Good afternoon. My name is Tania, and I will be your conference operator today. At this time, I would like to welcome everyone to the Blueprint Medicines conference call. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question-and-answer session. If you would like to ask a question during this time, simply press star followed by one on your telephone keypad. If you would like to withdraw your question, press the pound key. Please plan to limit yourself to one question. Thank you. Jenna Cohen, you may begin your conference. Thank you, Tania. Good afternoon, everyone, and welcome to Blueprint Medicines conference call to discuss the presentation of initial BLU-945 clinical data at the AACR 2022 annual meeting. You can access the press release announcing the data as well as the slides that we'll be reviewing today by going to the Investors and Media section of our website at www.blueprintmedicines.com. With me on the call today are Kate Haviland, our Chief Executive Officer, Dr. Fouad Namouni, our President of Research and Development, and Dr. David Spigel, the Chief Scientific Officer of the Sarah Cannon Research Institute. Dr. Becker Hewes, our Chief Medical Officer, will also join us for the Q&A portion of the call. Before we get started, I would like to remind everyone that statements we make on this conference call will include forward-looking statements. Actual events or results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties, and other factors, including those set forth in the Risk Factors section of our most recent annual report on Form 10-K filed with the SEC and any other filings that we may make with the SEC. In addition, any forward-looking statement made on this call represents our views only as of today and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update or revise any forward-looking statements. Now here's our CEO, Kate Haviland. Thanks, Jenna, and greetings from New Orleans, everyone. It's great to be back in person at AACR this year, and I can't think of a better way to wrap up my first week as CEO than to showcase our scientific leadership with new data from multiple programs across our portfolio. On today's call, we'll primarily focus on our EGFR programs, with an emphasis on BLU-945, which is the furthest along in clinical development. However, before we begin, I want to take a moment to talk about the incredibly strong position we're in today, as well as the exciting possibilities we have for future growth. First, we continue to build commercial momentum with the ongoing launch of AYVAKIT in advanced systemic mastocytosis, with a near-term opportunity to significantly expand the impact of AYVAKIT to patients with non-advanced SM. Second, we have one of the most important precision therapy pipelines in the industry, with opportunities to improve patient outcomes in difficult to treat and prevalent cancers. Third, we have a sustainable innovation engine driven by our exceptional scientists who have the proven ability to design compounds that achieve ambitious product profiles. Last, we have a strong balance sheet and an outstanding team at Blueprint Medicines who are motivated every day by a shared mission to improve and extend the lives of people with cancer or hematologic disease. This mission brings us to the commitment we have to improve outcomes in patients with lung cancer. At diagnosis, lung cancer patients in the U.S. face the terrible reality that their disease is a leading cause of cancer death among men and women, more than colon, breast, and prostate cancer combined. EGFR is one of the most common genetic drivers of lung cancer, impacting about 60,000 patients every year in major markets. The prognosis for EGFR-driven lung cancer patients has improved over the last decade with the advent of precision therapies that directly target EGFR mutations. Osimertinib, or Tagrisso, is now the standard of care for most patients and has greatly improved outcomes. It is also one of the most successful precision therapies ever marketed. However, osimertinib fails most patients, with about seven out of 10 progressing, largely due to the emergence of tumor resistance. This includes specific EGFR-driven on-target resistance as well as off-target bypass resistance. At Blueprint Medicines, we start our discovery efforts by understanding the patient needs we are trying to solve. In EGFR mutant lung cancer, we see four major opportunities to improve patient outcomes. The first is to improve efficacy against EGFR mutations, activating mutations. The majority of patients have one of two drivers, an exon 19 deletion or an L858R, or as we call it, LR, mutation. Osimertinib has demonstrated shorter overall survival and progression-free survival in LR patients, and there is an opportunity to improve outcomes by increasing pressure on this mutation in the first line of therapy. The second area of medical need is to shut down on-target resistance in EGFR. The most common mechanisms of EGFR-driven resistance are the C797S and the T790M mutations, which we call CS and TM. The frequency of these resistance mutations has been increasing over time as osimertinib has become the standard of care for first-line treatment. Therefore, treating or preventing these mutations from emerging is a priority to improve patient outcomes. The third opportunity is to address off-target or unknown mechanisms of resistance. Many patients progress due to off-target resistance, such as MET amplification or other mechanisms of resistance that may not be known. In some cases, multiple mechanisms of resistance may be present in the same patient in different tumor clones. To effectively treat these patients, tolerable combinations are needed that both maintain pressure on the EGFR pathway while also addressing the off-target bypass mechanisms. Finally, the fourth opportunity to improve patient outcomes is to more effectively prevent or treat CNS disease. In lung cancer, the brain is a common site of progression that has proven difficult to treat. New therapies with greater CNS penetration are needed to prevent and to treat brain metastases. Two primary goals drove the development of our EGFR portfolio at Blueprint Medicines. The first goal was to effectively shut down the EGFR pathway by potently inhibiting driver mutations and preventing or treating on-target EGFR resistance. The second goal was to enable well-tolerated combinations that keep pressure on the EGFR pathway while also enabling a wide range of combinations to address off-target resistance. Blueprint's expertise in designing potent and selective molecules enabled us to build the tools to pursue these goals, resulting in our clinical-stage portfolio of compounds, including BLU-945, BLU-701, and