What key insights are emerging from ongoing trials of menin inhibitor combination strategies in AML?

The AML Hub was pleased to speak with Joshua Zeidner, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, US. We asked, What key insights are emerging from ongoing trials of menin inhibitor combination strategies in AML? 

Zeidner provides an overview of currently approved menin inhibitors and discusses combination strategies in development for the treatment of NPM1-mutated (NPM1m) and KMT2A-rearranged (KMT2Ar) acute myeloid leukemia (AML). He highlights key data from ongoing trials of menin inhibitor combination approaches, which aim to improve outcomes in both newly diagnosed (ND) and relapsed/refractory (R/R) patient populations. 

Key points 

• At present, two menin inhibitors, revumenib¹ and ziftomenib,² are approved by the U.S. Food and Drug Administration (FDA) for the treatment of NPM1m AML, with revumenib also approved for KMT2Ar acute leukemia.¹ 
• Although menin inhibitor monotherapy regimens have demonstrated favorable response rates, they have shown limited durability, with median duration of response (DoR) of ~4–5 months.^3,4 
  • Therefore, the addition of menin inhibitors to existing regiments for AML treatment is being investigated in ongoing clinical trials, with the aim of further improving response rates and durability of responses. 
• Early studies combining menin inhibitors with hypomethylating agents (HMAs) and venetoclax (Ven) in patients with R/R AML have shown promising durability and overall response rates (ORRs). 
  • In the phase I KOMET-007 trial (NCT05735184), ziftomenib in combination with azacitidine (Aza) + Ven demonstrated a 65% ORR in patients with R/R NPM1m AML (n = 48), with a composite complete response (CRc) of 48% and median CRc duration of 39.9 weeks. The ORR in patients with R/R KMT2Ar AML (n = 32) was 41%, with a 28% CRc, and median CRc duration of 12.4 weeks.⁵ 
  • Additional investigational combinations include either Ven + Aza or oral decitabine/cedazuridine, with other menin inhibitors such as revumenib, enzomenib, or bleximenib.  
  • Ongoing research aims to identify which patient populations may benefit most from combination regimens vs monotherapy approaches. 
• Combination strategies in ND older or unfit patients with AML have also demonstrated promising clinical activity, with ORRs approaching 90% in this first-line setting. 
  • In the phase I KOMET-007 trial, ziftomenib with Aza + Ven resulted in an ORR of 89% and CRc of 86% patients with ND NPM1m AML (n = 37). After a median follow up of 26.1 weeks, the median duration of complete response and overall survival were not reached.⁶ 
  • In a phase I substudy (BAML-16-001-S17) of the Beat AML master protocol (NCT03013998), the combination of revumenib with Aza + Ven in ND older patients with NPM1m AML (n = 34) gave an ORR of 85% and CRc of 79%, with a median DoR of 12.0 months. In older patients with ND KMT2Ar AML (n = 9), the ORR was 100%, with a CRc of 89% and median DoR of 11.2 months.⁷ 
  • Randomized phase III trials are ongoing to determine whether the benefit of these combination approaches is clinically meaningful. 
• Overall, combination strategies with menin inhibitors represent a highly promising direction in AML, with ongoing trials expected to clarify their role in both R/R and ND AML. 

This educational resource is independently supported by Kura Oncology. All content was developed by SES in collaboration with an expert steering committee. Funders were allowed no influence.