Menin Inhibitors in the Second-Line Treatment of AML


The expert panel discuss emerging data on menin inhibitors in the second-line treatment of AML, including an overview of the KOMET-001 trial evaluating ziftomenib.


Naval G. Daver, MD: Now [let’s focus] more on where we are today in the relapsed state with the menin inhibitors. We [do not] yet [have] much data on the front line. Hopefully, next year when we do this, we’ll have a lot more exciting frontline data with HMA [hypomethylating agents]-VEN [venetoclax] with intensive chemo[therapy]. Dr Erba, if you want to walk us through some of the data presented by Amir Fathi, [MD, MPH, Massachusetts General Hospital, Boston] at the EHA [European Hematology Association] meeting in the relapse setting, maybe focusing on some of the efficacy. And then we can turn to Dr Wang to talk about some of the safety aspects.

Harry P. Erba, MD, PhD: I already reviewed for what I consider the top-line result here. With further follow-up, we had a 40% rate of CR/CRh [complete response/CR with partial hematologic recovery]. I think there was one other morphologic leukemia-free state. The median duration of those remissions was 8 months. However, if you censor at the time of transplant because some of these patients went on to transplant, it is shorter because you’re censoring at the time of transplant. It was 5 months there. But as I said, [this is] very similar to what got enasidenib approved in IDH2-mutated relapsed/refractory disease.

The only thing I’ll add to the efficacy data is what are we learning about resistance or the development of refractory disease? With revumenib, the Syndax compound, there have been a number of mutations—gatekeeper mutations—in menin that have been identified. What’s interesting [is] out of 12 patients that we had samples on with relapsed/refractory disease, only 1 of them had a mutation that potentially would interact and prevent binding of ziftomenib. And so maybe [this is] another differentiating point. Of course, when I saw that data, I immediately asked the sponsor, “OK, well, if it’s not point mutations in menin, then what is it that’s leading to relapse refractory disease?” So, we have a lot more work to be done. But again, as [Dr Wang] said, these drugs are different and, hopefully, it’s going to be good to have multiple options for our patients in the future.

Naval G. Daver, MD: [Dr Wang], do you want to highlight some of the safety and different menin inhibitors [and] how we should approach them? What are you doing in practice? We’ve talked about this in a lot of investigative meetings. When you start somebody on menin, how do you follow differentiation? How do you manage it at the first signs? Could you walk us through that, please?

Eunice S. Wang, MD: I think that what we’ve known and what we’re seeing now with the menin inhibitors in some patients is very potent hyperleukocytosis and development of what we call differentiation syndrome, which looks a little bit different from what we’re used to. I think with IDH inhibitors we got used to the effect that differentiation can occur late in the process, even up to 100 days after starting IDH inhibitor, and can present with fever, maybe some small infiltrates, and patients [who can be] managed in the outpatient setting. What we’ve seen with the menin inhibitors, maybe because of the bulk of disease or the number of cells that have the target aberration, [is] massive increases in white [blood cell] count, even patients having white [blood cell] counts going up to 100,000 over a matter of days.

Patients who come in and have a white count of 3, then it’s 6, then it’s 10, then it’s 30, then it’s 50, then it’s 100. And so, for those patients on some of these trials, I think [for] patients [who] have very high risk, we recommend cytoreducing their white [blood cell] count. Regardless, you [may] still see the response. Some of those patients may need to be hospitalized for the first few days for closer serial CBC [complete blood count] monitoring, early initiation of steroids, and for patients who have that hyperleukocytosis, maybe initiation of 1 or 2 doses of cytarabine or high-dose Hydrea [hydroxyurea]. What we’re seeing is not neutrophilia at that very early stage. What we’re seeing is this differentiation effect occurring usually within the first couple of weeks of starting the drug. What we’re seeing is actually an increase in blasts, which in some cases have had clinicians mistake that for [an] all-of-a-sudden explosion of the underlying AML. We have also seen that not only is attenuation of that differentiation syndrome really important, but to do so before other clinical manifestations result like pleural effusions, pericardial effusions, [and] significant weight gain.