BLU-451. The intersection of these investigational therapies' attributes such as their mutational coverage of driver and resistance mutations, their selectivity over the kinome, the selectivity over wild-type EGFR, and CNS penetration will enable our compounds to become the backbone of any combination regimen, as well as the potential new standard of care in first-line treatment. Having multiple compounds also allows for flexible solutions as we increase our understanding of complex resistance patterns and as the treatment landscape evolves. In recent months, we have made significant progress in advancing our EGFR portfolio into clinical development, and we are now actively enrolling patients in trials for all three of these investigational therapies. This includes our recently initiated trial of BLU-451 to target EGFR exon 20 insertions. Today, we are excited to share for the first time our near-term development plans to address the key areas of medical need in EGFR-driven lung cancer with our clinical-stage portfolio of EGFR therapies. We will focus our discussion on BLU-945, which is the furthest along in clinical development. Here at the 2022 AACR Annual Meeting, we are presenting promising early clinical data for BLU-945 from the first several dose escalation cohorts in our phase I SYMPHONY trial. BLU-945's therapeutic window to wild type in preclinical models is a unique attribute, and it distinguishes it relative to the field of other EGFR-directed therapies. On today's call, we'll review the data that demonstrate the early safety and activity benefits conveyed by this therapeutic window and discuss our plans to expand the BLU-945 development program to evaluate the potential benefit in a broad set of patients across lines of therapy. Let's start by reviewing the BLU-945 data with Dr. David Spigel, the chief scientific officer at the Sarah Cannon Research Institute and an investigator on the BLU-945 study. Dr. Spigel is a renowned lung cancer expert with deep expertise in targeted therapy development. In his role at Sarah Cannon, he oversees all scientific aspects of their clinical trial programs, including the application of translational medicine to guide drug development. We are very excited to have Dr. Spigel joining us today to share his perspective on the BLU-945 data. Thank you, Dr. Spigel. I will turn the call over to you. Yeah. Thanks, Kate. Really excited to be here. We've been thrilled to have an opportunity to explore what we think could be a great new option for our patients, where there's really been an unmet medical need. I'm gonna walk you through the presentation here at AACR. The title of this is Emerging Evidence of Activity of BLU-945 in Patients with Advanced EGFR-Mutant Non-Small Cell Lung Cancer Utilizing Circulating Tumor DNA in the phase I/II SYMPHONY Study. On behalf of my fellow investigators, I'm honored to present these data. Here are my disclosures, and I should mention Kate did a nice job of that as well. I am an investigator on this trial, and obviously we have patients on this at our center. I guess the important thing to say up front is, as good as therapies have been over the last really almost 15 years now, nobody is cured with even great drugs like erlotinib in the early period and most recently osimertinib, everybody recurs. There might be patients who have prolonged disease control, and I certainly care for some patients who are even close to a decade on even first generation EGFR TKIs, but everybody at some point progresses. It is a clear unmet medical need for which we do not have any standard of care. As Kate kind of nicely showed, osimertinib has been a fantastic drug, as shown on the left here. Patients do enjoy very extended progression-free survivals and overall survivals, and obviously those are medians. It's worth noting, though, patients with LR or L858R mutations tend to have a slightly worse prognosis when it comes to progression-free survival and overall survival compared with our patients with deletion 19s. On the right side of this slide, it's important to note a couple of things. There are patients, certainly outside of the U.S., that still receive first-generation drugs like even gefitinib and erlotinib, or even afatinib. Then later get osimertinib, but even those patients will develop resistance mechanisms to that class, those classes of drugs, whether it's T790M or whether it's C797S. Patients in the U.S. who primarily receive osimertinib up front also will ultimately experience some form of resistance. A lot of that is made up by C797S, and we recognize there are other mechanisms still yet to be discovered. There is an important need to address these problems, the fact that patients do not have options after osimertinib, and that there are unique resistance mechanisms. It may be that one drug can solve this, or that combinations more likely are going to be needed to address these problems. Kate also did a nice job of talking about BLU-945's development. Its clear advantage is that it has excellent potency against activating mutations in EGFR, like LR and deletion 19, but specifically LR. It also has selectivity for those mutations over wild type. As shown on the left here is a ratio of the IC50 for wild type over the IC50 for those activating mutations. You can see across the board whether you have LR mutations alone or LRCS mutations, LRTM mutations. I know the nomenclature gets complicated, but in every scenario, nine four five outperforms drugs that we have currently available. On the right here, this is an aggressive cell line model of cells that have LR mutations as well as C797S mutations. I'll walk you through this, but on the far left there is vehicle, of course, and osimertinib against this aggressive cell line. As we walk across the different colors there, Katie mentioned seven zero one, and I'll come back to that later. Seven zero one alone has activity. If we look at blue nine four five at a low dose level, it has activity. But if you look at the combination in dark blue, that is nine four five with seven zero one, there is overwhelming activity against this resistant line, clearly superior than osimertinib alone. Here's the Symphony study. This is a phase I/II study being run at multiple centers. This is looking at patients who have activating EGFR mutations, who've received at least one prior TKI. Certainly a lot of patients here, as I'll show you, have been on osimertinib. No other known additional driving mutations. All patients had good performance status. This trial is currently in the monotherapy escalation, as I'll walk you through, looking at several dose levels from 25 to 400 mg. 600 mg dosing is ongoing actually. An MTD has not been reached. We'll talk