Final Trial Data Show Success for Ziftomenib in NPM1 AML

The final analysis of a clinical trial focused on patients with acute myeloid leukemia (AML) with NPM1 mutations showed that ziftomenib (KO-539) produced deep, durable responses.^1,2

Results showed that ziftomenib was well tolerated with manageable differentiation syndrome, lack of clinically significant QTc prolongation, and low rates of myelosuppression. The phase 1B/2 KOMET-001 (NCT04067336)³ clinical trial was co-led by Chief of Leukemia Eunice Wang, MD, at Roswell Park Comprehensive Cancer Center.

Between January 2023 and May 2024, 92 patients between the ages of 33 and 84 were enrolled in the KOMET-001 study. Of the patients, 23% achieved a complete response (CR) with ziftomenib, and 67% had no detectable disease. The primary end point was met with a CR/CR with partial hematologic recovery rate of 22% (95% CI, 14–32; P =.0058). The overall response rate (ORR) was 33% (95% CI, 23%–43%) with a median duration of 4.6 months (95% CI, 2.8– 7.4). The median overall survival (OS) for patients was 6.6 months (95% CI, 3.6–8.6). Common any-grade treatment emergent adverse events included febrile neutropenia (26%), anemia (20%), and thrombocytopenia (20%), with 25% of patients experiencing differentiation syndrome (15% grade 3; no grade 4–5).¹

“Ziftomenib is a potent Menin inhibitor with proven efficacy for the treatment of adult patients with NPM1-mutant [AML] who have failed multiple lines of therapy,” said Wang in a press release.² “I am proud to say that Roswell Park patients were among the first in the world to be treated with ziftomenib, and we are continuing to treat patients with this agent in combination with chemotherapy in the newly diagnosed setting.”

About 30% of all patients with AML have the NPM1 mutation. Within a year of treatment, about half of patients experience relapse or the disease resists treatment. For more than half of patients with AML, there are no approved targeted treatments, often resulting in subpar clinical outcomes. Although outcomes can be favorable in patients with the NPM1 mutation after chemotherapy, patients with relapsed/refractory disease have a worse prognosis. Less than 10% achieve a CR to therapy, and the median OS is 6.1 months.⁴

“In this pivotal KOMET-001 study, ziftomenib demonstrated meaningful clinical activity in heavily pretreated relapsed/refractory NPM1-[mutant] AML, and the primary end point was met for improved clinical activity in this patient population,” said the authors of the phase 1B/2 KOMET-001 clinical study.¹ “Ziftomenib achieved clinically meaningful and deep responses in relapsed/refractory NPM1-[mutant] AML that exceeded the response rate with current standard-of-care.”

Kura Oncology is currently in a phase 3 clinical study (NCT0700312) involving ziftomenib in combination with venetoclax (Venclexta) and azacitidine in patients with untreated AML and an NPM1 mutation or KMT2A rearrangement..⁵

Due to the results of the international study the FDA is considering the approval of ziftomenib. The new drug application received FDA priority review with a target action date of November 30, 2025, under the Prescription Drug User Fee Act (PDUFA). If ziftomenib achieves full approval, it would be the first FDA-approved Menin inhibitor for relapsed/refractory AML with an NPM1 mutation.

REFERENCES:

1. Wang ES, Montesinos P, Foran J, et al. Ziftomenib in Relapsed or Refractory NPM1-Mutated AML. J Clin Oncol. 0, JCO-25-01694. doi:10.1200/JCO-25-01694

2. Final Landmark Clinical Trial Data Demonstrates Deep, Durable Responses to Menin Inhibition in Acute Leukemia Patients. News Release. Roswell Park Comprehensive Cancer Center. September 25, 2025. Accessed October 2, 2025. https://tinyurl.com/549njrru

3. First in Human Study of Ziftomenib in Relapsed or Refractory Acute Myeloid Leukemia. ClinicalTrials.gov. Updated August 6, 2025. Accessed October 2, 2025. https://www.clinicaltrials.gov/study/NCT04067336

4. Issa G, Bidikian A, Venugopal S, et al. Clinical outcomes associated with NPM1 mutations in patients with relapsed or refractory AML. Blood Adv. 2023 Mar 28;7(6):933-942. doi: 10.1182/bloodadvances.2022008316.

5. 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 September 18, 2025. Accessed October 2, 2025. https://www.clinicaltrials.gov/study/NCT07007312