will enroll high-risk metastatic disease uveal melanoma patients. Based on our preliminary projections, we anticipate that no detriment to Event-Free Survival results for this high-risk population will take approximately 2 years of data maturity to initial readout. Also based on the FDA meeting, the potential for a broad indication label in neoadjuvant uveal melanoma for subjects with low, intermediate and high risk for metastatic disease is feasible. A darovasertib dose of 30 milligrams twice a day was proposed as the move-forward dose for the registration trial. Next slide, please. This slide summarizes, from a high level, the proposed Phase III design for the darovasertib neoadjuvant study. Eligible subjects will be uveal melanoma patients with localized disease that are at high risk for metastases. There will be 2 cohorts of patients. Cohort 1 will include subjects who require enucleation based on large tumor size. The second cohort of subjects will be those who have tumors that are deemed eligible for plaque brachytherapy. In both cohorts, subjects will be randomized to either immediate local therapy versus 6 to 12 months of neoadjuvant darovasertib treatment followed by definitive local therapy. The primary endpoint for Cohort 1 will be eye preservation, and that for Cohort 2 will be time to vision loss. Key secondary endpoints will include Event-Free-Survival and safety. Additional endpoints to be discussed with the FDA include overall response rate, time to macular edema and predicted visual outcomes. Based on this high-level plan, we believe the study will include approximately 400 patients with the potential for an early data evaluation at approximately 2 years. This concludes the regulatory update to the darovasertib neoadjuvant program, and I'll pass it back to you, Yujiro.

Thank you, Darrin, for that terrific walk-through. And thanks to the entire clinical and regulatory team for the tremendous effort that enabled a successful Type C Meeting with the FDA. With that, I will now introduce our guest speaker, Dr. Carol Shields, a leading global key opinion leader in ocular oncology and the Chief of Ocular Oncology at the Wills Eye Hospital, who will walk us through the darovasertib neoadjuvant uveal melanoma Phase II clinical data update. Dr. Shields, please take it away.

