Ziftomenib Added to NCCN Clinical Practice Guidelines for NPM1-Mutant R/R AML

The National Comprehensive Cancer Network (NCCN) has updated its Clinical Practice Guidelines in Oncology for Acute Myeloid Leukemia (AML) to include ziftomenib (Komzifti) as a category 2A recommendation for the treatment of patients with relapsed or refractory AML harboring an NPM1 mutation.^1,2

According to the latest version of the guidelines, which were updated on November 24, 2025, ziftomenib is listed as preferred targeted therapy for this patient population alongside revumenib (Revuforj).²

The guideline update was supported by results from the phase 1/2 KOMET-001 trial (NCT04067336); these data also supported the November 2025 FDA approval of this once-daily oral menin inhibitor for the treatment of adult patients with relapsed/refractory, NPM1-mutant AML who have no satisfactory treatment alternatives.^1,3

“The addition of ziftomenib to the NCCN Guidelines in Oncology underscores the potential impact of ziftomenib for patients with relapsed/refractory NPM1-mutated AML and supports our commitment to ensuring that patients have access to this important treatment option,” Mollie Leoni, MD, chief medical officer of Kura Oncology, stated in a news release.¹ “NPM1-mutated disease carries a substantial risk of relapse and historically poor outcomes in the relapsed or refractory setting. We are pleased to have received inclusion in the NCCN guidelines so rapidly after FDA approval and are committed to making ziftomenib available to patients in the United States.”

What efficacy data from KOMET-001 have been reported?

In KOMET-001, ziftomenib produced a complete remission (CR)/CR with full or partial hematologic recovery (CRh) rate of 21.4% (95% CI, 14.2%-30.2%), meeting the study’s primary end point.³ The median duration of CR/CRh response was 5 months (95% CI, 1.9-8.1). The CR rate and CRh rates were 17.0% (95% CI, 10.5%-25.2%) and 4.5% (95% CI, 1.5%-10.1%), respectively.

Of note, 21.2% of evaluable patients (n = 66) who were transfusion dependent at baseline achieved red blood cell and platelet transfusion independence during any 56-day period after baseline.Among evaluable patients who were transfusion independent at baseline (n = 46), 26.1% remained transfusion independent during any 56-day post-baseline period.

Findings from KOMET-001 were previously reported at the 2025 ASCO Annual Meeting.⁴ In the phase 2 patient population (n = 92), at a median follow-up of 4.1 months (range, 0.1-19.7), the respective CR and CRh rates were 14% and 9%. Moreover, patients treated with ziftomenib achieved an overall response rate of 33%. The median time to overall response was 1.9 months (range, 0.8-3.7), and the median duration of overall response was 4.6 months (95% CI, 2.8-11.4). The restricted mean duration of overall response was 5.9 months (95% CI, 4.4-7.5).

What was the safety profile of ziftomenib in KOMET-001?

All patients in the phase 2 population experienced any-grade treatment-emergent AEs (TEAEs), with 93% of patients experiencing grade 3 or higher TEAEs.³ The most commonly observed TEAEs with ziftomenib were anemia (any grade, 22%; grade ≥ 3, 20%), febrile neutropenia (26%; 26%), thrombocytopenia (20%; 20%), diarrhea (29%; 1%), nausea (25%; 1%), hypokalemia (24%; 13%), differentiation syndrome (25%; 15%), pruritus (23%; 0%), peripheral edema (25%; 0%), and pneumonia (21%; 14%). Treatment discontinuation due to ziftomenib-related AEs occurred in 3% of patients.

How was KOMET-001 designed?

KOMET-001 was a first-in-human, dose-escalation, -validation and -expansion trial enrolling patients at least 18 years of age with relapsed or refractory AML who had progressed on or were ineligible for standard-of-care therapies, including hematopoietic stem cell transplant (HSCT).^4,5 In the phase 1b portion, patients were required to harbor either KMT2A rearrangements or NPM1 mutations; phase 2 included only those with NPM1 mutations.

Of note, patients were excluded if they had acute promyelocytic leukemia, chronic myelogenous leukemia in blast crisis, a donor lymphocyte infusion within 30 days of enrollment, clinically active central nervous system leukemia, or if they had undergone HSCT without adequate hematologic recovery.

In phase 2, patients with NPM1-mutant relapsed/refractory AML received ziftomenib at the recommended phase 2 dose (RP2D), which was determined in earlier cohorts.

The trial’s primary end points were determination of the maximum tolerated dose and RP2D (phase 1a), safety and minimal biologically effective dose (phase 1b), and CR/CRh rate (phase 2). Key secondary end points in phase 2 included duration of CR/CRh, CR/CRh minimal residual disease negativity, transfusion independence, and AEs.

References

1. Komzifti (ziftomenib) added to National Comprehensive Cancer Network (NCCN) guidelines for acute myeloid leukemia (AML). News Release. Kura Oncology. November 26, 2025. Accessed November 26, 2025. https://ir.kuraoncology.com/news-releases/news-release-details/komziftitm-ziftomenib-added-national-comprehensive-cancer
2. NCCN. Clinical Practice Guidelines in Oncology. AML, version 3.2026. Accessed November 26, 2025.https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf
3. FDA approves ziftomenib for relapsed or refractory acute myeloid leukemia with a NPM1 mutation. FDA. November 13, 2025. Accessed November 13, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ziftomenib-relapsed-or-refractory-acute-myeloid-leukemia-npm1-mutation
4. Wang E, Montesinos P, Issa G, et al. Ziftomenib in relapsed/refractory (R/R) NPM1-mutant acute myeloid leukemia (AML): phase 1b/2 clinical activity and safety results from the pivotal KOMET-001 study. J Clin Oncol. 2025;43(suppl_16):6506. doi:10.1200/JCO.2025.43.16_suppl.6506
5. First in human study of ziftomenib in relapsed or refractory acute myeloid leukemia. ClinicalTrials.gov. Updated November 10, 2025. Accessed November 26, 2025. https://clinicaltrials.gov/study/NCT04067336