about that. Expansion cohorts are planned. Importantly, in dark blue at the center of this slide, though, are plans to move BLU-945 into combination with osimertinib. Osimertinib given at a starting dose of 80 mg a day, the standard dose, the approved dose of osimertinib. Then of course, looking at expansions there. SYMPHONY is a pivotal trial to understand BLU-945's role alone and in combination with osimertinib, with traditional endpoints, including circulating tumor DNA, which I'll show you here in a moment. Here are the baseline demographics. There's been about 33 patients enrolled at the time of this analysis. Nothing really surprising here, but I wanna make two points here. Number one, about 64% of patients have CNS metastases in their history. That's critical because in this patient population, as in other monogenic driving settings of lung cancer, ALK, ROS, MET, CNS metastases are a clear problem for patients. You can have good systemic control but lose control in the CNS. You can see here that most patients have some history of growth in the CNS. Also, most patients, nearly all have received osimertinib, but others have received additional therapies, including platinum double chemotherapy regimens. Then on the right are the array of different mutations. This is an important and really a critical part in understanding the efficacy here, where does this drug work? We can see here there's a variety of different mutational profiles that include things like triple mutations, an activating mutation in EGFR, as well as T790M and C797S, and then various iterations thereof. Just wanna show one slide about toxicity. The take home here is that there have been no grade four or five events. There has been one grade three dose limiting toxicity in the form of transaminitis at the 400 mg dose, although it did require a dose interruption, the patient remains on therapy, so really not an unexpected side effect, and it appears to be very manageable. There's really been very little toxicity otherwise, a little GI toxicity in the form of vomiting. The important point here are the wild-type toxicities you don't see. In the traditional development of EGFR TKIs, we're used to seeing a lot of other side effects in the skin or the hair or even in the GI tract. We're really not seeing that here, and that's really a favorable toxicity profile for BLU-945 to date. This is a slide to demonstrate that the dosing clearly helps us understand what mutations may best be targeted. If you look at the right here by day 15, if you look at the 400 mg dose, which is in the orange there, it achieves a level that is effective at inhibiting T790M as well as C797S. Of course, we are still escalating dosing here, so exploring 600 mg here now. Two things from this slide. One is that a 400 mg dose very quickly appears to target those mutations at an effective IC90. The other thing is the half-life of this drug approaches one day, which helps really justify daily dosing for this medication. An important caveat when we think about what patients have been used to with drugs like osimertinib or erlotinib. This is really my favorite slide of the entire presentation. This is really fantastic. It's really where I think research is headed, particularly in lung cancer in these settings, where we're trying to understand what drugs are doing, how they're benefiting patients beyond traditional measures like RECIST. What is being shown here are the reductions in allele fractions of different genetic clones here. On the left here are the patients with EGFR T790, and on the right are patients with C797S clones. At the bottom, I know it's in fine print there, but you can see the mutational profile that was discovered on plasma ctDNA at cycle one, day one, and then the percent reduction in the allele fraction at the various dose levels, the reasons for the different colors. To help you through that on the far left there, if you look at the patient, for example, on the far right of that panel, in orange, that's a patient at the 400 mg dose level who has a reduction in allele fraction by two weeks, actually below the level of detection of the assay. As shown on the right, that is true for C797S. In both examples, whether it's TM or whether it's CS, nearly four out of five patients have significant reductions in ctDNA by day 15. What does this mean? It's hard to know, but it is a very favorable sign for what could be efficacy long term. This is gonna continue to be looked at in-depth at multiple time points and, of course, correlated with imaging. Here is a spider plot of those more traditional RECIST measurements of and again, the different dose levels in this early look at BLU-945, and of course, patients with a variety of prior treatments, but all pretty much received osimertinib. At different dose levels, you can see there's a variety of clinical benefit, including stable disease control. I want to highlight the patients below the horizontal at zero who appear to be benefiting, including two specifically who are approaching confirmed responses. Technically, one unconfirmed I'll walk you through and 1 that is very close. Here are these patient vignettes. We'll start with patient one at top. This is a 69-year-old female, no smoking history, which is pretty typical of our patients in this setting. She has had three prior lines of therapy, but the best this patient has achieved with even three prior lines of therapy has been disease control or stable disease. This patient has multiple target and non-target lesions that we've been able to follow, including lesions in the brain. Now, this patient is at the 400 mg dose, and of course, that dose is being pushed at the moment to 600 mg. What is shown on the left are the concentrations of that drug over time. Really, the impactful part of this slide I'd like you to recognize is on the right there. We talked a minute ago about the ctDNA profiles by day 15, so two weeks into treatment. What is shown here for this first patient is there is marked reduction in actually all three clones, so EGFR deletion 19, T790, and then in green there, the C797S mutation. Again, this patient's achieving essentially a PR. We just need more time to get a confirmatory scan, but it seems to be a clear partial response. The patient below is pretty similar. This is a 70-year-old patient, again, a non-smoker, advanced disease, of course, three prior lines of therapy. Now, this patient has received some benefit in the form of PRs previously, of course, has multiple lesions. This patient has been treated at a lower dose level at 200 mg daily. We'll just go right to the right side of the curve there. You can see that in all three settings, whether you're looking at EGFR LR or T790M or