The FDA has approved ziftomenib (Komzifti, Kura Oncology) for adults with relapsed or refractory (R/R) acute myeloid leukemia (AML) harboring a nucleophosmin 1 (NPM1) mutation, which occurs in up to 30% of newly diagnosed AML cases.

The once-daily oral menin inhibitor is the second menin inhibitor on the US market for R/R AML following approval of revumenib (Revuforj, Syndax) in November 2024. Revumenib, however, is for patients with a different genetic aberration, a lysine methyltransferase 2A gene (KMT2A) translocation. 

Menin is a regulatory protein that normally helps blood cells differentiate; the genetic aberrations derail its normal activity, driving unchecked growth of immature cells. Menin inhibitors block the abnormal activity, helping to restore normal differentiation and help curb leukemic proliferation. 

Several other menin inhibitors are in development for AML with activity in KMT2A translocations and/or NPM1-mutated disease.

Although newly diagnosed patients with NPM1-m AML can respond well to transplants or venetoclax-based treatment, relapses are common, and subsequent survival is often only a few months. Until now, there were no approved therapies specifically for R/R NPM1 mutated AML, Japan-based Kura Oncology said in a press release. 

Ziftomenib was approved as monotherapy based on the KOMET-001 trial in 92 adults with NPM1-mutated R/R AML. Subjects were a median age of 69 years and had a median of two prior lines of therapy, which included venetoclax in 59% and transplants in 24%. Ziftomenib was dosed at 600 mg once daily. Mutation status was determined by local clinical laboratories.

Thirteen patients (14%) had a complete remission, and seven (8%) had a remission with partial hematologic recovery after a median of 2.8 months, with a median remission duration of 3.7 months. Two responders went on to allogeneic stem cell transplants followed by ziftomenib maintenance.

The 22% remission rate “was significantly higher than the 12% historical standard-of-care response rate for patients with relapsed/refractory NPM1-m AML,” according to the study report. 

Median overall survival was 18.4 months among responders but only 3.5 months among nonresponders.

Grade 3 or worse treatment-emergent adverse events included febrile neutropenia (26%), anemia (20%), and thrombocytopenia (20%). A quarter of patients developed differentiation syndrome, which was grade 3 in 15%. Two patients stopped treatment due to differentiation syndrome and one due to vomiting. There were no ziftomenib-related deaths.

Kura plans two phase 3 trials of its menin inhibitor in frontline AML. One will combine the drug with venetoclax/azacitidine in adults with NPM1 mutations, and the other will add it to standard cytarabine/daunorubicin induction/consolidation chemotherapy in adults with NPM1 mutations or KMT2A translocations. 

Pricing for ziftomenib was unavailable at press time. By comparison, thirty 160 mg tablets of revumenib — a 2-week supply for adults taking strong CYP3A4 inhibitors — costs $20,023.15, according to drugs.com. 

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: aotto@mdedge.com