Thank you, Yujiro. Primary uveal melanoma represents 5% of all diagnosed melanomas, most, of course, occur in the skin. It's molecularly driven by GNAQ and GNA11 mutations. This tumor most often arises in the choroid, a layer of the back of the eye, and the treatment depends on several factors. In particular, tumor size, the height and width. Enucleation and plaque radiotherapy are the primary uveal melanoma treatments. There is no FDA-approved systemic therapy for primary uveal melanoma. And this highlights the high unmet medical need. Next slide. One method of management of this tumor is enucleation when a patient has a large tumor. And in these 4 diagrams illustrations, you can see we are removing an eye that will leave the patient with an artificial eye and no hope for vision from that artificial eye. Next slide. Another alternative for treatment is plaque brachytherapy. This is a meaningful treatment for uveal melanoma. On the bottom, you can see the radioactive plaque, which is sewn to the back of the eye, provides radiation to the melanoma inside the eye, and it is effective for treating this tumor, but it leaves the patient with complications such as radiation-related swelling of the optic nerve and swelling of the retina, which means vision loss. So many of these patients, or I should say, most of them, wind up blind from the radiation. Next slide. On this slide, we depict the biology behind the pathogenesis of uveal melanoma and the signaling pathway responsible for the growth and the survival of uveal melanoma cells. The vast majority of patients diagnosed with uveal melanoma have an activating mutation in GNAQ or GNA11 in their tumor cells. And these alterations are responsible for activating the PKC or protein kinase C downstream. And this is a key driver for this disease. Ultimately, this results in stimulation of downstream pathways such as RAS, RAF, MEK and ERK, all of which promote growth and survival of uveal melanoma cells. Darovasertib is an orally available, potent and selective inhibitor of protein kinase C. So in preclinical models, it demonstrated antitumor activity at drug exposures that could be safely achieved in humans. Therefore, the premise for the clinical testing of darovasertib in the neoadjuvant setting was to reduce tumor size, which could spare the need for enucleation and to treat with radiation reduction and ultimate reduction of metastatic disease and preservation of vision. Next slide. The global company-sponsored clinical trial design to test this hypothesis is shown in this slide. Two distinct uveal melanoma patient populations are eligible for the study. The first, labeled as Cohort 1, are subjects who have large, localized tumors that would have required enucleation or eye removal. In the second cohort are patients with small to midsize tumors that are planned for treatment with plaque brachytherapy. So in both arms, patients are eligible to receive darovasertib 300 milligrams BID as neoadjuvant therapy to maximum benefit or for up to 12 months of total therapy. Once definitive localized treatment is provided, patients are then eligible to receive darovasertib for 12 months in the adjuvant setting for reduction of metastatic disease. The primary endpoints for this study includes safety for both cohorts, and in addition, enucleation sparing for Cohort 1 and radiation reduction for Cohort 2. Additional endpoints include evaluation of tumor response, vision outcomes and local and distant relapse. Next slide, please. This slide provides the demographics of patients, the patient population that has thus far been evaluated in the company-sponsored trial. As of the cutoff date of August 15, 2024, there are 19 patients enrolled in the enucleation cohort and 19 patients in the plaque brachytherapy cohort for a total of 38 patients. Approximately 60% of patients were less than 65 years of age, and 40% over age 65. For those patients in the enucleation group, the median tumor thickness was 10 millimeters and median largest basal diameter, 17 millimeters. These are large tumors and that's consistent with an eye that requires enucleation. The median distance to critical visual structures, such as the fovea and optic disc was only 2 millimeters. For the plaque brachytherapy cohort, the tumors were a little bit smaller with a median thickness of 6 millimeters and a median base of 13 millimeters. These tumors were slightly further from the visual structures. Next slide, please. Here, we list the cumulative safety profile from the 38 patients treated with neoadjuvant darovasertib therapy in the company-sponsored trial. You will see that the most common drug-related adverse events were diarrhea, nausea, vomiting and fatigue, but they were all Grade 1 or 2, with the majority of adverse events being very low grade. Grade 3 or higher adverse events were uncommon as were serious adverse events. There was a low frequency of discontinuation of medication due to treatment-related adverse events. It was under 3%. And overall, darovasertib was well-tolerated in this treatment setting. Next slide, please. In this waterfall plot, we show combined data from both the company-sponsored trial as well as that from the investigated-sponsored trial recently presented at the American Society of Clinical Oncology in 2024. The investigated-sponsored trial evaluated darovasertib in the neoadjuvant setting for subjects planned for enucleation. The combined data shown here provides a comprehensive overview of the degree of tumor shrinkage seen when darovasertib is used as a neoadjuvant medication. There was a total of 49 subjects used for this analysis. As you can see from the waterfall plot, the majority of subjects treated with this medication experienced tumor shrinkage below the 0 mark, 59% had at least 20% tumor reduction and nearly 50% observed greater than or equal to 30% tumor reduction based on product of diameter measurements. Importantly, 61% of patients were spared enucleation, and that is a highly significant clinical outcome. We have never had a medication that can do this. In addition, tumor reduction of 20% or greater was found to correlate with enucleation sparing and radiation reduction in this population, 43% of patients were continuing on darovasertib neoadjuvant therapy at the time of the analysis. Next slide, please. So this is a swimlane plot of the same 49 patients. We review the treatment duration of subjects eligible for 6 months or more of darovasertib neoadjuvant therapy treated in the investigated-sponsored trial and the company-sponsored trial. As you can see from this plot, the majority of subjects received greater than 3 cycles of treatment, and several had sustained tumor shrinkage beyond 6 months of therapy. Subjects with large and small to midsized tumors responded similarly, and determination of the risk profiles of these subjects and its impact on response is currently being evaluated, 61% or 19 of 31 eye preservation rate observed in the enucleation patients, and the typical time to greater than or equal to 30% tumor shrinkage was about 2 months, and the typical time for conversion from enucleation to saving the eye and treating with plaque brachytherapy was about 5.5 months. Next slide, please. In the next few slides, I will show you some really interesting images demonstrating case examples of the impact of darovasertib, when given in the neoadjuvant setting, from the company-sponsored trial. In this first case, we have a man, very young, in his 20s with a very large intraocular melanoma that's impinging on the critical visual structures such as the macula and the optic disc. This patient has a mutation in the GNA11 gene. This patient was enrolled in the enucleation cohort, headed for enucleation or removal of the eye, but was subsequently converted to plaque brachytherapy due to substantial reduction in tumor size seen in the photos and the ultrasounds. After 5 months of treatment, the patient had 39% reduction in tumor thickness, 47% reduction in the product of diameter measurements and 54% decrease in tumor volume. Next slide, please. In this second case example was a man in his 60s who was enrolled in the plaque brachytherapy cohort due to tumor size. After 5 months of darovasertib treatment, the patient had 60% reduction in tumor thickness, 71% reduction in product of diameter measurements and 80% decrease in tumor volume. Reduction is in the simulated radiation dose to the critical eyes structures is listed at month 3 with patient continuing in neoadjuvant therapy past 6 months, allowing him to have further potential tumor size reduction prior to plaque brachytherapy. These 2 examples that I've just shown you show the impact that darovasertib has on preserving the eye in the first case and preserving the vision in the second case. Next slide, please. Neoadjuvant therapy with darovasertib can also have significant impact on patients with small to midsize tumors. In this population, due to a decrease in tumor size, a reduced dose of radiation can be used, which can subsequently lead to reduced radiation toxicity and improved visual outcomes. A few case examples are shown here. In the top graphic, we see a subject with uveal melanoma outlined in red, who required plaque brachytherapy, but was first treated with 6 months of darovasertib neoadjuvant therapy. This subject experienced tumor reduction of 64%, based on product of diameter measurements, and that's the smaller red circle top graphic. In the bottom panel, comparing the simulated radiation dose required for plaque brachytherapy at the time of enrollment to the simulated dose after darovasertib treatment, neoadjuvant therapy was associated with a radiation dose reduction of 63% to the fovea, which is the center of vision, and 63% to the optic nerve and 63% to the optic disc, both of which are the transmitters of vision. For the second subject, who is thus far received only 3 cycles of neoadjuvant therapy, tumor reduction of 30% was observed, which resulted in 40% to 50% reduction in radiation dose that was initially planned the key visual structures. On the left panel, there are currently a total of 10 patients who are evaluable for pre- and post-simulation data analysis. The mean reduction of radiation to key visual structures is shown in the left for the fovea, the optic nerve and the optic disc, all very important in vision. Importantly, 60% of these subjects had improved predictive visual outcome using a visual prognostication tool that can predict the likelihood of developing vision loss to 20/200 or worse, that is an outcome consistent with legal blindness. Therefore, in summary, neoadjuvant therapy with darovasertib was found to be an effective means to reduce tumor size in subjects with primary uveal melanoma. Further tumor reduction was associated with enucleation sparing, that is no need to remove the eye anymore, and radiation reduction, that is less radiation to the eye with improved predicted visual outcomes. I would like to take a breather and just give my personal opinion of this medication. This data that you have just seen is a true game changer for the management of uveal melanoma. I've practiced ocular oncology for 4 decades, and this is the first agent that can be used in the neoadjuvant setting to shrink an intraocular melanoma before definitive therapy. This is the first drug to be used as neoadjuvant and adjuvant, and this is truly remarkable. But what is more impressive is that this drug could actually be lowering the metastatic risk from uveal melanoma. I think we will soon learn of the myriad of benefits from this exceptional drug to shrink melanoma so that enucleation is not necessary, to shrink melanoma so that lower radiation dose can be given, to shrink melanoma so that less radiation-related lines occurs, and most importantly, to shrink melanoma so that metastatic disease might reduce or even might disappear. Imagine that, and it is all based on good science. Thank you.

