Good afternoon, and thank you for standing by. Welcome to the Black Diamond silevertinib phase II update webcast. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask the question during the session, you will need to press star one one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. Please be advised that today's webcast is being recorded. I would now like to hand the presentation over to your first speaker today, Mark Velleca, CEO of Black Diamond Therapeutics. Mark, please go ahead.
Good afternoon and welcome to our webcast. I'm joined today by Sergey Yurasov, Chief Medical Officer, and Liz Buck, Chief Scientific Officer. After our presentation, there will be time for questions. Today, we are excited to present compelling results from our phase II trial of silevertinib in frontline patients with non-small cell lung cancer. These data, demonstrating the robust progression-free survival delivered by silevertinib for patients with EGFR Non-Classical Mutations, will be presented at the ASCO annual meeting on May 30th by Dr. Julia Rotow of the Dana-Farber Cancer Institute. Before we proceed, I'd like to remind you that we will be making forward-looking statements. There is a high unmet medical need for non-small cell lung cancer patients presenting with EGFR Non-Classical Mutations, or NCMs. NCMs are sometimes also referred to as atypical or uncommon EGFR mutations.
As shown in the pie chart on the left, real-world sequencing data from over 11,000 cases of newly diagnosed EGFR mutant non-small cell lung cancer demonstrate the presence of Non-Classical Mutations in approximately one-quarter of the treatment-naive patient population. EGFR NCMs can be grouped into distinct structure-function categories. One subgroup of NCMs is PACC mutations, which are present in about half of all NCM patients and are often co-expressed with other Non-Classical Mutations. As shown on the right, patients with EGFR NCMs are most commonly treated with the EGFR TKIs afatinib or osimertinib, or with chemotherapy. None of these treatments work well in EGFR NCM patients, with progression-free survival of only 5-11 months. A therapy that delivers a median PFS of 15 months or greater for this patient population could be practice-changing. Currently available EGFR TKIs perform poorly in EGFR NCM patients for two reasons.
First, lack of potency across the full spectrum of EGFR mutations. EGFR NCMs comprise a broad spectrum of more than 50 unique mutations, which are commonly present as compound mutations. That is, more than one mutation found in the same tumor. Broad-spectrum potency is critical for delivering durable benefit to patients. The second reason that current-generation TKIs fail is suboptimal CNS penetrance. Non-small cell lung cancer patients with EGFR NCMs are highly vulnerable to CNS metastases, with approximately 40% of patients presenting with brain metastases at diagnosis and with CNS metastases being a major mechanism of disease progression while on therapy. As our data across phase I and phase II trials have demonstrated, silevertinib delivers robust clinical activity against a broad spectrum of mutations and shows remarkable results in treating CNS metastases.
Before I turn the presentation over to Sergey, I want to highlight the key takeaways from this phase II data set. We report a confirmed objective response rate of 60% and a CNS response rate of 86%, which has not changed since our disclosure in December. We now report a preliminary median PFS of 15.2 months. Median duration of response has not been reached. Importantly, more than half of patients remained on therapy, with the longest approaching two years. Remarkably, no patients have developed de novo brain metastases. Finally, we report a manageable and dose-dependent tolerability profile. These results demonstrate the practice-changing potential of silevertinib for the treatment of frontline non-small cell lung cancer patients with EGFR NCMs. I will now turn it over to our Chief Medical Officer, Dr. Sergey Yurasov, to present these exciting data.
Thank you, Mark. The data we're discussing today is from cohort 3 of our phase II study of silevertinib, which enrolled treatment-naive non-small cell lung cancer patients with EGFR Non-Classical Mutations or NCMs. Patients were enrolled based upon detection of an EGFR NCM by a local NGS test. Patients with asymptomatic brain metastases were allowed, and patients were required to undergo CNS surveillance by MRI while on study. Efficacy endpoints included objective response rate, or ORR, by RECIST 1.1 criteria and progression-free survival or PFS. All patients were treated with silevertinib at a daily dose of 200 mg based upon data obtained in the recurrent setting. At the time of an April 11th data cut, the median follow-up time was 11.2 months. Cohort 3 enrolled 43 patients, all of whom were treated at site in the U.S. and Canada. 74% of patients were Caucasian, and 16% of patients were Asian.
