Ziftomenib, an oral menin inhibitor, produced complete remission or complete remission with partial hematologic recovery in 22% of adults with relapsed or refractory NPM1-mutated acute myeloid leukemia (AML), according to a phase 2 trial published in the Journal of Clinical Oncology. The result, from the KOMET-001 study of 92 heavily pre-treated patients, met the trial’s primary endpoint and led to full FDA approval of the drug, sold as Komzifti, in November 2025, making it the first therapy specifically approved for AML driven by an NPM1 mutation.
Why NPM1 mutations matter in AML
NPM1 is one of the most commonly mutated genes in AML, present in roughly 30% of adult cases. Mutations in NPM1 disrupt the interaction between the NPM1 protein and chromatin, changing how the leukemia cell reads its own DNA and locking cells in an immature, fast-dividing state. Standard first-line chemotherapy achieves initial remission in most patients, but nearly half relapse within a year. Once AML relapses or fails to respond, historical complete response rates with further chemotherapy are under 10%, and median survival is measured in months. Before ziftomenib, no targeted therapy had been approved specifically for this subtype.
How ziftomenib works
Ziftomenib is a potent, highly selective, oral menin inhibitor. Menin is a scaffolding protein that binds the KMT2A (MLL) complex to chromatin at sites that drive expression of genes such as MEIS1 and HOXA9, which NPM1-mutated leukemia cells depend on to stay in their immature state. By blocking the menin-KMT2A interaction, ziftomenib disrupts that gene program. Leukemia cells stop dividing endlessly and begin to mature and die off naturally, an approach known as differentiation therapy. The same broad strategy underlies a long-standing, highly effective treatment for a different blood cancer, acute promyelocytic leukemia.
How the trial was designed
KOMET-001 was a phase 1b/2, open-label, multi-cohort trial. The registration-enabling phase 2 portion enrolled 92 adults with relapsed or refractory NPM1-mutated AML at sites across the United States, Canada, and Europe. Patients received ziftomenib 600 mg orally once daily in 28-day cycles. Enrollment ran from January 2023 to May 2024. The median age was 69 years, with a range from 33 to 84. Patients had received a median of two prior therapies, 60% had received prior venetoclax, and 23% had received prior stem cell transplantation.
The primary endpoint was the rate of complete remission with full hematologic recovery (CR) or complete remission with partial hematologic recovery (CRh). Key secondary endpoints included composite complete remission, duration of response, overall survival, and safety.
What the trial found
The primary endpoint was met. The CR/CRh rate was 22% (95% CI, 14 to 32; P=0.0058), exceeding the pre-specified historical control rate of 12%. The overall response rate was 33%. Among responders tested for measurable residual disease, 61% were MRD-negative, meaning no leukemia could be detected on sensitive laboratory testing. Median duration of CR/CRh was 3.7 months (95% CI, 1.9 to 7.4); the overall response duration was 4.6 months. Median overall survival across the phase 2 population was 6.6 months (95% CI, 3.6 to 8.6). Response rates were comparable regardless of whether patients had received prior venetoclax and regardless of the pattern of co-occurring mutations.
The most notable safety signal was differentiation syndrome, an inflammatory reaction that can occur as leukemia cells mature quickly. It occurred in 25% of patients in the phase 1b/2 pooled analysis and was manageable with protocol-defined mitigation using corticosteroids. Grade 3 or higher treatment-emergent adverse events occurred in 40% of the pooled population, most commonly cytopenias including febrile neutropenia, anemia, and thrombocytopenia. Only 3% of patients discontinued treatment because of drug-related adverse events. Ziftomenib was approved without a boxed warning for heart-rhythm changes and has few significant drug interactions.
How the effect size should be read
A 22% complete remission rate is meaningful in a population where historical response to salvage therapy is under 10%, and where 61% of responders were MRD-negative on sensitive testing. A median CR/CRh duration of 3.7 months is comparatively brief, and median overall survival of 6.6 months reflects how advanced these patients were at enrollment. Ziftomenib is not curative on its own. Its clinical role is to induce remission deep enough for some patients to proceed to allogeneic stem cell transplantation, which remains the only established curative option for AML. Ongoing trials are testing ziftomenib in combination with venetoclax and standard chemotherapy in newly diagnosed patients, where the earlier disease setting may yield larger and more durable responses.
What the evidence cannot yet answer
KOMET-001 was a single-arm phase 2 trial without a randomized control. The comparison to a 12% historical response rate is standard for salvage regulatory studies but cannot fully substitute for a head-to-head trial against best supportive care or an alternative regimen. Longer follow-up will be needed to characterize durability of response and any late resistance patterns. Combination trials of ziftomenib with venetoclax and standard induction chemotherapy in newly diagnosed NPM1-mutated AML are underway and will determine whether the drug’s benefit extends beyond the relapsed setting.
How it fits in AML care
Ziftomenib is now a category 2A recommended targeted therapy for relapsed/refractory NPM1-mutated AML in the National Comprehensive Cancer Network (NCCN) guidelines, alongside revumenib, another menin inhibitor. The two share a mechanism but differ in dosing, drug interactions, and specific safety profile. For patients with NPM1-mutated AML who have exhausted standard options, having menin inhibitors validates the broader strategy of targeting differentiation biology in AML, and it is expected to accelerate development of related drugs.
The KOMET-001 authors concluded that ziftomenib “demonstrates notable clinical activity in R/R NPM1-mutated AML and represents an important new therapeutic option in this patient population,” adding that the data “also support ongoing clinical trials of menin inhibitors in both fit and unfit patients with newly diagnosed NPM1-mutated AML.” For a population that has historically had few durable options, its approval marks the arrival of the first mechanistically targeted therapy in NPM1-mutated disease, and opens a therapeutic strategy the field is now moving quickly to build on.
References
- Erba HP, Fathi AT, Issa GC, et al. Ziftomenib in relapsed or refractory NPM1-mutated AML. Journal of Clinical Oncology, 2025. DOI: 10.1200/JCO-25-01694