All right. I am here with Black Diamond Therapeutics CEO, Mark. Mark, anything new today?
Lots new today. Really great to be here at the Stifel conference after disclosing new data from our phase II trial and a really positive outcome from our end-of-phase II meeting with the FDA. I will enjoy chatting with you for the next 30 minutes. Maybe I will just start real quickly with about silevertinib and what it is.
Yeah, absolutely. Want to summarize the update that you guys gave today and the drug, and then briefly, and then we can get more into Q&A as well.
Sure. silevertinib is what we believe a best-in-class fourth-generation EGFR TKI. I think everyone here knows the drug TAGRISSO, osimertinib, which treats about three-quarters of EGFR mutant non-small cell lung cancer patients quite well. Obviously, that drug does very well for AstraZeneca. I think what we've learned in the space, in the EGFR mutant non-small cell lung cancer space, especially over the last three or four years, is that while EGFR TKIs can control disease very well in the thorax in lung cancer, most of these patients progress in the brain. Many of these patients present with brain metastases. There's something about EGFR mutant non-small cell lung cancer where it likes to go to the brain, and that's ultimately when patients progress on therapy, even with drugs like osimertinib. Our drug was designed from the get-go to be highly brain penetrant, and it is.
We believe it is the most brain penetrant of any EGFR TKI. It also addresses not only these classical mutations that TAGRISSO goes after, but this other quarter of EGFR mutations, which is over 50 of them. They're often called atypical or uncommon, rare, but as a group, they're actually 25% of the population. Our drug very potently targets all of them, all 50+ of those, unlike osimertinib, which does not have potent activity. We've been developing this drug for the last two years in this frontline patient population. It's a phase II trial, 43 patients, conducted primarily in the U.S., a few sites in Canada.
We had an oral presentation at ASCO, and today we have now data, mature data, that I think we'll get into, that led to a highly positive end-of-phase II meeting with the FDA, where we now have a very clear path to accelerated approval, and capturing that entire non-classical mutation population.
I think, perhaps as an Analyst, one of the most exciting parts for me about that was that we no longer have to break down all the atypicals into all these rigorously defined little subgroups. It seems like if you don't have a classical mutation, if you don't have an exon 20 mutation, you can be enrolled in this trial.
That's right, and I think there's been some confusion. Our Chief Medical Officer, and he said this in our call this morning, calls it alphabet soup of mutations because there's so many of them. If you think about a prescribing physician, they get the NGS report. The first page says you have a classical mutation, L858R exon 19 del. Every doc knows what to do with that. You prescribe osimertinib. Exon 20 insertions, definitely some more treatment options like RYBREVANT. Then they get to the second page, and there's this laundry list of mutations, and they don't have a drug. There are a couple of competitors that are developing drugs in this space. They're focusing on a subset of those mutations called PACC, and that is confusing too, because what's PACC, what's not?
Our definition, agreed to by the FDA, is any mutation that's not a classical mutation or an exon 20 insertion. Home run.
Makes it a lot easier.
Makes it a lot easier to enroll a trial, because all these patients are getting NGS testing. It's like, "Oh, you don't have a TAGRISSO mutation? Come onto the trial." As a prescribing physician, ultimately, in the label, very easy to understand.
As far as the phase III, in addition to having this broad group of EGFR mutant lung, you are focusing in on patients with brain metastases. Unlike some of the competitors that you just referred to, you guys have discussed with the FDA potential for an accelerated approval path based on CNS ORR. Competitors are focusing on systemic ORR. Can you speak to the de-risking involved with using a CNS ORR relative to systemic?
Yeah. We can talk about why we are so confident that we can win in that patient population and still cover patients without brain metastases with this novel design. First, let us talk about CNS ORR as an endpoint. It has been used for many primary CNS tumors. It is actually, while it is not in the indication statement for tucatinib, it is a breast cancer drug, they do use CNS ORR for, is it in the label? The FDA issued guidance in 2020 for CNS active drugs. There are separate criteria to evaluate CNS ORR called RANO-BM. It is a more stringent criteria than RECIST, which is used for systemic ORR. That is kind of the regulatory backdrop.
So we walk into the agency, we have treated over 200 patients with this drug, 43 of them in the frontline setting. We have a CNS ORR by RANO-BM of 86%. 86%.
Can you contextualize that?
What is that?
