Ziftomenib in Relapsed or Refractory NPM1-Mutated AML

Abstract

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.

Trial registration: ClinicalTrials.gov NCT04067336.

FIG 1.

Flow diagram for patients with relapsed or refractory NPM1-m AML: phase II of KOMET-001. NOTE. Data Cutoff: October 28, 2024. ^aIncludes patients who signed the informed consent but did not receive any doses because of not meeting any inclusion criteria, meeting any exclusion criteria, withdrawal of consent, or death before the first dose. ^bOther reason included transition to comfort measures or care. NPM1-m, NPM1-mutated.

FIG 2.

Duration of overall response (A) and OS (B). DOR, duration of response; OS, overall survival

FIG 3.

CR/CRh rate in key subgroups. NOTE. Data cutoff: October 28, 2024. CR/CRh rate was defined as the proportion of patients who achieved best overall response of CR or CRh. The CI was calculated using the exact method based on binomial distribution. CR, complete remission; CRh, complete remission with partial hematologic recovery; ECOG PS, Eastern Cooperative Oncology Group performance status; HSCT, hematopoietic stem cell transplant; ITD, internal tandem duplication; TKD, tyrosine kinase domain.