C797S, the so-called triple mutation, by day 15, this patient has marked reduction in ctDNA, and this is starting to show a correlation with disease response by formal imaging, and hopefully, this patient will achieve a PR with time. I wanna just quickly before we finish here, show you 1/3 patient, which highlights a couple of important points. This is a little bit younger patient, also a female, 57, multiple prior lines of therapy, no brain metastases at screening, who received a very early dose of BLU-945, so 50 mg daily. This patient, unfortunately, did not benefit clinically and so early. In fact, by the second cycle, there was evidence of progression in terms of pleural effusion. Let's focus on the right side of this curve because I think this speaks to a couple of important points. Number one is the patient's ctDNA fractions for T790M and C797S did drop significantly by day 15. Note that the exon 19 deletion fraction has risen. This seems to correlate with what was happening with the patient clinically and also speaks to the polyclonal nature of lung cancer, not just EGFR lung cancer, but lung cancer. We know that there are other clones, in this case, the original activating mutation that may not respond to drugs like BLU-945 alone. This speaks to the promise of combination therapy. Could a combination of this drug plus osimertinib or BLU-945 plus BLU-701 help address the problem that this patient's experiencing? Also, could it just be a dose issue? This is 50 milligrams a day. How would this look if this patient got 240 mg or even 600 mg? Could it overcome that so-called escaped clone of deletion 19? To summarize, this is an ongoing, really pivotal phase I study that has demonstrated so far that BLU-945 is highly potent. It's a selective oral EGFR inhibitor. It appears to be generally well-tolerated, no MTDs to date, in patients who have heavily pretreated EGFR-mutated lung cancer and, of course, patients who've received osimertinib. There have been few adverse events characteristic of what we'd expect with wild-type EGFR toxicity, and that's really encouraging. Despite the presence of EGFR mutations that confer resistance to drugs like osimertinib, treatment with BLU-945 has resulted in rapid, by day 15, dose-dependent reductions in ctDNA consistent with the preclinical data and really how this drug was designed to behave. Increasing the BLU-945 doses so far have been associated with increased activity, as I showed you with those last two patients there. Tumor shrinkage has been noted even at doses of 200 mg daily and above, and of course, the unconfirmed partial response. The clonal evolution and resulting mutational complexity of EGFR-driven lung cancer, as demonstrated on that last patient example, demonstrates the need for precision medicine to help understand what rational combinations may be needed on an individual patient basis. The initial safety and clinical activity results I think support expanding the SYMPHONY study as well as other broader development of BLU-945 alone and in combinations with osimertinib, BLU-701, and perhaps even other regimens. I am honored to present these data. Very exciting time for our patients with really an unmet medical need, and excited to share this with you. Good afternoon, everyone, and thank you, Dr. Spigel, for taking the time to join us and for your contributions to our EGFR program. This is Fouad Namouni, President of R&D at Blueprint Medicines. Today, I focus my remarks on two areas, beginning with our comprehensive EGFR development strategy and concluding with a brief update on our CDK2 inhibitor. Let's begin with the next steps for BLU-945. With the data announced today, we are thrilled to see the translation of BLU-945's preclinical profile. Evidence of clinical activity early in dosing in dose escalation, combined with tolerability consistent with the BLU-945 selectivity profile, give us the basis to quickly and confidently expand our development program. Importantly, the data also confirm our understanding of resistance patterns and reinforce our approach to pursue combinations to maximize patient benefit. Cancer has complex dynamic and adaptive biology. With our EGFR program, we are at the forefront of understanding this complexity. For the first time, we are monitoring clonal evolution with rapid, non-invasive, and longitudinal circulating tumor DNA assessments that allow us to repeatedly interrogate tumor biology during treatment to understand resistance patterns and inform drug development. This work has reinforced our strategy to treat heterogenic polyclonal tumors with innovative combination therapies. It is only through combinations that we will be able to shut down the competitive evolution of tumor clones by putting pressure on all EGFR mutations, including activating and resistant variants, as well as off-target bypass mechanisms. Fundamentally, we believe tolerable broad-acting combinations will dramatically improve patient outcomes, and our therapies will lead the way by bringing comprehensive EGFR coverage and selectivity. That takes us back to the BLU-945 data, which strongly support our combination development plans. Later this quarter, we will initiate the dose escalation cohort in our ongoing SYMPHONY trial for BLU-945 and osimertinib, which we believe are highly synergistic. We will focus development of BLU-945 osimertinib combination in patients with LR mutations where BLU-945 is strong and has potential to address a key limitation of osimertinib. This quarter, we will start in second and third line patients with LRCS mutations, with or without TM mutations. Later this year, we plan to push forward into front-line LR population. We are pleased to announce today that we have initiated a clinical trial supply agreement with AstraZeneca, which will provide osimertinib for combination development in our ongoing BLU-945 and BLU-701 trials. In addition, we plan to rapidly extend development of BLU-945 to address broader populations. We will reach second-line patients with off-target resistance by combining our agents with chemotherapy and antibody drug conjugates to shut off bypass mechanisms. We will also combine BLU-945 and BLU-701 in second and first line to provide the broadest possible EGFR coverage. Importantly, the ongoing SYMPHONY and HARMONY trials will allow us to explore these combinations across many populations, including in early line treatment beginning this year. All of this development activity sets up multiple data disclosures over the next 12-18 months. Near term, we expect initial proof of concept for BLU-945 osimertinib combination and early dose escalation data from BLU-701 in the H2 of 2022. Longer term, we expect to see expansion data sets from the SYMPHONY