番茄社区

At December's American Society of Hematology (ASH) virtual meeting, a number of important chronic lymphocytic leukemia (CLL) trial updates were presented. 番茄社区 has 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 Dana-Farber Cancer Institute, and , Director of the CLL Program at Memorial Sloan Kettering Cancer Center, for a virtual roundtable discussion on the new and potentially practice-changing data from the meeting.

In this first of four exclusive 番茄社区 episodes, the discussion centers on the studies focused on combined ibrutinib plus venetoclax therapy, including the .

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.

One of the presentations that we would like to talk about today is the CAPTIVATE trial, an interesting trial of combined ibrutinib and venetoclax as upfront therapy for patients with CLL. Maybe, Anthony, you could tell us a little bit more about the design of this trial that we saw presented?

Anthony Mato, MD: Sure. It's an interesting design because this is a multicenter take on the original regimen that was developed at MD Anderson looking at the combination of ibrutinib and venetoclax together. The single-center experience was very active, and so this trial has a unique design where all patients get 15 months of therapy, 3 months of ibrutinib followed by a year's worth of combination therapy, and then there are some randomizations based on MRD status at 10-4 for insensitivity.

If a patient is MRD undetectable, they were randomized to ibrutinib versus observation or placebo. I don't remember if there was a placebo or not. There was... and then if they are MRD detectable at that same sensitivity, they're randomized to the continued doublet versus the monotherapy of ibrutinib. An interesting trial and attempted MRD-driven decision-making, and eagerly anticipated results that were presented.

O'Brien: Jennifer, you want to comment on some of the results?

Jennifer Brown, MD: Sure. This was the first time we heard some of the results from the randomization, and the primary endpoint was one-year disease-free survival. That was particularly interesting including MRD recurrence, for example, as an event and looking at the patients who'd discontinued all therapy versus continuing ibrutinib. There was no difference. It was 95% to 100% in all arms, suggesting that discontinuation is reasonable.

Now, I think one crucial point in the study design is that the qualifications for having undetectable MRD in this study were extremely stringent. When the undetectable MRD was previously reported for the end of combination therapy, it was in the mid to high 70s -- 75%, 78% -- but only 58% of patients qualified for the randomization as having undetectable MRD because they had to have at least three separate tests, including a bone marrow, that were all undetectable.

I think that from the standpoint in clinical practice that makes it a little bit hard to interpret the results because we're not likely to do that many tests and it might be more interesting to know based on the single time point, undetectable MRD, how that randomization would go.

O'Brien: I think one thing [...] of is the... well, let me back up. The primary endpoint for deciding in the randomization to continue to ibrutinib versus placebo was the disease-free status at one year and there was no difference, because I think it was 100% in the placebo arm and some 95% or 96% in the ibrutinib arm. However, my own take on that is maybe one year's really too short to draw that conclusion and I think what demonstrates that is that hardly anybody in the placebo arm lost their MRD response. It will be interesting with longer follow-up to see if the curves separate. It may be that continued maintenance in that subset, namely the ones who are MRD undetectable, is not going to make any difference, but I'm not so sure I would conclude that from this limited short-term follow up.

Brown: Right. Now, if we consider analogy to CLL 14, for example, we are seeing relapses even in the undetectable MRD group off therapy, particularly in the higher-risk patients, so I agree. I think not long enough follow-up.

Mato: I was a little bit surprised that that was the primary endpoint of this study. It just seems like it's a look that's a little bit too early in time to really have any meaning clinically, but of course, that's how the study was defined in terms of sample size, power calculation, etc. I agree, the longer we follow these patients, the more meaningful this study may become.

Of course, none of us are talking about the second randomization because I think we just have to acknowledge the fact that the ibrutinib plus venetoclax was just good at inducing undetectable residual disease. Very few patients were randomized for the ibrutinib versus doublet combination. I think it was about 30 per arm, so we're not going to learn a lot from that randomization. At least I didn't. I don't know if either of you got much out of that.

O'Brien: We might with longer follow-up. I think the point Anthony's making, for our viewers, is that because the rate of MRD undetectability at the end of one year, or one year of therapy, 15 months, was so high, the number of patients that were randomized within the group that's MRD detectable is much lower, so the numbers are much smaller.

Mato: Yeah.

O'Brien: I should also point out that in all of these ongoing trials that we're seeing with combined small molecules, either with or without antibody, just as Anthony said, there is always in every trial a lead-in. That's why here we're making the distinction of 12 months versus 15 months. There is always a lead-in. In many of the trials it's three months. In some of the others it's two, where ibrutinib plus or minus antibody are given first for several months before you go to the combination. Of course, the reason that that's being done is to try and minimize the tumor lysis that you would see with venetoclax, and so this was 15 months of therapy, but 12 months of the combination.

Brown: The other question that we're not even bringing up is whether combined BTK BCL2 inhibitor therapy is actually better, even in the time-limited matter, compared to, say, venetoclax anti-CD20. That remains a question that we need to have a randomized answer to, I think.

O'Brien: I think that's very important because I had several patients I enrolled in this trial and they said to me, "Okay, this sounds good, but whoa, whoa, whoa. What happens when my disease comes back? You've already used up two drugs." I think that was a very good question. What I told those patients is, "Well, the presumption is that when the disease comes back you'll be long off therapy, and because you won't be relapsing on therapy we can go back and use those same drugs." I think all of these trials are assuming that, and it sort of makes sense intuitively, but right now we actually have very little data to know that that is true.

The nice thing about venetoclax-obinutuzumab, as Jennifer pointed out, is we get pretty much MRD undetectability rates in that same range as the two small molecules. We're only using one molecule, albeit with an antibody.

Mato: Although we really don't know biologically if the... one thing that bothers me a little bit is when we say they're comparable MRD rates, whether biologically they're comparable in terms of the rate of regrowth once they're MRD undetectable, I have no idea. But you could speculate maybe the two pathways hit simultaneously somehow induces a slower rate of progression. I'm not sure. I'm extrapolating a little bit from the MD Anderson study. It's hard to know. I think, though, probably the lessons from some of this is that like not all MRD are created equal, even at the same depth of remission, but we'll see what's coming.

Brown: Well, it depends whether there are resistance mutations already in the MRD, right, potentially?

Mato: Yeah. It's true. But even there opens a can of worms because every resistance mutation assay I've seen so far has a different level of detection, from 5% at the cutoff down to 0.01%, and so you probably the deeper you go you will be able to find some level of resistance.

O'Brien: Right. Okay. Thank you, everybody.

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