Menin inhibitors are poised to become an important addition to the acute myeloid leukemia (AML) treatment paradigm, with anticipated roles in frontline combination regimens, post–stem cell transplant maintenance, and potentially as part of quadruplet regimens in patients with co-occurring mutations, according to Naval G. Daver, MD, and Eytan M. Stein, MD.
The activity of revumenib (Revuforj) across multiple genetically defined AML subgroups supports their broader applicability to HOX gene–mediated leukemias, including NUP98 fusions, which may require combination strategies due to relative resistance. In November 2024, the FDA approved the agent for the treatment of adult and pediatric patients aged 1 year and older with relapsed or refractory acute leukemia and a KMT2A translocation.
“Not only should menin inhibition work for NUP98 fusions, but the hope is that it will be effective in any HOX-mediated leukemia,” Eytan M. Stein, MD, chief of Leukemia Service and director of Program for Drug Development in Leukemia, Division of Hematologic Malignancies at Memorial Sloan Kettering Cancer Center in New York, shared with OncLive®. “There is both clinical evidence and strong preclinical rationale supporting the idea that the therapeutic benefit of menin inhibition could extend beyond the currently defined patient subsets for which there is approval or regulatory submission.”
Indeed, early frontline trials combining menin inhibition with standard therapies such as azacitidine (Vidaza) and venetoclax (Venclexta) have yielded high response rates, suggesting the potential for deep molecular remissions and time-limited treatment strategies.
Daver, a professor and director of the Leukemia Research Alliance Program in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, added “This strategy may represent the optimal way to use menin inhibitors to achieve deep, early, and complete molecular remissions, potentially allowing treatment de-escalation after 8 to 12 months, and possibly discontinuation of indefinite therapy, contingent on sustained molecular clearance. This approach could be a significant advance in the development of menin inhibitors.”
In their interviews, Daver and Stein discussed the prevalence and clinical significance of NPM1 mutations and NUP98 rearrangements in AML, the efficacy and evolving role of menin inhibitors like revumenib in these genetically defined subgroups in the relapsed/refractory setting, and the rationale for combining menin inhibitors with standard frontline therapies to improve patient outcomes.
OncLive: What is the prevalence of NPM1 mutations and NUP98 rearrangements in AML?
Daver: Menin inhibitors, including revumenib, are currently being evaluated across multiple genetically defined subgroups of relapsed/refractory AML, particularly those with NPM1 mutations, NUP98 rearrangements, and KMT2A rearrangements. [My colleagues and I] published a seminal paper looking at [these subgroups] and found that NPM1-mutated AML accounts for approximately 15% of the relapsed/refractory population, while NUP98 rearrangements occur in 3% to 5% of cases. KMT2A rearrangements are observed in approximately 6% to 8% of relapsed/refractory AML overall, with a higher prevalence in [patients younger than] 30 years [of age] and becomes a little less common as [patients] get older.
Then there are other fusions that may also be sensitive to menin inhibitors that are not as common and have not been a focus, but they have been evaluated in trials and case reports published on them. These include UBTF rearrangements, NU214 fusions, etc. [Although] individually uncommon, these additional aberrations contribute to a broader spectrum of patients who may benefit from menin inhibition.
Collectively, it is estimated that the total population of patients with menin-sensitive genetic alterations may represent 35% to 40% of relapsed/refractory AML. This proportion is comparable with the prevalence of FLT3 mutations in this setting, underscoring the relevance of this therapeutic class.
What are some of the unmet needs in NMP1-mutant AML that could be addressed by menin inhibitors such as revumenib?
Stein: NPM1-mutant AML is quite common. It occurs in approximately 30% of patients with AML. Fewer patients are relapsed/refractory, but those who are relapsed/refractory actually have a pretty dismal prognosis. Drugs that can address NPM1-mutant relapsed and refractory acute myeloid leukemia are needed.
What we’re seeing, at least with revumenib in the relapsed/refractory NPM1-mutant space, is very similar to what we saw in the KMT2A-rearranged space, in that there are high overall response rates in the range of 50% to 55%. We see rates of complete remission [CR] and CR with partial hematologic recovery [CRh] in the range of 23% to 26%. Those are impressive numbers. Those are numbers that allow a patient, hopefully, to get to a curative allogeneic stem cell transplant.
Similar to the prior experience, I do think that the durability of any menin inhibitor in NPM1-mutant AML is shorter than we want it to be as a single agent. If a patient can have a stem cell transplant afterward, it’s probably a good thing to do that.
What have data from the phase 1/2 AUGMENT-101 study (SNDX-5613-0700; NCT04065399) indicated about the efficacy of revumenib specifically in NMP1-mutant AML?
Daver: For NPM1[-mutant] relapsed/refractory disease, it’s important to highlight that this is no longer what we would consider a favorable type of patient population. In our paper [evaluating] the outcomes of relapsed/refractory NPM1[-mutant AML] compared with relapsed/refractory patients without NPM1 [mutations], we showed in a pretty big patient population that there was no difference in terms of survival in patients in second or third salvage with relapsed NPM1[-mutant AML]. The median survival is approximately 6 to 7 months.
