Mechanisms and rationale for menin inhibitor combination strategies in AML

The AML Hub was pleased to speak with Eunice Wang, Roswell Park Comprehensive Cancer Center, Buffalo, US. We asked, What are the mechanisms and rationale for menin inhibitor combination strategies?

Wang summarizes the rationale for menin inhibitor combination strategies for the treatment of NPM1-mutated (NPM1m) or KMT2A-rearranged (KMT2Ar) acute myeloid leukemia (AML), including their potential for improving outcomes and reducing the risk of resistance vs menin inhibitor monotherapy. Wang also suggests mechanisms by which combination strategies might mitigate the risk of differentiation syndrome. 

Key points

• At present, the U.S. Food and Drug Administration (FDA) has approved two menin inhibitors: revumenib monotherapy for the treatment of relapsed/refractory (R/R) KMT2Ar acute leukemia or NPM1m AML, and ziftomenib monotherapy for the treatment of R/R NPM1m AML.^1,2
• While clinical trials investigating menin inhibitor monotherapies have demonstrated encouraging efficacy and safety profiles, response rates and durations of response remain relatively short.^1,2
  • Menin inhibitor combination strategies are being explored with the aim of improving efficacy and extending the durability of response in patients with newly diagnosed (ND) or R/R NPM1m or KMT2Ar AML.³
• Menin inhibitor monotherapy has also been associated with development of further mutations, which may impair inhibitor binding, preventing effective disruption of the menin–rearranged KMT2A interaction, which drives leukemogenesis.^3,4
  • A preclinical study using CRISPR base editor screening to characterize the profile of MEN1 resistance mutations arising during menin inhibitor monotherapy found that MEN1 mutations are likely to occur with all menin inhibitors.⁵
  • In a subset of patients with AML in the phase I dose-escalation portion of the AUGMENT-101 trial (NCT04065399) who had received ≥2 cycles (>56 days) of revumenib (n = 31), MEN1 mutations were detected in 38.7% of responding and non-responding patients.^4,6
  • Menin inhibitor combination strategies may help minimize the development of on-target and off-target resistance mutations by more comprehensively disrupting leukemogenesis, potentially leading to more durable responses.⁶
• Differentiation syndrome has emerged as a potentially life-threatening class effect associated with menin inhibitors, occurring in up to 20% of patients treated with menin inhibitor monotherapy.^6,7
  • Symptoms of differentiation syndrome include respiratory compromise, pleural and pericardial effusions, fever, hypotension, and organ failure.^1,2
  • Strategies combining menin inhibitors with chemotherapy may reduce the risk of differentiation syndrome by decreasing leukemic burden and cytokine release.^6,8
• Early clinical trial data combining menin inhibitors (e.g. revumenib, ziftomenib, enzomenib, and bleximenib) with both intensive and less intensive regimens have demonstrated encouraging response rates, improved survival, and reduced risk of differentiation syndrome in patients with ND or R/R AML.^9–15
• Ongoing studies aim to identify optimal patient populations and treatment combinations to maximize benefit while addressing resistance mechanisms.

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.