The company, that'd be a great place to start.
Great. Thanks, Laura. It's a real pleasure being here at this Deaf World Conference, and welcome everybody. I joined Black Diamond Therapeutics as CEO a couple of years ago. I had been on the board and joined as CEO because I have a very strong conviction that our lead program, now called Silevertinib, can really be a transformational drug for patients, not only with lung cancer, but potentially with glioblastoma as well. The history of the company, founded by Liz Buck, was that this old paradigm of one drug, one mutation could be shifted to one drug that could address multiple mutations, and in fact, whole classes of mutations, this so-called master key approach. One key undoing many locks.
That went into the design principles of Silevertinib back in 2021, as it was going through IND enabling studies, and then entered the clinic back in 2022. It has been in over 200 patients now. The drug was specifically designed to address nearly all of the important mutations in non-small cell lung cancer in the epidermal growth factor receptor, or EGFR. This is a really important oncogenic driver for lung cancer. There is a great drug that addresses the two so-called classical mutations, Osimertinib or Tagrisso. That drug does $8 billion for AstraZeneca. It falls short on a large class of what we call non-classical or atypical mutations. There are about 100 of these, where Osimertinib is not as potent. Those patients really do not have a standard of care. There has been no drug to date that has been designed to address this group of non-classical mutations.
It was very important, again, for Liz, who's been looking at the EGFR receptor since she was way back when at OSI, one of the first EGFR inhibitors, said, "I think we can actually design a molecule to address these non-classicals." The other thing we knew was that, in addition to EGFR being an oncogenic driver in lung cancer, it also is in glioblastoma. That has been a challenging area of drug development. No one's been successful in getting an EGFR inhibitor to show benefit in glioblastoma. That is largely due to either lack of brain penetrance, and I know we'll talk about that. Again, this very now different group of mutations that drive GBM were also in the design principle. All in, this drug addresses these non-classical mutations, the classical mutations, and these mutations in GBM. It doesn't hit everything.
It has selectivity on wild type, which you need for tolerability. It doesn't hit exon 20, and that's a separate class of drugs that ORIC and ArriVent have. It doesn't hit T790M.
Yeah, no, it's definitely a huge opportunity here, especially talking to KOLs. They don't really know what to do with a lot of their first-line non-small cell lung cancer patients who do have the non-classical EGFR mutations. Maybe can you just spend a little time framing what this total addressable market looks like, and typically how these patients are treated currently?
Yeah. Again, it's about a quarter of all EGFR-mutant non-small cell lung cancer. That's about 8,000-9,000 patients in the G7. There is no established standard of care. We've done some real-world analysis with Guardant linked to claims data. About 60% of patients still get chemotherapy, which is unfortunate because that doesn't really deliver much benefit. The remaining 40% are split either between afati nib, which has a label for three of these non-classical mutations, or off-label Osimertinib, which is actually in the NCCN guidelines. None of those deliver the benefit that Osimertinib Tagrisso gives to patients who have classical mutations.
Yeah. One of your competitors is focusing purely on the PACC mutations. You guys are gearing up, or you guys are planning to focus broadly on all of these non-classical. What is really the breakdown of what % of patients have PACC versus non-PACC mutations?
Yeah. Of the broad bucket of non-classical mutations, which are found throughout the EGFR, about half of those non-classicals are PACC. PACC is defined by a common structure-function cohesive grouping of all of these mutations. They share a common structure and inherent resistance to Osimertinib. The other half of non-classicals is a broad bucket. There are so-called classical-like mutations, things like atypical exon 19 deletions. There are dozens of those, and many of them, most of them, Osimertinib is not active. There is one or two where Osimertinib does have activity. This 861Q mutation is a classical-like where Osimertinib is often used with some benefit. It is a broad bucket. The Firmamertinib, the drug from ArriVent, our closest competitor, only addresses actually a subset of the PACC mutation. We are at least double the market of that drug.
In your new deck, you guys had a really nice slide really showing the limitations of current standard of care on CNS disease specifically. Maybe can you elaborate a little bit more on this?