Importantly, patient demographics for this cohort reflect that seen in clinical practice. 44% of patients presented with baseline brain metastases, the majority of which were untreated. Seven of these patients presented with untreated and measurable brain metastases that could be assessed for response rate by RANO-BM criteria. Patients presented with 33 unique Non-Classical Mutations, including PACC and classical-like NCMs. More than a third of patients presented with compound NCMs. Let's start with looking at overall response rate. The waterfall plot shown here demonstrates that 26 of 43 patients achieved a confirmed radiographical response by RECIST 1.1 criteria for an ORR of 60%, which is consistent with our December data presentation. 25 patients experienced a confirmed partial response, and one patient experienced a confirmed complete response. As mentioned earlier, this patient population presented with a diverse spectrum of NCMs, which is what is expected in a real-world setting.
Approximately half of patients presented with PACC mutations. More than a third of patients presented with compound mutations. Responses were observed across all mutation subclasses, with the ORR ranging from 56%-73%. The disease control rate is over 90%. On this slide, you can see that silevertinib delivered robust pharmacodynamic responses as evidenced by clearance of variant allele frequency of VAF in all evaluable patients across 25 unique mutations. These data further support the potential best-in-class clinical activity we are seeing with silevertinib in patients harboring a broad spectrum of EGFR NCMs, including PACC. Let's turn our attention to durability for this frontline patient population. As shown on this swim plot, more than half of patients remain on therapy, the longest at 23 and a half months. It is evident that silevertinib delivers durable benefit across all mutation subtypes, including PACC.
Next, we will review Kaplan-Meier plots of progression-free survival, or PFS, and duration of response, or DOR. As shown on the Kaplan-Meier curve on the left, the preliminary median PFS is 15.2 months, which represents a 40% improvement over currently available therapies for these patients based on historical data. The Kaplan-Meier curve on the right demonstrates that median duration of response, or DOR, has not yet been reached. We know that patients with EGFR NCMs frequently progress through CNS metastasis, so it is striking that no patient in this study developed de novo brain metastasis. We believe that the robust CNS activity of silevertinib could drive long-term survival benefit for all patients. Next, we will look at updated tolerability data for silevertinib. The tolerability profile for silevertinib is consistent with other EGFR TKIs, primarily rash, diarrhea, paronychia, and stomatitis, with these managed by supportive care and dose reductions.
All patients received a starting dose of 200 mg daily. The majority of patients underwent dose reduction to 150 mg or 100 mg, with a median dose intensity of 134 mg daily. With dose reduction, the rate of Grade 3 or greater adverse events was reduced by half to 30%, consistent with silevertinib's dose linear exposure and tolerability. Dose reduction did not compromise clinical activity, and patients maintained or deepened their response after dose reduction. The totality of this data support 150 mg dose for our pivotal trial. As Mark mentioned earlier, silevertinib is highly brain penetrant, and in this trial we observed compelling CNS activity. Six of seven patients with untreated and measurable brain metastases showed a confirmed CNS response according to RANO-BM criteria for a CNS ORR of 86%.
These responses were observed across a range of EGFR NCMs, including four patients with PACC mutations and three patients with compound mutations. The majority of CNS patients underwent dose reductions, and we see deepening of CNS response for all patients following dose reduction. This is demonstrated by the dark blue bars showing radiographic nadirs seen at the 200 mg dose, and in the orange bars, even deeper radiographic nadirs that were measured after patients with dose reduced. Deep and durable responses, combined with an improved tolerability profile, give us confidence that 150 mg dose will deliver optimal efficacy and safety in the pivotal trial. To summarize, the phase II data presented today demonstrate the practice-changing potential of silevertinib to benefit non-small cell lung cancer patients with EGFR Non-Classical Mutations. This data shows silevertinib outperforming the historical benchmark for osimertinib and afatinib by more than 40%.
