iwAL 2025 | Menin inhibitors in AML: combinations, resistance, and future directions

Naval Daver:

Hello, my name is Naval Daver from MD Anderson Cancer Center in Houston, Texas, and it’s a pleasure to be here with Dr. Eytan Stein from Memorial Sloan Kettering, Dr. Joshua Zeidner from UNC, and Dr. Amir Fathi from Dana-Farber, Mass General. So we’re here today at the iwAL meeting. We’ve been discussing some of the updates on menin inhibitors and future directions. This is a very exciting area, but an area I think that we, at this point, don’t know as much as we would like. I think there’s a lot of learning to be done. But I’m going to start with some questions here, maybe starting with Dr. Zeidner, who actually spoke about the various combinations that are being developed with menin inhibitors. And Josh, can you tell us which combinations are you excited about currently in the frontline setting? And how do we think we can move these forward in the near future?

Joshua Zeidner:
Yeah, so I think we have now a lot of emerging data of menin inhibitors in combination with the aza-ven backbone for newly diagnosed older unfit patients. We published our data with the BEAT AML experience, and there’s now other menin inhibitors that are being investigated in the same aza-ven combo. And this is a regimen that has very high response rates, and we have to leverage that to find kind of the optimal long-term sort of dosing regimen of these agents. But I think that is a combination strategy, at least in the frontline setting, that has a potential to be a real game changer for this older population who can have potentially response rates in the 90% range, which is quite remarkable to think about where we came from in this patient population who had median survival of six to nine months before the advent of some of our therapies that we’ve seen in the last 10 years. So that is, I think, the combination strategy with menin inhibitors that I’m most excited about. And, you know, although there is now emerging data with intensive chemo combinations as well, I think my question for the field would be whether even intensive chemotherapy combinations are going to be necessary if we have such high response rates with an aza-ven backbone.

Naval Daver:
Okay. Let me ask you, Dr. Stein. So you spoke about relapsed/refractory disease and NPM1, and I really enjoyed the discussion. And, you know, as you mentioned, I think at this point, maybe in the standard of care, the choices are HMA-ven or ven-based therapy versus menin. But in the future, maybe they’ll be combined. So I think for your patients today, if somebody has had frontline Ven-based therapy, and let’s say they’ve had a good remission for a period of time, do you think there’s utility to switch the backbone, let’s say, doing cladribine or intensive chemo-ven? Or would you say, let’s just go straight with the menin inhibitor?

Eytan Stein:
That’s a difficult question. I think if the patient has an NPM1 mutation and has not previously received intensive chemotherapy and is fit for intensive chemotherapy and is going to go on to get an allogeneic stem cell transplant, I’d probably favor the intensive chemotherapy. The situation is usually that if they started with aza-ven, it’s because they couldn’t get the intensive chemotherapy. And then I think the question you raised is a good one, which is that what if they’ve started with aza-ven, been on aza-ven for a long period of time, and then relapse? I think then a menin inhibitor strategy is probably the one that makes sense. It is an interesting question whether giving, you know, that cladribine-based regimen that Dr. Kadia has pioneered would be something to do. We haven’t done that so much, so I’d probably go with a menin inhibitor alone.

Naval Daver:
Yeah, and you know, I mean, Gus in our group has also shown that the HMA-ven, menin, even after HMA-ven, seems to actually have quite a good response rate. So I think the combination partner here may actually be very important and even if you’re, you know, resistance is just a doublet, maybe the targeted therapy, whether it’s FLT3-menin combo, could still generate response. So I think that’s something we’ll have to learn about. So Amir, resistance, I think this is the area we know by far the least about right now in the menin field. Even in the FLT3, you know, we’re still, you know, 10 years in and still figuring it out. So, in your mind, from the existing data, which I agree is not much yet, but will be in the next one, two years, can you say what is the number one, two, three that you think are going to be the actual mechanisms of resistance? Is it clonal evolution? Is it on-target.. Is it epigenetic? Is it lots of target? What do you think will be the big ones?

Amir Fathi:
I think it’s guesswork. But I do think it’s most likely, if I had to guess, it would be a mixture of clonal evolution and emerging mutations in addition to what the patient had at diagnosis or at the start of treatment. Men1 resistance is certainly important. I mean, that’s the first one we picked up. But sometimes it’s difficult to know if that is something that emerges and drives the clinical resistance, which certainly it probably does for a proportion of patients because you see it. Or is it just a bystander sort of, you know, here for the ride effect, you know, that if you expose, you know, a patient to a targeted inhibitor, they’re going to pick up a specific mutation after a period of time in those cases. We’ll see. I mean, I may very well and almost certainly be wrong, but I think time will tell as we learn more. But it is a nebulous field still. I mean, I think that’s kind of the discomfort with this is that we’re still learning how to use this drug, still learning who may benefit from it, and still learning why patients don’t have a lasting therapeutic response in the relapsed/refractory setting. And I think part of the excitement is some of the work that I think all of us are involved in that Josh was just talking about bringing in these drugs more in the frontline setting so you can get the benefit early and maybe deal less with some of the potential headaches that can emerge with relapsed/refractory disease.