Yeah. Yeah. These patients with non-classical mutations, it really looks like the biology of their disease is a bit different. First of all, they often present with compound mutations, more than one, probably because those oncogenes are not quite as potent as they are for the classical mutations. Also, these patients present with brain metastases in about a third of cases. They already have CNS disease when they are initially diagnosed. It is critical to have a brain penetrant compound. Afati nib, which actually is quite potent on all of the non-classical mutations and is the only approved drug for, again, a subset of them, its Achilles' heel is it has almost no brain penetrance. If you look at the data, most of the patients on afatin ib progress because of CNS disease, which is unfortunate.
Many of the patients receiving Osimertinib also progress with CNS disease. Osimertinib has some brain penetrance, but it's suboptimal. The key design principle for this drug was brain penetrance.
Yeah. So maybe getting into the design of the phase II study, you guys have already presented some data in patients who had previously been treated with a TKI. In fourth quarter, you have your first-line non-classical EGFR patients in lung cancer data. Maybe just run us through the design of that study and kind of how many patients especially we should expect for this later in the year.
Sure. Maybe I'll start with the kind of phase I development started in 2023 or 2022, sorry. We started the phase II, which was your typical dose expansion phase, phase II. That started in 2023, and we presented, as you said, last fall preliminary data for two cohorts that were focusing on patients who had progressed on Osimertinib, so so-called recurrent disease. We'll have final data from those patients in the first half of next year. That data set was important for a couple of reasons. One is it gave us an opportunity to evaluate dose and do our dose optimization work. We randomized patients to either 100 milligrams or 200 milligrams. Based on the data, and again, we presented some of those data last fall, we're moving forward with 200 milligrams. The other thing it told us is, one, we saw CNS responses.
We saw activity on a broad range of mutations. It told us that, yes, these are actionable in the recurrent setting. They should probably be more actionable in the frontline setting. We started the frontline trial first half of last year. We have now enrolled 43 patients. The 43rd patient was enrolled in July of this year. It was kind of a typical ramp for a newly diagnosed trial, kind of slow, and then a lot of patients piling in in the first half of this year as more sites opened and docs started to talk about how the drug was working. We are getting very close to having that critical six months of follow-up on most of the patients and being able to get the data out later this quarter.
What we will have and what we think is important is an overall response rate, keeping everyone the opportunity to get through at least two scans so they'll be confirmed, the opportunity for PR confirmation. We won't have a lot of time on treatment because, again, the trial just started first half of next year and finished enrolling in July. We will have another opportunity in the first half of next year to look at PFS. What we will show in this data update that's upcoming is, in addition to a waterfall plot and an ORR table, a swimmer plot and a spider plot so you can kind of see the depth of response. Also in that swimmer plot, duration, at least for those initial 20-30 patients that were enrolled last year.
Yeah. I'm assuming a big part of this data set is going to be CNS activity as well?
CNS activity, critical. Again, we expect about a third of these patients presenting with CNS disease. A subset of those will have brain lesions that can be measured per RECIST. You can actually evaluate CNS response rate. You are going to want to look at CNS progression or lack thereof and how long those CNS responses last. The other thing is mutation, patient-level mutation data. I think, again, where Firmamertinib has pretty much focused on two of these PACC mutations. There are over 100 of these. We expect to see many more than two. Many of these patients will have more than one mutation. We will break it out by those who had PACC, those who had classical-like. For every single patient, you will see what mutation they presented with.
It sounds like the exact kind of data set that investors like to see, maximum amount of information.
Yeah.
What do you guys consider to be the bar here? I believe in your deck, you said 60% ORR would be a big win here.
Yeah. We think it would be. I mean, ArriVent showed with Firmamertinib, a 68% ORR. It was, again, in 22 patients with only these really two mutations. I think 60 would clearly hit the efficacy bar. We will not get to CPFS data until the first half of next year, but there you would want to see definitely north of a year, north of 15 months even, again, with a big focus on those patients with CNS disease. Tolerability is important. This is an EGFR TKI. What we showed in the recurrent setting is quite good tolerability. We do not have non-EGFR TKI AEs. We do not have LFT elevations. We do not have QTC. We do not really have anything off target. You do see the typical EGFR TKIs, especially rash and diarrhea. Those come with the territory.