Can you contextualize that?
Well, for afatinib and osimertinib, which are the only drugs available for these patients, it's in the mid-30s a t best. And those datasets come from patients who have had, some of them, prior radiation. Our patients at 86% came from patients who did not have radiation.
Yeah.
You walk in with that kind of data combined with PFS data that's now 16 months maturity. We have median follow-up of 16 months. Our PFS in that patient population is 12.2 months. The PFS for afatinib and osimertinib, again, recent published data, big study just published on osimertinib out of Memorial Sloan Kettering, hundreds of patients. The PFS is 5.1 months for osimertinib.
Yeah.
5.1 months. We're at 12.2. It's very simple. Accelerated approval on CNS ORR, full approval on PFS. There's your benchmarks. You're twice both of them. You can run a relatively small trial, 300 patients, randomized one-to-one, physician's choice. We're ready to go.
Can you speak to powering, like what kind of delta you think you'll need to hit on the CNS ORR, and also if you can comment on the PFS endpoint at this point as well?
So, I can definitely. I won't get into super details. I will tell you that we talked at length with the agency in this end-of-phase II meeting about trial design, powering, number of patients, alpha spend. Nominal alpha will be spent on the CNS ORR endpoint.
We believe it's adequately powered to pick up a difference of about 35 points. Even if we come down into the 70s and those controls go up to 40, adequately powered. What's really interesting in this trial and completely different than the trial that our competitors, systemic ORR only has to be similar.
Yeah.
No statistical comparison. As long as you're similar, which means your confidence intervals overlap with systemic ORR, that's fine. Now for PFS, again, we're at 12.2. Very recent data with osimertinib, which included patients who had radiation, which our patients won't.
Yeah.
They're at 5.1. Afatinib's at 6.1. So, even with somehow that control gets a little better, we're not quite as good. Even though our 12.2 isn't mature, our upper bound is still NE. So that 12.2 might get bigger. We're confident we're more than adequately powered for PFS with 300 patients, 1-to-1.
Can you speak to the control arm? I think afatinib is pretty broadly believed to be not super CNS active. Osimertinib, yes, but not necessarily in this population.
Yeah.
What kind of conversations did you have with the FDA regarding the selection of this control arm?
Yeah. So, the FDA does believe, and it's true, it's the only drug labeled for these non-classical mutations, right? Osimertinib is widely used in the U.S., because it has NCCN guidelines for those three mutations that afatinib has. So this will be a global trial.
Yeah.
We have about 40 sites, about 30 sites in the U.S., another bunch in Canada. Most of the docs in the U.S. will keep osimertinib, and most of the sites in the U.S. will be osimertinib. Some use afatinib, but it'll be a global trial. So certainly in Canada, Mexico, Brazil, Eastern Europe, Singapore, Taiwan, big parts of China, afatinib is widely used.
Yeah.
Some pockets in Western Europe, again, more osimertinib. So a global trial, I think a good mix of afatinib and osimertinib, and the agency did suggest, again, we use both of those, because if you think about global usage, there is both afatinib and osimertinib.
As far as dose of the control arm TKIs, does it have to be by labeled dose?
Yes.
Okay.
Labeled dose. Yep.
Okay.
Yep.
Another, I think, big thing investors were looking for in this disclosure that you guys had was dose for the phase III.
Yeah.
There had been some concern that maybe 150 mg, the FDA would make you run a lead-in trial for, but it seems like you guys came to pretty good terms on this.
Very good terms.
Can you speak to the discussion?
Yeah.
Yeah.
Yeah. I'll speak about the discussion and kind of also the dataset that we had walking into that meeting. The AEs that we had at 200 mg, and the amount of dose reductions were a bit high, right?
You'd want to see in a frontline patient population a lower rate of initial AEs. Now, what's clear is that these AEs were all EGFR mediated, right? Nothing new. It's rash, diarrhea, mostly. With dose reductions, they come down immediately. You give standard supportive care that patients on osimertinib and afatinib get. Nothing alarming about the AEs, but the rate of dose reductions was relatively high. We went to the agency and showed them 200 patients' worth of exposure- response data from our phase I, where we went all the way from 50 to 300, to dose optimization that we did in the recurrent setting. Showed them that we had CNS response data at 100 mg. Showed them that the median dose intensity from this 43-patient trial was 126 mg. When we suggested 150 as the dose for the pivotal, they said, "Makes sense.