and HARMONY trials in 2023. These data will begin to characterize the clinical potential of multiple combinations and inform registration strategies, including opportunities for accelerated approval in area of high patient need. Altogether, the early BLU-945 data provides strong start to our comprehensive development program. Our goal is to shut down the EGFR pathway and enable combinations that transform treatment for large number of patients. We look forward to sharing additional data later this year that will continue to drive momentum for our efforts. Now, let's switch gears for a brief update on our CDK2 inhibitor. As a reminder, CDK2 is a cell cycle regulator and an important cancer target with relevance across multiple malignancies, including estrogen receptor-positive breast cancer and other CCNE1-amplified tumors. In breast cancer, CCNE1 is implicated in CDK4/6 resistance, and we see opportunities for our CDK2 inhibitor in combination with hormone therapy in previously treated patients, as well as front-line patients in combination with CDK4/6 and hormone therapy. In CCNE1-amplified tumors, including subsets of ovarian and endometrial cancers, we plan to explore biomarker-driven strategies with our CDK2 inhibitor alone and in combination with standard of care. At the AACR meeting, we will present the first preclinical data for BLU-222, which shows potent CDK2 inhibition with a potentially best-in-class selectivity profile. In addition, preclinical data in ovarian cancer model show CDK2 inhibitor was well-tolerated and highly active alone and in combination with standard of care therapies. Recently, we initiated the VELA trial, and we are actively enrolling patients in phase I dose escalation. All of us at Blueprint are incredibly enthusiastic about this program, given the strength of the underlying science and its potential to impact population of cancer patients with important medical needs. Finally, I will wrap up our prepared remarks today with a look forward to the near-term progress we expect to see across our R&D portfolio. We discussed today we expect multiple near-term inflection points, including registration-enabling data from our PIONEER trial of avapritinib in non-advanced systemic mastocytosis, proof of concept for the combination of BLU-945 and osimertinib in EGFR-mutant NSCLC, and the disclosure of multiple new research programs at our R&D Day later this year. Together, these anticipated milestones will highlight the power of our innovative research to change the course of disease and improve the lives of patients. We could not be more excited to share our progress with you in the months ahead. With that, I'll turn the call over to the operator for questions. Operator? Thank you. The first question is from the line of Mark Brunn with Cowen. Your line is open. Thanks for taking my questions, and congrats on the data here for BLU-945. Maybe just one question. The ctDNA announced on that 50 mg patient, you know, pretty powerful that the core target alterations are going down, but maybe the exon 19 struggling a little bit to match it as kind of preclinical IC50/IC90 data. At higher doses, 200 mg and so, you know, you seem to be getting very good coverage of at least everything that's L858R-driven, but not everyone's kind of starting to show PRs. Do you see evidence in the ctDNA that there's other, again, bypass mechanisms coming up there? You know, are there other kinds of explanations, maybe a subclonal disease that's, you know, has some of these other iterations that have a little bit less broad coverage? Hi, Mark. This is Becker. Thank you for the question. BLU-945 is performing as we expected it to in preclinical studies. As you noted, we have very early coverage of the triple mutation or patients whose tumors contain the T790M mutation. As we dose escalate, we're looking at the exposure in the blood. Keep in mind that the exposure in the tumor is a bit different. As we escalate even further with this well-tolerated compound, we'll be looking both at circulating tumor DNA and at additional reductions in tumor volume to understand the full breadth of activity of this compound. Okay. Then, you know, given the exposure you're seeing so far and, you know, obviously the adverse events are, you know, showing it's definitely sparing EGFR wild-type pretty well. Is there a chance that the higher doses you're actually gonna manage to cover kind of all the forms of exon 19 disease as well? Or, you know, with just monotherapy? Or, you know, are you kind of starting to get out of the linear range of exposure, so maybe that's off the table? That, that's definitely on our radar. We've been very pleased with the tolerability. One thing to remember is that these are really heavily pretreated patients, as Dr. Spigel indicated, including some patients who have been intolerant of prior EGFR TKIs. We're gonna continue to escalate, and we'll continue to look for activity against all of the mutations in the rest of the study. Okay. Thank you. Thank you, Brunn. The next question is from the line of Dane Leone with Raymond James. Your line is open. Hi. Congratulations on the data and presentation, and thank you for taking the questions. One of the key focuses I think of the data as we look at it and we have you know a question on when you're thinking about the dose escalation from here and the grade three transaminitis event you know is there anything specific to that case that makes it unlikely to have that event maybe recur again at that dose intensity which presumably would then create an MTD at the 400 mg two-day dose? Is there another way of thinking about that? Is there any kind of speculation in terms of, from what you're seeing now, whether that could be exacerbated, when you are dosing in combination with osimertinib? Dane, thank you for the question. This is Becker. With respect to LFT elevation, particularly in heavily pretreated patients, we certainly watch this and you know, things like this can be dose limiting in general. I think that you have to take the patient into consideration and I don't see this as necessarily a harbinger of things to come, but we'll continue to watch it. When we think about the combination, though, it's really on-target EGFR inhibition that we look for. That's been the case in other combinations with osimertinib that you start to hit wild type EGFR with two compounds, and that often will limit tolerability. With BLU-945, given its wide window to wild type, we're expecting this to be a much more combinable compound, both with osimertinib and other EGFR inhibitors, as well as other modalities, whether it be chemotherapy or things addressing other off-target inhibition mechanisms. We're looking for good