MECHANISM OF ACTION — NPM1 mutations occur in up to 30% of patients with AML; they are associated with a poor prognosis in patients who are refractory to treatment.1 Ziftomenib blocks the interaction of lysine [K] specific methyltransferase 2A (KMT2A) with menin, disrupting the oncogenic activity of mutant NPM1, resulting in antiproliferative and antitumor activity in leukemia cells.

STANDARD TREATMENT — Cytarabine plus an anthracycline (daunorubicin or idarubicin) is the standard induction therapy regimen for patients who are candidates for intensive chemotherapy, but longterm cure rates and overall survival rates are low.2

CLINICAL STUDIES — In an open-label trial (KOMET-001), 92 patients with relapsed or refractory NPM1-mutated AML received ziftomenib 600 mg once daily until disease progression or unacceptable toxicity occurred. The rate of complete remission (CR) plus complete remission with partial hematologic recovery (CRh) was 22% and the median duration of response was 4.6 months. The overall response rate was 33% and median overall survival was 6.6 months.3

No trials directly comparing ziftomenib with revumenib are available. In one clinical trial in 84 patients with relapsed or refractory NPM1-mutated AML who received revumenib, the rate of CR plus CRh was about 23%, the median duration of response was 4.7 months, and the overall response rate was 46.9%.4

ADVERSE EFFECTS — Common adverse effects of ziftomenib in clinical trials included infection, hemorrhage, diarrhea, nausea, fatigue, edema, and musculoskeletal pain. QTc-interval prolongation can occur. The label of ziftomenib contains a boxed warning about the risk of differentiation syndrome, which can be life-threating.

DRUG INTERACTIONS — Ziftomenib is a substrate of CYP3A. Concurrent use of moderate or strong CYP3A4 inhibitors can increase serum concentrations of ziftomenib. Concurrent use of ziftomenib and moderate or strong CYP3A4 inducers, QT-interval-prolonging drugs, H₂-receptor antagonists, antacids, or proton pump inhibitors (PPIs) should be avoided.5,6 If administration of an H₂-receptor antagonist or antacid is necessary, ziftomenib should be given 2 hours before or 2 hours (antacid) or 10 hours (H₂-receptor antagonist) after the acid-suppressing drug.

PREGNANCY AND LACTATION — In animal studies, administration of ziftomenib during organogenesis was associated with embryofetal mortality and structural abnormalities. Females with reproductive potential should use effective contraception during treatment with ziftomenib and for 6 months after the last dose. Males who have female partners with reproductive potential should use effective contraception during treatment with ziftomenib and for 3 months after the last dose.

No data are available on the presence of ziftomenib in human milk or its effects on the breastfed infant or milk production. Breastfeeding is not recommended during treatment and for 2 weeks after the last dose.

DOSAGE, ADMINISTRATION, AND COST — Komzifti is supplied as 200-mg capsules. The recommended dosage is 600 mg taken once daily on an empty stomach for at least 6 months or until disease progression or unacceptable toxicity occurs (revumenib is taken twice daily). The capsules should be swallowed whole; they should not be opened or chewed. Ziftomenib should not be started until the WBC count is <25 x 10⁹/L. An ECG should be obtained before starting treatment, at least once weekly for the first four weeks of treatment, and at least monthly thereafter. The label contains dosage adjustments that should be made if adverse effects occur. The wholesale acquistion cost (WAC) for a one-month supply of Komzifti is $48,500.7

CONCLUSION — In one small clinical trial in patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible nucleophosmin 1 (NPM1) mutation, about 23% of patients taking ziftomenib (Komzifti) achieved complete remission or complete remission with partial hematologic recovery. The drug appears to be similar in efficacy to revumenib (Revuforj), the other menin inhibitor approved for this indication.

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