Hello, everyone. My name is Farzin Haque, one of the biotech analysts at Jefferies. It's my pleasure to introduce Mark Velleca, CEO of Black Diamond Therapeutics. This is a Fireside Chat format. Thank you for joining us today, Mark. Maybe to start off, can you provide a quick overview of the company and then we'll dig into the specifics of the recent update at ASCO? Yeah, thanks, Farzin. It's a real pleasure to be with all of you here today and those joining via webcast. We're a precision small molecule oncology company. Our lead program is called silevertinib. It's a potential first and best-in-class fourth generation EGFR inhibitor that's in a phase II trial for patients with non-small cell lung cancer and also glioblastoma. We are just coming from ASCO where we had two presentations, an oral presentation on Saturday, really exciting data in the frontline setting in patients with lung cancer, then a poster on Sunday of patients in the recurrent setting. Look forward to talking about those data. Maybe to start off, what is the addressable patient population in the U.S. for these non-classical EGFR mutation settings? Yeah. We all know EGFR is a major oncogenic driver for patients with non-small cell lung cancer. In this country, in the U.S., there are about 10,000 patients a year who have one of these non-classical mutations. If you consider all EGFR mutations, most of them are the two classical mutations that are addressed by the drug osimertinib, an $8 billion drug on its way to $10 billion. There's about a quarter of patients, this 25%, who have one of these non-classical mutations. This is a group of upwards of 50 to 60 distinct mutations all falling into this group of non-classical mutations for which there is no standard of care, and their outcomes is much worse than those patients with classical mutations who get osimertinib. Short answer, about 10,000 patients in the U.S., about 25% of the market. More importantly, what proportion of these patients have brain mets at baseline? Also, what proportion of patients have compound mutations that is more than one non-classical mutation? Yeah, these patients with non-classical mutations, they're different than the patients with the two known oncogenic drivers that those patients get osimertinib. They're more smokers. There are more patients that have more than one mutation, these so-called compound mutations, a little more than a third, and many more patients who have brain metastases at diagnosis. Typically, in patients with classical mutations, it's about 20%. For non-classical patients, it's about 40%. A substantial fraction with CNS disease at diagnosis in the metastatic setting. Your ASCO update showed a very nice preliminary median PFS of 15.2 months. That's in the frontline setting. How do you contextualize this against historical data? That's something that's a reference point for existing therapies. Yeah. I mentioned there really is no existing standard of care. If you think about a physician encountering one of these patients where they get the sequencing report and everyone in this country gets some level of next-generation sequencing at diagnosis. They see one of these non-classical mutations, they don't know what to do. Many patients get chemotherapy, about a half. The other half are split between afatinib, which is a drug that has a label for three of the more than 50 non-classical mutations, but only three, or osimertinib, which is given off-label. It is included in the NCCN guidelines for those three mutations, but it's given off-label. The outcomes for those patients are anywhere from six to at best 11 months. Six months for chemo, eight, nine, 10, maybe 11 months, depending on the published study. There have been numerous published studies over the last three or four years where interest in these non-classical mutations has picked up. That's in contrast to what you see with patients with classical mutations where you see PFS in the 14–20-month range. Here we are at 15.2 months. Important to realize more than half of the patients are still on therapy. It's a 43-patient data set. The median time of follow-up is only 11.2 months, and we're already at 15.2 months PFS. Given that, and I know we'll get into this, the CNS activity of the drug, we think this is a number that could get substantially longer. You reported 60% objective response rate across 43 patients and those with 33 distinct non-classically different mutations, including the compound and PACC mutations. Can you elaborate on responses seen across the mutation subtypes like the PACC versus ectodomain versus kinase domain, like do you see consistency? We do. This non-classical group or bucket has distinct structure function categories. The PACC class is well known. It's about half of the non-classical group, and it's characterized by resistance to osimertinib. There are mutations, as you mentioned, in the kinase domain and the ectodomain, and also these compound mutations, more than one. We see consistency anywhere from high 50% response rates to low 70% response rates across all of those distinct categories, giving us this average of 60% ORR. That's a RECIST 1.1 ORR, all confirmed across the ITT population of 43, and that's a number that has not changed since our top-line disclosure in December. Nice. 53% of the patients remain on therapy, like 23 out of 