There’s a huge unmet need there, and the menin inhibitors have been showing good efficacy. In the AUGMENT-101, for the relapsed NPM1[-mutant AML patient population] specifically, revumenib has a CR/CRh [rate] of close to 25% and an overall response rate [ORR] of approximately 50%. This is quite encouraging because historically we have seen that in the advanced salvage NPM1[-mutant] setting, the CR/CRh rates are between 10% to 15%, and ORRs are less than 30% to 35%. This seems to be an improvement.
[Additionally], the duration of remission here is close to 6 to 7 months. This is an incremental improvement with a single-agent menin inhibitor vs what you may see with standard therapy. [However], we will see the maximum benefit of these drugs as we move them either upfront into the combinations or potentially even salvage in combinations.
What is the rationale for evaluating the use of revumenib in patients with AML harboring NUP98 rearrangements?
Stein: The general rationale is that menin is a protein involved in any leukemia characterized by upregulation of HOX genes. Menin binding to KMT2A is important for any HOX-mediated leukemia. NUP98-[rearranged AML] is a rare subset, but is definitively a HOX-mediated leukemia.
We have clinical data showing that if you give a menin inhibitor, such as revumenib, to patients with NUP98 rearrangements, you can achieve CRs similar to what is observed in KMT2A-rearranged and NPM1-mutant leukemias. [We do not see] a large number of patients with NUP98 rearrangements enrolled on those studies, so the true response rate remains somewhat unclear to date.
The hope is that [menin inhibition] will be effective in any HOX-mediated leukemia. For example, in early studies of another compound, ziftomenib, there were a few patients who had neither KMT2A rearrangements, NPM1 mutations, nor NUP98 rearrangements, and they achieved CRs.
What activity has been seen within the NUP98–rearranged population with revumenib?
Daver: To my knowledge, there have not been focused presentations aggregating those data, but there have been responses with that population. What we know from the preclinical data is that NUP98-rearranged AML tends to be more resistant. We find that there’s [varying] sensitivity when it comes to menin inhibitors and how they work with different mutations. The most sensitive on that scale is KMT2A-rearranged [AML], the second seems to be NPM1, and then the least sensitive, or more resistant—requiring either higher doses or prolonged exposure to menin inhibitors—has been NUP98-rearranged [AML].
That being said, we have seen a handful of responses across various menin inhibitors. If we do achieve a response, especially in the NUP98-rearranged [patient population], we are nervous and cognizant that this may be short lived, given how aggressive it is, and we do try to move those patients to transplant quickly. A combinatorial approach is likely going to be the best approach, and we’re looking at those going forward.
Given the activity we’ve seen with menin inhibitors in NMP1-mutant and KMT2A-rearranged AML, just how applicable might these agents be for patients with AML as a whole?
Stein: Theoretically, these agents could be applicable to a broader population if the HOX-mediated hypothesis holds up clinically. Approximately 50% of AMLs may be characterized by HOX gene dysregulation, suggesting that adding a menin inhibitor could provide benefit in a substantial proportion of patients.
This potential for broad applicability could ultimately lead to a significant clinical impact. However, companies have primarily focused development efforts on NPM1-mutant and KMT2A-rearranged AML because the regulatory pathway for these subtypes is more clearly defined.
To expand into the broader category of HOX-mediated leukemias, it would be necessary to develop a validated, FDA-approved assay capable of reliably detecting HOX gene upregulation. Such an assay does not currently exist, making the path toward regulatory approval in this broader group more complex. Nonetheless, there is a reasonable expectation that menin inhibition could ultimately benefit a larger subset of patients as the field evolves.
Why have menin inhibitors been increasingly investigated in combination with standard-of-care approaches in the frontline?
Stein: The rationale for the combinations is based on leveraging distinct mechanisms of action: specifically, combining broadly effective agents such as chemotherapy, azacitidine, or venetoclax with a targeted menin inhibitor to achieve both cytotoxicity and differentiation of malignant cells. This strategy is consistent with prior approaches involving differentiation agents such as all-trans retinoic acid, arsenic trioxide, and IDH inhibitors, which have demonstrated enhanced remission rates when used in combination with chemotherapy.
An additional rationale for pairing menin inhibitors with cytotoxic agents is the potential to reduce the incidence and severity of differentiation syndrome. Menin inhibitors are known to cause differentiation syndrome, which can be severe in some patients. Administering chemotherapy up-front may help debulk the leukemia burden before initiating the menin inhibitor, potentially mitigating this risk.
What have the data shown about the frontline combination of azacitidine and venetoclax with revumenib?
Daver: Azacitidine/venetoclax works very well on the hematopoietic stem and progenitor [cell] populations, whereas menin inhibitors seem to work better on the more differentiated and monocytic [cell] populations. Preclinically, this finding supports combining these agents to target both early hematopoietic stem/progenitor cells and the more differentiated monocytic/monoblastic [cell] populations, which can cause resistance to azacitidine but remain sensitive to menin inhibition.