Silevertinib effectively addresses a major vulnerability for EGFR NCMs patients, which is the high incidence of brain metastasis at baseline and higher rates of CNS progression. Therefore, we are thrilled to see the high CNS response rate and that not a single patient has developed de novo brain metastasis while on silevertinib. This data bodes well for overall survival in all patients, including those with PACC mutations. With robust durability data in hand, we look forward to a productive conversation with the FDA on a pivotal development plan for this promising drug. Thank you for your time today. We look forward to Julia Rotow's presentation of this data and engagement with the oncology community at the upcoming ASCO annual meeting on May 30th.
Thank you, Sergey, for that presentation. That concludes our prepared remarks. Operator, please open the line for questions.
Thank you. Ladies and gentlemen, as a reminder to ask the question, please press star one one on your telephone, then wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Laura Prendergast with Stifel. Your line is open.
Hey, guys. Congrats on the exciting update. Could you speak to the adversities that you're seeing after dose reduction? It seems like not much has been added to that table since the last update, but assuming what we're seeing, a lot of it was driven by the 200 mg. If you could kind of provide any commentary on what patient quality of life is like on the reduced dose, that would be great.
Yeah, sure thing, Laura. Sergey?
Yes, thank you, Laura, for your question. The most common adverse events are rash, diarrhea, paronychia and stomatitis, which what is known for all EGFR TKIs. To your question about quality of life, that would really matter, particularly in the frontline setting, and that's why I think it's really important to recognize how many patients are still ongoing and that we have a number of patients that chose to continue on study drug beyond progression. I think overall, with a dose reduction and supportive care, that is a well-established part of practice. We're confident that progression-free survival in this patient population, if anything, will get stronger.
Yeah. The overall AEs on the table on the right, they all went down with dose reduction, which explains why the overall rate of Grade 3 AEs is now 28% after dose reduction.
Do patients see alleviation of some of the most common AEs upon those dose reductions?
The most common adverse events leading to dose reduction?
No, did they see alleviation of the-
Oh, yes, absolutely. The good news about the profile of the drug, that it's a very linear relationship between the dose and the frequency of adverse events, as Mark just mentioned, we're seeing a decrease approximately in half across all of those events.
Just regarding how you think about the dose for phase III, would there be a lead-in required to confirm this, or do you think it's possible that you could run the phase III with a reduced dose?
I think with the totality of this data, and we now treated more than 200 patients with this drug, we think that 150 mg dose will present with an optimal risk-benefit profile for frontline setting. Of course, ultimately this has to be discussed and agreed upon with the FDA. I think what is important in the other part of this is that we know that these patients continue to maintain durable responses. The choice of 150, I think, is a very solid proposal at this point based on the totality of exposure response analysis.
Got it. Thanks, guys. Congrats on the update.
Thank you. Our next question comes from the line of Farzin Haque with Jefferies.
Hi. Congrats on the progress, and thank you for taking my question. Just also a follow-up on the safety. What proportion of the patients that experienced Grade 3 stayed on therapy? Are they resolved, or they still are experiencing those events?
Yeah. Let me start with the end of it, with the last part of your question. Yes. All the adverse events are actually successfully managed through dose reduction and supporting measures. The definition of successful management is that they get reduced to Grade 1 typically or disappear altogether. That's the answer to your second part. The first part, there are six patients who discontinued study treatment due to an adverse event. The proportion overall is quite small.
Got it. On the regulatory front, with this great PFS data in hand, what will be the kind of conversation you'll have with the FDA? Could there be an accelerated approval path in play, and how big the study and comparator arm needs to be? Because you have a broad mutation coverage, right?
