Exploring Potential Combination Treatments for AML

EP: 1.The Role of Molecular Testing in Diagnosing Acute Myeloid Leukemia

EP: 2.When to Perform Molecular Testing in Relapsed AML

EP: 3.Barriers to Molecular Testing in AML

EP: 4.Treating Newly Diagnosed Acute Myeloid Leukemia

EP: 5.Treatment Options for a Young, Fit Patient Newly Diagnosed with AML

EP: 6.First-Line Treatment Options for NPM1-mutant AML

EP: 7.First-Line Treatment Options for AML With KMT2a Rearrangements

EP: 8.The Potential Role of Menin Inhibitors in the Front-Line Treatment of AML

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EP: 9.Exploring Potential Combination Treatments for AML

EP: 10.Menin Inhibitors in the Second-Line Treatment of AML

EP: 11.The Role of Menin Inhibitors in the AML Treatment Armamentarium

EP: 12.Determining Which Patients Will Benefit the Most From Menin Inhibitor Treatment

EP: 13.The AML Treatment Horizon

EP: 14.Menin Inhibitors in Acute Myeloid Leukemia: An Overview of “Encouraging” Early Data

Transcript:

Naval G. Daver, MD: We’ve also had a lot of experience here with all…6 different menin inhibitors and I have to say they’re all different. It’s going to be, if I had to predict, it’s going to be like the FLT3 inhibitor space. We’re going to have midostaurin, we have sorafenib, we have gilteritinib, we have quizartinib, crenolanib. With the menin, I think it’s going to be even more striking. The differences in safety, the kinetics and timing of differentiation syndrome is very, very different. When we were using Syndax [revumenib], ziftomenib and others, we’ve often said, “Well, we think the differentiation syndrome maybe a little bit overhyped or over concerned.” And with Syndax, I think that’s true. I think Syndax does have a little bit of sweet spot where differentiation is more predictable, it’s slower. It’s more like the IDH differentiation syndrome.

You give them Syndax, you control it, you don’t see explosive things. But with some of the others, Kura [Oncology], [Johnson & Johnson], Daiichi [Sankyo], we have used these, it is a little bit more aggressive, it can happen, [it can be] a little bit unpredictable. Now, whether this will also play into their efficacy and whether this may eventually lead to benefit when they are used in combination intensive chemotherapy, I think remains to be seen. But I do think that combining them is the way to go. I totally agree that when you look at these survival curves with Syndax, 7.5 months, one would say, “Well, why are you excited?” We’re excited because for salvage, MLL[-positive AML] would all be going to hospice at any of the centers, big academic centers, 5 years ago. Today you have a 35% response [rate], 7- to 8-month survival.

But really why we’re excited is because we think and know that when we move this up front in combination with HMA + VEN with chemo[therapy], then it will actually improve survival 20% to 30%, like the FLT3 inhibitors, like venetoclax. I think that’s where we want to go. I think those trials are fantastic combining chemo[therapy], HMA + VEN, but we have to get there. Dan, HMA + VEN-based combo, do you see a path here for adding a menin inhibitor, sequencing a menin inhibitor? How would you do this with an available menin inhibitor for older patients [for whom] you don’t want to give intensive chemo[therapy]?

Daniel Pollyea, MD, MS: I think this is something we should prioritize beyond even any other considerations for triple therapies, because like I said before, I think that there’s a weakness with venetoclax + HMA with this subset, this biological subset. They don’t do as well. They’re more resistant. They’re more likely to be refractory to venetoclax-based regimens if they do respond it’s typically brief. So, this scenario is one that I find very appealing to think about adding a menin inhibitor. Specifically how to do that, I think we have to be respectful of the toxicity profile of the doublet, the venetoclax + HMA. And we have to learn more about single agent toxicity of all these different therapies. As you pointed out, there does seem to be some significant differences in the landscape here. I don’t think it’ll be a one-size-fits-all [approach].

My inclination would be…there’s some other scenarios where I’ve advocated a little bit more for waiting to introduce the targeted therapy until the patient is in a remission, for instance, maybe patients with FLT3 or IDH [mutations] because response rates are pretty high in those subsets with just HMA + VEN [azacitidine or decitabine, and venetoclax] alone. This is a situation where I do think it would be advantageous to try to introduce the menin inhibitor in the up-front setting with the venetoclax based regimen. And frankly, this might be a scenario where there’s no added value to the menin inhibitor with the venetoclax specifically.

There are some scenarios where we’re really focusing on refractory subpopulations that venetoclax might have no role and a menin inhibitor plus some other therapy, maybe HMA or something like that, might be better. And so, we have to be open to that possibility as well. I think we’re in our infancy in doing this. I know there are a couple of menin inhibitors that have ventured into the up-front space and I’m very excited about those plans and opportunities. But I think we all have to be really open minded about how to do this and I think there may be multiple different ways to do it with some of the different therapies and this might be 1 of the ways these 6 different therapies, as you’ve said, are able to distinguish themselves a bit.

Naval G. Daver, MD: Let me ask any of you, because I haven’t seen this data, maybe I missed it. Do we know what the actual CR/CRi and OS is in KMT2A with HMA+ VEN? Is that something that’s been presented or published?

Daniel Pollyea, MD, MS: There are some small single-center publications of this that, if my memory serves me correct, show that it’s not quite the 70% response rates that you would expect and also that it had shown that the remission durations are shorter. I think there’s quite a bit of overlapping Venn diagrams between this disease subtype and others that have porous biology, RAS pathway mutations, monocytic disease. So, I think a lot of these are peas in a pod, and all maybe are representative of subtypes that don’t do as well. It would be nice to have even more data on this. As you know, given the relative rarity of this subtype, particularly in the older unfit population, I think there’s a dearth of data out there beyond some of these small, single-center retrospective studies. So, you’re right. I think we do need to get better data to understand this better.

