Okay, thanks everyone for continuing to join us at the Stifel Healthcare Conference and joining us on the webcast. My name is Brad Canino, Senior Biotech Analyst here. Very happy to be joined for the next fireside with Black Diamond Therapeutics. We've got Mark Velleca, CEO. Mark, thanks so much for joining us.
Good morning, Brad. It's a real pleasure to be here this morning and I look forward to chatting more about Black Diamond.
Okay. To start off the conversation, can I just ask you to take stock of Black Diamond after moving through an important phase 2 data release and company restructuring in the recent period?
Sure. Yeah, it certainly has been an eventful 2024. We remain highly committed and with strong conviction in our lead program, which is BDTX-1535, the most advanced fourth generation EGFR inhibitor for patients with non-small cell lung cancer. We like the progress that we've made with that drug, and we very much appreciate the activity that this drug has across a broad spectrum of mutations for patients with non-small cell lung cancer.
And if you consider what you referenced, the recent phase two readout, which was really the first glimpse of phase two data, again, encouraged by what we saw, good tolerability, and I know we'll talk more about that, which is really important not just for patients in the recurrent setting, but for frontline patients, which is an important readout for next year. There were questions after our phase one data about dose, you know, what's your dose?
We think we've nailed the dose at 200 milligrams, and I know we'll talk about that as well, and most importantly, activity across a broad spectrum of mutations. We hit the mark as far as our response rate. We expected something in the 30%-40% range, and indeed that's what we saw. So again, remain really encouraged about that drug, high degree of conviction about what it can do for patients with non-small cell lung cancer.
Now, recognizing that we need to move that forward into a pivotal program, we need to be good stewards of investor capital and make some hard decisions, which we had to do in October, and it meant deprioritizing a program, 4933, which is a pan-RAF inhibitor. We were fortunate that that program had kind of reached a point in dose escalation that we could pause it.
We're actually seeing some encouraging activity there and tolerability and have a handful of partnering conversations. I think a good decision recognizing the competitive landscape across RAS and RAF, that that is a program that's best moved forward with a partner. What we accomplished in that restructuring was a significant extension of the runway, and in no way, shape, or form do we miss the opportunity to advance 1535. Nothing that we did in October affects our ability to execute on 1535.
Okay. And then maybe to set the stage as we go to talk about the data, can you describe the patients you enrolled into the phase 2 for 1535? Because I think that's always an important element to think about as we try to figure out what a response should be and who should respond.
Yeah, definitely an important question to set the stage who those patients are. So these are patients with EGFR mutant non-small cell lung cancer, the vast majority of which, over 90%, received osimertinib, which is the standard of care for frontline patients. So this is the recurrent setting, second line patients who just received osimertinib, but also some third line patients who also received chemotherapy.
This is also called the relapsed refractory setting because I think it's important to remember that unfortunately these patients don't do well with current standard of care. If you consider current standard of care in second line is the platinum doublet, pemetrexed plus cisplatin or carboplatin, response rates maybe 30% and durability of only five, maybe six months. In the third line, response rates only in the low teens and durability of only three or four months, and that's with a taxane-based regimen.
So again, not great options for these patients. They have accumulated mutations over many months, if not years on osimertinib. And as we'll talk about in a minute, many of those mutations have nothing to do with EGFR. However, for those that have stayed on pathway, those are the ones we enrolled, and we enrolled them into two cohorts.
One cohort was for patients who had what we call a non-classical mutation, so a mutation other than exon 19 deletion or L858R, which are the two major classical mutations for which patients are given osimertinib. And the other cohort was for patients who had the C797S resistance mutation, which is really only seen post-osimertinib. So the demogs, these are mostly older patients over 60. The ECOG status is zero to one. Again, mostly second line, but a fair number of third line patients as well.
Okay. And now you mentioned you hit the activity level that you wanted to see within the 30%-40% band. One of the questions I know you've gotten from investors is why you chose to delineate within the non-classical subgroup between two different non-classical groups as you went to produce the denominator for that efficacy analysis?
Yeah, it was really one of the learnings of the trial. So as patients progress on osimertinib, about 25% of those patients post-Osi stay on pathway. In other words, they accumulate or acquire additional EGFR mutations that are resistant to osimertinib. And those really come in kind of two flavors. One is the PACC subset of non-classical mutations. So that definition of a PACC mutation is resistant to osimertinib.