43, and the longest is at 23.5 months. One of the key questions is basically, given the dose reductions that you had to implement during the trial, what proportion of these patients who reduced the dose either maintained or deepened their responses? How does this inform your conviction on the 150 mgs go-forward dose? Yeah, we did have a substantial fraction of patients requiring dose reduction, and I know we'll get into the safety profile in a moment. What we know is this dose reduction from 200 mg to 150 mg, and then some patients down to 100 mg, has not sacrificed depth or durability of response. It has not sacrificed depth of durability or response. We know the average response for these patients is in the first cycle when they get their first response. The deepest response is at seven months, and most of these dose reductions are happening in the first cycle. Again, deepening of response after dose reduction. The fact that 23 patients remain on drug, more than half, also speaks to the durability that we're seeing at these lower doses. We're also sitting on over 200 patients' worth of data. This went into our phase I dose escalation trial. We have 83 patients of phase II data in the recurrent setting. We have a mountain of PK data coupled with PK response efficacy exposure data to really understand the PK profile of the drug. It's very well-behaved. It's dose linear. We know that when you go from 100 mg to 200 mg, you see an increase in AEs. You see a slight uptick in efficacy, you see efficacy at 100 mg starting doses in the recurrent setting. We have a very strong conviction, given the dose linearity of the PK, how well-behaved the molecule is, that we'll see this efficacy at 150 mg, potentially even better when you think about durability. You also disclosed the ctDNA, the allele frequency reductions, across 25 unique non-classical mutations. This PD effect, how should we think about the significance in the context of durability? Have you observed any correlation between the depth of the ctDNA reduction and the PFS benefit? It's interesting coming out of ASCO again, because this started to be a topic three, four years ago when people started to look at ctDNA correlations with PFS. It actually looks like ctDNA reduction could be a better indicator of progression-free survival than radiographic responses. We're really encouraged to see in every evaluable patient with ctDNA, we saw substantial reduction of variant allele frequency, complete clearance in more than 80% of those patients. To your point, have we looked on a per-patient basis? It's a pretty small data set, and most of them completely cleared, and most of our patients are still swimming. We do think it bodes well for, again, potentially longer PFS than we've put out in this preliminary release. Makes sense. Now the exciting part. The CNS mets part, you showed CNS responses of 86% and the observation that no patients, again, no patients, developed de novo brain mets. That's perhaps the most striking finding at the ASCO's data set. With 11.2 months of median follow-up, is it too early, or can you make definitive claims about CNS prevention? Yeah, it is the most striking finding of the data set. When we talk to KOLs and investigators, and we talked to over 30 over the past two weeks with this data set, they're all struck by the CNS activity. The 86% confirmed RANO-BM response rate in patients with measurable brain lesions, and not a single patient developing de novo brain mets on therapy. To put it into context again, about 40% of these patients will be diagnosed at time of diagnosis with baseline brain mets. If you look at currently available therapies, many of those patients will progress through the CNS. Patients getting afatinib, for example, if you look at them after they have progressed, 85% of them will have progressed through the CNS. Why is this important? It's obviously important for frontline patients for long-term survival. It is critical if you're thinking about using this therapy in the adjuvant setting, which is an enormous opportunity to benefit patients. We know osimertinib is now being used in the adjuvant setting, a label for three years that is now patients are on therapy three, four, five years. Where do these patients break through when they're given adjuvant therapy? The CNS. The lack of any de novo brain metastasis, we think bodes well for long-term overall survival in this frontline setting and opens up a really large opportunity to benefit patients in the adjuvant setting. Can you potentially use this as a, well, it's too early to tell, but as a novel co-primary or key secondary endpoint in the pivotal trial? I think for pivotal development, it does point to this area of significant unmet medical need. Again, in talking to docs over the past couple of weeks, they all have patients with CNS disease, and other than the radiologist giving radiation, they don't really have anything to adequately treat them. If they had a systemic therapy to both shrink the existing mets and prevent new ones, they would use it. As far as trial design, you could focus on those patients with highest unmet medical need, i.e., those with brain metastases. You could, to your point, look at CNS progression. I want to point out the PFS numbers that I gave for osimertinib and afatinib, eight, nine, 10, maybe 11 months, they're