We accept your justification, but we do need to see some data starting at 150." We've actually been enrolling at 150 since August, and we will bring them sufficient number. They didn't say, "Has to be this number with this much follow-up." Just bring us sufficient data, safety data to show that you're dropping that dose reduction.
Okay.
We're very confident we'll be able to do that without impairing the timeline for phase III initiation, which is expected in the second quarter.
Do you guys plan on, to the investment community, disclosing that?
I think what we'll do is, when we announce FPI-
we'll say, "Here's an updated safety cut," and then at a medical meeting in the second half of the year, show all of the data. But to, again, what the FDA wants us to do is check the box. You've shown us some safety data at 150. It's better than at 200 as documented by the rate of dose reductions, which happens in the first six weeks, so not a lot of follow-up.
Yeah.
Then disclose the data at a medical meeting.
To be clear, there's no specific requirements the FDA want. They're not going to be looking at efficacy.
No.
They're not going to be looking for a reduction in any specific AEs.
Sufficient amount of safety data primarily focused on rate of dose reduction.
How quickly do you think you can get that to the FDA and then move into the initiation of the phase III trial?
Both in the second quarter.
Okay. Got it. Also today, you guys disclosed that this phase III will also have a single arm, a cohort for patients without brain metastases, and you believe that you can almost follow the precedence of osimertinib and rely on NCCN Compendia to support utilization there in the real world.
Yeah.
Can you speak a little bit more to the strategy and thoughts the FDA gave as far as feedback there?
Yeah. We didn't specifically speak about the potential for approval in single arm for because they know that they want to see randomized data especially for PFS. What we did say is, "Look, we want to have a one-trial approach.
The umbrella is if you have a non-classical, if you do not have a classical mutation or exon 20 insertion, you are in the trial. We know that at least 40%, maybe more, are going to have brain mets. They are going in the randomized portion. If you do not, you come onto this single-arm cohort. It is 80 patients. Our PFS in the 24 patients of phase II data that we have in that patient population is currently at 23.5 months. Not a single one of those patients in 16 months has developed a brain metastasis. That is unheard of. We did talk to the agency about that, and again, it is not a label discussion now. Could it be when you have the data? Maybe. At a minimum, we believe it will allow for NCCN inclusion.
For a doc who is looking at a drug that can control CNS disease as well as this drug, we think it is going to be very straightforward for them to make the choice to prescribe silevertinib in all of their non-classical patients if they have reimbursement based on NCCN.
The data that you showed breaking out PFS earlier today by brain mets versus non-brain mets almost makes all the cross-trial PFS comparisons that we've been doing over the last couple years a little silly, to be honest, now that I think about it. How do you kind of think about that moving forward as you think about positioning of your drug and how important maybe it is to consider that baseline characteristic when doing these cross-trial comparisons?
Well, I think it's so interesting, right? Because EGFR mutant non-small cell lung cancer, it's a different disease. It has this propensity to go to the brain, and we have really good drugs like TAGRISSO, but again, this recent publication, it's very clear that there's still significant unmet medical need, and it's all due to CNS progression. The way that patients are managed now is they have to get radiation, which has significant sequelae. If docs have an option that can spare the patient radiation and live longer because again, the data from that paper, half those patients had radiation. They still only had a five-month progression-free survival.
Can we actually dive into that a little bit more?
Yeah.
I think, you're kind of thinking about expectations for performance of osimertinib in your control arm without radiation there. What should we expect?
Well, again, 5.1 is based on 44 patients of data from Sloan Kettering following these patients, half of whom had radiation. The PFS was five months. In our trial, they're not going to have had radiation. I think it's hard to assume that it's going to go up.
Again, I think we're more than adequately powered for PFS.
And in the 43 patients, or in your data set had patients, what percent of patients, or I guess how many patients had not had prior radiation?
None of them had prior radiation. None of them. And we are at 12.2.
Yeah.
So again, I think it is more than adequately powered. I think when you double PFS in a patient population, that is clinically meaningful to patients.
Because osimertinib in classical mutations is kind of the gold standard for EGFR, can you remind us how in the FLAURA trial osimertinib did in patients with brain mets versus patients without brain mets?
Yeah. So, for us, in patients with non-classical mutations, no brain mets, we're at 23.5 months. In the FLAURA study, now again, in the FLAURA study, they allowed radiation.