This rationale has led to several combination studies, with the most mature data coming from the [phase 1/2] Beat AML trial [NCT03013998]—a frontline trial presented [in 2024]. In this study, all 24 response-evaluable patients who underwent end-of-cycle 1 marrow assessment achieved a response [with this triplet].
A few caveats include that durability of response remains too early to assess. Additionally, prolonged count recovery and longer intervals between treatment cycles have been observed. In response, the investigators have been considering reducing venetoclax duration from the initial 28 days to 21 or even 14 days, as is being done in other triplet regimens, to mitigate prolonged myelosuppression.
Importantly, the high response rates have not been associated with higher-than-expected early mortality, severe infections, or ICU admissions.
Key end points to watch moving forward include minimal residual disease clearance, especially in NPM1-mutated patients and, if data permit, in KMT2A-rearranged AML; duration of remission; and overall survival [OS]. Historically, the median OS with azacitidine/venetoclax is approximately 15 to 18 months overall, but it is higher in NPM1-[mutant AML] and somewhat lower in KMT2A-rearranged AML. It will be important to see what incremental benefit the triplet combinations offer, comparing similar patient populations.
Several other trials [of various revumenib combinations] are underway. Comparative evaluation of myelosuppression, QTc impact, differentiation syndrome rates, molecular clearance, and durability among these combinations will help determine whether differences emerge.
Assuming that the data continue to be positive, what role do you ultimately see for menin inhibition in the AML treatment paradigm?
Stein: If historical [precedent] is any guide, the likely future trajectory for menin inhibitors in AML will involve their incorporation into frontline regimens for patients with NPM1 mutations, KMT2A rearrangements, and potentially other HOX-driven leukemias. In younger, fit patients, this would likely involve use in combination with intensive chemotherapy, whereas in older or unfit patients, menin inhibitors would be paired with hypomethylating agents [HMAs] and venetoclax.
Many patients receiving these frontline regimens may proceed to allogeneic stem cell transplantation, and there is a strong rationale for evaluating menin inhibitors in the post-transplant maintenance setting. Likewise, for patients not proceeding to transplant, use of menin inhibitors as maintenance therapy may also be appropriate.
As these agents move earlier in the treatment paradigm, the need for their use in the relapsed/refractory setting will—ideally—diminish due to better up-front disease control. However, menin inhibitors may also play a role in combination strategies with other targeted therapies in both newly diagnosed and relapsed/refractory settings. For example, NPM1-mutant AML often co-occurs with FLT3 mutations, and FLT3 inhibitors are standard of care when given with intensive chemotherapy. It is conceivable that future regimens may incorporate 4-drug combinations that include a menin inhibitor, a FLT3 inhibitor, and intensive chemotherapy.
Key questions moving forward will center on optimal sequencing of these agents, whether they should be given concurrently or sequentially, [and] which components may be dropped over time. These evolving strategies will provide ongoing opportunities for clinical research to refine treatment paradigms and improve outcomes in AML.
Daver: Targeted therapy has made significant progress in AML, beginning notably with FLT3 inhibitors. Historically, FLT3 mutations were considered adverse-risk when first characterized in 2002, with 5-year survival rates around 20% to 25%. Today, for younger patients with FLT3 internal tandem duplications, survival rates approach 70% [at 5 years], leading to a reclassification of FLT3 mutations from adverse to intermediate risk, and in some cases even favorable. This evolution represents a clear success story.
A similar trajectory is anticipated with menin inhibitors. Currently, KMT2A-rearranged AML is classified as adverse risk per the 2021-2022 National Comprehensive Cancer Network and European LeukemiaNet guidelines. However, as menin inhibitors are integrated into frontline regimens—whether combined with intensive chemotherapy, HMAs, or venetoclax—it is expected that outcomes will improve substantially, potentially reclassifying KMT2A-rearranged AML into intermediate or even favorable risk categories.
Beyond KMT2A, menin inhibition may similarly improve outcomes in NPM1-mutated AML, NUP98 rearrangements, UBTF rearrangements, and other fusion-driven leukemias. Although NPM1 mutations are generally considered favorable, it is important to contextualize that a median OS of 25 to 30 months is still suboptimal; improvements extending median OS beyond 40 months or achieving cure represent meaningful clinical advances. Moreover, the ability to deliver effective, time-limited frontline therapies—potentially akin to acute promyelocytic leukemia paradigms—using menin inhibitors combined with HMAs to achieve deep molecular remissions and discontinue therapy with close monitoring would be a significant breakthrough.
Future directions include combining menin inhibitors with FLT3 and IDH inhibitors, as well as refining patient selection using RNA-based profiling approaches. It is plausible that 40% to 45% of patients with AML could ultimately benefit from menin-based therapies. Overall, menin inhibitors are poised to become a major addition to the targeted therapy landscape alongside FLT3 and IDH inhibitors.
Reference
FDA approves revumenib for relapsed or refractory acute leukemia with a KMT2A translocation. FDA. November 15, 2024. Accessed July 7, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-revumenib-relapsed-or-refractory-acute-leukemia-kmt2a-translocation