Thank you, Dr. Shields, for that wonderful walkthrough, and for all your contributions to the darovasertib program, including as a key investigator in the ongoing Phase II neoadjuvant uveal melanoma clinical trial. We will now transition to our closing remarks. We believe pre-metastatic uveal melanoma is a significant indication opportunity for darovasertib that has both an annual incidence and total prevalence that is multiples of metastatic uveal melanoma. Next, the unmet need in both the neoadjuvant and adjuvant uveal melanoma settings are significant, with currently no FDA-approved systemic therapies available for patients and a strong desire from the physician and patient communities to have better alternatives to highly invasive procedures such as eye removal and high radiation dose plaque brachytherapy. The FDA Type C meeting provides IDEAYA important clarity on the primary endpoints of eye preservation and time to vision loss, as well as the secondary endpoint of no detriment to Event-Free-Survival for potential regulatory approval in the neoadjuvant uveal melanoma setting. We're particularly excited that the FDA agreed with the sponsor's view of the clinical importance of eye preservation and time to vision loss is primary endpoints for full approval. We believe based on the Phase II clinical data shared today, including the majority of patients observing greater than 20% ocular tumor shrinkage and eye preservation, we have a potential path for darovasertib to achieve these clinical endpoints in the neoadjuvant uveal melanoma setting. We are now seeking to rapidly advance darovasertib to a registrational trial for neoadjuvant uveal melanoma, alongside our ongoing registrational trial in frontline metastatic uveal melanoma. We believe these collective efforts advance our broader strategic objective to position darovasertib as the first-line standard of care in both the pre-metastatic and metastatic setting. We have now concluded our prepared remarks. And operator, you may now proceed to the analyst Q&A portion of our webcast.