Correct. I think that's where I would like to start, that if we go back to that pie chart that Mark presented, we have a very good chance to provide substantial improvement in care for 25% of EGFR-positive patients, so the entire cohort of NCM patients. The path there is always subject to negotiation with the FDA. PACC is half of those patients and well-defined and well understood by the FDA as one of the highest challenges among the NCMs. I think the end game for this drug is to be able to cover the entire quarter of EGFR-positive space.
Got it. Could there be an accelerated path or potentially?
I think we really look forward to bringing these data to the agency. Stay tuned.
Okay. Thank you so much.
Thank you. Our next question comes from the line of Marc Frahm with TD Cowen. Your line is open.
Hi. Yes, thanks for taking my questions. Just a follow-up on a couple of the earlier questions. I completely understand, yeah, there's a pretty broad safety experience across this. Can you just talk to how many people and what total exposure time you have at that 150 mg dose, when you look across the various cohorts that have been enrolled? On the idea of maybe some accelerated path, would there be some potential to maybe split up the EGFR population that you're trying to address into maybe smaller portions, some of which might require a randomized trial, while maybe others might be more amenable to single-arm approvals?
Let me start with the second part of your question. There is definitely an opportunity to discuss that. Right? PACC is a structure function-defined subgroup that the FDA recognized, and certainly considering how poor the outcomes are for currently available therapies, it's definitely worth raising a question of accelerated approval path. Again, ultimately, I don't want to lose the sight of the total prize of providing new therapy for the entire NCM population. Going back to your exposure question, which is very important, I think absolutely relevant. We're presenting now data in the frontline setting that is approaching a 12-month follow-up. The median time to dose reduction that we actually shared back in December is approximately two and a half months.
What you're looking at is a very, as I would call it, stable, quote unquote, data set with exposure with the median dose intensity that is listed there at 134, that gives us confidence that the 150 mg dose is the sweet spot, not because of the response rate that we knew the response rate back six months ago, but because actually of a progression-free survival now as we watch these patients for 12 months. The progression-free survival for this population is still preliminary because I think to get to maturity, we will probably need another five, six months to get to 50% of events, and I think it will get stronger as we go there.
I think the other point, Sergey, you mentioned time to the dose reduction, maybe the time to the deepest response after the dose reduction.
Thank you. That actually is I should have brought it right there. The median time to dose reduction is approximately two and a half months. The median time to nadir that patients achieve is approximately six and a half months. That to us really seals the deal that 150 mg dose that most of these patients are staying actually for now for long period of time after dose reduction is efficacious. Maybe I should use cautious to the word efficacious, but to individual patients, it delivers benefit.
Okay. That is very helpful. Maybe to that idea that the PFS may get even stronger with more follow-up, just can you speak to when you'd like to talk to the FDA? Do you think you want to use this data or is there value to maybe wait for the PFS to get a little bit more mature and maybe have even more compelling arguments to make?
We reached a point which everyone would expect on durability at least 12 months observation. We have it today. That is a good trigger start to have a productive conversation with the agency. That, as Mark pointed out, is exactly our plan ahead. I don't think we need to wait for extra three or four, five, six months, as I mentioned, because if we look at the benchmark on afatinib, which is approved for three mutations, it's 11 months. If we look at a benchmark on progression-free survival for osimertinib for the same mutations, it's nine months. We're coming in with a 15 months with a 12 months follow-up. I think the data is mature for productive conversation.
Yeah. As you know, Marc, I'll say here on the call, we have not requested the meeting yet. It starts a clock when we do, and there's plenty of additional time there, and you can certainly bring data that would be a few months from now to the agency for that conversation. We definitely feel the data in hand is strong enough to request the meeting, put the package together, and then, yeah, bring data that's freshly updated at the time of the meeting.
Okay. Thank you.
Thank you. Our next question comes from the line of Kelsey Goodwin with Piper Sandler. Your line is open.
Hey, thanks for taking our questions. Congrats on this update. Going back to the breadth of Non-Classical Mutations that are included in this study, could you remind us how this trial compares to key competitor trials in terms of the number of distinct Non-Classical Mutations that you enrolled? I guess in this context, how do you think the 15.2-month PFS compares to key competitors? Thank you.
