乌鸦传媒

At the American Society of Hematology (ASH) virtual meeting, a number of important chronic lymphocytic leukemia (CLL) trial updates were presented. 乌鸦传媒 brought together three expert leaders in their field: Moderator , of Chao Family Comprehensive Cancer Center, University of California Irvine Health, is joined by , director of the CLL Center at Boston's Dana-Farber Cancer Institute, and , director of the CLL Program at Memorial Sloan Kettering Cancer Center in New York City, for a virtual roundtable discussion on the new and potentially practice-changing data from the meeting.

In this third of four exclusive 乌鸦传媒 episodes, the discussion centers on the LOXO-305 study.

Episode 1: The CAPTIVATE trial

Episode 2: Where U2 Will Fit in CLL Treatment Landscape?

Following is a transcript of their remarks:

Susan O'Brien, MD: Hi, everyone, and welcome to this roundtable where we're going to discuss CLL presentations at ASH 2020 this year. I'm Dr. Susan O'Brien from the Chao Family Comprehensive Cancer Center at the University of California in Irvine, and I'm joined by two esteemed colleagues, Dr. Jennifer Brown from Dana-Farber and Dr. Anthony Mato from Memorial Sloan Kettering.

I think we're going to talk about a very exciting presentation at ASH this year, which was the trial of LOXO-305. I think we're all very excited about this new class of agents, the non-covalently binding BTK [Bruton tyrosine kinase] inhibitors. I'm going to let Anthony, since he was the presenter for this slide presentation, talk about the data.

Anthony Mato, MD: Sure. This is the phase I/II BRUIN trial, which was a multicenter trial looking at the non-covalent BTK inhibitor LOXO-305 in patients with CLL and other B-cell malignancies. My presentation today really focused on the subset of patients with CLL, which were about 170 total patients. 139 of them were efficacy evaluable.

This is a standard phase I 3+3 design dose-escalation study looking at the doses between 25 and 300 mg, and then an opportunity to expand phase I, and then once the go-forward dose was determined, then to expand to phase II to look across certain subgroups of interest. A rapidly accruing trial. I presented, I think, seven CLL patients last year and 170 this year.

LOXO-305 is a very interesting molecule. It's highly BTK-specific, but it has a different binding mode in that it non-covalently binds. The half-life was about 20 hours. In terms of endpoints here, the primary endpoint was obviously safety, determination of the MTD [maximum tolerated dose], and then in the phase II the primary endpoint was response.

A couple of different points that I want to highlight about this study and I think were most interesting. 1) The molecule appeared to be incredibly well-tolerated in this patient population. One of the first times I've seen so few AEs [adverse events] greater than 10% all causality. There's only three, actually: fatigue, diarrhea, and a hemorrhage event, which was a grade 3 hemorrhage that was listed.

A very small proportion of patients developed BTK-associated adverse events. Less than 1% afib. I think it was 0.6% percent. Again, one grade 3 event in terms of major hemorrhage. So somewhat of a distinct AE profile with the caveat that this was a relatively short follow-up period.

Then in terms of activity, you have to interpret the overall response rate data in the context of the patient population, and so this was an overall three median prior therapy patient population. But if you look at the 86% of patients who got a BTK inhibitor before, it was four, and then a very large proportion of patients that had chemo, CD20, BTK inhibitors. Two-thirds of the BTK inhibitor-treated patients had had progression of disease or resistance.

You take that into account and you see an overall response rate with relatively short follow-up of 60%. Then across the board, no matter how you look at the patient population, even patients who had failed five prior classes of therapy, you see response rates that are quite similar. Then as time goes by, the response rate increases to over 80% for patients who had had more than 10 months worth of therapy.

This isn't a randomized trial. It's early data. It's still mostly phase I patient population. But I think what's unique here is this is the first prospective data for a BTK inhibitor following another BTK inhibitor in the setting of progression where we see across a large patient population pretty significant activity and durable remissions. I think that's my take on the data summary, and I'm curious to hear what you guys thought of the data.