[Operator Instructions] Our first question comes from Anupam Rama at JPMorgan.

Congrats on the update. Just two quick ones for me. The first one, in your discussions with the FDA, what remains the kind of push-pull levers to consider here with [ diameter ] ORR as a basis for early accelerated approval in the neoadjuvant setting? And then second question, and sorry if I missed this, can you give a little bit more color on what the Grade 3 AEs were and if they resolved or how they were addressed?

Sure. Thanks, Anupam, for the question. Darrin, do you want to take that?

Sure. With respect to some of the other endpoints that would be highly relevant for a study like this, like overall response time to macular edema, radiation reduction, things that we're looking -- many of the things that we're looking at already in the 09 trial, those will still be an important component of the go-forward registration plan, but we're still working with the FDA to determine what's the best way to operationalize those endpoints to be an important component of the regulatory filings. So the good news is the FDA agreed with eye preservation and time to visual losses, key primary endpoints, they feel like these are endpoints that could certainly give us full approval. And so these additional endpoints could be helpful as the data evolves, for example, at an interim analysis. With respect to your second question around the adverse events, I have to tell you, although not shown in the slide deck today, we've actually collected data from all of our monotherapy trials with darovasertib because we wanted to get a good comprehensive overview of the safety profile. So looking at the initial Novartis Phase I trial, as well as our 01 study, and then including patients who are in the neoadjuvant trials, both run by our investigator-sponsored study in Australia as well as our own 09 study, the Grade 3 or greater adverse event rate is extremely low. I mean the highest adverse event was 5.7%. Everything else is below that. So to be quite honest, as a monotherapy, darovasertib's very well-tolerated. SAEs or serious adverse events are extremely uncommon. Discontinuation due to adverse events is low. So I got to be quite frank, there's really not a lot to talk about there, to be honest, These are case examples of adverse events, but overall, extremely well-tolerated. And if you look at the kind of impact that we're having in terms of antitumor activity, I think that just speaks to the fact that we're definitely on the key driver, we're basically putting the brakes on the gas pedal, which is protein kinase C, and we're doing it in a way that patients tolerate very well, which is exciting.

