Anytime when you're ready.
Oh, perfect.
Okay.
Welcome to our next Fireside Chat. I'm Robert Burns, Managing Director and Senior Biotech Analyst at H.C. Wainwright. I'm joined today by Liz Buck, the CSO of Black Diamond Therapeutics. Liz, thank you for joining us today.
Thank you for having me.
For those who might not be familiar with Black Diamond, can you provide a brief overview of the company and its pipeline?
Yeah. We're a company focused on precision medicine in oncology. Specifically, we are developing silevertinib, a best-in-class EGFR inhibitor, a CNS-penetrant EGFR inhibitor, positioned against a broad spectrum of oncogenic EGFR mutations. Our development is focused on both non-small cell lung cancer as well as in glioblastoma. Our most recent data release was at ASCO Conference this year, where we described our frontline data for silevertinib in patients with EGFR-mutated non-small cell lung cancer, those patients presenting with what we'll describe as non-classical oncogenic driver mutations. With that positive data in hand, we are now going to the FDA for discussions on pivotal development strategy. Also in development in the setting of glioblastoma, where we initiated a phase II trial in newly diagnosed EGFR-mutated patients, just this past spring.
Yeah. When we think about the EGFR mutational landscape, obviously it sort of goes into three buckets, right? You got the classical, the exon 19, exon 21, but then you got the exon 20 insertion mutations, and then this other bucket of atypical.
Yeah
PACC sort of looped in there. Maybe provide some color for investors because obviously, the different mutational profiles here, different treatment approaches for each of those mutational profiles. It can get quite complex for an investor who's not really in the weeds with the science. Maybe talk to us a little bit about the epidemiology of these atypical mutations and how are they typically treated?
Yeah. First and foremost, in non-small cell lung cancer, there's a group of mutations which we call non-classical oncogenic driver mutations. These mutations comprise roughly a quarter of all patients newly diagnosed with EGFR-mutated non-small cell lung cancer. Now included in this bucket are groups of mutations that are sometimes in the literature referred to as atypical mutations, uncommon mutations. About half of those mutations fall into a category which is termed PACC mutations. PACC is just a subset of the full spectrum of
Yeah
Non-classical mutations. There are many additional mutations in conjunction with PACC mutations. When we consider silevertinib is active against both the classical EGFR mutations, L858R or an exon 19 deletion, in addition to this quarter of that space, which is non-classical oncogenic driver mutations. In clinical study, we have demonstrated confirmed radiographical responses in 29 unique types of those mutations.
Yeah.
The broadest spectrum that is really reported among EGFR inhibitors. The other aspect, when we consider for these mutations and what is standard of care for this patient population, I think it is important to note that these patients with non-classical oncogenic driver mutations are especially prone to brain metastasis. What we see is roughly 40% of patients at diagnosis actually present with a brain metastases, and then on progression with currently used therapies, over 80% of those patients will develop a brain metastases. What that means for patients with non-classical driver mutations is that almost every patient at some point in their disease will develop a brain metastases. Now, current therapies, there really isn't a standard of care for this.
Yeah
Patient population. Chemotherapy, osimertinib, afatinib are the most commonly used therapies, but none of them serve this patient population well at all. Afatinib has an approval in that setting, but afatinib is not brain penetrant at all. Osimertinib does not have an approval in that setting, but it does fall within the NCCN guidelines.
Yeah.
We're seeing median progression-free survival between eight and 10 months in the newly diagnosed setting. When you consider those patients with baseline brain mets, those median progression-free survival figures roughly drop in half. So median progression-free survival of only between five and six months for afatinib and osimertinib in this patient population.
Yeah.
This means with silevertinib, we have the ability to not only address the broad spectrum of non-classical driver mutations, but we can address the highest unmet medical need in that patient setting, which is treating CNS disease. If we were to deliver a median progression-free survival in the CNS patient population of 10 months or more, this would double the median PFS.
Yeah
For currently used therapies, and that would be practice changing.
Yeah, no, I completely agree with you there. You presented some data at ASCO 2026, which I found fascinating. Maybe provide a review of that dataset, walk us through, and what.
Yeah
Are some of the key takeaways associated with that dataset?
Yeah. So really excited about the oral presentation and the data we reported at ASCO. This was for our frontline cohort, which was comprised of 43 newly diagnosed cases of EGFR-mutated non-small cell lung cancer with these non-classical mutations. These patients were enrolled entirely at sites within the U.S. and Canada. We enrolled patients with a broad spectrum of oncogenic driver mutations. We actually had 33 unique non-classical mutations present in that patient population. Baseline brain mets were heavily represented in that patient population, 44%. 19 patients or 44% of that patient population with baseline brain mets. And we delivered data that really showed best-in-class potential for this molecule, confirmed overall response rate of 60%, median progression-free survival of just over 15 months. Again, that compares very favorably to what has been observed for 8- 10 months for afatinib and osimertinib.
