Perfect. All right, welcome everybody to our next session of the Piper Sandler Healthcare Conference. My name is Kelsey Goodwin. I'm one of the senior analysts here. With our next session, we have Black Diamond Therapeutics. With me, I have the CEO, Mark Velleca. Welcome.
Thank you, Kelsey. A real pleasure to be here with you and everyone else today listening on the webcast.
Perfect. And a very exciting time as you released data yesterday, so we'll get into that. But for those newer to the story, let's just start with a quick one- to two-minute summary of Black Diamond and where we stand kind of heading into 2026.
Sure, so we're a precision small molecule oncology company. The lead program is a fourth-generation EGFR tyrosine kinase inhibitor called Silevertinib. We released just yesterday the first data from a Phase II trial in frontline lung cancer patients. Really excited about those data and what this drug can do for patients. This drug also has potential in patients with EGFR-driven glioblastoma, and we had some news there as well yesterday that I know we'll get into. As far as 2026, as we head into what will be a very busy year, I think all eyes are on the next piece of data that will come from that Phase II trial, which is progression-free survival, and that'll be the second quarter of next year.
Perfect. All right, diving into Silevertinib, your lead asset. Walk us through what differentiates this asset mechanistically from others emerging in the class.
Yeah. So this is a true fourth-generation EGFR TKI. So there were first-generation molecules like Tarceva, second-generation like Afatinib. The EGFR inhibitor that almost everyone knows is Osimertinib/Tagrisso, a nearly $8 billion annual sales drug. A terrific drug that does a lot of benefit for lung cancer patients with what are called classical EGFR mutations. Again, terrific drug. However, there are about a quarter, as we'll get into, EGFR mutations are so-called non-classical mutations, and they don't do nearly as well on Osimertinib. So Silevertinib was designed specifically to address not just the classical mutations, but this very broad category of non-classical mutations. So that's one key feature. The other, it was designed to be brain penetrant because we recognize in lung cancer that the primary area for metastasis that leads to death is the CNS. So key design principles, broad spectrum coverage of these non-classical mutations, and CNS penetrance.
It is a true fourth-generation molecule, different chemical scaffold than drugs like Furmonertinib, which are highly related to Osimertinib and are really third-generation molecules.
Understood. On that and diving a bit into the non-classical mutations, maybe just walk us through what are they, how prevalent are they, how are they treated, what's their outcomes?
Yeah. So back 20 years ago when the first EGFR inhibitors were approved, we only knew about these two mutations that were the classical ones. Now almost everyone in lung cancer in the U.S. and indeed across the world are getting some level of next-generation sequencing. And we now appreciate there are greater than 100 of these other mutations, so-called non-classical mutations, that drive oncogenesis in lung cancer. Now those mutations are, again, not covered well by Osimertinib, though patients are prescribed Osimertinib about 1/3 of the time. Another third of patients get a drug called Afatinib, and about 1/3 of patients get chemotherapy. The outcomes with all three of those are subpar, primarily because of CNS disease. So non-classical EGFR-driven lung cancer is different than classical. More patients present with brain metastases, and more patients progress because of CNS disease.
So a tough disease, no good treatment options, and where CNS is a real issue.
Got it. And in terms of the broad spectrum of coverage that Silevertinib has, I guess, what level of proposed coverage does it have? What have we seen so far? What percent of these non-classical mutations could Silevertinib actually address?
Yeah. So it very potently inhibits the classical mutations because sometimes you see these non-classical mutations in conjunction with the classical mutation. It covers the full spectrum of non-classical mutations. We've shown this. Our collaborator, John Heymach, has showed this at AACR last year. More than 50 of these non-classical mutations, including this category of non-classicals called PACC mutation, which is about half of the non-classical group. It also hits a very important resistance mutation called C797S, which is seen in patients who have already received Tagrisso, so it has the broadest spectrum of any EGFR TKI described.
Great. Okay, really great setting the stage. Now we can dive into yesterday and the exciting update that you shared. So you presented the Phase II frontline data for Silevertinib in these non-classical mutant patients. Walk us through the key highlights of yesterday.
