Ziftomenib Shows MRD-Negative Responses in Pretreated NPM1+ AML

“The pivotal KOMET-001…study met its primary end point, demonstrating that ziftomenib resulted in statistically significant higher CR/CRh rates than historic control,” according to investigator Eunice Wang, MD.

Clinically meaningful minimal residual disease (MRD)–negative responses occurred in those with heavily pretreated relapsed/refractory acute myeloid leukemia (AML) harboring NPM1 mutations following treatment with ziftomenib (KO-539), according to a presentation on data from the phase 1b/2 KOMET-001 trial (NCT04067336) at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

In the phase 2 population (n = 92), at a median follow-up of 4.1 months (range, 0.1-19.7), 23% of patients had achieved complete remission (CR; 14%) or CR with full or partial hematologic recovery (CRh; 9%). The overall response rate (ORR) was 33%, and the rates of CR with incomplete hematologic recovery (CRi)/CR with incomplete platelet recovery (CRp), morphologic leukemia-free state (MLFS), and partial response (PR) were 3%, 5%, and 1%, respectively. The median time to CR/CRh was 2.8 months (range, 1.0-15.0), the median duration of CR/CRh was 3.7 months (95% CI, 1.9-not evaluable), and the restricted mean duration of CR/CRh was 4.3 months (95% CI, 3.1-5.6). The median duration of composite CR (CRc) was 4.6 months (95% CI, 2.8-11.4), and the restricted mean duration of CRc was 5.9 months (95% CI, 4.0-7.7). The median time to overall response was 1.9 months (range, 0.8-3.7), the median duration of overall response was 4.6 months (95% CI, 2.8-11.4), and the restricted mean duration of overall response was 5.9 months (95% CI, 4.4-7.5). The MRD negativity rate was 63%.

In the pooled phase 1b/2 population (n = 112), 25% of patients achieved CR (18%) or CRh (7%). The ORR was 35%, and the rates of CRi/CRp, MLFS, and PR were 4%, 5%, and 1%, respectively. The median duration of CR/CRh was 3.7 months (95% CI, 1.9-7.7), and the restricted mean duration of CR/CRh was 5.2 months (95% CI, 3.6-6.7). The median duration of CRc was 5.1 months (95% CI, 2.8-8.1), and the restricted mean duration of CRc was 6.4 months (95% CI, 4.6-8.1). The median duration of overall response was 4.6 months (95% CI, 3.6-7.7), and the restricted mean duration of overall response was 6.5 months (95% CI, 4.9-8.1). The MRD negativity rate was 65%.

“The pivotal KOMET-001…study met its primary end point, demonstrating that ziftomenib resulted in statistically significant higher CR/CRh rates than historic control,” Eunice Wang, MD, stated in the presentation. “In these heavily pretreated, relapsed/refractory patients, similar response rates were seen, regardless of multiple lines of therapy, prior transplantation, as well as prior venetoclax [Venclexta] exposure.”

Wang is a professor of oncology, leader of the Leukemia Clinical Disease Team, chief of the Department of Medicine – Leukemia, and an assistant member of the Tumor Immunology Program in the Department of Immunology at Roswell Park Comprehensive Cancer Center; as well as an associate professor in the Department of Medicine and an associate scholar at the Jacobs School of Medicine and Biomedical Sciences at the State University of New York at Buffalo.

Mechanism of Action and Study Design

Ziftomenib is a potent, highly selective, oral, investigational menin inhibitor that has demonstrated activity as both monotherapy and in combination regimens for adult patients with relapsed/refractory NPM1-mutant AML.

KOMET-001 enrolled patients at least 18 years of age with relapsed/refractory AML who had progressed on or were ineligible for any approved standard-of-care therapies, including hematopoietic stem cell transplantation (HSCT).² Patients needed to have an ECOG performance status of 0 to 2, a life expectancy of at least 2 months, adequate liver and kidney function, and peripheral white blood cell counts at or less than 30,000/μL.

The completed phase 1a dose-escalation portion enrolled patients with disease states such as NPM1 mutations or KMT2A rearrangements.¹ Patients received ziftomenib at daily doses ranging from 50 mg to 1000 mg. The primary objectives of this portion were safety/tolerability, pharmacokinetics, and early evidence of antitumor activity.

The completed phase 1b validation cohort portion treated patients with NPM1- or KMT2A-rearranged AML with daily ziftomenib doses of either 200 mg (cohort 1) or 600 mg (cohort 2). The primary objectives of this portion were safety/tolerability, pharmacokinetics, and clinical activity.