in half for those patients with CNS disease. Patients with baseline brain mets getting afatinib or osimertinib, three recently published studies, five or six months PFS. If that's the patient population go after, you double that PFS, it's a huge win for those patients. What has been the feedback at ASCO on the data set? The CNS progression and then have they said anything about what the phase III should potentially target? Do you have a streamlined path, like the KOLs are thinking that you should get a faster path to approval, or should it be something different? Again, given the unmet need and the lack of any therapies out there, any kind of existing standard of care, the feedback's been very positive on the data set. We've gotten valuable input on the pivotal plans that we've put in front of those investigators under CDA. We've gotten really positive feedback that we can get this drug to market quite quickly by focusing on those distinct patient populations with the highest unmet need, where the endpoint would happen, again, quickly if you focus on patients with just CNS disease at baseline, or if you focus on certain mutation classes like PACC, where there's considerable resistance to osimertinib. Coming back to the safety, a key debate point. Your Grade 3 AE profile, you had a decline to 28%, you had a nice column showing basically low rates of rash, diarrhea, and all of that. These patients, what gives the confidence that starting 150 mg QD can preserve the CNS and systemic efficacy while basically the same as the 200 mg starting dose? Yeah, again, it's knowing this drug really well based on 200 patients' worth of data. We've obviously been working with clinical pharmacology team, PK team. We understand the dose linearity that we see in going from a 100 mg starting dose to a 200 mg starting dose. You literally can draw a straight line with an R-squared of one, you can point to the middle, and you can see that you cover very well the mutations that we need to cover, and that you spare wild-type EGFR, and therefore will see better safety. Remember, in the recurrent setting, we saw confirmed responses across many mutations at 100 mg starting dose. Going down to 150 mg, we do not think will compromise response rate. It actually could benefit patients because you'll see fewer dose holidays and interruptions and reductions. The AE profile, most of them are on target and like rash, diarrhea, paresthesia, stomatitis. How does this compare to the approved third-generation TKIs? I don't think investors realize that osimertinib in phase III, they showed 34% Grade 3s. Even lazertinib, that one had the 240 mgs go forward dose in the pivotal. That one has 21% Grade 3, including non-EGFR related QT prolongation. First, we only see EGFR mediated AEs. We don't have QTc, we don't have any liver signal. The rate of Grade 3 or greater AEs, as you mentioned, is 28% after dose reduction. We expect to see something similar, something in the low 30s when we start at 150 mg, which would be identical to what osimertinib showed in FLAURA, 34%. We need to demonstrate that at 150 mg, and we will. As far as dacomitinib, clearly has QTc liver signal, as well as EGFR mediated toxicities. On the discontinuation rate, you had 14%, so six out of 43 due to AEs. What was the nature of this discontinuation, the types of AEs, and were they early or late events that led to the discontinuation? Just to clarify. Yeah, they were early and they were EGFR mediated, things like rash and diarrhea. Got it. The key question that people are waiting for is basically regulatory clarity. You're going to meet with the FDA later in this year and discuss the pivotal development path. What are the key open questions that still needs to be addressed, specifically around the feasibility of accelerated path and the selection of the comparator arm? Yeah. Our goal again, is to get the therapy to patients as quickly as possible. We have the data set in hand to request the meeting, which we will do shortly. We expect that meeting to happen in the third quarter. We'll be able to give feedback early fourth quarter. That meeting will be focused, again, on finding the fastest path. We have a couple of strategies. I can't really comment on specifics other than to say they will focus on patients with the highest unmet medical need, and those fall into basically two categories. Those patients with CNS disease at diagnosis, where again, PFS outcomes are five, six months on standard of care. That's potentially one trial. Could be randomized, would address Project FrontRunner. There is potential a single arm path as well in patients with PACC mutations, which are known to be resistant to osimertinib and response rates in the 30s. It could be actually a combination of two smaller trials that would give us an accelerated path and obviously a full approval based on a randomized trial. Is there any reason to believe it could be as large as the FURVENT study, or could it be more streamlined? We definitely think it could be more streamlined because it's a very different drug. It has two distinct differentiation advantages to FURVENT. Remember, FURVENT is a third-generation drug given at 3x the dose of its approved dose for classical mutations. They're doing a 480-patient randomized phase III with PFS as the endpoint. Our drug hits a very broad spectrum