Yeah. So first, let's consider the trial itself. So this was a trial conducted in North America, primarily in the US, a few sites in Canada. 43 patients. And it was very much a real-world population of patients, right? These are patients that presented with 35 different non-classical mutations. So really the full spectrum of these mutations for which there are no good treatment options. More than 1/3 of them presented with brain metastases, untreated. And a good fraction of those seven patients actually had such large brain metastases that they could be measured as target lesions. So it was a real-world patient population, broad array of mutations, and extensive CNS disease. So the data. Most importantly, we set a benchmark for ourselves that this drug needed to deliver 60% response rate. We delivered.
Again, we saw it across the spectrum of non-classical mutations, not just in one class versus another. We saw very high rates of response in patients who had more than one mutation, so-called compound mutation. Way too early to talk about durability of response. In fact, it has not been reached yet. We are at 7.2 months of median follow-up time. Certainly too early for progression-free survival. That's coming in the second quarter of next year. Initial signs of durability, if you look at the swimmer and spider plots that we provided, certainly look encouraging. I think what excited us a great deal is the CNS activity. Out of the seven patients who, again, had measurable target lesions in the brain, six of them have confirmed responses. The seventh patient has had a response. We're awaiting the confirmatory scan.
That's remarkable because, again, close competitor drug Furmonertinib had a nice robust response rate, 68%, but the CNS response rate was much lower, 43%. We're at an 86% response rate, with the potential, should that seventh patient who has an initial response confirm, of 100%. This is critical because it's ultimately that is the compartment where these patients will progress. So we think this bodes well for long-term progression-free survival.
Understood. In terms of outstanding investor questions, what do you think still needs to be answered after this data set?
Yeah. I think certainly number one is durability, and again, that's coming in the second quarter medical meeting, so that will be answered definitively in the second quarter of next year. I think the other questions that came up had to do with our dose and the adverse event profile, so we can talk about that next, the AE profile. Make a couple of points. One is this was a trial done in North America, so predominantly Caucasian population in North America. Number two, it's a frontline setting, and it's well documented that patients in the frontline setting have a higher rate of AEs, typical for EGFR agents, EGFR TKIs, like rash and diarrhea, than those patients in the recurrent setting, and that's indeed what we showed because we had shared recurrent setting data last year, and indeed our AE rates were higher.
I think the other piece that investors are looking at is, again, they're looking at durability. We had many patients that required a dose reduction. It's very clear, and we showed this again on the spider plot, those dose reductions have not compromised efficacy. In fact, many of the patients did not achieve their first response until after they received a dose reduction. And most patients deepened their response after a dose reduction. Make one final point on AEs. We have five patients who continue to take Silevertinib after they've had a radiographic progression. So these are patients who have other treatment options. They have technically progressed on our study. And they could go and get Amivantamab. They could go get an ADC. They have chosen to stay on this drug because they believe they are getting clinical benefit. Their physician believes they're getting clinical benefit.
The AE profile is tolerable. I think that also speaks to, yes, there was a higher rate of AEs, but this is a tolerable profile that can be well managed.
Right, right. In terms of the frontline versus recurrent setting and why AEs might be more prevalent in frontline, maybe just walk us through the rationale there.
Yeah. I mean, again, there's published data. It's interesting. You take patients who have been on Osimertinib, which has a very nice safety profile, and then they progress and they get exposed to another EGFR TKI. So the same patient, they will report lower rates of those EGFR TKI AEs in that second-line therapy. We think that's because patients literally get tolerized to these. And again, it's mostly rash and diarrhea. And after prolonged exposure to the agent, they have less side effects.
And then you spoke to it a bit, but I guess in your view, how important is CNS activity?
We think it's critical, especially in this patient population, especially knowing it is the primary site where patients are progressing and knowing the shortcomings of other agents.
So after this update, you've guided to engaging with the FDA in the first half of next year to align on the pivotal path forward. What are your expectations for what a pivotal trial may look like?
Yeah. So PFS data is certainly going to be required for that conversation. And we look forward to having it once we have those data. We do know what, again, our competitor, ArriVent, is going to be doing with Furmonertinib. In fact, they just started that trial. It's a pretty large 500-patient trial against physician's choice of Afatinib or Osimertinib. That's a different drug. It's a third gen. The data that they've generated to date in 22 patients, primarily on two mutations. We have a much larger data set. We have a much broader spectrum of activity across 35 different mutations. And we'll see where our PFS data lands. So I think certainly some expectation for a randomized trial for sure with PFS and OS as endpoints. I think what the comparator arm is really the key wildcard here. And I can't answer that question until we see the PFS data.