The completed phase 1b expansion portion expanded the population of patients with NPM1-mutant disease who received the 600-mg dose, which was identified as the recommended phase 2 dose (RP2D). Notably, the continued enrollment to the 600 mg validation cohort was consistent with the FDA’s Project Optimus. The primary objectives of this portion were safety/tolerability, pharmacokinetics, and clinical activity.

The phase 2 registration-enabling portion, which has completed enrollment, included patients with NPM1 mutations, who received ziftomenib at 600 mg daily. The primary end point was CR/CRh rate. Key secondary end points included duration of CR/CRh, CR/CRh MRD negativity, transfusion independence, and adverse effects (AEs).

Between January 26, 2023, and May 13, 2024, 112 patients were enrolled and treated with ziftomenib at the RP2D across 40 sites in 7 countries. All 20 patients who received ziftomenib in the phase 1b portion discontinued treatment due to progressive disease (PD; n = 9), AEs (n = 6), death (n = 2), study withdrawal (n = 1), and other reasons (n = 2). At a data cutoff of December 20, 2024, among the 92 patients in the modified intention-to-treat population of the phase 2 portion who received ziftomenib, 83 discontinued due to PD (n = 34), AEs (n = 17), lack of efficacy (n = 12), study withdrawal (n = 8), death (n = 3), and other reasons (n = 9).

Phase 2/Pooled Population Baseline Characteristics

The baseline characteristics were similar between the phase 2 and pooled populations.¹ In these respective populations, the median age was 69 years (range, 33-84 vs 22-86). Additionally, most patients were at least 65 years of age (64% vs 63%), female (53% vs 56%), White (82% vs 79%), and had an ECOG performance status of 1 (53% vs 56%). A slightly higher proportion of patients from the pooled population were from the United States/Canada (51%) vs the phase 2 population (49%). The median bone marrow aspirate blast count was slightly higher in the pooled population as well, at 44.0% (range, 0.5%-98%) vs 39.5% (range, 0.5%-98%).

Among patients with available co-mutation data at baseline, in the phase 2 population, patients had FLT3-ITD (45%), FLT3-TKD (11%), IDH1 (13%), and IDH2 (20%) mutations. The prevalence of these respective mutations in the pooled population was 42%, 11%, 13%, and 23%.

In both the phase 2 and pooled populations, patients had received a median of 2 prior lines of therapy (range, 1-7), including prior HSCT (phase 2, 24%; pooled, 23%), venetoclax (59%; 60%), and a menin inhibitor (1%; 1%).

Additional Efficacy Data

The investigators observed comparable CR/CRh rates across prespecified subgroups of patients from the phase 2 cohort, regardless of prior HSCT status (yes, 18% [95% CI, 5%-40%]; no, 24% [95% CI, 15%-36%]), prior venetoclax status (yes, 24% [95% CI, 14%-38%]; no, 21% [95% CI, 10%-37%]), or FLT3/IDH co-mutation status. Among patients with FLT3-ITD–co-mutated, FLT3-TKD–co-mutated, and FLT3-ITD/TKD wild-type disease, the CR/CRh rates were 13% (95% CI, 4%-28%), 33% (95% CI, 8%-70%), and 32% (95% CI, 18%-48%), respectively. Among those with IDH1–co-mutated vs IDH1 wild-type disease, these rates were 50% (95% CI, 19%-81%) vs 20% (11%-31%), respectively. Among those with IDH2–co-mutated vs IDH2 wild-type disease, these rates were 31% (95% CI, 11%-59%) vs 22% (12%-34%), respectively.

Regarding transfusion independence outcomes in the phase 2 cohort, 21% (95% CI, 13%-31%) of transfusion-dependent patients (n = 82) converted to transfusion independent post-baseline, and 20% (95% CI, 3%-56%) of patients who were transfusion independent at baseline (n = 10) maintained transfusion independence post-baseline. Regarding red blood cell (RBC) transfusion, 24% (95% CI, 15%-35%) of RBC transfusion–dependent patients (n = 75) converted to transfusion independent post-baseline, and 12% (95% CI, 2%-36%) of RBC patients who were RBC transfusion independent at baseline (n = 17) maintained transfusion independence post-baseline. Regarding platelet transfusion, 17% (95% CI, 9%-28%) of platelet transfusion–dependent patients (n = 71) converted to transfusion independent post-baseline, and 38% (95% CI, 18%-62%) of patients who were platelet transfusion independent at baseline (n = 21) maintained transfusion independence post-baseline.

Among all patients in the pooled population, the median overall survival (OS) was 6.1 months (95% CI, 3.8-8.4). At data cutoff, 24 patients remained alive and on study, and 9 patients were still receiving treatment.