What was really impressive about that data set is the CNS activity. Silevertinib was designed as a molecule to have best-in-class CNS penetration. This is what we thought is one of the most differentiated properties for this molecule.
Yeah.
We reported a CNS overall response rate, confirmed response rate for brain metastasis of 86%. The other important factor here is not a single patient developed a de novo brain metastases on study, which is unprecedented in a patient population where over 80% of these patients on current therapies develop brain metastasis quickly.
Yeah. No, I must say that CNS activity was surprising, but in a good way. You don't really see that level of activity for a lot of other agents, and of which there are a few that are also going into this sort of setting. Obviously, also at ASCO, we saw data for amivantamab plus lazertinib in these uncommon mutation, EGFR mutations. But we have seen also additional data from ORIC- 114.
Enzovertinib from ORIC, as well as ArriVent's furmonertinib. Considering that, as well as the compounds and combos that they're also going to be evaluating these in this subset of patients, right? A lot of it's mainly PACC, which is a smaller sliver than what you guys are going to be going after. How do you view those compounds from a competitive landscape perspective, and where do you see points of differentiation for silevertinib relative to them?
Yeah. I think there's two major points of differentiation to point out here. One is broad-spectrum coverage. We talked about the mutations which we were enrolled in our frontline cohort, 33 unique EGFR mutations. We have seen confirmed responses in 29 unique types of EGFR mutations. This is a far greater spectrum of mutations that have been described by any of our competitors. Namely, even for ArriVent with furmonertinib, they describe their frontline cohort. There are really only four different types of EGFR non-classicals represented there. ORIC has described their dataset . There were really only two non-classical mutations presented there. So they're not even describing the full subset of PACC mutations. It's a much smaller collation of mutations versus the broad spectrum that we're addressing with silevertinib.
Yeah.
The other major point of differentiation is CNS penetrance. We designed silevertinib to be the best-in-class brain-penetrant molecule. We have definitive data to demonstrate that silevertinib actually penetrates both compartments of a brain tumor that are critically important for efficacy. Those two compartments are what we call an enhancing compartment, called enhancing because even contrast agents get in there. Lots of drugs can penetrate enhancing regions. But then there's non-enhancing regions, and non-enhancing regions are those areas where the brain barrier is intact. Contrast agents don't get in there, and most drugs do not penetrate those regions. It is well established that you need to penetrate both compartments of a brain tumor for efficacy. Silevertinib is the only EGFR small molecule that has demonstrated strong penetrance into both contrast-enhanced and non-enhanced brain tumor regions.
Necessary to cover the targeted mutations. This is why we are seeing such an impressive overall response rate in our non-small cell lung cancer patients with baseline brain mets compared to our competitors. For others, even for furmonertinib, we are seeing erosion of activity for patients with baseline brain mets. They are seeing an overall response rate of 42%. That is no better than what osimertinib delivers
Yeah
In patients with baseline brain mets. You mentioned amivantamab and lazertinib, and amivantamab and lazertinib is not considered to be a brain-penetrant regimen.
Oh.
In fact, in all of the amivantamab studies, patients with untreated brain metastasis are not allowed.
Yeah.
Every patient there had to have prior treatment. They had to have radiation treatment for their brain tumor, and that was also true of patients enrolled in CHRYSALIS cohort C.
Yeah. No, I completely hear you there. One of the things I find interesting, at least, going after this sort of indication, because I know silevertinib doesn't attack the T790M mutation. Because there's really no standard of care here where they're not going to see first- or second-generation EGFR TKIs, you don't really have to worry about that issue, right?
That's right.
When we shift over, on the other hand, to the C797S population, right? Of which there are a few competitors. Talk to me a little bit about, is the lack of activity against T790M really a liability here? I want to get your thoughts there.
Mm-hmm. No. We do not believe that. T790M is a mutation that really primarily emerged following treatment with the early generation of EGFR inhibitors, Tarceva, gefitinib, and such.
Yeah.
Those agents not in use. This is not a mutation that emerges from osimertinib therapy. It's also almost never seen in the setting of non-classical mutations. It's a mutation that really pops up.
Sure
In the setting of classical EGFR mutation disease. For C797, silevertinib also covers the C797S mutation. And early on in our clinical study, we had a documented, confirmed response in patients with C797S. That was our first entry point into non-small cell lung cancer, but it is not our top focus right now.
Yeah.
It is a much smaller patient population. Those patients typically have a lot of heterogeneity in terms of other pathways going on, so durability can be an issue in that setting. We are following the setting of highest unmet need in frontline patients, which is EGFR non-classical EGFR mutations.
I completely agree with you there. I know that you're planning on receiving FDA feedback on pivotal trial design later this year.
Yeah.