combination tolerability there. Yeah, Dane, this is Kate. I think since we have Dr. Spigel here too, I mean, I know Dr. Spigel, you want to comment on just what you're seeing with BLU-945 in this data and your experience with combinations generally. Yeah, no, it's a good question and something we're always kind of worried about with combinations in drug development. Watching that closely, obviously a class effect in terms of seeing with other generations of TKIs, even osimertinib as you know, commercially, it's something we worry about. We bring patients back in day 14 for LFTs. Even in those situations, you can get by it. We'll have to see. I mean, we're early in the data. We're escalating. LFTs have not been an issue beyond that. But obviously we'll need to watch that closely. This is Fouad Namouni. As we are moving the development, Dane, we don't see 400 being the MTD. We just move it to 600 mg, and we continue the escalation. I think more data, more dose escalation will inform the single agent, and then when we start the combination, we'll apply the same rules. Thank you. If I could just ask one housekeeping question on the data. Do you guys know in terms of the spider plot that you presented what the evaluable patient number actually was for the EGFR exon 19 T790M and C797S triple mutants? I think people are just trying to understand the partial response within the context of what the denominator might have been for the evaluable patient population. Thank you. Yeah. Well, I mean, I'm sorry, then Becker, you can add in. I think you fully understand that, Dane, that's kind of the lens that people will look through. I mean, I think from our perspective, you know, what we didn't anticipate or aren't looking for here at this point is some type of response rate. I think we've talked about that before. I mean, we are still dose escalating, and I think what we are seeing is that, you know, BLU-945 is acting exactly as we have designed and as we hoped it would. It's that we're seeing that in the ctDNA, which shows we're hitting mutants that other therapies have not been able to hit in the past, and that we're seeing that its window over wild type is really going to allow it to be that perfect combination partner. We believe it'll be the backbone of therapy across multiple regimens, which is what we're pursuing in the expansion. I don't know, Becker, if you have anything else. Yeah, I guess the one thing I would say is that when you look at the patient, just looking at circulating tumor DNA profile is not the full picture. We're continuing to look at biopsy data and the rest of the ctDNA over time to better understand the actual profile of the patient to eventually be able to provide denominators for various populations of patients. Thank you. Congrats on the data. Thanks. Thank you, Mr. Leone. The next question is from Reni Benjamin with JMP Securities. Your line is open. Hey, good afternoon, everyone. Thanks for taking the questions and congrats on the data. I guess just starting off with the ctDNA, can you help me understand a little bit more regarding the correlation between ctDNA and response? As I look at patient number one, it looks like, you know, you've got a reduction, but patient number two seems to have a much greater reduction in the ctDNA, yet, you know, a response that's taking longer to get to the PR. I'm trying to just get, you know, more educated on that. And then also, do we have any sort of comparative data, ctDNA data with other drugs like osimertinib or any of the approved drugs out there? Yeah. Well, yeah, Becker, I'll let you comment as well. I mean, your question is what we all wanna know, right? We're trying to understand this. It's not, as you know, a part of routine clinical care at this point. It's a part of active investigation. We have seen data in other settings, like, there's been some data from Japan looking at patients with ALK rearrangements who've been on ALK inhibitors and following ctDNA and trying to assess those that have clones that disappear quickly may benefit the most. You know, there's ongoing work in the EGFR space looking at this question with academic institutions trying to understand if you start OC and you don't clear by a certain day, should you have something added to your care, like chemotherapy, for example. The bottom line is we don't know and at the moment, don't even know what day 15 means in terms of is that gonna be something that perpetuates and correlates with benefit. We do know from Charles Swanton, you know, his work that in early-stage disease, you know that if you don't get rid of the clone, those patients seem to do the worst long-term. Of course, that's a different scenario. We're not looking at response rates. You're looking at disease that you thought was removed and gone and may be at high risk for recurring. I think the science is there. It's just we'll need more prospective data to correlate. I hope it pans out because it could be a great strategy to manage patients even beyond lung cancer. This is some of the earliest work you're gonna see at any meeting. I bet you at ASCO and other meetings you'll be seeing more of this across tumor types. Becker, sorry. No, the only thing I would have to add to that is just remembering that circulating tumor DNA seeing that reduction is really necessary to have a good outcome. We'll continue to look at the tumor shrinkage to add to that data set. Terrific. Thank you for that. Just as a quick follow-up, when we think about the doses and the transaminitis that you've seen, at what point might you employ some sort of a change in the dosing regimen, maybe a BID instead of QD or any such changes? Or do you feel based on the pharmacokinetics that this, you know, it needs to be a QD dosing going forward, and you would just choose a dose? I think it's a great point. We have already built into the study the option to do BID dosing, whether it be for tolerability or area under the curve coverage for various mutations. We have the ability to explore that. We've also built in the combination. We'll look at all the permutations to find the right regimen for the next phase. Yeah. It also, you know, we're continuing to escalate, and we'll escalate both BID and single agent. We'll get a good picture of both dosing regimens. Terrific. Thanks, and congrats on the data. Thank you. Thank you, Mr. Benjamin. The next question is from the line of Brad Canino with Stifel. Your line is open. Afternoon, great suite of data here. It's really amazing to see that rationale behind and make the table of AEs for BLU-945. Yeah. Thinking forward for that, you know, you've shown good efficacy of the combination 701 and 945 in mice, and it was on slide 11. I'd also like to ask, have