Our next question comes from Maurice Raycroft at Jefferies.

Congrats on the update. For the registrational study, what are the landmark times for measuring eye preservation and vision loss, respectively? Or is this something that is still being determined with FDA and we'll learn more about this later this year? I guess how could that be operationalized in the study?

Darrin, do you want to take that?

Well, landmark is probably not the right term, because landmark implies that we're going to look at specific times. But we, from the perspective of what we plan to do is an interim analysis, obviously, and then a final analysis. And then at the interim, we'll be looking at time to vision loss. And looking at this patient population that we plan to enroll, this is going to be a patient population that's going to be exposed to a significant amount of radiation, which means their likelihood of being blind, 3 years down the road, that is legally blind is actually quite high. And then if you look at the fact that we're going to look at a visual outcome, something like loss of 15 letters that can happen much sooner before someone goes blind, it allows us the opportunity to be able to look at the time of visual decrement in the control group, which should be rather robust and compare that to the treatment arm, which we believe will have a significant impact because of the tumor shrinkage and the radiation reduction that Dr. Shields has talked about. And with that, we'll be able to get an early read. And I think the enucleation part speaks to itself. It's very likely, very early. And we're going to see lots of eyes saved. In addition, based on looking at 15 -- best-corrected visual acuity 15 letters, it's likely we'll be able to get a good early view on visual decrement as well, and that will put us in a great place at the first interim analysis, which would be approximately 2 years down the road. Does that answer your question?

Yes, that makes sense. And then for measuring and controlling radiation reduction in the registrational study, can you talk about what worked and what didn't work in the Phase II? And what is the most likely scenario for how you'll operationalize that in the Phase III?

Say that again, which?

For measuring radiation reduction and controlling radiation reduction in the registrational study.

Well, yes, so we did that with simulation, right? So we did that, baseline had patients simulated and then post treatment had them simulated again. Again, if radiation reduction is going to be something that we look at very, very carefully, we'd have to do the same. Whether we do it independently or not, I think it's still to be determined. Currently, it is being done independently from the sites. So we have sort of an unbiased view of what at least our central reviewer sees in terms of what they think the radiation dose would be prior to neoadjuvant therapy and what the radiation dose would be post neoadjuvant therapy. So we're still thinking about what level of scrutiny to put on that for this since it's just going to be a secondary endpoint. We know what the key primaries are. But yes, we would be using simulation pre- and post-therapy, just like we're doing in the 09 study.

Our next question comes from Gregory Renza.

Great. Yujiro and team, congrats on the updates. Maybe a question for Dr. Shields if Dr. Shields is still on the line. Just thinking about the adoption and the use of darovasertib, what percentage of your uveal melanoma patients do you think the percentage just in clinical practice would you and others prescribe darovasertib if this is potentially approved? And just curious, just given a fraction of the slow progressing patients or certainly put under monitoring, at what point during the disease course would you think a patient should be put on darovasertib based on the benefit risk that you've seen from the data so far?

Great question, Greg. Dr. Shields?

Yes. Thanks for the question. I honestly think that there will be fairly universal adoption of this medication. It's not been difficult for us to enter patients on the trial currently because patients understand that, if we go to enucleation, they lose their eye, and that's it. Or if we go to radiation, they're getting a big dose of radiation, and that's likely to cause vision loss. So currently, about 20% of patients that have uveal melanoma lined up with enucleation and 80% with plaque radiotherapy. And I think patients will understand the importance of the new medication, whether it's used for 3 or 6 months to shrink tumor and provide them with better outcomes. But I also think there's an underlying enthusiasm from ocular oncologists and medical oncologists that we might be reducing metastatic disease, which is really the ultimate goal.

Congrats again.

