iwAL 2026 | Menin inhibitor combinations and strategies to overcome resistance in AML

Joshua Zeidner

Hello, I’m Joshua Zeidner, professor of medicine at University of North Carolina in Chapel Hill. And I’m here at iwAL. We’re here in Boston and just had a very exciting morning session that was very vibrant, talking about menin inhibitors and a lot of future directions and future thought about where the field is going. I’m here with my esteemed colleagues, Dr. Searle and Dr. Watts. Do you wanna introduce yourselves?

Emma Searle

Thanks, Josh. My name’s Emma Searle. I’m a haematology consultant based in the UK at The Christie Hospital in Manchester.

Justin Watts

Thanks Josh for having me and thanks to the iwAL team here. it’s been a great meeting. I’m Justin Watts from the University of Miami. and yeah, happy to be here.

Joshua Zeidner

So I I guess to first kick off, Dr. Watts gave a really, I think, brilliant talk about all the development of menin inhibitors from first generation now to potentially second generation and you know where the field is moving, at least in the relapsed/refractory setting. Dr. Watts talked a lot about mechanisms of resistance. And, you know, my question to you, Dr. Watts, is if you could kind of summarize

where you think the field is currently and where it’s moving to in the relapsed/refractory setting, just to put a framework to to the current treatment landscape.

Justin Watts

Yeah, I mean the field’s been moving so fast it’s hard to keep up with. We now have two approved menin inhibitors, two more that are possibly close to approval, others in development that are potentially second or third generation, and already multiple combination studies ongoing at the same time in the frontline setting with chemotherapy, with then HMA and in the relapsed/refractory setting are coming with novel combinations. it’s hard to know what to make of it all until we

see how these studies read out, especially the frontline studies, how that’s going to impact second line. In terms of just keeping it to single agents, I think, you know, we’ve seen kind of what we get with revumenib and ziftomenib for KMT2A in the case of revumenib and NPM1 for both of them with response rates of around twenty percent, twenty-one, twenty-three percent for CR/CRh with either one of them in those mutations in relatively short duration. Early

or emerging data with enzomenib and bleximenib look to be maybe doubling that CR/CRh rate to more in the 50, 40, 50% range remains to be seen, but encouraging and possibly extending the duration of response, suggesting that they may not necessarily be more potent menin inhibitors, but just have better binding properties or somehow be preventing resistance, at least in the early stages, leading to longer duration of response and perhaps better differentiation of the clone.

I think in terms of the future, I think in frontline is probably going to be with chemotherapy or VEN-HMA backbones in the relapsed/refractory setting when they’re already exposed to menin and probably then it’s going to be tough. I think there we need to think about differentiation therapy. What agents can we add to menin to either resensitize it if it’s menin-resistant or if it’s menin-independent relapse, how can we

avoid chemotherapy other than cytoreduction and really differentiate off the clone. we talked about FLT3 as being one of the obvious ones, but there’s also a lot of non-genetic targets that we kind of touched on today, but I think we still have a ton to do and learn about there in the lab and in the mice before we can bring those into patients. Yes.

Joshua Zeidner

I I think that is a really excellent overview of some future directions with menin inhibitors and combinations. Dr. Searle, you gave a really, I think, brilliant and forward-thinking talk about what’s next with menin inhibitors. We’re already moving into the frontline setting as Dr. Watts kind of alluded to, but what happens after frontline combinations and if you could kind of give, you know, your perspective and maybe some areas that you’re most excited about, you know, that are maybe early in in development.

Emma Searle

Yes, I think the work of Justin and others has taught us an awful lot about menin resistance, but the problem within academic centres that we’re already seeing of these patients that have already had venetoclax, have already had menin, either at the same time or sequentially, what do we do with those patients now? And that’s a problem that’s already in our clinic and a problem that’s going to grow. And I summarised the data, but it’s clear that

while there might be something to be gained from VEN re-exposure, particularly in patients who have had perhaps a gap and there may be a little bit of a synergistic effect. The response rates are disappointing to the triplets of VEN, HMA, menin inhibitor in patients who have already had VEN exposure. And we need to look at other novel combinations. And we’re just starting to see the first signs of those combination studies arriving.