you learned anything pre-clinically from your models that gives you even more confidence that 945 and 701 can be combined at their predicted therapeutic doses and still maintain that EGFR wild-type sparing capability with those two drugs on board? Thank you. Becker, do you wanna take that? Yeah, I'll take that. I think, Brad, what we've learned clinically is more impactful than any pre-clinical data with respect to tolerability of the combination. You know, if you think about the fact that we saw reductions in circulating tumor DNA at 25 mg and 50 mg, and we're now at 600 mg, it gives us a really wide range to use in combination with a number of different agents in order to get coverage of all the different mutations. You may not need as high a 945 dose with 701 if you're trying to cover all of the mutations. Seeing 945 really as a backbone of a number of different therapies, I think that it provides us a large window to be able to combine. I just don't know that we're gonna have to push both drugs at the same time to close the wild type. Okay. Thank you. Congrats again. Thank you, Mr. Canino. The next question is from the line of Salveen Richter with Goldman Sachs. Your line is open. Good afternoon. Thanks for taking my question. As you're approaching the combination arms and thinking about which ones to prioritize per line setting, can you just help us understand how you're thinking about that as we look to chemo versus ADCs versus OSIs and osimertinib, and in particular with ADC, what target you're thinking about here? Thank you. Salveen, this is Fouad. When our team designed BLU-945 and BLU-701, for BLU-945, the design was really to make it the partner of choice backbone therapy with a wide therapeutic index, highly selective for a wild type, allowing combinations with multiple agents. That really give us multiple options in our development strategy. First and second one. We are looking at combination with osimertinib. We will look at combination with 701 for the on-target resistance. For the off-target resistance, as for now, we're adding combination with chemotherapy and working on adding combination with ADCs and maybe other agents in addition beyond the ADCs. Moving to first line, I really believe that's where we're going to really give our best possibilities to patients with EGFR to prolong their PFS and their overall survival. The combination of osimertinib and 945, but also 945 and 701 will have the broadest coverage and creates for patients two options to tackle the first line challenges versus osimertinib. In addition, bypass mechanism or off-target mechanism will be also explored with other combinations, including systemic chemotherapy and antibody-drug conjugates and so on. When you look at the program we have on the slide here, it's broad. A number of cohorts will really inform what we believe could bring a strong potential to really help resolving the resistance to osimertinib or to prevent it in the first line. Thank you. Thank you, Ms. Richter. The next question is from Michael Schmidt with Guggenheim. Your line is open. Hey, guys. Thanks for taking my question. I just had a follow-up on development strategy as well. You know, obviously there are a lot of opportunities to pursue these combinations and patient subsets, but just wondering how you think about, you know, areas where you could envision pursuing an accelerated approval pathway versus larger randomized studies. Thanks so much. Thank you, Mike. Great question. I would start by saying first and foremost, as Dr. Spigel talked about it, EGFR mutated non-small cell lung cancer is a devastating disease. As much as osimertinib has helped a large number of patients, at the end, seven patients out of 10 will progress and see this progressing, one-third of them probably in the brain. It is a devastating disease, and there is a high medical need for these patients. Therefore, the combination we are developing in our development plan strategy are targeting this population in the late stage where there is nothing. There could be strategies with regulatory approaches to it when the data will be available to us. Also strategies where you go with large-scale studies, like looking at progression-free survival in the front line. Our goal is to really put the pressure on the EGFR pathway from the very late stage to the very early stage and creating a potentially new standard of care by combining these agents together. Great. Thanks. Thank you, Mr. Schmidt. The next question is from the line of Yilin Yang with Jefferies. Your line is open. Thank you. I have two questions, one for Dr. David Spigel. As Blueprint Medicines is planning for the first-line combination opportunities, in order to justify combining the two drugs, whether it's going to be with the osimertinib or BLU-945 or BLU-701 or different permutations, how much does the combination have to be better than osimertinib alone in order to justify combination with the more likely a little bit more toxicity? It's a fantastic question, because as was pointed out, you know, osimertinib has been a great addition to our kind of treatment toolbox, so to speak. But it's not perfect, and so can you get higher responses? That remains to be seen. I think what the two things I'd wanna know with a combination where I would be looking forward to giving that to my patient would be, can I delay progression that's gonna be really critical for the patient, specifically in the CNS? Can I come up with a better strategy to mitigate that dreaded problem that we all experience where even systemically, patients seem to be doing well, but there's so-called, I hate the term, but failure in the brain. The second is, can I extend how long they can live without having to do something else? You know, although chemotherapy, we've made such great advances, nobody wants to be on it. No one wants to be on it. Immunotherapy is not an option. Patients see the commercials, but they really are not gonna be candidates for, you know, checkpoint inhibitors at this point. There really isn't anything. At least my patients, and I've been doing this a little bit, don't want to come off something that's been working. Can you extend what's been working? You know, I would think that a combination could outperform a single agent. We've seen that to be the case with, you know, it's a different paradigm, but if you think about melanoma and what RAF inhibition, and people forget, MEK inhibition alone worked in melanoma, but the combination is much better and actually less toxicity, which is interesting in terms of squamous skin cancers. We see in other settings too, you can rationally combine drugs without compromising safety. Yes, it's extra therapy patients have to take, but if