Naval Daver:
Yeah, and I do think that’s going to be really important, right, with resistance, because we can also try to borrow a little from what we already know. And we saw this in FLT3. For example, if you use quizartinib as a single agent, you would get about 30% on-target TKD-driven resistance, well-published. But when you’re up front with intensive chemo, in our experience with HMA-Venquiz, we’re actually seeing almost none as emergence. So I think we may be able to overcome by hitting it early before you have multiple clones, you know, before the leukemia is kind of already becoming resistant. But I do think, and I’m kind of surprised, hopefully maybe some of you are doing it, or other labs, we haven’t seen much single-cell sequencing or clonal data. You would think that that should be available, right? With single-aid men and inhibitors, they relapse through single-cell sequencing on 10 patients. And this is how Catherine Smith and the group first found the RAS/MAP kinase and BCR-ABL and FLT3. So hopefully, that kind of data will come and be able to guide us.

Joshua Zeidner:
And we’re doing that on the BEAT-AML study. The good challenge is that we don’t have a lot of relapses with the upfront combination strategies. I think, to Amir’s point, what dominates resistance mechanisms with single agent in the relapsed setting may be entirely different than combination strategies that we’re talking about, whether it’s frontline or not. As you mentioned, maybe you can rescue even responses with an HMA-VEN-menin inhibitor if someone had previously been exposed to menin inhibitors in the relapsed setting. So I think that’s a whole wealth of knowledge that we haven’t even…that’s uncharted territory in this field.

Naval Daver:
So let me ask each of you a little bit of a loaded question. So we have four menin inhibitors. And of course, among those, and I’m not going to say which is best because we don’t know, but what are the key differences between these drugs? And how do you think these may impact how we use them in the future in combinations? So we’ll start with you, Eytan, and we’ll go to Josh…

Eytan Stein:
Yeah. I think the one big difference is revumenib has an issue where it causes QT prolongation. That’s something that in clinical practice I don’t think is a huge issue, but it does require a little bit more monitoring, a little bit more of electrolyte repletion than you get with the other agents that are out there. So I think that’s going to be one factor. The other factor is taking a drug once or twice a day. That’s always an issue. I believe ziftomenib, there’s an issue with pruritus, with itching. I haven’t used a lot of ziftomenib, so I don’t know exactly how bad it is. I think those are the big distinguishers that I would think about.

Joshua Zeidner:
Yeah, I think from a side effect standpoint, that is exactly right. I think, you know, when I think of differentiators, I mean, you look at the clinical activity. We’ve all made these kind of tables and charts showing each of the four, you know, advanced menin inhibitors. And, you know, you’re kind of slicing the numbers to really see any huge difference, at least from a response rate standpoint. We may begin to see differences in durability and survival that that will be coming. But I think where some of the differentiation may be is half-life of these agents, you know, what the chemical properties are, what some of the off-target effects, and then how can we combine these with other agents. And all of these agents are being combined now with, you know, with frontline and other combination strategies. And I think that is where we’ll kind of learn how to differentiate these agents, so to speak, for the field moving forward. Because I think many of us want to move past single agent menin inhibitors as well.

Naval Daver:
Yep. Great. Amir?

Amir Fathi:
I’m not sure if I have much more to add. I think it’s all been said. But I will say, you know, most of the issues that arise from menin inhibitors are beyond the QT, the itching, the drug-drug interactions. I think they’re important for specific patient populations, and grade three events are much less common. I think ultimately, as in many scenarios where there is competition, oftentimes the drugs that are first out of the gate are at an advantage, you know. The other big advantage is how well you design clinical trials and think through your endpoints because you have to accrue successfully, you have to make sure that you pick the right endpoint, the statistical design is sound. If you have those in place, I think I don’t see a substantial difference between these drugs that would otherwise waylay what you’re going to ultimately accomplish. Yeah, I mean, I think, sure, twice a day, always less ideal than once a day. A little bit of itching here. I shouldn’t say, I shouldn’t discount itching. I mean, some patients have terrible itching. Maybe a QT prolongation in some patients. But I think overarchingly, it’s not going to make that huge of an impact. And then across the board, we haven’t really talked about DS or differentiation syndrome. You know, I think with this class, and I think Eytan brought this up, you know, I completely agree, DS seems to be a little bit different. You get the traditional differentiation syndrome sometimes, but sometimes you get this thing, and I call it the differentiation crisis, which is really hard to put that fire out, and with leukocytosis and thrombocytosis and DIC and TLS. And it happens earlier than with other agents. So those are the types of things that we need to sort of think about, both in the clinical trials and ultimately when they get more broadly used in the community.

Naval Daver:
Yeah, I do think, I mean, I’m hoping, and we’ve seen this with IDH as well, that when we combine these drugs up front, I think there’s already signals the DS issue will be mitigated to a very large extent, hopefully, and that may be one thing. But I think you’re right. I think this is one scenario where trial design and endpoints is really going to matter because it’s very competitive. and you know usually if your drug is good let’s say like gilteritinib and you know trial design could be plus or minus you’re going to get it approved because you’re the first player there’s no competitor here I think it’s going to make a big difference you know and then we talk about MRD, flow may not give you relevant information it may have to be molecular what you know are the end points what are your comparator arms so I think a lot of us are going to be thinking about those things and then hopefully getting positive results and then figuring out again which one to use and how. So I think with that, we’re going to close out today. Thank you all very, very much for discussion here at iwAL and see you all later.

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