What does the future hold for next-generation menin inhibition in AML?

The AML Hub was pleased to speak with Eunice Wang, Roswell Park Comprehensive Cancer Center, Buffalo, US. We asked, What does the future hold for next-generation menin inhibition in AML?

During this interview, Wang discusses emerging strategies to optimize the efficacy of menin inhibitors for the treatment of acute myeloid leukemia (AML), including sequential treatment approaches to address acquired resistance, their integration into combination regimens for KMT2A-rearranged (KMT2Ar) or NPM1-mutated (NPM1m) AML, and their use alongside other targeted therapies for patients with co-occurring mutations.

Key points

• Two menin inhibitors are currently approved by the U.S. Food and Drug Administration (FDA): revumenib, for the treatment of relapsed/refractory (R/R) KMT2Ar acute leukemia or NPM1m AML; and ziftomenib, for the treatment of adults with R/R NPM1m AML.^1,2
  • Despite their clinical activity, response rates and durability remain limited, with median durations of response (DoR) of ~4–5 months.^3,4
  • Acquired resistance is also a challenge; menin inhibitor monotherapy has been associated with development of further mutations such as MEN1 mutations, which may impair menin inhibitor binding and affect the efficacy of treatment.^5,6
• Several approaches involving menin inhibitors, including revumenib and ziftomenib, as well as next-generation therapies such as bleximenib and enzomenib, are under investigation to address these limitations and improve treatment outcomes for patients with KMT2Ar or NPM1m AML.
• One potential approach to address acquired resistance is sequential treatment with other menin inhibitors following loss of response, guided by the presence or absence of specific MEN1 mutations. Proof of concept for this strategy has been reported in clinical case studies, suggesting it may help overcome acquired resistance and restore responses.^7,8
• Menin inhibitors are also being investigated in combination with intensive or non-intensive regimens for patients with newly diagnosed (ND) KMT2Ar or NPM1m AML, with early-phase studies reporting encouraging response rates.
  • In the phase Ib ALE1002 trial (NCT05453903), bleximenib 100 mg BID plus intensive chemotherapy demonstrated a composite complete remission (CRc) rate of 87.5% in patients with ND KMT2Ar or NPM1m AML (N = 24).⁹
  • In the phase I KOMET-007 trial (NCT05735184), ziftomenib + venetoclax + azacitidine demonstrated CRc rates of 28% and 48% in patients with R/R KMT2Ar (n = 32) and NPM1m (n = 48) AML, respectively.¹⁰
• An emerging approach is dual-targeted treatment for patients with co-occurring mutations. Clinical trials are investigating menin inhibitors in combination with FLT3 inhibitors, such as revumenib + gilteritinib (NCT06222580), and IDH inhibitors, such as ziftomenib + olutasidenib (NCT07411586), to target complementary disease pathways and potentially improve treatment efficacy.^11,12
• Given their effects on chromatin regulation and gene expression, menin inhibitors are also being investigated beyond AML, with preclinical research exploring their potential in other acute leukemias such as B-cell and T-cell acute lymphoblastic leukemia.^13,14
• The development of next-generation menin inhibitors and novel treatment strategies may help overcome current limitations of menin inhibitor therapy, improve outcomes for patients with AML, and potentially expand their application to a wider range of hematologic malignancies.

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