And the other is the C797S, which is a classic drug resistance mutation. So we actually had 19 of those patients in the trial. That's the 19 denominator. They either had a PACC mutation or a C797S mutation, and 42% of those patients responded. Now, as I mentioned before, the cohort design was any patient with a non-classical mutation. So we actually had some patients who just had a non-classical mutation and no either acquisition of a PACC or a C797S.
That denominator is 22. Now, those patients, what we've learned now, they were sensitive to osimertinib. It's not clear how they ultimately progressed, and we don't think any drug that was still an EGFR inhibitor would have been able to treat those patients. So that was the 22 denominator that led to the 36% response rate.
Now, going forward, again, major learning in the recurrent setting, we will focus on patients with either PACC mutations, which is a large subset of non-classicals, or C797S post-osimertinib. Frontline, all non-classicals are available to us.
Okay. And why is it that you expect these non-classical mutations that are not responsive post-Osi to be responsive to your drug in frontline?
Other drugs tell us that afatinib, furmonertinib, and we know the preclinical activity of our drug against those same mutations. So we expect those mutations to be highly sensitive when they're presented in patients in the frontline setting. Now, again, in the recurrent setting, if that's the only mutation that's there and they've already progressed post-osimertinib, they were sensitive to Osi, they now have some mechanism of resistance that's not going to respond to any EGFR inhibitor.
Now, in terms of responses, what was the longest confirmed response that you saw in the study?
At the time of the cutoff for the September update, it was nine months. It was basically one of the first patients we enrolled.
Yeah. Now, I know you got some pushback around the data being early across the cohort where there were many responses that had not yet had the opportunity to be confirmed. What's your confidence that 1535 is durable and will match that early first patient anecdote?
Yeah, I think if you look at time on treatment, most of these patients from a tolerability perspective, no problem with discontinuations. I think as far as unconfirmed responses, the expectation in the recurrent setting is that most of these will confirm. Ultimately, we need to deliver the data. I think having, and we'll talk about what's coming next, more patients, and now that we're enrolling all at 200 milligrams, the opportunity for additional patients, I think we'll put that to rest.
Okay. And then just generally in oncogene-driven lung cancers, where there's low tumor mutation burden that's off the oncogene driver, stuff like EGFR, ALK, ROS1, do you generally see these responses confirm?
Certainly in frontline. I mean, in frontline where, again, you don't have a lot of mutations accumulating, the mutation burden is low and it's really an onco-addicted tumor, nearly all of those. In the recurrent setting, it's a bit more of a mixed bag. Maybe it's not quite so many responses confirming, but certainly in frontline, nearly all should.
Okay, and now the other question that came up is, why did some of the patients remain on drug despite having a tumor scan progression?
Yeah, this is really a clinical call by the doc in consulting with the patient. So let's back up and consider RECIST criteria. RECIST criteria are there to evaluate radiographic response. Can the drug shrink the tumor? And these are target lesions that are picked out because a radiologist can measure them accurately over time. Now, patients have other disease that affects them clinically.
And when they take a drug that is shrinking their tumors, and remember the number one complaint of a lung cancer patient is they can't breathe or they have difficulty breathing or they're short of breath or they can't exercise or they can't walk because they get short of breath. If the drug is shrinking their overall tumor burden, they feel better, they can breathe, and they're tolerating the drug, right? They're not having side effects that affect their quality of life.
So if the clinician sees a target lesion increase by 20% or more, radiographically, yes, that's a progression. But if the patient's overall tumor burden remains low and they feel good and they're tolerating the drug, that patient is going to stay on the drug. So to us, that's clinical benefit, and that's often called a clinical benefit rate, either prolonged stabilization of disease or patients staying on post-progression.
Okay. Now, on the safety profile, how would you describe 1535 on a spectrum with osimertinib on one end, where sometimes that's an analogy to vitamins in terms of its safety profile, and then afatinib on the other end, which is the first generation EGFR and tends to be thought of as having a lot of toxicity associated with it?
Yeah, it's definitely more osimertinib-like than afatinib-like. And if we consider kind of the main AEs for EGFR inhibitors, it's typically rash and diarrhea. We actually see just a bit more rash than osimertinib, but actually less diarrhea. So osimertinib is high 50s, 57%, 58% of each rash and diarrhea.
We're slightly higher on rash, but lower on diarrhea and very little, if any, grade three, no grade three diarrhea for sure, and a small fraction of grade three rash. So again, slightly higher than Osi. For afatinib, the major AE that actually inhibits its use and many dose downs and discontinuations is grade three diarrhea, and we don't see any of it.