What we know is those patients in the recurrent setting tend to tolerate EGFR TKIs a little better because they've seen them already. Whereas newly diagnosed patients, those rates are higher. We will look at the data, but the expectation is that that profile on AEs will be slightly higher in the frontline setting. Still, well-managed with standard supportive care measures, no prophylaxis. For a subset of patients, a short delay between treatment or a dose reduction can be done.
Remember last year in your data set with pretreated patients, you actually had some patients whose target lesion progressed and the patient opted to stay on therapy longer. Can you maybe elaborate a little bit more on that?
Yeah, it's interesting. If you talk to lung cancer patients, many times if they have a lot of thoracic disease, they have trouble breathing. One of the things when their target lesions are shrinking is that they can breathe better. If they progress radiographically based on something happening outside of their lungs, they may still be experiencing clinical benefit from the drug. As long as the tolerability is okay, they'll continue to take the drug. Yeah. I think that speaks to, again, well-tolerated, still delivering clinical benefit, even though technically you've had a progression.
This is something that's seen in the real world with Osimertinib, correct?
100%. Yeah, it's really important that patients have an opportunity if they're deriving clinical benefit to stay on a drug. That's harder with a more toxic IV-based regimen where you have to bring a patient in and they're experiencing a high rate of AEs.
You guys have treated quite a few patients to date, right?
About 200. All in. That includes the 20, actually with the IST, almost 50 patients with GBM.
Yeah. So now thinking about regulatory path forward and what a phase III might look like, you guys have guided for some feedback in the first half of 2026. Regarding the design of a phase III, given this concern with Osimertinib not working for a lot of the mutations, afati nib not having great CNS activity, chemo being maybe the preferred use for a lot of these non-classicals, how do you guys think about what a phase III might look like?
Yeah. First, I think we've listened to the oncology division carefully over the past few years and know them well. Our development team has worked with them on other therapies. What we know is in a frontline patient population, you're going to have to ultimately look at survival. Certainly, PFS is your primary and then ultimately OS as the trial finishes. Again, frontline setting, randomized trial. That choice of comparator arm is critical. Chemo, in one way, makes sense because it's the most commonly used, but I think the agency might see it as a lower bar. Typically in later line settings, you can use chemo as your comparator arm. Afati nib is the only FDA-approved drug, so that could be a comparator arm. It could be physician's choice of chemo or afati nib.
The Firmamertinib phase III, their comparator arm is afati nib or Osimertinib, which I think is a challenging control arm. It is a relatively large trial, 480 patients so that they can potentially see a difference. That will be a conversation with the agency. It will be based on the totality of the data that we have, not just in the frontline setting, but in the recurrent setting. A key driver of that decision-making process will be PFS data that we have. Again, we will not have that until next year.
Just to be clear, you guys have said that you don't plan to have a mature duration of response either this year?
Yeah. We won't quote a DOR number because the confidence intervals will be too wide. I think people will calculate one based on the swimmer plot and they'll see duration of treatment. Yeah, it's with a little bit more than six months of median follow-up time. It's just too early.
How much do you think FDA is going to weigh safety and CNS activity as well?
CNS activity for sure. Again, we're going to really educate on the importance of CNS progression for patients with non-classical disease because it is the primary mechanism of progression for patients on afati nib and a major mechanism for patients on OC. Tolerability has got to be there. I think what's important, it's got to be manageable. Manageable either with standard supportive care measures that do not require prophylaxis or a simple dose reduction where you do not lose response or a dose interruption and then patient restarts potentially at a lower dose. As long as you are not losing response, you want to give that patient the best chance for a response, see if they tolerate it. If they do not, you have a way to manage it so that the patient can stay on therapy.
Yeah. Yeah, that's an interesting point. I believe another, I believe a new slide in your deck actually references that current standard of care maybe only has less than or equal to eight months of actual time on treatment. Is this something that you think is going to be portrayed in your data set, like trends towards time on treatment?
Yeah. Yeah, you'll definitely see on the swimmer who's still on treatment and how long some of those patients have been able to stay on.
Why is this time on treatment so low with current standard of care?
For afati nib, probably some AE component. Some could be just progression. Yeah, the PFS for any of those treatments, Osimertinib, afati nib, or chemo is suboptimal, less than 10 months.