Among responders, the median OS was 16.4 months (95% CI, 9.6-20.4). Conversely, the median OS among nonresponders was 3.5 months (95% CI, 2.5-4.0).

Safety Overview

Wang noted that ziftomenib was well tolerated and had a safety profile consistent with that seen with the agent in previous studies.

Treatment-Emergent Toxicities

Among patients in the phase 2b population, any-grade and grade 3 or higher treatment-emergent AEs (TEAEs) occurred at rates of 100% and 93%, respectively. The most common TEAEs included 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%).

Among patients in the pooled population, any-grade and grade 3 or higher TEAEs occurred at rates of 100% and 94%, respectively. The most common TEAEs included anemia (any-grade, 22%; grade ≥ 3, 21%), febrile neutropenia (22%; 22%), thrombocytopenia (20%; 20%), diarrhea (32%; 4%), nausea (28%; 1%), hypokalemia (26%; 12%), differentiation syndrome (24%; 13%), pruritus (23%; 0%), peripheral edema (22%; 0%), and pneumonia (21%; 15%).

Ziftomenib-Related Toxicities

Among patients in the phase 2b population, any-grade and grade 3 or higher ziftomenib-related AEs occurred at rates of 70% and 40%, respectively. The most common TEAEs included anemia (any-grade, 5%; grade ≥ 3, 5%), neutropenia (7%; 7%), differentiation syndrome (24%; 15%), pruritus (16%; 0%), nausea (9%; 0%), diarrhea (9%; 0%), increased alanine aminotransferase (ALT) levels (7%; 2%), and decreased appetite (5%; 0%).

Among patients in the pooled population, any-grade and grade 3 or higher ziftomenib-related AEs occurred at rates of 69% and 40%, respectively. The most common TEAEs included anemia (any-grade, 5%; grade ≥ 3, 5%), neutropenia (5%; 5%), differentiation syndrome (23%; 13%), pruritus (14%; 0%), nausea (12%; 0%), diarrhea (9%; 2%), increased ALT levels (6%; 2%), and decreased appetite (5%; 0%).

Additional Safety Data

In the overall safety population, the investigators reported low rates of ziftomenib-related myelosuppression. Moreover, no grade 4/5 differentiation syndrome occurred. Wang noted that differentiation syndrome was well managed with protocol-specified mitigation strategies.

Additionally, no patients had clinically significant QTc prolongation. Among the 3 patients with investigator-assessed QTc prolongation, 1 had grade 2 effects, and 2 had grade 3 effects. All 3 of these patients were concomitantly receiving additional medications associated with QTc prolongation to manage electrolyte abnormalities (n = 2) and a prior diagnosis of atrial fibrillation (n = 1).

A total of 3% of patients discontinued treatment due to ziftomenib-related AEs.

Next Steps for Ziftomenib Study

Based on the KOMET-001 data, on June 2, 2025, the FDA granted priority review to the new drug application seeking the full approval of ziftomenib for the treatment of adult patients with relapsed/refractory NPM1-mutated AML.³

Additionally, Wang explained that “given the efficacy and particularly the favorable safety profile demonstrated in this monotherapy study, ziftomenib has been considered to be an attractive partner for combinatorial studies.”

Additionally, the phase 1 KOMET-007 trial (NCT05735184) is evaluating the agent in combination with venetoclax and azacitidine (Vidaza), venetoclax alone, or 7+3 chemotherapy alone in patients with either newly diagnosed or relapsed/refractory AML harboring NPM1 mutations or KMT2A rearrangements.⁴ The phase 1 KOMET-008 trial (NCT06001788) is evaluating ziftomenib in combination with FLAG-IDA (fludarabine, cytarabine, idarubicin, and granulocyte colony–stimulating factor), low-dose cytarabine, or gilteritinib (Xospata) in patients with relapsed/refractory, NPM1-mutated or KMT2A-rearranged AML.⁵

References

1. 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
2. First in human study of ziftomenib in relapsed or refractory acute myeloid leukemia. ClinicalTrials.gov. Updated April 18, 2025. Accessed June 3, 2025. https://clinicaltrials.gov/study/NCT04067336
3. 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 June 3, 2025. https://ir.kuraoncology.com/news-releases/news-release-details/kura-oncology-and-kyowa-kirin-announce-fda-acceptance-and
4. 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 26, 2024. Accessed June 3, 2025. https://clinicaltrials.gov/study/NCT05735184
5. Safety and tolerability of ziftomenib combinations in patients with relapsed/​refractory acute myeloid leukemia. ClinicalTrials.gov. Updated February 13, 2025. Accessed June 3, 2025. https://clinicaltrials.gov/study/NCT06001788