Ziftomenib promising for relapsed or refractory NPM1-mutated AML

medwireNews: Ziftomenib – a selective inhibitor of the menin–KMT2A interaction – has demonstrated encouraging clinical activity and manageable safety in people with relapsed or refractory acute myeloid leukemia (AML) carrying NPM1 mutations in the early-phase KOMET-001 trial. Speaking at the EHA2023 Hybrid Congress in Frankfurt, Germany, investigator Amir Fathi (Massachusetts General Hospital, Boston, USA) explained that “NPM1 mutations and KMT2A rearrangements drive overexpression of the HOXA9 and MEIS1 genes, which are critical for the transformation to [AML],” and the menin–KMT2A interaction also “sits upstream of major AML targets,” such as FLT3 and DNMT3A. “Menin inhibition downregulates HOXA9/MEIS1, leading to differentiation of leukemic blasts” and clinical response, he continued. KOMET-001 is a phase 1/2 trial of ziftomenib, with the current presentation focusing on the 20 participants of the phase 1b dose expansion phase with NPM1 mutations who received the drug at a dose of 600 mg/day. These patients were aged a median of 70.5 years and the majority (70%) were women. At a median follow-up of 8.8 months, the complete remission (CR) rate was 35%, including a rate of 33% among the six patients with FLT3 co-mutations and 50% among the eight with IDH1/2 co-mutations. Overall, the composite CR rate – which additionally included CR with partial hematologic recovery and CR with incomplete count recovery – was 40%, and the overall response rate, which additionally included morphologic leukemia-free state, was 45%. The presenter noted that ziftomenib monotherapy appeared to drive durable responses, with a median duration of response of 8.2 months. He drew attention to one patient who remained on ziftomenib in CR, having received 36 cycles of treatment at time of analysis. The toxicity profile of ziftomenib was similar to that of previous reports and there were no new safety signals, Fathi told the audience. Treatment-related adverse events (TRAEs) of all grades occurred in 60% of participants, with the most common being nausea and differentiation syndrome, each in 20%. Grade 3 or more severe TRAEs were observed in 30% of patients. Fathi pointed out that just one of the incidences of differentiation syndrome was of grade 3 (the others were grade 1 or 2) and it was “manageable with mitigation strategies.” There were no reports of drug-induced QTc prolongation. In conclusion, he said that “the pivotal KOMET-001 study continues its phase 2 cycle, recruiting patients with relapsed or refractory NPM1-mutated AML.” The investigator continued: “The KOMET-007 study is also open for enrolment, studying ziftomenib in combination with existing intensive chemotherapy and nonintensive chemotherapy standards of care in newly diagnosed patients with NPM1 mutations or KMT2A rearrangements.” medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2023 Springer Healthcare Ltd, part of the Springer Nature Group EHA2023 Hybrid Congress; Frankfurt, Germany & Virtual: 8–15 June

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Ziftomenib promising for relapsed or refractory NPM1-mutated AML

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