iwAL 2024 | Current data on menin inhibition in AML

Joshua Zeidner:

Hi, I’m Joshua Zeidner from University of North Carolina.

We had a very exciting session here at the 2024 iwAL conference discussing menin inhibitors and this exciting class of new agents that is being explored, both as single agents in relapsed/refractory AML, as well as potentially moving into the front line space.

I’m here with my esteemed colleague Dr Eunice Wang from Roswell Park. And I’ll first start by maybe asking Dr Wang to discuss some of her exciting data of these agents in the relapsed/refractory setting.

Eunice Wang:

Thanks, Josh. Yes, so as we discussed here today in Phoenix, Arizona, there’s been a great deal of excitement and promise about this new targeted therapy for acute leukemia, specifically those with NPM1 and KMT2A rearrangements.

So what I discussed was some of the relapsed/refractory patient population data that is quickly moving forward to potentially our FDA approval of one, if not even two, menin inhibitors in this particular disease setting as early as December of this year.

So as I discussed, there are currently at least four clinically active menin inhibitors in development right now for which we have relapsed and refractory leukemia data. Now overall, the majority of these patients have been adults, although there is some data in pediatric acute leukemias, with one drug, revumenib. And they have largely focused on patients with KMT2A acute leukemias, primarily AMLs, but also ALLs, as well as those with NPM1 mutation.

Now, the relapsed data has been, as one would expect, in a pretty refractory patient population, patients failing two, three, four lines on average of therapy. About half of them failing prior transplantation, and up to two-thirds or even 88% of them failing prior venetoclax therapy. So pretty heavily pretreated, mostly older individuals, and across all of the agents.

And currently we have revumenib, which has completed Phase II, ziftomenib, which has also completed Phase II, not yet reported. And two early drugs, bleximenib and enzomenib, which are both in Phase I. All have data showing clinical efficacy.

Now, there’s some differences between these drugs, as we talk about, and I know you’ve been working with revumenib. Revumenib, really the most advanced Phase II studies in KMT2A, showing about 18% CR rate, about 23% CR-CRH rate, and some toxicities. As we know, the dose-limiting toxicity in Phase I was the QTc prolongation and differentiation syndrome, which is seen across all the agents.

Ziftomenib data, primarily in NPM1 coming out. That’s the subset that they’re really targeting, because they had some differentiation syndrome, our KMT2A patients. And they’re seeing, in a very small study, about 35% CR rate, 45% overall response rate. And so we’re expecting to see NMP1 specific data coming out potentially later this year.

Two earlier agents, bleximenib, which is the Johnson & Johnson drug, that is moving quickly forward, some early data in some combinations with ven-aza. And that drug looks to be very well tolerated, clearly effective. Again, 20%, 25%, as well as some differentiation syndrome.

And lastly enzomenib, which is the newest kid on the block. And that has been only purported out in Phase I. And that shows some differentiation features, potentially very little DS, really saw very minor DS, no need for any mitigation strategies, no QTC prolongation. So toxicity profile is something that may be slightly more favorable than some of the earlier agents, but all of these drugs moving forward.

There’s even second-generation menin inhibitors early in development from a number of companies. But clearly we are looking forward to this being like the next targeted therapy.

But there have been reports of resistance. Most primary resistance, maybe 60%, 70% of patients not having a response or any clinical benefit. As well as documentation at least on one of the drugs, revumenib, of the significance in development of up to 39% of patients developing quickly menin-resistant mutations, now in the laboratory epigenetic resistance mechanisms.

So clearly when we start to see some of these mutations popping up, and then potentially being some differences between the agents, we’re going to be turning towards our backbone therapies to overcome them and push that efficacy up even higher.

So I know we’re really excited about your data with Beat AML, where they’re moving revumenib actually from the relapsed/refractory setting up front in combination with ven-aza. So maybe you could tell us, I think this is probably the talk of the symposium this year, is some of the early data that you’re seeing with the combos.

Joshua Zeidner:

Yeah. So this has been an incredibly exciting field, as you pointed out, and these menin inhibitors, I think we all believe, is really going to have a huge role in all sort of settings of AML. And we’re learning more about different subsets, beyond maybe even NPM1 mutations and KMT2A rearrangements, that may benefit.

