Jennifer Woyach:

Hi, I’m Jennifer Woyach, from the Ohio State University.

Adam Kittai:

And I’m Adam Kittai, also from the Ohio State University. We’re happy to be here at ASH 21 in Atlanta, Georgia, speaking to VJHemOnc about CLL and the exciting abstracts that were presented here. We’ll start off by talking about some of the exciting abstracts that were presented in the treatment naive setting. I think there were four abstracts to talk about here. One was the CAPTIVATE study, where we saw some follow-up data of the patients who had undetectable, minimal residual disease who received ibrutinib plus venetoclax for 15 cycles and then were randomized to either placebo or continued ibrutinib.

Adam Kittai:

We also have the GLOW study, which also combined ibrutinib plus venetoclax for 15 cycles and it compared it to chlorambucil plus obinutuzumab. Lastly, we had CLL13, which was a combination study of various venetoclax regimens either with obinutuzumab, rituximab, or ibrutinib. It was compared to patients who got chemoimmunotherapy.

Adam Kittai:

I think there’s a take-home point here on all these studies is that, I think the exciting thing about treatment-naive CLL is that we might have a new indication of ibrutinib plus venetoclax for the frontline setting. The question is, where does this fall when we have so many other good options for CLL, including ibrutinib, or acalabrutinib plus, minus obinutuzumab, or venetoclax plus obinutuzumab. I think all of these different studies answer a small different question when we are looking at this in the big picture.

Adam Kittai:

Let’s start with the GLOW trial. The GLOW trial was a registrational study. The goal of this study was to get a FDA approved indication for ibrutinib plus venetoclax. And it compared it to chlorambucil plus obinutuzumab. I think the biggest complaint about this study is that chlorambucil plus obinutuzumab is not typically used in the frontline setting anymore in patients who have CLL in America. A lot of people think that this particular comparator arm is not the best comparator arm. It was no surprise that ibrutinib plus venetoclax met its primary endpoint and was superior to chlorambucil plus obinutuzumab. But it doesn’t help us answer where we should place this combination therapy moving forward.

Adam Kittai:

Do you want to talk a little bit about the CAPTIVATE study?

Jennifer Woyach:

The CAPTIVATE study is a Phase II trial. It’s a really interesting design. There’s two cohorts, a MRD cohort where the depth of minimal residual disease at the end of the one year of therapy determined whether patients continued with maintenance ibrutinib, or discontinued. The other cohort was fixed duration where everybody got the same amount of ibrutinib plus venetoclax, and then everybody stopped therapy.

Jennifer Woyach:

What we heard here at ASH was a follow-up of the MRD cohort. We see that… really at this point, it seems like it doesn’t matter whether patients who have undetectable MRD continue on with maintenance ibrutinib, or placebo. Same thing with patients who have detectable MRD, where they were randomized to either ibrutinib, or ibrutinib plus venetoclax. We have about a year additional follow-up from what we saw last year and excitingly really not any more progressions. It does appear that this is, at least in the short term, a durable regimen. I think importantly, it is confirming what we’ve seen in some smaller studies of either the doublet of ibrutinib plus venetoclax or the triplet with obinutuzumab where the studies that have come before this one also showed very durable remissions.

Adam Kittai:

Then lastly, we have the CLL13 study, which was the one that combined venetoclax with either an anti-CD20 monoclonal antibody rituximab or obinutuzumab, or venetoclax plus ibrutinib plus obinutuzumab. And it compared it… these three regimens to chemoimmunotherapy, whether bendamustine rituximab or FCR. I think once again, we all weren’t surprised that a met is primary endpoint that the venetoclax arms were found to be superior to the chemoimmunotherapy arms, which was exciting to see. I think some of the interesting points about this particular trial was that the obinutuzumab plus venetoclax arm, and the ibrutinib, venetoclax, obinutuzumab arm had very high rates of MRD higher than 80%. And what was interesting was that the rituximab plus venetoclax arm only had MRD rates about 50% and was not superior to the chemoimmunotherapy. We all thought that was very interesting that the rituximab just appeared to not look as good as the obinutuzumab. And also begs the question of whether or not adding ibrutinib to venetoclax obinutuzumab has any benefit.