of non-classical mutations. Their drug, they've only shown data really in two mutations. We've seen data in dozens of mutations. Their drug does not have the CNS activity that ours does. They've seen an erosion of CNS activity. Their response rate is 60-ish%. Their CNS response rate is low 40s. Our response rate is 60%, our CNS is 86. That affords us these pathways that could accelerate the approval of the drug that aren't available, or were not available to ArriVen t with. We also saw changes, updated OS data at ASCO, so amivantamab plus lazertinib. Maybe talk about how does that inform your path as well? Yeah. Ami laz, it's approved in patients with exon 20 insertions. They show this data, this so-called CHRYSALIS trial, Cohort C, which is focused on these uncommon or atypical mutations, as they call non-classicals. Response rate, I think, was 58%, so certainly in line with ours. I think what was generating some chatter was, wow, the overall survival was 3+ years. A couple important things to remember. One, all those patients with CNS disease, they had to have had prior treatment. They did not allow patients with untreated brain mets onto that trial. I don't think most people realize that. That tells you something about the lack of CNS activity of that regimen. Number two, 70% rate of Grade 3 AEs. It's a cumbersome IV, soon to be sub-Q regimen, not getting good uptake in patients with classical mutations. I don't expect it will get good uptake in patients with non-classical mutations, and it is not a regimen that will ever get moved into the adjuvant setting. Right. That's the key distinction. It does tell you that basically, if you think broadly, if you have a CNS-penetrant drug, you should do better than three-plus years. We really look forward to presenting OS data. Stay tuned. May not come until a while. Yeah. Certainly not until later next year. Yes, we think the fact that there are patients who are still on therapy post-progression because they feel well. While they may have had a radiographic progression, they're still on drug. If you look at the swimmer plot, they're still on drug. I think that bodes really well for overall survival. In the last few minutes, I also want to talk about the glioma program. You're on track to start a phase II randomized control trial. What is the bar for success, and what would you need to convert the phase II into a potential registration study? Yeah. Really tough disease. We recognize that people have tried to drug EGFR before and failed, primarily because they didn't have a brain-penetrant drug, which we do, or a drug with broad-spectrum activity, which we do. We're going into the newly diagnosed patients right after they've had their surgery and their chemoradiation. They get randomized to silevertinib plus standard of care, which is temozolomide versus temozolomide. Trial's started. We've already enrolled the first cohort. What's the bar? PFS in that population is about, unfortunately, six months. Should we show three, four-month improvement, we would certainly take those data to the agency. While it is a randomized phase II trial, it's PFS by BICR. It's monitored by an IDMC, so it has all the features of a trial that could be converted to a registrational trial. You talked about potential partnering. Actually, by the way, when should we see the data? First half of 2028. Okay, it's relatively near-term. You have both these programs running in parallel. You have talked about potentially partnering for moving these assets into phase III. What is the current status, and what capabilities would an ideal partner bring? Yeah, we certainly were busy at ASCO talking to potential partners as well. I'll just say we're in a position to run this pivotal study on our own. We always want to find the lowest cost of capital while preserving long-term shareholder value to execute that pivotal study. A partner who can bring a global footprint and could execute part of the trial in Asia could be helpful. Ultimately, we need to preserve long-term shareholder value and do the best deal for all stakeholders. If you were to move this trial on your own, how much would a reasonably sized phase III cost? I think everyone can do their per-patient cost. I won't comment until we have specific feedback from FDA. We think this is something we can certainly execute with a reasonable capital raise. What is your cash position and the key catalyst that investors should focus in the next six months? Actually, you might have a data update in the second half. Maybe also talk about that. Yeah. We ended the first quarter with $118 million. I think people should realize we're 18 people. We're a virtual lean team. Every dollar we spend is in clinical development. What are the key catalysts? We have cash until the second half of 2028, so it funds the GBM trial. We do need to raise and/or partner for the pivotal in lung. Key catalyst is FDA feedback. What is that design? What are the capital requirements? More data in lung coming in the fourth quarter. Initial OS data potentially late 2027, and then the GBM piece coming in first half of 2028. The OS data is from this currently non-sponsor like I said? Correct. Yeah, I guess certainly could be coming second half of 2027. Cool. Thank you so much for your time. Thank you, Farzin. Thanks to everyone. Thank you. Thank you so much.