Got it. Maybe just high level, when thinking about the options for the control arm, how might one versus another versus another impact how you think about how big the trial needs to be?
Well, chemo would certainly be a preferred option in that comparator arm. And I think what's interesting about chemotherapy and why it's used so often in this setting is, again, it does have activity in CNS mets. So even just including chemo in the physician's choice would be helpful. And we think would mean a higher chance for a win.
Okay. And you've obviously been open about wanting to seek a partner for this program. What kind of partner are you looking for? When might be the best time to seek a partner? And is that something that you're prioritizing ahead of this FDA meeting?
Yeah. So partnerships, that's a dialogue that takes a long time. That's why we started talking about it in August when we first started to have these conversations. What we know we need is a partner who really values what this drug can do for patients, not just with lung cancer, but also glioblastoma. So that's number one. Number two, we have to have a deal structure that rewards shareholders or preserves long-term value, especially in the U.S. And number three is timing. We don't want to do the wrong deal at the wrong time or even the right deal at the wrong time. It has to be the right deal at the right time. If that partner is by our side during the FDA discussion, great. If we have the FDA discussion first and then a partnership, that's also fine.
I think what's clear is that in lung cancer, in order to execute a large Phase III study, having a global partner, especially with a footprint in Asia, would be really helpful, but preserving the economics for shareholders is paramount.
Okay. Understood, and then I guess maybe taking a step back and looking at kind of the market opportunity longer term for Silevertinib, how do you see that in non-small cell lung cancer first before we shift gears?
Yeah. So definitely a quarter of that EGFR segment, which is pretty big, Tagrisso, is an $8 billion drug. This would be a $2 billion drug. There is opportunity in the recurrent setting, though that's quite crowded. But we do have some nice data in the recurrent setting. There is potentially an opportunity in patients who have the L858R mutation that don't do as well on Osimertinib, primarily because of co-expression of non-classical mutations. But right now, it's frontline.
Understood. Okay. And shifting gears to glioblastoma, you announced yesterday you'll be advancing Silevertinib into a Phase II trial here for patients with newly diagnosed glioblastoma. Maybe just remind us, what do we know so far about EGFR inhibitors in glioblastoma?
Yeah. So we've known for almost as long about EGFR in lung cancer as we have about EGFR as an oncogenic driver in GBM. In fact, it's a higher prevalence. About half of patients with GBM have an EGFR oncogenic driver. But we've had zero success there with EGFR agents. Why is that? It's really two reasons. Most of the TKIs, the EGFR TKIs, do not cover the mutations that drive GBM. It's a different set of mutations. The most prevalent and highly oncogenic is EGFR vIII. It's about 30% of all GBM. And drugs like Osimertinib do not inhibit EGFR vIII. The second key reason is lack of brain penetration. And this is, again, what excites us about Silevertinib. We know this drug produces dramatic CNS responses in patients with lung cancer.
If these EGFR and it's an if these EGFR alterations in GBM truly are oncogenic and actionable, we would expect to see activity because we have potent activity on the full spectrum of EGFR variants that cause GBM and high brain penetration. But the reason for all the past failures is for the lack of one of those two attributes.
Understood. And then I guess building on that, then what makes Silevertinib unique specifically for GBM?
Yeah. So again, in addition to the broad spectrum of non-classical mutations, we've documented, and it's in our updated corporate deck, potent preclinical activity on EGFR vIII and all of the other variants that are co-expressed with variant III. So very low nanomolar potency and high brain penetrant. And the brain penetrant has, I think, been more rigorously demonstrated than any other EGFR TKI, not just, again, based on the responses that we're seeing in lung. So we did a study with an investigator at the Ivy Brain Tumor Center where patients come in, and on their five days before their scheduled resection, start taking Silevertinib. Then five days later, and they take it daily, their tumor is removed, and they look in the brain tumor tissue for levels of Silevertinib. And they're not just looking in the entire tumor. They're looking at what's called non-contrast-enhanced regions.
So these are regions of the tumor where the blood-brain barrier is intact. And many times people take out a tumor and say, "Oh, the drug's there." But the drug is there in places where the blood-brain barrier is broken. And so it leaks, and you find drug there. But the tumor is growing in these non-contrast-enhanced regions. And we've rigorously shown in more than 20 patients that we exceed our target exposure in these non-contrast-enhancing regions. So I think we have a really good shot of delivering benefit to GBM patients because of that high brain penetrant.