Adam Kittai:

I don’t think we’re going to have the answer to this question until we see results of maybe the CLL17 trial, which is a Phase III trial that compares ibrutinib to ibrutinib-venetoclax, to venetoclax-obinutuzumab. And that trial is powered to show if there’s a difference between those three arms, as opposed to CLL13, which wasn’t powered to show a difference in venetoclax as far as I understand the trial to be, is that correct?

Jennifer Woyach:

Yeah.

Adam Kittai:

I think that all three of these trials are really exciting because we’re looking at ibrutinib plus venetoclax in three different ways of giving the medications. I think that will probably have an FDA approved indication for ibrutinib-venetoclax in the near future. But I think the question remains, where will it fall in terms of competing with the other treatment naive arm… a treatment naive regimens that we have currently.

Jennifer Woyach:

I think some of the studies that are going to answer that question are the current NCTN trials. The Alliance A41702 study in older patients and the ECOG 1912 study in younger patients. Those were both studies comparing a doublet of ibrutinib-obinutuzumab, to the triplet ibrutinib, obinutuzumab, venetoclax. Hopefully we’ll start to answer some of those important questions. Also, at ASH this year in the frontline setting, we’ve seen longer term follow up on both the Alliance, A41202 study, and the SEQUOIA study of zanibrutinib.

Jennifer Woyach:

The Alliance study was a three arm trial that was designed to compare ibrutinib based regimens to chemoimmunotherapy in patients over the age of 65. The chemoimmunotherapy arm was bendamustine rituximab, and patients also were randomized to either ibrutinib or ibrutinib plus rituximab. Now we have a 55 month medium follow up and four years we see that the ibrutinib and the ibrutinib plus rituximab arm still have a similar progression-free survival at about 75%. And the bendamustine plus rituximab arm is still inferior to that with a progression-free survival at that point of 47%.

Jennifer Woyach:

Importantly, and what is another common theme that I think has come out at ASH this year is that in the frontline setting, some of these high risk genetic abnormalities don’t seem to play a role, most notably 17p deletion and TP53 mutation. We always have thought of this as our most high risk abnormality in CLL. And indeed in the relapse setting with even our novel therapies, it appears that patients with TP53 abnormalities have inferior outcomes, but with the Alliance follow-up, as well as a retrospective study that was done at MD Anderson, it looks like in a frontline setting that may not be the case. Maybe we’ll see that with longer term follow-up, but it’s hard to say at this time.

Jennifer Woyach:

We also saw a longer term follow-up of the SEQUOIA study, which is a randomized study of zanibrutinib versus bendamustine-rituximab in patients who do not have 17p deletion. There’s another arm on the study for patients with 17p deletion that was presented where they were received zanibrutinib in that arm as well. In the primary comparison, the non 17p deleted, we do see, as you would expect a progression-free survival advantage for zanibrutinib compared to bendamustine rituximab that looks really excellent and pretty similar to what we’ve seen with both ibrutinib and acalabrutinib in this setting. Importantly, in those patients with 17p deletion, we actually see about the same PFS at the time point that we have, which is only two years, but again, something that we’re going to be watching really closely in the future.

Adam Kittai:

I think also what’s exciting about this study, it showed once again, that zanibrutinib had a very low rate of atrial fibrillation, which we’re always worried about when we put patients on ibrutinib. That was exciting to see. Let’s move on to the relapse/refractory data. How about that?

Jennifer Woyach:

Just like in the treatment treatment-naive setting there was a lot of interesting data coming out in the relapse refractory setting. To me, one of the important and influential abstracts we saw were two of the reversal BTK inhibitors, and these are pirtobrutinib and MK1026. Whether these molecules bind two Bruton’s Tyrosine Kinase or BTK in a different site than the covalent inhibitors do, and rather than binding irreversibly, they bind reversibly. Initially they were strategized to play a role primarily in patients who have developed resistance mutations to the covalent BTK inhibitors. We saw very short-term follow up with both of these drugs. Pirtobrutinib been presented multiple times… and I think on this presentation, there was actually a hundred more patients than we saw last time. It is looking like a very excellent drug in this setting.

