FDA Approves Ziftomenib in NPM1-Mutant Acute Myeloid Leukemia

The US FDA has approved the new drug application (NDA) for ziftomenib (Komzifti, formerly KO-539) in the treatment of relapsed or refractory (R/R) mutant nucleophosmin 1 (mNPM1) acute myeloid leukemia (AML).^1,2

Final data from the phase 2 KOMET-001 trial (NCT04067336) underpin this decision, which met the study’s primary end point of complete remission (CR) plus CR with partial hematological recovery (CRh).³ Initially, 22% of the total patients with R/R mNPM1 AML (n = 92) had achieved either CR (14%) or CRh (8%) following treatment with ziftomenib, with a median time to CR/CRh of 2.8 months (95% CI, 1.0–15.0) by the primary analysis cutoff. An additional CRh that occurred after the primary analysis cutoff increased the cumulative CR/CRh rate to 23% (95% CI, 15%–33%).

Further efficacy outcomes included a 33% overall response rate (ORR) (95% CI, 23%–43%), median duration of overall response of 1.9 months (range, 0.8–3.7), and median overall survival (OS) of 6.6 months (95% CI, 3.6–8.6).

The agent was also well tolerated by patients, with a safety profile consistent with previous reports and favorable risk-benefit profile. The majority of patients (93%) experienced grade ≥3 treatment-emergent adverse events (AEs), with the most common including febrile neutropenia (26%), anemia (20%), and thrombocytopenia (20%). Differentiation syndrome occurred in 25% of patients, with 15% of events being grade ≥3. Ziftomenib-related AEs occurred in 70% of patients; importantly, only 3% of these events led to treatment discontinuation.^2,3

With this latest approval, patients harboring the NPM1 mutation will now have access to a novel targeted therapy that offers potential for deeper remissions and meaningful survival benefits in what has historically been a relapse-prone, treatment-resistant disease.

Tracing Ziftomenib’s Clinical Development Journey

The clinical development journey of ziftomenib, a potent and selective oral Menin inhibitor, has been marked by regulatory designations and promising data readouts. In April 2024, ziftomenib received FDA breakthrough therapy designation for the now-approved indication. In June 2025, the FDA granted priority review to ziftomenib’s NDA that has now been approved.

KOMET-001, which began dosing patients in 2023, is a first-in-human, multicenter, open-label phase 1/2 study evaluating ziftomenib as monotherapy in adult patients with R/R mNPM1 AML.⁴ The objectives of the phase 1 study, which consisted of phase 1a dose-escalation and phase 1b dose-expansion portions, was to determine the maximum tolerated dose and/or the recommended phase 2 dose (RP2D) and evaluate the safety, tolerability, and minimal biologically effective dose in ziftomenib in various biomarker-specific cohorts. Here, patients received oral ziftomenib at doses escalating from 50 to 1000 mg once daily in 28-day cycles, determining a RP2D of 600 mg.

In phase 2, which sought to assess the primary end points of CR/CRh and secondary end points of clinical benefit, safety, and tolerability, 92 patients received the 600-mg RP2D of ziftomenib once daily. Full results were presented earlier this year at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.

Other ongoing early investigations of ziftomenib include the phase 1 KOMET-007 trial (NCT05735184) and phase 1 KOMET-008 trial (NCT06001788). KOMET-007 is evaluating ziftomenib in combination with venetoclax (Venclexta) and azacitidine (Vidaza), venetoclax alone, or 7+3 chemotherapy alone in patients with newly diagnosed or R/R mNPM1 AML,⁵ while KOMET-008 is evaluating the agent in combination with chemotherapy or gilteritinib (Xospata) in patients with R/R mNPM1 pr KMT2A-rerranged AML.⁶

Finally, further development of ziftomenib is underway in the randomized setting. The recruiting phase 3 KOMET-017 trial (NCT07007312) is evaluating ziftomenib in combination with either intensive (7+3) or low-intensity venetoclax plus azacitidine. The trial aims to enroll 1300 patients newly diagnosed with untreated AML harboring a NPM1 mutation or KMT2A rearrangement.⁷

REFERENCES:

1. FDA approves ziftomenib for relapsed or refractory acute myeloid leukemia with a NPM1 mutation. News release. US FDA. November 13, 2025. Accessed November 13, 2025. https://tinyurl.com/4kcam475

2. Kura Oncology and Kyowa Kirin Announce FDA Acceptance and Priority Review of New Drug Application for Ziftomenib in Adults with Relapsed or Refractory NPM1-Mutant AML. News release. Kura Oncology. June 1, 2025. Accessed October 30, 2025. https://tinyurl.com/4eseb356

3. Wang ES, Montesinos P, Foran J, et al. Ziftomenib in Relapsed or Refractory NPM1 -Mutated AML. J Clin Oncol. 2025;43(31):3381-3390. doi:10.1200/jco-25-01694

4. First in Human Study of Ziftomenib in Relapsed or Refractory Acute Myeloid Leukemia. ClinicalTrials.gov. Updated August 6, 2025. Accessed October 30, 2025. https://www.clinicaltrials.gov/study/NCT04067336

5. A study to investigate the safety and tolerability of ziftomenib in combination with venetoclax/​azacitidine, venetoclax, or 7+3 in patients with AML. ClinicalTrials.gov. Updated October 9, 2024. Accessed November 10, 2025. https://clinicaltrials.gov/study/NCT05735184

6. Safety and tolerability of ziftomenib combinations in patients with relapsed/​refractory acute myeloid leukemia. ClinicalTrials.gov. Updated November 10, 2025. Accessed November 10, 2025. https://clinicaltrials.gov/study/NCT06001788

7. Studies to Assess Ziftomenib in Combination With Ven+Aza or 7+3 in Patients With Untreated NPM1-m or KMT2A-r AML. ClinicalTrials.gov. Updated October 22, 2025. Accessed October 30, 2025. https://www.clinicaltrials.gov/study/NCT07007312