Right? In classical mutations without brain, it was 19 months. So, we're at 23 and a half, they were at 19.
So, as far as changing of the paradigm and not needing radiation to get this big type of PFS, how do you think about new enrollment in your trial in the context of, will docs want to give radiation just because that's what they know works best with osimertinib?
Yeah. Well, we've gotten that question a lot from investors, like, "Well, is this going to complicate trial enrollment? Aren't the docs going to want to reflexively do radiation?" This is where you really understand the specifics. If a patient has a symptomatic brain lesion where you can go in and irradiate, let's say they're having a seizure, they can irradiate that lesion, and they are almost certainly going to have other lesions, they can still go on the trial.
Okay.
Because you can count those other lesions as target lesions.
And the radiated lesion, because you got to do what's right for the patient, right?
Yeah.
You are never going to jeopardize the patient's wellbeing. You are going to treat it if it is symptomatic. They can still be eligible. That is the other interesting thing, reading this recent publication. When these patients present, it is typically with more than one lesion, and that one lesion that is symptomatic can be irradiated, and they are still on the trial. So you can have both.
Yeah. That 23+ month PFS that you guys showed, were you guys, in the patients without baseline brain mets, were you guys actively surveilling for brain mets?
Oh, yeah. Yeah. I am glad you asked that too. You cannot detect things if you are not looking for them. We look every six weeks. So every six weeks, patients are getting a surveillance MRI. So at 23 and a half months, a single patient has, we have seen, or at 16 months median follow-up, 23.5 months PFS, not a single patient have we seen brain mets. That is with every six-week surveillance. Not always done in every other trial. And again, competitor trials, not always done.
And maybe getting a little ahead of things, because I know OS hasn't. You just need to show non-inferiority on OS in the phase III, correct?
Actually, no detriment.
No detriment.
Non-inferiority is a big statistical hurdle. No detriment.
Okay. Even easier.
Yep.
But in the phase II trial, you did see meaningful amounts of treat beyond progression.
Yeah.
Is this, by protocol, going to be allowed in the phase III trial? Is this something that you think would be reflected in the real world?
I don't know the specific answer to the protocol since Sergey's not sitting next to me, so I don't want to answer it wrong. We do think it has real-world impact. Again, because if patients are experiencing clinical benefit, they should continue to take this drug. If they've had a radiographic progression in the thorax that's not symptomatic and their brain disease is under control I think most of those patients will decide to stay on the drug, and that will have meaningful OS implications.
Yeah. Why did the FDA agree to no detriment? That seems very unlike the FDA, especially in lung cancer.
Because they know we have a great drug with great CNS activity. We need to adhere to their guidelines. CNS ORR is in the guidelines for a brain-active drug. PFS is clearly in the guidelines for lung cancer showings.
Statistically improvement in PFS will give us full approval.
Can you speak to the data disclosures that you guys will have coming for this phase III trial?
Yeah. For the phase III, we'll have the cohort four data that we mentioned next year. There are two, the open-label cohort we spoke about. Interestingly, the agency said, "You have this brain-active drug, leptomeningeal disease patients, these are patients really with the worst prognosis.
You should run a small cohort there because there's a high unmet need. We're running a small-
For those who are less familiar with this indication, can you-
Yeah. Leptomeningeal disease is, these are so your CNS, your brain, spinal cord's covered in meninges, and when patients have what's called leptomeningeal disease, there's small studded metastases throughout. It's almost like the brain is encased in a metastasis sheet.
It's a miserable prognosis. It's two, three, at best four or five months PFS. No good treatments.
Yeah.
Could this drug give benefit to those patients?
The FDA brought it up to you? You didn't bring it up?
They brought it up to us. They said, "You should really consider doing this." We're like, "Okay, so we're going to enroll it." That trial will read out preliminary.
The open-label non-CNS will read out 28, and the CNS ORR in 29.
Okay.
We also have a GBM trial, and we have six minutes left. We can talk about GBM if you want.
Yeah. Just last.
We're fireside, so.
Last question on CNS ORR. For the accelerated approval endpoint, the catalyst you're guiding to in 2029, can you speak to what percent of the, would all patients have to be enrolled? Would there have to be a certain amount of tolerability?
All patients would be enrolled, but we expect that at that time of final patient enrollment, we will have the data we need to go to the agency.