O'Brien: Jennifer, you want to comment?

Jennifer Brown, MD: Right. I've also worked with this drug, and even before we had the data it was pretty clear to me that it's a very highly active and very well-tolerated drug. One thing that I think is interesting -- and I'm not really sure of the significance of this -- but despite the fact that two-thirds of the patients progressed on their prior BTK inhibitor, only 25% or so had a BTK mutation and...

Mato: Oh really?

Brown: ... that is definitely unusual. It's been clear, I think, for a while that there are other mechanisms of resistance to BTK inhibitor. But this one was specifically, in a way, developed to target that C481S mutation, but clearly has activity even in patients with other mechanisms of resistance.

Mato: Just to answer that, I think a couple of different points. 1) They would argue designed not specifically for that patient population, but to be a very widely applicable BTK inhibitor. But to address what you're saying, I agree.

The denominator is 91 for that 26% or 27%, so they're still gathering, prospectively, data on samples that were captured to look for that mutation, and so it may be that as the denominator increases with the more recently accrued patients that the percent changes.

The other thing is that -- and I tried to make this point in the presentation -- is not all BTK mutation assays are created equally. At centers like OSU [Ohio State University], the digital droplet PCR probably goes down to 1% or 0.01%. The assay that was used here was a very standard commercial assay where a positive was called at 5%, so we don't know how many patients were between 1% and 4% that would have changed that percentage, and honestly, I'm not sure. Maybe Jennifer or Susan have a good interpretation of what a clinically meaningful positive percent is at this point, especially after I watched this biology session yesterday where they tried to convince us that any small BTK-resisting clone changes the microenvironment and confers a survival advantage to their wild type cells, and so I'm not really sure how to interpret these facts anymore.

O'Brien: I think that's consistent with the fact that probably Ohio State has published the biggest series on this and their numbers are all over the place. The patients are clinically resistant and yet have clones as small as single digit, 5% to 6%, so I think that's a wide-open question. It's been a question a long time, how can these low-frequency clones be conferring all this clinical resistance? I didn't actually hear that paper yesterday, but I'm going to go back and look at it since you've just mentioned it. I think that's really interesting and potentially could be an explanation.

Brown: They don't have evidence of how that clone may be influencing the microenvironment directly. That was more or less of a hypothesis based on the RNA expression that they're seeing in the cells that are the lymph node efferents. I think it suggested that it's very complicated, which is not too surprising.

Mato: Definitely that, for sure. At one point, I guess the clinical data speak for themselves, assuming that these are truly progressors, which I think a lot of thought went into verifying that. I think now the work has to happen to try to explain biologically what we're observing clinically. But the clinical numbers, I think, were pretty impressive, and I agree with you, Jennifer.

I gave patients this drug at 25 mg who had had five prior therapies and I was seeing response, and I have worked with other agents that were similar and not had that same experience, so there was something really unique about this molecule early on. I still have patients on 25 mg or 50 mg.

Brown: I do too. That's similar to the early days of ibrutinib [Imbruvica] and idelalisib [Zydelig] was actually like that too. Even at the lowest doses we saw responses. It's really quite striking.

Mato: Yeah. I was going to speculate you and Susan were there from the beginning with those molecules and so you probably have the same experience.

O'Brien: I don't think there is any question that this data's really fantastic, not only in terms of the efficacy, but the safety profile. It's very impressive.

Mato: What did you think of the trials that are proposed now, moving forward, the ones that I got to... actually, I asked them permission if I could mention them, but they gave me permission to talk about their development in terms of how to move this forward.

O'Brien: My first thought was if they're doing a frontline trial compared to ibrutinib, "Whoa, how long is that going to take?"

Brown: Yeah. There's no surrogate endpoint either, really. Is that going to be enriched for high-risk patients, at least? Although the data at this meeting suggest that that won't help that much.

Mato: I honestly don't know. I'm not really sure the patient profile that that's being aimed at.

O'Brien: Okay. Thanks, everyone.

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