Our next question comes from Andy Berens at Leerink.

Congrats on the data and the progress. Just a couple for me. If you guys can do an interim look using ORR, would you also have to show a trend in Event-Free-Survival? Could that trend be non-inferior? And if so, how long do you think the agency would want to see this trend maintained to have [ conviction ] in the interim results? And then you also mentioned in the press release, earlier stage uveal melanoma. Are you referring to patients that have very early disease like indeterminate lesions? Will they actually be enrolled in the trial? And if not, how much does that impact the addressable market? And then I have two for Dr. Shields, too, if that's okay.

Sure. Darrin, do you want to take the first portion?

Yes. Let me think. So the first one was around -- because I got confused, listening to the second one about who's going to get enrolled. The first one was about the endpoint. So remember, the primary endpoints are enucleation prevention and time to visual detriment, right? So overall response isn't the primary endpoint. So think about it this way. Where we'd like to be as the trial reads out in its first interim is we'd like to have a significant number of eyes saved. As you've seen, it's 60% or greater. So that's wonderful. So at the first interim, we have saved 60% of eyes. We've seen, hopefully at that time, some visual preservation. So there'll be some evidence of that. And then additional secondary endpoints that go along with that would be something like we could say, hey, look, the time to macular edema seem to be longer in those patients who got neoadjuvant therapy, the tumors shrank significantly in those who got neoadjuvant therapy. If we decide to simulate radiation doses, the amount of radiation those patients got was reduced. So really, it's a constellation of things. And with respect to Event-Free-Survival, the great news is, I think in the FDA's wisdom, the way we will design the trial is we don't have to show superiority with respect to Event-Free-Survival. We don't need to show non-inferiority. I think the idea is to make sure that we had enough events at the time that we read this out to show that we're not providing any detriment to patients' outcome by providing neoadjuvant therapy. That's the key. I mean, I think to the FDA, credit to the FDA, they want to make sure that if you're delaying radiation therapy, if you're delaying definitive treatment to the eye, you're not having an overall detriment to the patient. And to a credit, they recognize this is an orphan indication. These trials could be rather big, if you power them to show superiority or non-inferiority. And it was felt that I think the results were significant enough that being able to show with a hazard ratio that implies that there's no harm in addition to significant outcomes such as saving the eyes and reducing the amount of patients who either lose vision or become legally blind, those -- that would be a great position to be, that would be great for patients, and it would imply really no harm to patients, and all of that together would be a path forward to get this to patients as quickly as possible. Does that answer your first question?

Yes. Just on -- and in the definition of it of that, would enucleation count as an event? Or will that be excluded?

No. No. Yes, right.

Yes, I think this would be survival-related. [indiscernible].

Yes, [indiscernible] relapse is kind of what the main thing is.

And then, Andy, I'll just quickly answer your second question. I think you had asked about some of the smaller ocular tumors. So I think there, perhaps what you're referencing, which was noted in the release, is that here, we'll likely target to study the high-risk metastatic group, primarily because in that population, we anticipate we'll get an earlier readout on endpoints such as EFS. However, as part of the FDA meeting, at least our understanding of that meeting, there would be potential openness to considering a broader label to also include these lower-risk and medium metastatic risk patients. So that's what that was referencing. And then I think your third, you had some questions for Dr. Shields, so we'll let you ask those.

Yes. I was just wondering, in the patients that had enucleation converted to brachy and the eye was preserved, wondering what you would expect the longer outcome to be in these patients? Would they likely avoid it in the future? Or would most of them eventually have their eye removed? And then just in the context of other options that could be available in the future like Aura Biosciences' bel-sar. I was just wondering how she sees this intervention could fit into the treatment paradigm versus what they're targeting?

Yes. So Andy, on the second one, I just sort of like Dr. Shields to just sort of focus on our update, I think, just as a practice, probably better not to talk about other programs for this purpose. But Dr. Shields, do you want to maybe address the first question?