Jennifer Woyach:

Many of the patients had received a BTK inhibitor and a Bcl-2 inhibitor, some had even received also a PI3-kinase inhibitor and chemoimmunotherapy. The response rates were around 65% actually in just about every one of those subgroups, which is pretty impressive. We don’t really know much about progression-free survival for the majority of patients. However, they did show that the double refractory patients, BTK and Bcl-2 inhibitor refractory patients had a medium progression-free survival of about 18 months at this time, which is notably better than anything else we have to offer these patients.

Adam Kittai:

The other thing that I thought was really interesting about pirtobrutinib is that… remember pirtobrutinib acts on BTK and the subsequent molecule after BTK is PLC-ɣ2. And so when patients become resistant to our first generation BTK inhibitors, you usually have a BTK C481S mutation. Sometimes they also have a PLC-ɣ2, which is downstream of the BTK. I thought it was super interesting that it seemed to look like it worked, and someone even asked a question about this, in patients who had both a BTK mutation, as well as a PLC-ɣ2 mutation. I think the number of patients was quite small. If I remember correctly, it was like 23. I’d like to see further follow from that, but I thought that was super interesting. What do you think about that?

Jennifer Woyach:

I think that’s really interesting, also the other piece of information that I would love for them to share in a previous… in a subsequent presentation is what exactly are those mutations. Because there’s actually a lot of snips in PLC-ɣ2 and a few verified hotspot mutations that we know can’t have the potential to drive resistance to the covalent inhibitors. I also thought that that was a really interesting point.

Adam Kittai:

Then also the safety data looked remarkable for pirtobrutinib as well. Right?

Jennifer Woyach:

Yep. Pirtobrutinib is a really, really selective BTK inhibitor, probably the most selective that we’ve seen in clinical development so far. As a consequence of that, it has a remarkably clean safety profile. I think that toxicities that they even mentioned things like fatigue… I think there was some… a little bit of bruising were kind of things that you expect to see just in patients with CLL in general, which was really exciting to see.

Adam Kittai:

I think when they look at where they’re taking pirtobrutinib from here, there’s some exciting trials on the horizon. I think one that strikes to me is they’re doing pirtobrutinib plus venetoclax, plus rituximab versus as a randomized Phase III trial, venetoclax plus rituximab in the secondline setting. I think those things are really exciting.

Jennifer Woyach:

I absolutely agree. Then the other reversal BTK inhibitor that was presented was MK1026. This was formally known as ARQ531 in previous presentations. This is kind of the opposite of pirtobrutinib in terms of selectivity. This is actually a really non-specific BTK inhibitor. And with that, having potentially an advantage in some senses that it is actually a little bit more cytotoxic than pirtobrutinib to CLL cells specifically. This study as well, had quite a few less patients in the pirtobrutinib study. We were presenting the data for patients who were included on the dose-expansion cohort at the previous recommended phase two dose of 65 milligrams daily. We saw a response rate of about 58% in those patients. So still really excellent in these very heavily pretreated patients. Again, most of them were BTK and B Cell 2 inhibitor refractory. Again, very short follow up, so duration of remission is really unknown, but at least in the short term, it is looking like you have some very nice remissions.

Jennifer Woyach:

The toxicity profile it is probably a little bit less clean than we see with pirtobrutinib, just because it has so many other targets, but it was a generally very well tolerated molecule too. There was some rashes, some GI side effects, dysgeusia but most of those things were not therapy limiting.

Adam Kittai:

I have two questions for you. Is it nemtabrutinib? I saw the name nemtabrutinib. How do you say it?

Jennifer Woyach:

I’m not really sure.