Yeah. So you guys are pursuing partnerships for both glioblastoma and for the lung cancer side of the program. Obviously, the first-line lung cancer, non-classical EGFR market is open for the taking. It's a very attractive market. When you're thinking about partnerships, what add do you think glioblastoma might add there as well?
Yeah. Lungs, it's a bigger opportunity for sure, but it's also more competitive. It's not just ArriVent, but ADCs and bispecifics and other approaches. You definitely need a global partner. There is a higher prevalence of EGFR in Asia. Having a partner who could execute part of the trial in Asia, we think is critical. Having that partner to initiate the trial, we think would be preferable. I think GBM is quite interesting. There's literally no competition in EGFR because I think many approaches have failed. We know why. Investigators know why. There's never been a drug like Silevertinib that maybe could overcome those reasons for past failures.
I think what we want to make sure of, if and when we do a partnership, is that we're getting full value for the drug, that no one's just looking at it and saying, "This is a lung cancer drug." I think what we've seen with the IDH inhibitors and the RAF inhibitor and the drug from Chimerix, I mean, these CNS malignancies, they just have been really tough. When you can deliver benefit, I mean, it's transformative for patients. If we had that opportunity in glioblastoma, we're going to run with it.
I know investors have been more so focused on lung cancer over the last couple of years. Can you maybe highlight what you're hearing from your investigators who I believe are running an IST for your glioblastoma program?
Yeah. We certainly have been talking to that one investigator, but we also will have a small presence at SNO in a couple of weeks. We continue to talk to folks about what they're seeing based on our phase experience with the trial that we ran, potential trial designs. They love the brain penetrance. I mean, the data that we've definitively shown that you have free fraction of drug in brain tumor tissue. No one's really ever shown that with an EGFR inhibitor and this kind of broad spectrum activity, especially on variant three, which is in about 30% of all glioblastoma patients and a really tough oncogene to drug. And we have low nanomolar IC50 on variant three. So yeah, we continue to talk to investigators. We're not doing anything. We're not spending any investor capital currently. Yeah, we're sharpening the pencil on that for sure.
Absolutely. I believe you guys have kind of put the opportunity here around $2 billion plus. Can you elaborate a little bit on how you guys are getting to that number?
Yeah. So again, if you think about, I mean, one kind of crude way to do it is Osimertinib's an $8 billion drug. You take a quarter of that, it's $2 billion. But that's with AstraZeneca having marketed Osimertinib quite effectively. And look, it's a great drug. I think you arrive at the $2 billion by taking a piece of the lung and GBM and in aggregate, you get $2 billion plus.
Yeah. So now regarding cash runway, can you elaborate on what your cash runway is and what's baked in? You guys have seemingly been very disciplined with your spend over the last year, which absolutely buys you a lengthy amount of time to present data and to engage with the FDA at the right pace.
Yeah. I'm here with our Head of Finance, Ericka Jones. She's done a brilliant job managing the cash of the company and operations. We're only 21 people. We're virtual. We all know how to develop drugs. We leverage consultants very effectively. Our OpEx is de minimis compared to what we're spending in drug development. What's baked in? Initiation of a pivotal first half of next year. The burn will start to go up. When we say runway till the end of 2027, it's not like we're just sitting and waiting. We're starting to ramp first half of next year. Equally important is what's not baked in. We did a partnership with Servier. I got a $70 million upfront in March. There are meaningful development milestones in that deal that weren't fully disclosed. Can't be. Those are not baked in.
There's an opportunity for further runway extension should those milestones materialize in the near term.
Are there any specific near-term milestones, potential near-term milestones?
I can't comment, but they will be noted in queues should they materialize.
Regarding, you noted that the cash runway does make in initiating a phase III study. How are you thinking about that in regards to a partnership? Would you initiate the study independently? Would you wait for a partner?
Stay tuned.
Sounds good.
I can't answer it yet. Don't have the PFS data. I've got to let those data mature. I have to let these conversations mature. I have to keep sharpening the pencil on GBM. See what we can do, what we need a partner to do.
Absolutely. And so this data set that you have later in the quarter, should we expect this to be a press release and a company event?