In the recurrent GBM studies, I guess, was there any activity measured, any learnings that we had there?
Yeah. Well, certainly safety. I mean, we can give this drug safely to patients with GBM. In fact, the AE profile looks a little better for GBM patients. We saw the PK data that I just mentioned. Some patients have been on therapy a lot longer than you would expect in that setting. In that setting, you're typically off of your therapy in four or five months. We had several patients beyond six months, a couple beyond 10, and one at 16. But yeah, really hard to know because in that recurrent setting, lots of other things are happening in the tumor other than EGFR oncogenesis. So moving to the frontline setting allows us to intervene when we really think EGFR is what's driving the tumor. And hence now moving to a Phase II study in the frontline setting.
Understood. And those updates were presented at medical conferences specific to neurological oncology. So I guess, what was the feedback live from the conference? Or what have you heard from KOL since having presented this from the data generated?
Yeah, so we had a very active presence at the Society for Neuro-Oncology meeting just last month in Hawaii. We talked to just about everybody. Many of them will be on our steering committee for this Phase II trial, as well as members of the independent data monitoring committee. They love this drug because it really is potentially the first time to deliver a potent EGFR inhibitor that's brain penetrant.
Understood. And then so in terms of the Phase II trial design, I think that was the first look we saw yesterday. Maybe just walk us through the key design features, endpoints, and when we might see a first look at the data.
Yeah. So it's a randomized trial. It is in what's called the maintenance setting. So their patient journey is you have glioblastoma, you need the tumor taken out because you're typically having some behavioral or motor deficits. So the tumor comes out by a surgery. And then you get a very short course of radiation and temozolomide, so-called chemoradiation. After that, patients can be randomized to either receive temozolomide, which is standard of care, even though it delivers very limited benefit, two and a half months of OS, or they will receive temozolomide plus Silevertinib. So it'll be Silevertinib on top of TMZ. So randomized to standard of care versus standard of care plus Silevertinib.
Got it. And how many patients and when we might expect to send?
Randomize 75 to each arm. We will have an independent data monitoring committee to protect the integrity of the data across the two arms. The PFS will be by BICR, Blinded Independent Central Review, by RANO criteria. So really rigorously powered trial. The primary endpoint is PFS. We'll be able to deliver initial PFS data in the first half of 2028. The secondary endpoint is OS.
In terms of, like you said earlier, wanting to make sure you get value for non-small cell and glioblastoma in these partnership discussions, I guess, what do you think you'd need to show a partner to get them kind of on board to attribute what you think this drug should be worth for GBM?
I think it's really that Phase II data. So it is a longer time horizon, but it's something we can do ourselves. So you can think of some interesting partnership structures where maybe the partner is shouldering most of the load in lung cancer and we're running GBM. That could be a really interesting structure. But where we, again, get rewarded for good data in GBM. And what we don't want to do is a deal that's based on value in lung alone. Because if this drug works in GBM, it'd be the first approved therapy in 20 years.
Yeah. Yeah. Understood. Okay. I think we're doing great on time. Earlier this year, you licensed out your RAF inhibitor to Servier. Maybe just remind us what the next steps are there and where it stands right now.
Yeah. So that was a partnership done in March. It was an out-license. So they are really in control of the asset. We do know that it is being advanced just based on their disclosures. And you can see that in ClinicalTrials.gov. That was $70 million upfront that's given us this runway that we have until the second half of 2028. What we did disclose is there's $710 million in milestones. That's a combination of both development milestones and commercial milestones. So we have a very good chance of receiving some of those development milestones in the near term. They are not in our runway calculation. I can tell you, Servier, I like the drug very much. And I think they'll be a great partner in moving it forward.
Okay. Great. With our last minute, why don't you just remind us, cash runway? And then final thoughts heading into next year, what we have to look forward to?
Yeah. Again, Erika Jones, our head of finance with me today, has been a terrific steward of investor capital. We're 21 people. We're virtual. Every dime we spend is for patients and our clinical trials. We are really excited about what this drug can do for patients. As far as what investors can look forward to in 2026 is PFS data in the second quarter.
Perfect. Okay. Great. With that, I think we will wrap it up. Thank you so much for joining us. Thanks, everyone, for coming.
Thanks, Kelsey.