Clearly, FLT3 is such an important driver of leukemogenesis that where FLT3 is present, should we be, my first thing to reach for would be a FLT3 inhibitor. But again, there’s this sense from the real-world data that is being published currently that in patients who’ve had menin before, who we then try and treat with a single-agent FLT3 inhibitor, that perhaps the responses are poor.

So could that be overcome with a different type of menin inhibitor? You know, they’ve had a first-generation menin inhibitor in the frontline. Can we then pivot to a second-generation menin inhibitor, add in a FLT3? I think it’s an interesting strategy. I summarized briefly the RevuGILT data that’s there, but I you know, I accept there’s some confounders about whether you’re giving a CYP3A4 inhibitor. But, you know, it looks to me like probably just not the right choice of menin inhibitors to combine with gilteritinib.

And so I’m looking forward to seeing some of the other studies in that space read out. And then as somebody who has a particular interest in Phase I trials, clearly my eyes are on the novel combinations, say, or novel novel, you know, there’s next-generation menin inhibitors plus other agents. I think the mezigdomide story has a very compelling biological basis. It’s a hypothesis-driven piece of clinical research.

It’s an agent that we’ve got a vast amount of experience of giving to older patients in the myeloma setting. And certainly it won’t be without its challenges combining with menin inhibitors because of some overlapping hematological toxicity and some prothrombotic issues. But I think the science is, it excites me about that combination. I’m definitely excited about the KAT6/7 inhibitor story as well.

And it’s nice that for a long time, you know, we’ve been hoping that Pfizer would show an interest. I don’t know whether that will happen or not. But there are other KAT6/7 inhibitors out there now that, you know, hopefully give us more than one opportunity to explore that combination, which has got Armstrong’s work has so elegantly shown maybe a potential strategy for recapturing menin responsiveness in patients who are refractory to menin.

Joshua Zeidner

Yeah, so I mean, I think you summarized this beautifully. It’s such an exciting time a few years ago in these we we had these menin inhibitor sessions, and we were just talking about single-agent menin inhibitors. We moved into combinations. We’re already talking about future directions with novel strategies, and I’m really excited about the science with mezigdomide and some other combination strategies and maybe a bit overcome some of the resistance that Dr. Watts kind of alluded to.

And I sort of in my last session I really wanted to highlight the updated and really impressive frontline data with triplet therapy, AZA-VEN-menin inhibitors in the older unfit setting. We’ve now seen three menin inhibitors, revumenib, bleximenib, and ziftomenib combined with AZA-VEN with very impressive high response rates. We have three ongoing randomized Phase III studies that we’re very hopeful

will be potentially practice-changing for newly diagnosed NPM1-mutated or KMT2A-rearranged AML patients. But my real excitement and interest is to move these agents into the frontline setting for younger fit patients and not just older unfit patients, but specifically for the KMT2A-rearranged subgroup. The NPM1-mutated population is still one where we’re trying to cure with, I think, frontline intensive chemotherapy and may not need a transplant.

KMT2A-rearranged patients we know have very poor outcomes and will really need a transplant for long-term survival. So I’m leading a study called the RAVEN trial, which is sponsored in part by Syndax. And we’re gonna be investigating AZA-VEN-revumenib for newly diagnosed younger fit KMT2A-rearranged patients to use that potentially as a safer and more effective strategy as a bridge to transplant, tagging along from the PARADIGM results that Dr. Amir Fathi recently published in the New England Journal of Medicine. so I think a lot, kind of more to come next year. I hope we’ll have even more exciting novel combination data to present about, you know, overcoming resistance mechanisms. Many of the frontline trials are gonna, I think, take some time to read out. but this is a field that is rapidly evolving and, you know, I believe is gonna make a huge impact in our patient population now and in the future. So thank you all for listening and it’s a pleasure to be here with my colleagues.