Adam Kittai:

Okay. We’ll find out. I guess the next question is where do you see these two molecules fitting in the treatment paradigm for CLL?

Jennifer Woyach:

I think that that is just a million dollar question right now. Certainly they’ve… I think proven… once obviously we have a Phase III study showing against a comparator, but I think they’ve really proven themselves to have activity and potentially a role for these patients that have progressed despite our other standard therapy options, specifically those who had received a BTK and a Bcl-2 inhibitor. I think that it’s really tempting even in the relapse setting to say, “Hey, we would like to continue in the same class”. And so patients who are on a BTK inhibitor initially, maybe transitioning them to a reverse BTK inhibitor rather than going straight to venetoclax at that point. Then as well, both of those drugs are being moved into studies in the frontline setting. I think it’ll just take some time, I think, to understand what’s going to be their role in that really upfront group. But I think that they’ve already established the potential role in the relapse setting.

Adam Kittai:

Yeah. Because I think it’s super exciting that pirtobrutinib appears to have a great adverse event profile, but the question remains, if you have somebody who’s on pirtobrutinib as a frontline treatment, will they develop resistance like we’ve seen with ibrutinib-acalabrutinib? And well then what will we do after that? Can we use another type of BTK inhibitors? Is really unclear at that point. I think it’s very interesting that we’re moving it forward. I think a lot of us are worried that they’re going to develop some sort of resistance mechanism moving forward as well.

Adam Kittai:

What about some basic research abstracts that you’ve seen? What do you think is interesting?

Jennifer Woyach:

There’s actually quite a lot of molecules and preclinical development that are looking really exciting for CLL new targets, new therapies. A couple ones that I just wanted to mention. One is a CDK-9 inhibitor, and this is VIP 152 and there was a oral presentation looking at this in patients with CLL… patient samples with CLL, as well as mouse models. Looking really exciting. We’ve seen previous CDK inhibitors be active, even in refractory CLL drugs like flavopiridol and dinaciclib. There really hadn’t moved very far in development. This drug, we hope has a potential to move even further. And as well potentially have some activity in Richter’s transformation as well as CLL. Another one that we’ve seen is a dual Bcl-2, Bcl-xL inhibitor called LP-118. This is a drug that binds Bcl-2 a little bit differently than venetoclax does. So potentially could be active in patients who have Bcl-2 mutations and as well has some weak activity on Bcl-xL, which is another way that patients can become resistant to Bcl-2 inhibitors by upregulating some of those other BH3 anti apoptotic proteins.

Jennifer Woyach:

Again, in CLL cells, patients either sensitive to or resistant to the venetoclax as well as mouse models. It does look like this drug has some potential activity. These are just a couple of examples, many more have been presented, but I think that the outlook for studies and CLL is really bright and we just have a lot of exciting things moving forward.

Adam Kittai:

I think the last part that I thought was really interesting about this ASH is that I think undetectable minimal residual disease is really being highlighted as an endpoint that we need to strive for. I think moving forward, we need to figure out how deep does undetectable minimal disease need to be. Does it need to be to the 10 to negative four, or 10 to negative six? Is it good enough to be in the peripheral blood? Is it good enough to be in the bone marrow? And what does that mean for our patients? Which patients can we stop therapy on?

Adam Kittai:

I’m excited to see this… not necessarily new, but this endpoint being evaluated appropriately and also maybe clinically relevant as we move forward in our treatment CLL. I think there’s a lot of exciting things in CLL and I’m looking forward to the future.

Jennifer Woyach:

Yep. Absolutely. Well, do you have any other comments that you want to make?

Adam Kittai:

No, I think the last comment… well, I should say yes, because the last comment is I’m just happy to be here with my colleagues and get to see everybody in person as opposed to virtually. I think that’s been a really good thing about ASH 2021 as well.

Jennifer Woyach:

Yeah, Absolutely. That has definitely been a real treat. Thank you for being with us today. We’re really excited again, to be here with VJHemOnc highlighting ASH 2021.

Adam Kittai:

Thank you.