Okay. Now, you completed some Project Optimus work as well. Talk about what was done and then why those data weren't presented also as part of the data update that you disclosed recently.
Yeah, so let's talk about Project Optimus, which didn't exist a while ago, but it's something you need to do to demonstrate that you have evaluated the lowest dose. At the end of our phase 1, our end of phase 1 meeting with the agency a year ago, we told them we were going to randomize 40 patients, 20 at 100, 20 at 200, and evaluate safety and tolerability and efficacy and come back to them.
That's exactly what we did. They had no issue with us continuing to enroll only at 200 milligrams. Now, the data is not complete. We're obviously enrolling an additional 60 patients, right? We have a total of 80 patients in the recurrent setting, only 20 of which got 100 milligrams. Our goal in 2025 is to get all the data out there, including the 100 milligram cohort.
We don't think it would have served investors well to deliver a data set that wasn't mature. So we'll get all the 100 milligram and 200 milligram data out when those 80 patients have been enrolled.
Okay. And now, how many patients, maybe we'll speak to just the phase 2 portion, at the 200 milligram RP2D required a dose reduction, and what was that dose reduced to?
Yeah. So typically we've seen, and this has held up as we continue to enroll, about one in five, about 20% of patients, the doc will want to reduce. And they reduce to 150 milligrams. So we have two tablet strengths, 100 milligrams, so it's twice a day. That's the starting, sorry, two tablets a day starting dose. We also have 75 milligram tabs, so easy to dose them down to the 75 mg strength, two tablets a day. And that typically is done again for rash.
Now how do you analyze if durability is maintained or lost at the reduced dose, maybe both what you know clinically and how you think about that preclinically as well? Because I know we're trying to hit a lot of different mutations here where the exposure levels that you need can be variable.
Yeah. Well, it's interesting. When you think about a patient at 200 who is having a level of toxicity, again, usually rash, those are patients that typically are high exposers, right? I mean, you think of how small molecule drugs are metabolized by a population of people. You have some patients who get a lot of exposure and therefore they're going to get a lot of rash and therefore need to come down.
So I think on average, yeah, 150 milligrams gives you less coverage than 200. But for that actual patient that may have been a high exposure, maybe not so. To answer your question, that's what long follow-up looking at swimmer plots and spider plots could possibly tell you, that for that individual patient, did 150 milligrams actually make a difference or not as far as durability or efficacy? That's again a question that we'll be able to answer with this next update in 2025.
Okay. And maybe just to be clear, because you've touched on this through some of your answers, but what work is ongoing for the second line cohort? And what parameters do you need to reach before you come back and update investors on the data in, I think you've termed as 1Q25 as the event date?
Yeah. And we're pushing, we're trying to get enrollment essentially completed, and we're well on our way to accomplishing that. Again, 20 patients at 100 done, more than 20 at 200, total of 80 patients. So this would be of the 27 that we had that were available for a first scan of an additional 53 patients.
So sizable number of additional patients all at 200 milligrams. So the goal is to get them enrolled. I think what we learned is people want to see two scans, so we'll really push to make sure that we have two scans on all of those before we get the data out there.
Okay, and have you changed enrollment criteria as I think about the non-classical mutations, those that are going to be sensitive versus?
We have not. We have not. We certainly will for the next trial.
Okay. And now what do you hope to have in terms of regulatory alignment as well when you announce the data? And what should we assume today as a base case second line trial design for registrational purposes?
I think you always have to plan and budget for a randomized trial as a base case. And if the data is compelling enough, you may have a single arm strategy available. And we won't know that until we see the data. I think as far as what you come out of an FDA meeting with, the word reasonable is critical to see in the minutes that they think that that design is reasonable, but ultimately approval will be a review issue.
Okay. Now you also have the phase 2 frontline cohort that's been ongoing, and we expect an update on that next year. Maybe talk about the types of mutations you are enrolling into that cohort.
Yeah. So we think this is really a big opportunity for the drug, right? If you look at our ESMO presentation from October where we really, I'm sorry, mid-September, where we really talked about the wide array of different non-classical mutations that are seen in newly diagnosed patients, right? These are not just the PACC mutations, but also mutations that are elsewhere in the kinase domain or the juxtamembrane domain or indeed in the extracellular domain.
So these are all mutations that drive non-small cell lung cancer. And the other major point that we made in this presentation at ESMO is there aren't great therapies for these patients. So most of these patients still get chemotherapy, about 60%, close to 60%. And that remaining 40%, about half get osimertinib off label and the other half get afatinib. But the outcomes for all of those are not great.