And because we’re seeing activity in the relapsed/refractory setting, we’re now beginning to explore these agents in the front line setting. So I presented updated data from a Beat AML Phase I dose escalation study, where we’re adding revumenib to front line aza-ven for newly diagnosed older adults unfit for intensive chemotherapy.

These patients enrolled in two different dose levels. So it was initially a Phase I dose escalation study, we’re now expanding at both dose levels to really determine the optimal dosing. But I think there are several kind of key features that I’ve seen in this study and that I’m very excited moving forward.

We’ve enrolled 26 patients to date on two different dose levels. Both dose levels have been safe, tolerable, easily able to be well tolerated without dose-limiting toxicities. That was obviously the most important part of the initial phase of the study, to make sure that we can safely combine these agents with the aza-ven backbone in a frontline approach, and we’re able to safely do that.

But what we’re really beginning to see is just very high activity. So we’ve seen 100% response rate in 26 patients, a 96% composite remission rate. And really that remission rate is probably in reality 100%, because of just the definitions of how we’re defining complete remission based on blood count recovery in the protocol.

So we’re seeing fast responses. These responses are occurring generally after the first cycle of therapy, very few patients needing even a second cycle to achieve a remission. No patient needing three cycles.

And as we know with azacitidine and venetoclax, about half patients maybe achieve a remission in the first cycle, but cycles two and three are sometimes necessary to really achieve that response. So these responses are really fast and potentially deep by different MRD assays. We’re very interested in exploring more of a molecular assay to see if the NPM1 mutations are being cleared.

But overall, a safe regimen, highly active regimen, 26 patients. We’re expanding now to look at both dose levels in a more comprehensive way to determine the best dose moving forward. And again, this is for newly diagnosed older adults unfit for intensive chemotherapy, with either NPM1 mutations or KMT2A rearrangements.

And I think the data is quite compelling to move this even further. So we’re exploring randomized Phase III study designs from an international standpoint, to really see if revumenib in particular in this case can improve outcomes compared with aza-ven.

Revumenib, as you mentioned, is one menin inhibitor that is perhaps the most advanced in this field, but there are several other menin inhibitors that are also very promising and being explored. So it’s just been an honor to be part of this field and we’re excited about the merits of these agents moving forward.

Eunice Wang:

Yeah, no, there was a lot of discussion, I think there was a long line of questions about how we’re going to move this drug into combinations. Discussion about a Phase III right now that’s planned internationally in NMP1-mutant patients.

But there was some support from the audiences to say NMP1 patients do really well with both intensive chemo as well as 7+3, and without adverse commutations. A lot of discussion about commutation status, secondary mutations, as well as TP53 or FLT3, IDH1 mutations.

Do we really think that the menin inhibitor added to ven-aza or added to intensive therapy is really going to be able to change the already excellent outcomes? And so I know there was discussion about that, and why not focus on the KMT2A? I mean, I think there are trials that are with multiple agents looking at both, but I think that you had some thoughts about that.

Joshua Zeidner:

Yeah. I mean, I think both can be true. So I think that not all NPM1 mutations are, A, created equal, and, B, do well with even front-line aza-ven.

But just focusing solely on the older adults, because I think the younger population’s a bit different with NPM1 mutations, they have high response rates with aza-ven. How much can we improve upon that? Hard to know. Of course 100% is 100%, but as you pointed out, some of these patients, 80%, 90% perhaps response rate with aza-ven without menin inhibitors.

But I think what’s going to be critical is the durability. And if we can really eradicate these NPM1 mutant clones perhaps with the addition of menin inhibitors, revumenib, I do think that this could lead to a survival and durability benefit.

And as I mentioned, NPM1 mutations aren’t all created equal. About half of these patients also have signaling mutations, FLT3, ITD, NRAS, KRAS, and those are the patients that really do quite poorly actually with frontline aza-ven. So I think that’s a population amongst the whole that can really benefit from the addition of menin inhibitors.

But to the second point, I think that the KMT2A rearranged group is by far the higher unmet need. These are patients that do very poorly with standard therapies, aza-ven or intensive chemotherapy. And I think that this regimen might be a vehicle to move forward for a KMT2A rearranged group across all ages. And NPM1 mutations is a bit more complicated, because they do have favorable outcomes perhaps with intensive chemotherapy and could be cured.

But that’s an area that I think is very exciting to me. And I think both can be focused on simultaneously.