Right. The conversion of enucleation down to smaller size so that we can save the eye with plaque brachytherapy is the reality. In this study, 61% of patients have their eye saved. And yes, it is lasting. So when we do plaque brachytherapy for uveal melanoma, we give an [ APEX ] dose that is lasting. And we, in our hands, we have maybe only 1% of patients show recurrence. So we do think it's going to be lasting. And there was a big study done called the Collaborative Ocular Melanoma Study. It was done in the 1980s, 1990s. And it was a comparison of enucleation versus plaque brachytherapy. And we found in the long run, the risk for metastatic disease was no worse in either arms so that plaque brachytherapy, if you can shrink a tumor down to the point that you can treat it with plaque brachytherapy, you can provide the patient equivalent prognosis.

Okay. That's very helpful. And congrats again.

Our next question comes from Yigal Nochomovitz at Citi.

Could you just clarify, Dr. Shields, if you wouldn't mind, you mentioned the simulation of the radiation dose before daro and then after daro, I'm just curious, why wasn't it compared to the actual dose delivered post daro versus the simulated dose? .

I can take -- do you want me to take that, Carol?

Yes, go ahead.

Yes. Essentially, the sites do their own simulation, but what we wanted to do is have sort of independently reviewed using the eye physics software we had. And it's kind of like when you do response, right, obviously, you -- in some of these registration trials, particularly single arm Phase IIs, you get blind independent central review. This was just a way to get a view of what an independent reader would have argued that the radiation dose would have been before and after therapy. But obviously, if you're going to use that as a key endpoint, like it would be -- if we were going to use it as a primary endpoint, you'd want to have both sight in blind independent central review results at the same time. But since it's a secondary here, we're likely to go with one or the other.

Okay. And then can you just confirm that in the patients that were spared enucleation, that all of them achieved at least the 20% or greater tumor shrinkage that was considered clinically meaningful by your advisory board?

If you look at the graphic that was provided, you can see that there are little hatched arrows above each one of those bars in the waterfall plot that shows you who are the folks that required enucleation. And you can see that the vast majority of them fall under the 20% shrinkage point. There were a few exceptions that we had less than 20% shrinkage and were spared enucleation. But for the most part, it's the same with radiation reduction. There's always exceptions to the rule. But the preponderance of the results that we've seen thus far imply, at least at this point in time, that a minus 20% or 20% reduction in tumor measurements correlate well with both radiation reduction and eye preservation.

And Yigal, the slide Darrin's referring to, Slide 19, there are 3 patients that were below the 20% that had their eyes saved, one right below that 20% line.

Okay. And then with the discussion with the FDA on EFS, did you come to an agreement on the number of events that would require to trigger the interim analysis? Because I recall for Kimmtrak, that took much, much, much longer. I think it was over 5 years before they got to an answer.

So the number of events thus far is still being constructed as we put together the final protocol and the synopsis. So I don't want to dig into exquisite details, but suffice it to say, like I said, at that first interim analysis of 2 years, I mean, it doesn't take -- it's not hard to imagine. We're going to have a lot of eye saved. The answer is if the data continues to look like it looks now, the answer is yes. Are we going to have significant improvement in visual outcomes at that period of time if we're looking at best corrective visual acuity 15 letters, the answer is probably yes. So I think at the end of the day, it's all going to be about how mature the data is required by the FDA on EFS. And we don't have a lot of clarity, but I can tell you this. I don't think it's going to be a huge amount. I think that they're going to be reasonable, knowing that this is having the kind of impact that Carol talked about, just a major impact on patients. And of course, don't want us to follow it over time. But that first interim analysis will allow us to have that discussion with them. Look at the number of events that happen. And remember, this is going to be a high-risk patient population, right? So high-risk patient population means a significant proportion are going to relapse in that 2- to 3-year time period. So this is a great opportunity, I think, at that first interim to hopefully do everything that we see in the 09 trial, which is save the eyes, preserve the vision, do this without harm to patients. And with that, we'll be in good shape. But I think we're doing everything we can in terms of designing the trial to get the outcome as quickly as possible.

