Menin Inhibitor–Based Combinations Are Central to Ongoing Research in KMT2A+/NPM1+ AML

Maximilian Stahl, MD

Menin inhibitors such as revumenib (Revuforj) could address unmet needs in the treatment of patients with relapsed/refractory acute myeloid leukemia (AML) harboring KMT2A rearrangements or NPM1 mutations, and the ultimate role for these agents could be in combination therapies to provide bolstered options for patient populations with generally poor prognosis, according to Maximilian Stahl, MD.

The first menin inhibitor joined the AML treatment paradigm on November 15, 2024, when the FDA approved revumenib for the treatment of adult and pediatric patients aged 1 year and older with relapsed/refractory acute leukemia with a KMT2A translocation.¹ This regulatory decision was based on data from the phase 1/2 AUGMENT-101 study (NCT04065399).

“Going with a targeted agent [such as revumenib] that specifically targets a pathophysiology of KMT2A-rearranged leukemias has a lot of promise and has shown very good response rates,” Stahl explained in an interview with OncLive^® during the 2024 ASH Annual Meeting.

In the interview, Stahl discussed the unmet needs in treating patients with relapsed/refractory AML, highlighted the impact of the FDA approval of revumenib for patients with KMT2A rearrangements, and explained why combination therapies could represent the ideal use of menin inhibitors in AML.

Stahl is a physician of Hematologic Oncology and a member of the Adult Leukemia Program at Dana-Farber Cancer Institute, and he is also an instructor of medicine at Harvard Medical School in Boston, Massachusetts.

OncLive: What are the primary treatment challenges in the AML space? How could menin inhibitors add to the targeted therapy options for these patients?

Stahl: The treatment landscape for relapsed/refractory AML has changed for the better, but patients still have an overall poor prognosis if they experience a relapse. [One of the] options that we currently have approved and commonly use is a venetoclax [Venclexta] and hypomethylating agent [HMA]–based regimen, which is often used in the frontline setting as well. However, [this strategy] can be used after chemotherapy in patients with relapsed/refractory [disease].

Additionally, targeted therapies are also approved [in AML]. We have a FLT3 inhibitor [quizartinib (Vanflyta)] approved [in combination with chemotherapy for patients with newly diagnosed, FLT3-ITD–positive AML], as well as an IDH inhibitor [olutasidenib (Rezlidhia)] approved [for patients with relapsed/refractory AML with a susceptible IDH1 mutation].

[Looking at] menin inhibitors, this has always been a question: how [do we] target 2 other molecular abnormalities that have not been targetable thus far? This includes NPM1 mutations and KMT2A rearrangements, and that's where menin inhibitors come into play.

How does the FDA approval of revumenib address the specific gap in care for patients with relapsed/refractory acute leukemia harboring KMT2A rearrangements?

Revumenib is a menin inhibitor by Syndax Pharmaceuticals and is now approved for patients with [relapsed/refractory] KMT2A-rearranged leukemias. It's not yet approved for patients with NPM1-mutated leukemia, although the data look good as well for that subset of [patients]. We hope an approval [for patients with NPM1 mutations] will be imminent in [2025].

[The 2024 approval] fills a critical void for [patients with] KMT2A-rearranged leukemias. Those are what we consider adverse-risk leukemias in the sense that many of those patients are resistant to classic, traditional chemotherapy. Generally, giving those patients more chemotherapy is not that helpful.

[In the data that supported the 2024 approval,] revumenib showed in [AUGMENT-101] that patients who have [KMT2A] rearrangements in the relapsed/refractory [setting] had a complete remission [CR] plus CR with partial hematological recovery rate of 21.2% [95% CI, 13.8%-30.3%]. The [overall] response rate was higher, and [23%] of patients were able to proceed to an allogeneic stem cell transplant.² It is a critical part [of treatment for] patients with relapsed/refractory leukemia to get them to transplant because that is the only potentially curative approach for them.