And those patients may need to be closely monitored in some settings, in the inpatient setting, for the first several days of their cycle 1. What we’ve also seen is that patients who are responding, particularly some of the [patients with] NMP1-mutant disease, are responding after a few cycles of therapy. So, like any differentiation syndrome, whether it’s ATRA [all-trans retinoic acid] + arsenic or IDH1/IDH2 inhibition, or menin inhibition, you may need to administer the drug for 2 to 3 cycles minimum before you start to see the blast starting to clear. So, again, [this is] something that we’re monitoring for. Dr Erba brings up the point of menin resistance, and there have been, in patients treated with the revumenib menin inhibitor, reports that 39% of patients on treatment were found to have developed a treatment-related or treatment-induced mutation in the menin mutation that renders those cells newly resistant to treatment with revumenib monotherapy. Those have not been identified. I think now the data are up to 29 patients treated with the ziftomenib. But at the EHA meeting, there were data from [Florian] Perner, [MD, Greifswald University Hospital, Germany,] whose group initially described the menin mutations in the revumenib-treated genes, describing a novel mechanism of menin resistance which is not genetically based and appears to be due to upregulation of other genes that are independent of that pathway.

And so there are newer data suggesting that for those particular types of resistance, that the AML cells are still responsive to menin inhibition, but now no longer care because they’re no longer addicted to the menin as a process for driving tumor growth. I think there’s a lot to learn. What those data suggest is that again, with all of our therapies, gilteritinib is effective; for example, monotherapy IDH inhibitor is effective in monotherapy in relapsed/refractory setting. But as demonstrated by Dr Daver’s point, the AGILE trial (NCT03173248), IDH1 inhibitor [ivosidenib] + azacitidine [treatment] is leading to prolonged overall survival in a combination regimen in the up-front setting. So, combining these targeted therapies [and] moving them up front may result in the greatest benefit for those patients rather than single monotherapy. Once a patient relapses, their disease goes out of control. It’s like, as Dr Erba says, “whack a mole.” As soon as you whack something down, something else emerges. And so, I think combination approaches may be the way to go. I agree with Dr Pollyea that menin inhibitors maybe should be started with the first up-front therapy for greatest efficacy.

Naval G. Daver, MD: To go through some of the other menin inhibitor data as well for balance, [the] Syndax [compound revumenib] also has shown very effective data published recently in the Nature. Ghayas Issa, [MD,] from MD Anderson [Cancer Center, in Houston, Texas,] was the first author. [Eytan M.] Stein, [MD, Memorial Sloan Kettering Cancer Center, New York] was the last author. They led these efforts. And I find it interesting. But of course, in that state, the focus was much more on the KMT2A MLL, partly because that is where they were seeing responses. Whenever I speak to [Dr Issa] or [Stein], they basically said that that’s because the ship moved that way. It’s kind of like magrolimab, where we saw the activity in TP53 was an unmet need and so everybody just loaded it with that and then now we really don’t know in the wild type until the randomized study.

But there was the activity in the wild type as well. So that’s what they think happened, is that because of the need for MLL KMT2A relapsed treatment, the early signal there, you see the study is heavily enriched. I think they had a smaller number of NPM1. In that smaller number, the response rates look numerically lower. I don’t know [if], with time, they’re going to be able to expand that. On the other hand, I think with the Kura [menin inhibitor ziftomenib], we are seeing more focus and movement into the NPM1. So, just to highlight with this index, their overall response rate was close to around 40%, [and the] CR/CRi [CR with incomplete blood recover] rate [was] 35%. This was at the target dose in the KMT2A rearranged [disease]. These were about third [or] fourth salvage, so a very advanced salvage. And I think both of these agents, as Dr Erba has highlighted a couple of times—and I completely agree—these are numbers very similar to not just enasidenib, ivosidenib, but even gilteritinib. When you look at the response rate, the CR/CRi rate was 34%, almost exactly the range you’re seeing with the Kura and Syndax [compounds], and the survival was around 9.5 months. But remember that was in first salvage setting, primary refractory or relapsed population. So to see this in the third, fourth salvage with these agents, I do think that really they should have a good chance of hopefully getting regulatory path approval [for] a single agent, but then really doing the more exciting work to move it up front, combine it, and then really improve the survival.

Transcript is edited for clarity and readability.

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