Cautious Optimism For Menin Inhibitors in AML Treatment
- Menin inhibitors have had a significant impact on the treatment of acute myeloid leukemia (AML), particularly in genetically defined subtypes such as NPM1-mutated and KMT2A-rearranged AML.
- In relapsed or refractory AML with NPM1 mutations or KMT2A rearrangements, menin inhibitors have demonstrated composite complete remission rates of approximately 20 to 35% and overall response rates of 45 to 65%, even in heavily pretreated populations.
- As with any new targeted therapy, early efficacy signals raise important questions about where menin inhibitors truly fit within the evolving AML treatment paradigm — particularly across different molecular subgroups.
- Despite the enthusiasm surrounding these approvals, experienced clinicians caution against over-interpreting response rates outside their intended setting. “For MPN1m patients, this is valuable in the approved setting [relapsed or refractory disease]. However, in both instances the response rate is modest — welcome, but modest,” Dr. Jorge Cortes, Director and Chair at Georgia Cancer Center, tells SurvivorNet Connect.
Menin inhibitors have had a significant impact on the treatment of acute myeloid leukemia (AML), particularly in genetically defined subtypes such as NPM1-mutated and KMT2A-rearranged AML.
These agents disrupt the menin-KMT2A interaction, leading to downregulation of leukemogenic gene expression and induction of myeloid differentiation. In relapsed or refractory AML with NPM1 mutations or KMT2A rearrangements, menin inhibitors have demonstrated composite complete remission rates of approximately 20 to 35% and overall response rates of 45 to 65%, even in heavily pretreated populations. A subset achieved measurable residual disease (MRD) negativity, enabling subsequent allogeneic stem cell transplantation.
As with any new targeted therapy, early efficacy signals raise important questions about where menin inhibitors truly fit within the evolving AML treatment paradigm — particularly across different molecular subgroups.
“Menin inhibitors are a major advance for the treatment of AML and I am very excited about the approvals,” Dr. Jorge Cortes, Director and Chair at Georgia Cancer Center, tells SurvivorNet Connect. “I see their value different depending on the indication. For the initial application for KMT2Ar AML (revumenib), it fills a significant gap because of the poor prognosis these patients have.”
Despite the enthusiasm surrounding these approvals, experienced clinicians caution against overinterpreting response rates outside their intended setting.
“For MPN1m patients, this is valuable in the approved setting, (relapsed or refractory disease). However, in both instances the response rate is modest — welcome, but modest,” Dr. Cortes adds.
Of the four menin inhibitors currently in clinical development (revumenib, bleximenib, enzomenib, and ziftomenib), only two are FDA approved for the treatment of AML: revumenib (brand name Revuforj) and ziftomenib (brand name Komzifti).
Revumenib is FDA approved and is an NCCN Category 2A option for:
- Relapsed or refractory acute myeloid leukemia harboring an NPM1 mutation (R/R NPM1m AML).
- Relapsed or refractory acute myeloid leukemia harboring an KMT2Ar mutation (R/R KMT2Ar AML).
Recent FDA Approval: Komzifti
Last november, the FDA granted full approval to ziftomenib for adults with relapsed or refractory acute myeloid leukemia harboring an NPM1 mutation, who have no satisfactory alternative treatment options.
This marks the first approved targeted therapy specifically for NPM1-mutated AML, addressing a critical population with historically poor outcomes and limited therapeutic choices.
The KOMET-001 clinical trial established ziftomenib as a potent, selective oral menin inhibitor with significant activity in relapsed or refractory acute myeloid leukemia (AML) harboring NPM1 mutations. In the phase 2 registration cohort, ziftomenib 600 mg once daily achieved a complete remission (CR/CRh) rate of 22% and an overall response rate of 33% in heavily pretreated NPM1-mutated AML, with 61% of responders achieving measurable residual disease (MRD) negativity.
Responses also occurred relatively quickly: the median time to first response was 2.7 months and, importantly, they were durable, with a median CR/CRh duration of 5 months.
Responses were observed regardless of prior venetoclax exposure or co-mutation status, and the median overall survival was 6.6 months.
The safety profile was manageable, with differentiation syndrome occurring in 25% (grade 3 in 15%, no grade 4-5), and low rates of myelosuppression and QTc prolongation. Only 3% discontinued due to drug-related adverse events.
How Do Menin inhibitors Compare to Chemotherapy?