Liz?
Yeah. I'll take the first part of that question. This is really a unique trial in the frontline setting in that we enrolled patients who presented with such a broad group of mutations. We had patients presenting with 33 unique Non-Classical Mutations, and that really differentiates from the majority of our competitor that we see who really have run trials where just very narrow focus with one or two unique Non-Classical Mutations. I think the thing that excites us so much about this data, we're seeing confirmed responses across patients representing a diverse number of these mutations. That includes systemic response as well as brain response.
Maybe I can now tackle your first part, which is how it compares to other potential competition in the field.
Yeah, pharma.
I can start with the furmonertinib, which is probably what you have in mind, and I think it's really apples and oranges, right? When we look at the furmonertinib data that we have available today and presented at World Conference on Lung Cancer and published recently, they had a 22-patient cohort of treatment-naive patients that had 77% of patients were coming from Asia, and the mutation spectrum there was really limited to 719 and 768, with few patients who had couple other mutations. The other important piece there is baseline CNS disease. We have 44% of our patients with baseline CNS disease. They have 32%. Again, it has a tremendous impact on survival. When we look at the CNS ORR rate that furmonertinib reported, it's 43% versus our 86%. I think their number of PFS was 16. Our number is 15.2.
Their duration of follow-up at that point was 16 months, so that PFS was mature. It's not likely to get better. Our PFS is 15.2 months with 11.2 months follow-up. I think our PFS has a decent chance of actually getting stronger as we follow these patients longer. That's the pharma piece.
For the hour.
Yeah.
Yeah. If that answered your question, Kelsey, we can probably squeeze in one or two more.
Thank you.
Kelsey, I guess you're good? Okay.
All set. Thank you.
Our next question comes from the line of Robert Driscoll with Wedbush Securities. Your line is open.
Great. Thanks, guys, and congrats on the update here. Maybe just on the CNS activity, obviously some very impressive data in the RANO evaluable patients. Anything to say in the patients with those brain metastases that weren't RANO evaluable? Just kind of broadly, how often would patients scan here for those CNS metastases? Thanks.
I can certainly address it. It's a major part of patient population with Non-Classical Mutations. As we mentioned in the introduction, we present here real-world experience in North America. We know that it's 40% of patients will have brain metastases as a baseline. That's one piece. What we also know from historical data that was published for osimertinib and afatinib, those patients with CNS disease have dramatically worse outcomes. Which brings me to the real importance of this current data set. When we see no emergence of de novo metastasis after 12 months of a follow-up, I think it will have a direct positive impact on progression-free survival. When we see an 86% response rate, including four patients with PACC mutations, that's the highest hurdle to beat. We got there. Also those nadir bars are very informing as well.
If you look at the Swimmer, you can see in the last row or column of the table to the left how many patients had CNS, and you can see how many patients are still swimming who have CNS lesions that weren't target lesions.
Okay. Yep. See that now. Yep. Thank you.
I think we have time for one more.
Our final question comes from the line of Sean McCutcheon with Raymond James. Your line is open.
Hey, guys. Thanks for the question, and congrats on the data. Maybe just high-level thoughts on some phase III study design considerations. Can you speak to the strategic advantage of enriching for and powering for pulling out a statistical signal of CNS benefit in the phase III study, and then any high-level commentary on how you're thinking about potential possibilities for a comparator arm? Thanks.
I think we have to reserve those remarks or that answer specifically until we've spoken to the agency. Sergey did answer this in a previous question. We'll definitely want to look at potential subset analyses, pre-specified of course, that could represent accelerated opportunity paths. Whether that's CNS or certain mutation groups. Comparator arm, I think, yeah, we're very different than furmonertinib, so I think that is a very open question.
Understood. Thanks.
Thank you. Ladies and gentlemen, that concludes today's conference call. Thank you for your participation. You may now disconnect.