Company event. Yeah. Yeah. We'll have full disclosure in a web call with KOL feedback and opportunity for Q&A.
PFS data in the first half of next year. Is this something that you would present more formally, maybe together with?
We're leaning that way. ASCO, obviously, is a critical meeting. We do have to update the recurrent setting data. We still have patients on therapy in the recurrent setting, but that'll be a final data set. The opportunity to say, "Here's 125 patients' worth of phase II data," could make for a nice presentation at a medical meeting.
We did not talk too much about that pretreated patient population in lung cancer. I think to me, one of the most interesting things about that data set when it comes to a fourth-generation TKI, and you guys are not a typical fourth-generation TKI, but you showed efficacy in the L858R patient population. I believe some competitors have failed there. That is very much so involved in compound mutations together with atypicals. How are you thinking about that data?
That's where this could be coupled for a $5 billion drug, right? If you actually look at the old Osimertinib, Flora data, it did not deliver a survival benefit in patients with L858R. The way you fix that is you give Osimertinib with chemo. This drug is more potent on L858R. And L858R, as you just said, co-expresses with these non-classicals. That's a whole, and there's a slide in our deck. That's a whole nother segment. That's a big market. Now you're talking 20,000 patients, not just eight or nine. Yeah, again, that's a big trial to run. We're not going to do a head-to-head versus Osimertinib and L858R, but.
It's definitely a strong signal to have there. Yeah. So when a patient with an L858R classical mutation gets diagnosed in first line, if they also have an atypical mutation.
They'll still get Osimertinib.
Okay. You suspect these are the patients who are kind of driving that OS curve down for the.
Partly.
Okay. How do you think, I know we're mostly focused on first-line lung and glioblastoma. We've talked about evaluation for potential partnership. In the wake of the Flora 2 data that we recently saw, where it seems like Osimertinib is going to have a strong hold in first line, what kind of feedback are you hearing? How relevant do you think a fourth-generation TKI is going to be in the pretreated lung cancer setting?
You know, the C797S opportunity is interesting. It's a very well-defined patient population. We have shown some benefit. We'll be able to update those data again next year. Maybe combination of Silevertinib with an ADC or a bispecific could be interesting in the recurrent setting. I mean, we're focused on frontline because we think that's where an oral TKI can deliver the most benefit to a patient. Yeah, I still think there's something that could be done in the recurrent setting.
When you guys update this pretreated patient population data set, it was all in one phase II . Should we expect this to come together with maybe the.
Potentially. Could be two presentations. Could be one. TBD.
Yeah. And then maybe because CNS is such a big part of the story here, can you elaborate a bit more on what you saw as far as CNS responses?
We did not have a CNS response rate because we did not have that many patients with CNS-resistant lesions. There is very clear demonstration of CNS responses in patients with disease. I think with a 43-patient frontline data set where you are going to have more than a couple, that is when we can really start to say, "Is this more than 40%?" which is what I am familiar with.
Absolutely. Anything else that you want to note as far as the upcoming catalyst?
No. No. Look forward to engaging later this year on that.
Yeah. No, it's going to be very exciting. I've been waiting a while for this. You guys have remained a little bit head down over the last year. I think there's a lot of investors out there who are really excited to see what you guys have been working on and working towards.
We're excited to present later this year. Thank you.
Of course. With that, maybe we can start taking any questions if there is any in the audience. Maybe I'll ask a couple more. Yeah. Regarding the dose selection, when you last presented data, you had just submitted a package to the FDA of the 100 milligram and 200 milligram dose. Seems like 100 is clearly the move-forward dose.
200.
200, sorry.
That's right.
What was part of the decision-making there? I know this is more of a project optimist.
Yeah. I mean, we have to satisfy project optimists. We randomized 20 patients, 100, 200. The agency had no objection to us continuing to move 200 forward. Ultimately, that'll be another conversation as we initiate the phase III because we're in a frontline patient population. We feel good about the 200 milligram dose.
Yeah. That is really all the questions I have for you. I could go on and on, but I do not want to poke you for more insight on the fourth quarter data set.
No, I cannot disclose that. Thank you.
Absolutely. I really appreciate the time today. Thanks for being here.
Great. Thank you.