Nothing is delivering anything like osimertinib does for the classical mutations. Our goal for this drug in the front line is to deliver outcomes that are much more like osimertinib for classical mutations. What we're doing there is enrolling all of those different mutations. If you consider some of our competitors that maybe aren't looking at all of those mutations, we're confident we have activity on PAC,
Other kinase domain mutations, juxtamembrane, extracellular domain, even amplification, which is not such an issue in non-small cell lung cancer, but actually could be in other tumor types. We're opening the funnel to all of those mutations.
There is a subset that we would love to enroll, but it's pretty challenging, and that's those patients who have an L858R classical mutation and a non-classical. Hard to get a doc to not give osimertinib if they have an L858R mutation, but we really do think those patients would respond well to the drug.
Yeah. Now, you mentioned the outcomes for the current standards that are used are quite poor. I guess what is that benchmark as you think about it from what this study is going to give for a comparison basis, which is ORR? But then I also think you've collected a lot of real-world data, and we've seen academia do that as well in terms of durability outcomes with these drugs for these patients. And what have you seen there?
Yeah. So durability with these other regimens clearly six, eight, maybe nine months. So you'd want to see durability of a year. And as far as response rates, definitely clearing 50, if not 60% response rates.
Okay, and now how many patients and what degree of follow-up do you need to first present this cohort to the street?
Yeah. So we've only been enrolling this trial less than nine months. We started in the spring. Again, I think we learned what investors want to see as far as two scans. So we're pushing to try and get a reasonable quanta of patients, and that's about 20 patients with two scans.
We're currently targeting Q1, but again, we want to make sure we have two scans. Time of follow-up, if we've only been starting the trial in the spring, we can't deliver a year's worth of follow-up on that timeline. So we're pushing enrollment, enrollment in the community, definitely different dynamic than in the recurrent setting, but doing everything we can to deliver those data in 2025.
Okay, and maybe talk about the balance sheet and what that allows for Black Diamond in order to prosecute both the second line and frontline development.
Yeah. Certainly enrolling, getting all of these data milestones out there in 2025, not a problem. We have cash well into the middle of 2026. And then initiating that next study and full speed ahead on that next study, whatever it may be in the recurrent setting. And that's more to come on that in 2025. And that was the purpose of the restructuring.
Okay. And now how do you calculate the market opportunity for what you're undertaking, both in the second-line setting where you've got C797S and the PAC resistance mutations, and then the first-line where you've got the broader non-classical group you're targeting?
Yeah. Yeah. We're talking about a patient population that's tens of thousands of patients across the G7, but let's break that down. So post-osimertinib, about 20% of patients we think will have either a C797S or a PAC mutation. So about 20% patients post-OC could benefit from our drug.
And again, we're looking at a DOR of about six months. And total number of patients there, about 8,000 in the G7. Now, if you look at frontline, non-classical, that's about 25-ish% of all EGFR mutant non-small cell lung cancer. So about a quarter of what the osimertinib total addressable market is.
But there, the time on therapy is much longer, obviously at least a year, if not longer. Now, that patient population in the G7 is about 20,000 with, again, longer time on treatment. The additional opportunities are this L858R opportunity, the adjuvant opportunity, the post-adjuvant opportunity.
If you take all of those together, that's an additional 40,000 patients. So remember, osimertinib is currently doing $6 billion, on its way to $8 billion. If you got a substantive fraction of that, you can clearly get to this being a $2 billion plus opportunity across those lines of therapy.
Yeah. Could you spend a minute maybe to close on the L858R opportunity? Why it is you think that 1535 does have a potential path to go head to head against osimertinib in a population that I think we all would at baseline consider does pretty well in?
You know, it does pretty well with OC, but if you actually look at the FLAURA data, there was no survival benefit with osimertinib on L858R patients versus first-gen TKIs. So they did FLAURA2, gave chemo, and then there was a survival benefit. So it's clear that OC has not as good activity on L858R, so that's one. And we have 10- to 100-fold better potency on L858R.
And then the other point, and this was also in the ESMO presentation, L858R often is seen with non-classical mutations. About 10, 15, maybe even 20% of L858R patients have another non-classical mutation that, again, typically isn't well addressed by OC. So we think head to head, this could be a better drug for patients who have an L858R mutation because of better intrinsic potency on L858R and coverage of these co-occurring non-classical mutations.
Great. Thank you, Mark, for joining us. Look forward to a very busy first half of next year.
Great. Thanks so much.