Promising data for ziftomenib in relapsed/refractory NPM1-mutated AML

Ziftomenib displayed encouraging clinical activity in a population of heavily pre-treated patients with relapsed/refractory (RR) NPM1-mutated acute myeloid leukaemia (AML). The agent was well-tolerated and the lack of predicted adverse drug-drug interactions suggests that ziftomenib could be explored in combination with other agents.

“NPM1-mutant AML is a large genetic subset with a high unmet need,” stated Dr Amir Fathi (Massachusetts General Hospital, Massachusetts, USA). “The 5-year overall survival rate is approximately 50% and in the second line, the median overall survival is only 7.8 months [1,2]. Also, there is no FDA-approved NPM1-mutation-specific therapy for the AML population.” To address the unmet need in this NPM1-mutated AML population, the phase 1/2 KOMET-001 study (NCT04067336) evaluated the use of ziftomenib, which targets the menin-KMT2A pathway, an important target in NMP1-mutated AML. Dr Fathi presented the results of the phase 1b part of the trial, where 20 participants with RR-NPM1-mutated AML received 600 mg ziftomenib daily [3].

The overall response rate was 45% and the complete remission rate was 35%. The median duration of response was 8.2 months. Dr Fathi added that co-mutations in FLT3 and IDH1/2 did not appear to affect the responsiveness to ziftomenib.

The most common adverse events were diarrhoea (45%), hypokalaemia (40%), nausea (30%), anaemia (30%), and back pain (30%). Thrombocytopaenia (20%) and anaemia (25% were the most frequently reported grade ≥3 events. As a treatment-related adverse event, the differentiation syndrome was observed in 20%, but only 1 of the 4 cases was a grade 3 event. Treatment-related nausea was seen in 20% of the participants. “These findings are in line with previously reported publications on this agent,” commented Dr Fathi.

These encouraging results warrant further evaluation of ziftomenib in combination with other agents in AML.

1. Angenendt L, et al. JCO. 2019;37(29):2632─2642
2. Issa GC, et al. Blood Adv. 2023;7(6):933─942
3. Fathi AT, et al. Activity, tolerability and resistance profile of the menin inhibitor ziftomenib in adults with relapsed or refractory NPM1-mutated AML. Late-breaking oral session, EHA 2023 Annual Congress, 8─11 June, Frankfurt, Germany.

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Posted on 2 August, 202323 April, 2024