Eunice S. Wang, MD: I would agree. I think we’ve looked at this data a little bit and we think the overall response rates to VEN + HMA-based therapy in KMT2A-rearranged [disease] is probably in the range of 30% to 50% or sort of more like an FLT3-mutant or a TP53-mutant than NPM1 and IDH1, IDH2, which tends to respond really well. …I would agree that the different menin inhibitors have different [adverse] effects, differentiation [syndrome] being a particularly troublesome one with the menin inhibitors. But I remind you that when we first developed ATRA [all-trans retinoic acid] + arsenic [protocol] and we first developed the IDH inhibitors, we had grade 5 events from differentiation syndrome. We still do have grade 5 events from differentiation syndrome with, for example, ATRA + arsenic.

That doesn’t prevent us from using ATRA + arsenic for patients with [acute promyelocytic leukemia (APL)] because of the extremely high response rates and long-term cure. I think we’ve learned over the time how to manage differentiation syndrome in IDH inhibitors in APL to try to mitigate or minimize that because of the potential obvious benefit of those agents. We also used to see grade 5 events with CAR T[-cell] therapy, [such as] cytokine release syndrome. And with the introduction of aggressive tocilizumab and steroid use, we certainly have moved forward with CAR T. So I think that the differentiation syndrome that we see with the menin inhibitors is certainly something that we can learn from and manage. And some of the differences, for example, the Syndax revumenib compound, their drug was limited by QTc prolongation as their DLT [dose-limiting toxicity]. If they didn’t have the QTc prolongation, they could have escalated further and could have had a higher incidence of differentiation syndrome had that occurred. We certainly do, as Dr Erba mentioned, see a difference between KMT2A-rearranged leukemia and NPM1[-mutated disease].

Whether that’s a difference in agents or a difference in biology, we discovered that a lot of our [patients with] KMT2A rearrangements actually have extramedullary disease, which we didn’t know about in the majority of patients until all of a sudden they blew up with joint inflammation and effusion. I think we didn’t see that with the NPM1-mutant [disease]. So, whether it’s a drug effect, a dose effect, or maybe a completely different disease biology, we just don’t know. I think this is something that we’ll be learning. I know that we do have as outlined in a trial in progress abstract at ASCO [American Society of Clinical Oncology Annual Meeting] this year, a trial where ziftomenib will be combined with either 7 + 3 or venetoclax + azacytidine [AZA] initially in potentially relapsed patients to get safety and tolerability. And then subsequently, we hope in the up-front setting to try to see whether we can integrate menin inhibitor and targeting this foundational mutation earlier which I think is really where we want to see that drug go.

Harry P. Erba, MD, PhD: In my own limited experience in the [patients with] KMT2A rearranged [disease], both relapsed/refractory and previously untreated older patients, I haven’t seen a single response out of—it’s less than 5 patients, like 4 patients. And that’s the difficulty in these rare subtypes. And again, a plug for the NCI [National Cancer Institute]-sponsored MyeloMATCH [NCT05564390], the real beauty of this platform is that every patient is going to have sequence and mutational data turned around within 72 hours. So that’s for the patient. And for clinical investigation, we would love to see ideas coming forward for the [patients with] KMT2A rearrangements receiving novel therapies because it’s going to be very hard to do these studies in subpopulations unless you have the power of a North American inter-group study.

Eunice S. Wang, MD: Well, we do have that, Dr Erba. As you know, we have a menin inhibitor trial for younger [patients with] AML within MyeloMATCH and a proposal for a menin inhibitor study in combination with VEN + AZA in the older patient population. And hopefully, we can harness the power of the cooperative groups for these, particularly [patients with] KMT2A rearrangements, to gather cooperative national data as well as to make some of these inhibitors available to centers across the country that may only have a few of these patients, but really these patients could benefit from that drug available on a nationwide level.

Harry P. Erba, MD, PhD: I think there’s a way of recognizing the mentorship and leadership of Dr Wang in MyeloMATCH. She’s shepherding those along.

Naval G. Daver, MD: Great. So, hopefully, we’ll see MyeloMATCH open and start enrolling in the near future and get some data from that. I think I agree that with HMA + VEN, as you know I’ve been working a lot with these triplets, I think it really depends on what disease. And again, it’s not one size fits all. I agree with what Dan and, I think, Eunice were saying. For the really bad actors—…TP53, MLL, RAS— I think it makes sense to hit it hard right away if you can get a deep response. And now the nice thing is we have molecular technology that can get us to 10−5 or even 10−6 for FLT3, maybe for MLL having PCRs [polymerase chain reactions], maybe for NPM1, TP53, [having] digital droplet PCR. And then we will see if we can really improve the outcome, whether these patients eventually go to transplant or not.

But then there are certain subsets where I think that’s a really difficult proposition like IDH1, IDH2, [and] NPM1. We had a lot of discussions at EHA [European Hematology Association] about this. For IDH, as you may know, now ivosidenib [IVO] is showing 29 months overall survival. So, for a triplet, the bar is very high because those patients, of course, could get AZA + IVO 29 months, yes, and then at relapse, they could get AZA + VEN. And 2 retrospective analyses are showing close to 60% CR [complete response]/CRi [CR with incomplete recovery] with another 11- to 12-month survival… . So I think that bar is going to be really tough at 35, 40 in an older population, whereas maybe with the KMT2A,TP53, 10 to 11 months, can you beat that? Can you move ahead? So, I think we’re going to see a lot of interesting things.

Transcript is edited for clarity and readability.