When we think about it from the investor perspective, will this sort of look like what ArriVent's doing with the ALPACA trial? How are you thinking about this trial design from both primary, secondary endpoints, competitor arms, and overall enrollment size?
Yeah. We have a very different package that we're bringing to the FDA.
Okay.
First off, we're able to bring in, before the FDA, our 43 patients enrolled in the U.S. and Canada. Our profile for this molecule is also highly differentiated, and it provides us with opportunities when we consider pivotal development strategies. First and foremost, we're enrolling patients with a real-world distribution of non-classical mutations. I also want to turn our attention back to the CNS component. All patients with non-classical mutations, or almost all patients, are ultimately highly vulnerable for brain metastasis.
Okay.
The strong activity that we have seen in that setting provides us with an opportunity for an expedited pivotal development path.
Okay.
What that means is that when we look at our competitor molecules with afatinib and osimertinib, the median progression-free survival in patients with baseline brain metastasis is only five to six months. When we consider what we could deliver with silevertinib, median progression-free survival of 10 months or more would be doubling that. This would be practice-changing in that field. That could allow us to run a much smaller and faster clinical trial.
Okay.
That's an opportunity that is available for us for silevertinib that would not be potential for other competitor molecules, including furmonertinib and others, where they just see erosion of activity in patients.
Yeah
With CNS disease. We are really excited about what we can come back with later this year on our strategy with the FDA.
Yeah, no, that's definitely a potential advantage with the expedited development timeline that you could actually have here, and the fact that other players can't really operate within that space. You are going to get the FDA feedback in the fourth quarter. When do you think that you might be able to initiate this trial? What sort of timings until we see potential initial data from that trial?
Yeah. We believe we can initiate that study mid-next year.
Okay.
We are in full throttle moving forward with those discussions with the FDA and the design of what that would look like. We are not to comment on the size of that trial and what that would look like, but really excited about the potential for us to go into a study that would provide us with the fastest route to get this to patients as quickly as possible. Again, I want to emphasize that CNS patient population, greatest unmet need.
Yeah
Median PFS, five to six months. But it's not the area where we would— that's not the end of the story for silevertinib. This is where we believe that this is the best drug for all non-classical patients. Again, 25%, roughly a quarter of all patients.
Yeah
With newly diagnosed EGFR-mutated lung cancer.
Yeah. I also know that you recently initiated a phase II trial in newly diagnosed GBM.
Yeah.
Maybe talk to us a little bit about that trial design. What the sort of market opportunity looks here. When we think about from an indication prioritization standpoint, given the current resources, where do you feel like you're going to put most of your eggs in the basket, right? Are you going to prioritize GBM or the non-classical? Talk to me a little bit about that.
We are incredibly excited about both of those opportunities. I am really glad that you bring up GBM. GBM is a tumor type where roughly half of those patients carry oncogenic EGFR alterations, 7,000 patients in the U.S. alone. It has been an area that has been quite poorly understood.
There have been no good brain-penetrant EGFR inhibitors that have really been tested there. We believe, together with our investigators, that we have the right molecule with silevertinib to finally bring a good precision medicine for that tumor type. We have initiated our phase II study for silevertinib this past spring. Again, this is with in hand the incredibly strong data we have for brain penetration of this molecule in patients with glioblastoma tumors. That phase II study is a randomized study, versus temozolomide together with silevertinib in the highest unmet medical need patient population, which are those patients which have a status called MGMT unmethylated.
Meaning that those drugs perform very poorly in that sector of the patient population. This is designed not as a pivotal study. It has median progression-free survival as the endpoint would read out in 2028. This is a study that has an interim analysis that is monitored by an IDMC, and if at that interim analysis the data are compelling, this could permit a pivot to a study with overall survival as the endpoint and could be pivotal at that point. Again, this is an exciting opportunity for us in the setting of GBM as well.
Assuming that interim PFS analysis is compelling enough, would you have to also increase the sample size for that secondary endpoint, OS, which would then move to a primary endpoint?
Yeah. This is all dependent on what that interim analysis. But again, I want to just remark that this is not initially designed as a pivotal study, but there is potential for that also to be a registrational study, again, monitored by the IDMC.
Okay. Since we are running up on time now, maybe walk us through the clinical catalysts that investors should be paying attention to over the next 12- 18 months. What was your cash on hand as of end 2Q, and what sort of a runway does that provide?
Okay. End Q2 this year, we were at just over $110 million. This provides runway for us through 2028. This allows us to fully execute on the GBM program, which we have outlined. We have important catalysts coming up, even this year. This is feedback from the FDA on our pivotal development strategy in non-small cell lung cancer, frontline non-small cell lung cancer. We are really excited about the prospects for rapid development in that sector of space. You will hear from us updated data from that frontline study as well.
Awesome. I really look forward to it. Thank you so much, Liz, for joining us today.
Thank you.