Ziftomenib in Relapsed or Refractory NPM1-Mutated AML

Purpose: Ziftomenib-a potent, highly selective, oral menin inhibitor-was well tolerated and demonstrated encouraging clinical activity as monotherapy for relapsed/refractory NPM1-mutated (NPM1-m) and KMT2A-rearranged AML in the KOMET-001 phase I trial. Methods: In the registration-enabling phase II part of KOMET-001, patients with relapsed/refractory NPM1-m AML received ziftomenib 600 mg once daily. The primary end point was the rate of complete remission with full hematologic recovery (CR)/CR with partial hematologic recovery (CRh). Results: From January 26, 2023, to May 13, 2024, 92 patients (median age, 69 years [range, 33-84]) were treated. The primary end point was met, with a CR/CRh rate of 22% (95% CI, 14 to 32; P = .0058); 61% were negative for measurable residual disease. Overall response rate was 33% (95% CI, 23 to 43), with a median duration of 4.6 months (95% CI, 2.8 to 7.4). Prespecified subgroup analyses showed comparable CR/CRh regardless of previous therapy, including venetoclax, or type of comutations. Median overall survival was 6.6 months (95% CI, 3.6 to 8.6). Common grade ≥3 treatment-emergent adverse events were febrile neutropenia (26%), anemia (20%), and thrombocytopenia (20%). Differentiation syndrome occurred in 25% of patients (15% grade 3; no grade 4-5) and was manageable with protocol-defined mitigation. Three patients (3%) discontinued treatment because of ziftomenib-related adverse events. Conclusion: Ziftomenib demonstrated significant clinical benefit and deep responses in patients with heavily pretreated, relapsed/refractory NPM1-m AML. Ziftomenib was well tolerated with a safety profile consistent with previous studies, including manageable differentiation syndrome, lack of clinically significant QTc prolongation, and low rates of myelosuppression.