Eunice Wang:

Okay. Any idea… I know there’s some documented menin mutations, there’s like four identified in monotherapy. And the monotherapy duration of responses are usually six to eight months, that type of thing.

I know you’ve had a couple of relapses, I mean, I know despite this amazing 100% overall response rate or clinical activity. Any idea what those responses are? I know there’s questions, are they being driven by FLT3 or RAS, or something like that?

Joshua Zeidner:

Yeah. So we’ve had three relapses to date, so fortunately we haven’t seen a lot of relapses to really uncover the mechanism. But two of the three patients had a KMT2A rearrangement, so there’s only been one NPM1 mutant relapse to date. And maybe that’s as expected, because they do better.

Eunice Wang:

They do poorer, yeah.

Joshua Zeidner:

The NPM1s do better than the KMT2A.

We’re very interested in looking at all this, looking at menin resistance mutations, seeing what happens over time. And in those who relapse, are they acquiring new mutations? We don’t have that data yet. We don’t have any data that there’s new clonal evolution happening.

But again, this is a relatively small study and small numbers of patients who have relapsed, so I think these are really important questions. Whether the same mechanism of relapse occurs with a combined approach versus a monotherapy, I think is something we need to explore.

Eunice Wang:

And I heard there’s amendments, as we know the drug’s pretty well tolerated. Usually get some differentiation, QTc prolongation. I think we’ve been able to overcome those with omission of azoles. And I think there’s putting an amendment through to extend the revumenib monotherapy throughout the duration of their treatment course even after transplant.

Joshua Zeidner:

Correct, yeah. So I think the post-transplant maintenance is a really exciting area of menin inhibitors in general. We have a foundation with FLT3 inhibitors where we know that these agents can be safely given post-transplant in certain settings and can improve outcomes.

And in particularly the KMT2A rearranged group, they have poor outcomes even after transplant. So I think these studies will be really important from a maintenance standpoint.

What we’re trying to do is find ways to continue to move the needle in this disease where we’re already seeing better outcomes. But that’s an area that we’re exploring in this study and others as well, as you pointed out.

Eunice Wang:

Yeah. I mean, I think that one of the questions is, is there a best menin inhibitor, best in class? We don’t know yet. I mean, I think there’s at least four in development, and I think we need a lot to learn still about the differences.

And whether the question is one menin inhibitor, revumenib, is going for approval in KMT2A, ziftomenib may be going for approval in NPM1, I think that might just be a regulatory thing. And then there’s two newer ones coming around, and they’re all being investigated now in different populations.

And I think one of the interesting combos that has garnered a lot of interest is the combination of a FLT3 inhibitor and a menin inhibitor for both relapsed/refractory, and then also moving it up into the upfront setting.

So really this looks, I think, to be the really hot area, right, right now. You would agree? I think there’s a lot of interest in your study and in similar studies.

Joshua Zeidner:

I couldn’t agree more. I think, you kind of pointed out initially, this is the new target, the new targeted therapy of AML. And I think the target is going to expand. I think we’re still learning more about different subsets that might benefit from these agents.

Eunice Wang:

Right. Like NUP98, or maybe ALL, right?

Joshua Zeidner:

Right. And smaller slices of the pie, these really rare kind of abnormalities that are upregulated by HOX and MEIS1 genes, and so forth.

So I mean, being part of this field, certainly it’s exciting across the board, but I can see these agents really benefiting patients. And I think this is definitely the new wave of therapy for AML.

Eunice Wang:

I mean, I think when we think about it, KMT2A, NPM1, FLT3, IDH1, IDH2, I mean, I think if you look at the overall spectrum of, say, AML disease, I mean, that encompasses more than half of patients. I mean, NPM1 being a third, KMT2A 5% to 10%, then like a third maybe FLT3, IDH1, IDH2.

I mean, we’re starting to develop precision medicine for more than half of our AML patients. And as you said, we might envision a time when we’re moving away from intensive chemotherapy. Maybe they should get a ven-aza backbone for all NPM1-mutant or KMT2A patients in combination with the menin inhibitor. So I think more to come, I’m looking forward to next year’s meeting.

Joshua Zeidner:

Yeah, I think there’ll hopefully be a lot more exciting data for next year in this space. So it’s great to be here and hear about all these exciting advances.

Eunice Wang:

Yeah. Me as well.