it's gonna extend their life and prevent something like CNS failure, then I think that's something patients will wanna do and clinicians are gonna choose. We heard from physicians that CNS penetration with osimertinib is pretty good. Can you kind of give us? Yeah. What to expect for your compound? Yeah, no, it's very good. It's not perfect, but could. You know, this is tough, right, with biopsies from the tissue or, you know, somehow correlating what we're detecting in the blood with what's going on in the brain. Presumably, what's escaping in the brain is something that could have a resistant mutation that 945 addresses. You know, 945, we believe, will penetrate the brain and help address that. 701 will do that as well, and there's probably gonna be synergy there. I think that's something you'd wanna take a chance on. Great. Thank you. Then. Yeah, I had one thing to add. Sure. One thing to add to that is that if you remember that in hematologic malignancies, the depth of the response early on will impact progression free and overall survival. You know, we have a very high rate of CNS disease in this study, and the real goal is to prevent this. One way to do that is to try and kill as many of these clones as you can at the beginning. When I think of the response rate, I don't just think of the number, the percentage of patients having a response, but the depth of the response. We think that in combination, peripherally, having a deeper response could even prevent central nervous system spread in the future. That's helpful. Thank you. Then, one question to the company. As you are planning first-line various combinations, the first-line clinical trials could be pretty large and long. If this is something that Blueprint Medicines is planning to do alone or are looking for a partnership? Thank you. Hi, Yilin. This is Kate. I'll take that one. So we are well positioned to move the program forward ourselves, both in terms of resources and expertise. You know, as we showed on the slide, I mean, we're kind of with a really encouraging profile of BLU-945 as we've seen in these early clinical data. We're expanding the program as we had planned if we were to see data like this. We're in a very good position to do so. The clinical collaboration with AstraZeneca is key to that in terms of being able to move forward. Often in these types of trials, the cost of comparator is actually one of the biggest costs that we experience, and so we're in a really good spot in terms of how that is. We're expecting just kind of typical from what we've seen over the last two years, you know, moderate quarter-over-quarter growth in expenses that is predominantly driven by R&D as we expand this promising program and think about also expanding the BLU-222 program at the right time. Thank you. Thank you, Ms. Yang. The next question is from Joel Beatty with Baird. Your line is open. Hi. Thanks for taking the question. Could you discuss the activity that you saw in brain tumors and how that compares to the effect that you saw on tumors outside the brain? Are you asking about the clinical data, Joel? Yeah. Yeah, exactly. In the clinical data in the patients being presented today. The target lesions? Yeah, yeah. The patients that are described in the study were primarily following their peripheral lesions. They do follow the brain. There were some patients very early in the study that had CNS progression at the very lowest doses, but that hasn't been a feature of the patients at the higher doses. We'll continue to follow these patients as they stay on study over time to get a better sense of the CNS activity of the compound, particularly at the higher doses, where we hope to get to exposures before we hit any wild-type toxicity that could get it at higher concentrations in the brain. Got it. Thank you. Thank you, Mr. Beatty. The next question is from Andrew Berens with SVB Leerink. Your line is open. Hi. Thanks. Congrats guys on the data and the collaboration. Just a question on the Asian patient that almost responded but then developed a pleural effusion. Do we know the etiology of the effusion was a malignant in nature or related to something else? And then, just in terms of the potential drug interactions with Tagrisso, do you expect BLU-945 to change the metabolism of Tagrisso, or do you think there'd be any impact on some of the known Tagrisso side effects like QT prolongation or interstitial lung disease? Becker, do you wanna take that? Yeah. With respect to the worsening pleural effusion, we don't have any additional data on that. We don't collect pathology on those. As you know, this is pretty common in lung cancer to have malignant pleural effusions, but you never know. It's a great point. With respect to overlapping toxicities, particularly with BLU-945, we do not expect specific overlapping toxicities. I think with any tyrosine kinase inhibitor, you need to watch the QT signal, but we don't have a specific signal with BLU-945, and I don't see overlapping toxicities, and there's no indication that we're gonna have a drug-drug interaction in this program. Okay. Thanks, and congrats again. Thank you. Thank you, Mr. Berens. The next question is from Peter Lawson with Barclays. Your line is open. Great. Thanks for taking the questions. Just a couple of quick questions on the patients on study. How many patients remain on study? Remind me, is patient one and patient two, are they both on study? We're continuing to dose escalate. There are many patients that are still on study. It's interesting, we have a waiting list of about 99 patients right now. We'll be updating the progress of the patients at a future data update. Gotcha. Patient one, can that patient potentially be confirmed? In order to confirm a response, we'll need to follow up for subsequent scans, and we'll update that at a future data update. Gotcha. Okay. Thank you so much. Thanks for taking the questions. Thank you, Mr. Lawson. That concludes the question and answer session. I will now pass the conference over to Kate Haviland with any concluding remarks. Thanks everyone for taking the time to join us today. You know, it is early days in our EGFR clinical program, and we are very encouraged by what we are seeing with the BLU-945 profile as it translates from PK and ctDNA and now we get the beginnings of clinical activity. We're really looking forward to updating you again soon on this program as well as kind of all of our other programs coming over the next 12-18 months, where we'll just have a significant amount of clinical data to be able to talk to you all about. Have a great day and we'll talk to you soon. That concludes the conference call. Thank you for your participation. You may now disconnect your lines.