As with any emerging targeted therapy, enthusiasm around menin inhibitors must be interpreted in the context of historical outcomes and their intended line of use. For decades, therapeutic options for relapsed or refractory AML were largely limited to high-intensity cytotoxic chemotherapy, a strategy associated with substantial toxicity and modest survival benefit in the salvage setting.
“In the past we only had high intensity chemotherapy induction, that’s extremely toxic,”Dr. Mohammad Maher Abdul Hay, a hematologist at NYU Langone’s Perlmutter Cancer Center, notes. “… Now, we are trying to get more targeted therapy, less toxic and better efficacy … and actually the data is much better.”
The development of targeted agents, including menin inhibitors, reflects a broader shift in AML treatment toward molecularly driven approaches that aim to improve efficacy while reducing treatment-related morbidity. Importantly, the clinical data supporting menin inhibitors must be interpreted within their approved indication (largely the relapsed or refractory setting).
When viewed against historical salvage chemotherapy outcomes, the survival signals seen with menin inhibitors appear clinically meaningful, even if responses remain modest in absolute terms.
“All these drugs [menin inhibitors] were used in second line, if you go and compare them to medium overall response, for example, they were six, nine months. If you compare historically any chemotherapy, high intensity, whatever chemo you used in subsequent line, the overall survival was three months,” Dr. Abdul Hay says.
The availability of an oral, targeted agent that can extend survival in a heavily pretreated population represents a tangible advance, particularly given the toxicity profile of prior approaches.
“So now you have an oral medication, that you’re doubling, deepening survival if compared to previous [extremely toxic] chemotherapy … so I think that’s what makes it exciting,” Dr. Abdul Hay adds.
Resistance, Clonal Evolution & the Challenge of Sequencing
As menin inhibitors move rapidly from early-phase trials into clinical practice, a critical unanswered question is the durability of responses and the potential for resistance.
AML is a biologically adaptive disease, and emerging data suggest that selective pressure from targeted therapies may drive clonal evolution, including secondary mutations that bypass menin dependency or activate alternative leukemogenic pathways.
Dr. Abdul Hay highlights this concern by pointing to early signals of resistance observed in clinical practice.
“Say someone on revumenib. Revumenib is the first menin inhibitor that went into the market, so we have the most data on it. If they do have certain mutations, they can be resistant to it [revumenib]. The question is: can you overcome it with other menin inhibitors? To my knowledge, the only case that we are aware of … there was a case that you could overcome from revumenib to bleximenib. They failed revumenib, went to bleximenib and went to complete remission,” he explains.
While intriguing, this observation remains anecdotal and highlights a significant gray area in the current understanding of menin inhibitor resistance. Whether resistance mechanisms are drug-specific or class-wide — and whether cross-resistance exists among different menin inhibitors — remains unknown.
Dr. Abdul Hay notes that this uncertainty reflects the early stage of development for this therapeutic class.
“This is a very, very new class of drugs. We are just getting to know about them. I think the more we see, the more we understand, the more we do analysis of the mutations, we will learn more about them … to understand if we can sequence them and to understand which mutation they may not work for to start with,” he adds.
Taken together, these observations underscore both the promise and the complexity of menin inhibition in AML.
What Does the Future Look Like?
Despite the need for caution, most experts agree that the long-term impact of menin inhibitors will likely be realized through rational combination strategies and refined sequencing, rather than single-agent use alone.
“Unquestionably the future is in combination with other drugs,” Dr. Cortes tells SurvivorNet Connect.
Potential strategies span a wide range, including integration with established chemotherapy backbones, venetoclax-based regimens, and other targeted agents. Moving menin inhibitors into earlier lines of therapy may ultimately yield the greatest benefit, particularly in biologically high-risk populations.
“There are many possibilities, from combination with the standard combinations, with other targeted agents. Ideally, we want to move them to the frontline setting, which is where the greatest impact maybe. This is particularly true for KMT2A-mutated patients, because they have a poor prognosis,” he adds.
Beyond response rates alone, future studies will need to clarify how menin inhibitors influence deeper endpoints that increasingly guide AML management.
“It will be interesting to see not only the response rates, but also the impact in minimal residual disease, long-term continuation therapy and how they affect decisions about transplant and use after transplant,” Dr. Cortes says.
The path forward may differ by molecular subgroup. In NPM1-mutated AML, where outcomes with standard therapy are often more favorable, demonstrating added benefit in the frontline setting may be more challenging.
While many questions remain unanswered, the expanding menin inhibitor landscape offers multiple avenues for investigation. As Dr. Cortes emphasized, this breadth of opportunity underscores both the promise of the class and the importance of careful, data-driven integration into clinical practice.