Okay.
Yep.
Glioblastoma.
Yeah. This is a drug that has best-in-class brain activity. We have known for 20 years that half of patients with glioblastoma have an EGFR alteration. They are different than the EGFR alterations you see in non-small cell lung cancer. And there is also EGFR amplification, which is very different, and it is seen in colorectal cancer and head and neck cancer. Again, silevertinib was designed at the get-go to potently target those EGFR alterations in glioblastoma and is the only EGFR TKI to potently inhibit EGFR amplification. So we did a phase I study in glioblastoma, recurrent glioblastoma, very tough to treat. We saw a response. We saw some prolonged stabilization of disease, decent tolerability.
So we started this phase II trial. We had this window of opportunity data, knowing that the drug gets into the brain really well. And we have gone through the safety run-in. Not surprisingly, the dose is 150. We are combining it with the standard of care, temozolomide, the last drug to be approved for glioblastoma 21 years ago. It is silevertinib plus temozolomide versus temozolomide alone. It is a randomized phase II trial, governed by an IDMC, an independent data monitoring committee. The company is now blinded. Now, that IDMC is tasked with looking at an interim PFS endpoint. If that PFS endpoint is positive, they will say, "That endpoint is positive," and we will then convert the trial to a phase III with OS as the endpoint. We will have that interim PFS data in the first half of 2028.
Got it.
That's a call option, if you will, on the investment. We all know how tough GBM is to treat. Every reason an EGFR inhibitor has failed, silevertinib addresses. Brain penetrance, potency on the mutations, paradoxical activation. We are not a paradoxical activator.
Can you speak to TAM of the population you're going after?
Yeah. It's almost 50,000 patients globally with an EGFR mutation in GBM. It's, yeah. And the unmet need, there's no higher in oncology.
Yeah.
There's no higher in oncology.
And as far as cash runway, what is baked in?
Yeah. So what is baked in is certainly the GBM trial, getting the lung trial started.
But we will need additional capital to get through those approval endpoints. And my job is to bring that capital so that we can get this drug to patients, and I am confident that we can, whether that is through dilutive or non-dilutive sources.
Mm-hmm. There is also a meaningful ex-U.S. market here. Are partnerships potentially on the table as well?
Certainly in the mix to talk about ex-U.S. rights.
For the phase III in lung cancer, you noted that this was a global trial. Were you guys already initiating activities outside of the U.S. and Canadian sites you are involved in?
We are. Certain things you have to do in Japan for example, to stand up a trial. Well underway. We were busy at ESMO talking to international investigators from Singapore, Taiwan, China, Western and Eastern Europe, South America.
Mm-hmm. As far as manufacturing, drug supply, is everything ready to go?
Not an issue. Registration batches made, stability done. We've done our radiolabeled study
in healthy volunteers. So all of the kind of ADME work that you I mean, this is truly a phase III, big pharma phase III-ready program.
Yeah. Have you guys received more engagement maybe from strategics since
I think just like investors, people want to know whether the FDA is with you or against you. So we're really pleased the FDA is with us.
Very much so. Seems like it.
Yeah.
On the 150 mg dose, considering this isn't something that you originally investigated in the phase II trial, was this like a new pill that you had to formulate?
No. Great question. The pill strengths are 100 and 75.
The 200 mg dose was 100, two pills. The step down was two 75s. Now we start with two 75s. We can go to 150, or sorry, to 100, single 100, then we can even go to 75.
Okay.
We had patients go all the way down to 75 from 200. But again, we haven't lost any efficacy.
Yeah.
None.
Yeah. You guys even saw some deepening of responses after dose reduction.
Deepening of responses after dose reduction. Those dose reductions happen in the first four to six weeks.
What dose are you guys using in the glioblastoma trial?
150.
Okay.
Yeah. That was the safety run-in. A nice concordance there be tween what's going to be two 75 mg tablets.
Great. We're just about out of time. We have another minute if there's anything else that you want to say that has gone unsaid.
Not at all.
We covered a lot.
Not at all. Thank you, Laura. It was really great to be here on an important day for Black Diamond, and more importantly, I think an important day for patients with non-small cell lung cancer with brain metastases.
Absolutely. We appreciate you guys being here. It's, I know, a very busy day for you guys.
Yeah. Thank you.
Of course.
All right.