Yes. I think, Yigal, there, maybe just to end with, less it relates to EFS, right? I think this was, at least we think, best-case scenario, right, secondary endpoint, no detriment, and that's why we emphasize if we focus on the high-risk population, at least we would anticipate, we'll be able to get that initial read sooner.

Our next question comes from Matt Biegler at Oppenheimer.

I also had a question on timelines and kind of tagging on to Yigal's here, because Kimmtrak's adjuvant trial, I think, is estimated on ClinicalTrials.gov at around 8 years. So it sounds like from the previous question that you think that you can do it faster based on a degree of benefit that you're seeing here. And obviously, we're going to get that interim look at 2 years. And then I also had a question.....

Let me stop you there, just hang on a second, because you said something really important that I may have missed from the last question, which is you're talking about adjuvant, right? So you're talking about the Kimmtrak adjuvant trial. We're talking about neoadjuvant. We're in a totally different ball game here, right? The adjuvant is a whole different kettle of fish. And as you know, we're very interested in the adjuvant setting, too, and we're looking at that but those timelines are very, very different. So I wouldn't get those confused with the neoadjuvant setting that I've just described. Very important, you're right, the adjuvant setting could indeed take longer, depending on how you do it. And again, it depends on the patients you enroll. Kimmtrak is enrolling patients, I believe they are all stage 3. Some of the early stage 3 patients may be not metastasizing for a bit longer than some of the others. But if you really refine the patient population for the Class II, the BAP positives, et cetera, the ones they're going to relapse early, your timelines can vary. But again, don't get the adjuvant confused with the neoadjuvant. The timelines are very, very different. Neoadjuvant can happen much faster.

Yes. And maybe, Matt, I'll be brief. But if you just sort of break it apart, right, I think what Darrin is referring to, obviously, typically for neoadjuvant in this case, we're talking about Event-Free-Survival, right. For adjuvant, it's different. It's Relapse-Free-Survival. So those are obviously not exactly the same. Second, typically for adjuvant trials there as a primary, with the need to show superiority on RFS. And again, there, that directly impacts the hazard ratio, therefore, the amount of patients you have to enroll as well. So that's why we had, I think, tried to emphasize around no detriment to EFS as a secondary is we think, significant because that would obviously dramatically change what we would need in terms of statistical thresholds, therefore, how much we would have to enroll. So we have modeled similar ranges, Matt, as you mentioned, for adjuvant. But again, as neoadjuvant, you're talking different endpoints, different setup.

Got it. I think you actually just answered my second question for Dr. Shields, so I'll jump back in the queue.

Our next question comes from Charles Zhu at LifeSci Capital.

Thanks for providing the update and congrats on all the progress. One clarifying question here. Is vision loss, as it pertains as a regulatory endpoint, a binary outcome based on whether or not the patient is legally bind? Or is there a spectrum to consider based on visual acuity measures like letters or remaining letters the patient is able to visualize. And how do things like peripheral vision factor into this, if at all?

Yes. First, maybe I'll first start there. So here, Charles, just to be really specific, so this would be time to vision loss, right? And you would have that readout in a randomized fashion versus your control arm. But Darrin, do you want to answer the rest?

Yes. And Charles, to your point, the 20/200 vision legally blind is different than a visual decrement of 15 letters, right? And so obviously, the time for you to go legally blind is going to be longer than the time that perhaps you lose 15 letters or some degree of visual loss. And so we're going to define how we are going to measure that. We think 15 letters is good, but we may want to do something similar to that. But essentially, it's some way of visual loss over that period of time of 2 years that can be measured between the 2 groups very accurately to show that level of visual decrement, which is not necessarily blindness, occurs in the control arm, but is preserved in the treatment arm.