What are the key considerations in identifying patients with relapsed/refractory AML who may be eligible for revumenib or other targeted therapies, particularly with respect to RNA vs DNA testing for KMT2A rearrangements and other markers?

Generally, for targeted therapies, we need to have in-depth genetic testing. This is a new realization in the field of AML, that one should wait for these test results before making a final treatment decision. For the menin inhibitors in particular, for the KMT2A rearrangement, you sometimes do pick them up on standard chromosome analysis—what we call cytogenetics. However, there can be rearrangements that are cryptic that we [therefore] cannot see on cytogenetics easily. Therefore, it is important to test for them with other techniques that are more sophisticated.

[In regard to] RNA-based tests, we use a fusion test that looks at multiple fusions using RT-PCR from RNA. That is an important test to run because otherwise, you might not find a patient who would be appropriate for [revumenib]. NPM1 mutations can be picked up by standard DNA sequencing via next-generation sequencing. Both [testing approaches] are important if we want to [identify] more patients who are potentially eligible for menin inhibitors.

Identifying KMT2A rearrangements is important for prognosis because most of them are associated with an adverse prognosis. This means that with chemotherapy alone, those patients can often not be cured, and that's why we do see a lot of relapses in this patient population.

Even the menin inhibitors are not curative per se, at least not as a single agent. What we have seen in the trial that led to the approval of revumenib is that although patients have a response—and there's a good population of patients who do have a response—this population of patients does not have a lasting response beyond several months. They respond for a couple of months, and then often they develop resistance mechanisms that make their disease come back and relapse. That's why transplant is such an important part of that treatment. When they have a response, try to get them to transplant.

For patients who are not transplant eligible, combination approaches with menin inhibitors will be even more critical. There have been several abstracts have looked at combining menin inhibitor with venetoclax- and HMA-based backbones, or intensive chemotherapy backbones. What we see is that patients generally have high response rates, and those responses seem to be very durable. The future of menin inhibition will be in combination therapy.

With the advent of more targeted therapies, it is essential to take that time and wait for genetic testing results. Often, that can take up to a week to get genetic testing back. However, it is time worth spending because it leads to better treatment options for patients.

What ongoing research with menin inhibitors could further illustrate the importance of timely identification?

The use of menin inhibitors as single agents marks only the start of their exploration in AML. The future is in combination therapies, and as we saw at the 2024 ASH Annual Meeting, and we will continue to see at future meetings is that it's a very busy field. There are several companies [developing] menin inhibitors, and they are testing those inhibitors in different ways with multiple different combination partners.

We saw promising data at ASH with [ziftomenib in combination with] the standard backbone of 7+3 chemotherapy. This was presented by Amer M. Zeidan, MBBS, MHS, of Yale University in New Haven, Connecticut. There are also other combinations with venetoclax and HMAs for patients who cannot tolerate intensive chemotherapy. Similarly, [these combinations have generated] high response rates, including high minimal residual disease–negative response rates.

Additionally, menin inhibitors will be explored [in combination] with other targeted therapies. There are now trials that combine them with a FLT3 inhibitor, including a trial that I lead at Dana-Farber Cancer Institute, which combines a menin inhibitor with intensive chemotherapy and a FLT3 inhibitor for patients who have both an NPM1 and FLT3 mutation. There will be many combinations [tested]. We'll have to see how those trials read out, but there is a lot of promise in this field.

References

1. FDA approves revumenib for relapsed or refractory acute leukemia with a KMT2A translocation. FDA. November 15, 2024. Accessed December 17, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-revumenib-relapsed-or-refractory-acute-leukemia-kmt2a-translocation
2. Syndax announces FDA approval of Revuforj (revumenib), the first and only menin inhibitor to treat adult and pediatric patients with relapsed or refractory acute leukemia with a KMT2A translocation. News release. Syndax Pharmaceuticals. November 15, 2024. Accessed December 17, 2024. https://ir.syndax.com/news-releases/news-release-details/syndax-announces-fda-approval-revuforjr-revumenib-first-and-only