KOMET-001 Leads to Ziftomenib Approval for NPM1-Mutated AML
Key Points
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The menin inhibitor, ziftomenib, was approved by the FDA for patients with relapsed or refractory NMP1-mutated acute myeloid leukemia (AML).
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Ziftomenib and other menin inhibitors feature a novel mechanism of action that may support combinations with current standard agents.
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Treatment with ziftomenib is generally well tolerated, though physicians should monitor for differentiation syndrome and QTc prolongation.
Ziftomenib Approved in NMP1-Mutated AML
On November 13, 2025, the FDA approved the oral menin inhibitor ziftomenib for patients with relapsed or refractory AML with NMP1 mutations, based on the KOMET-001 trial. Lead author of the trial, Eunice Wang, MD, of Roswell Park Comprehensive Cancer Center, joined the Oncology Brothers podcast to discuss the trial and how the approval impacts the treatment landscape for this patient population.
The standard upfront treatment for AML is induction chemotherapy for eligible patients or hypomethylating agents plus venetoclax. With the advent of menin inhibitors, a targeted therapy is now available for more than half of patients with AML, and the treatment paradigm for AML will likely shift to incorporate next-generation sequencing and targeted agents, said Dr. Wang.
In NMP1-mutated AML, ziftomenib inhibits menin proteins from activating aberrant KTM2A transcriptional complexes. “If we block the interaction between this menin protein and this complex, we can downregulate the whole transcription process, changing the entire biology of the disease and leading to clinical responses,” Dr. Wang said.
KOMET-001 Trial Design and Findings
At the 2025 American Society of Clinical Oncology Annual Meeting, KOMET-001 authors presented data on patients with NMP1-mutated relapsed or refractory AML who received ziftomenib 600 mg once daily. The phase 2 primary endpoint was complete remission with full or partial hematologic recovery (CR/CRh), and secondary endpoints included a composite complete remission (CRc) rate, duration of CR/CRh or CRc, and safety.
The analysis covered pooled phase 1b/2 patients (n=112) with a median follow-up of 4.2 months. The CR/CRh rate was 25% (n=28; 95% CI, 17-34; P = .0058) and the overall response rate was 35% (n=39; 95% CI, 26-44) across all patients. The median duration of CR/CRh was 3.7 months (95% CI, 1.9-7.7), and 17 of 26 (65%) evaluated responders tested negative for minimal residual disease.
Interestingly, rates of response to ziftomenib were not affected by prior ventoclax-based therapy, suggesting that the mechanism of action for ziftomenib is independent of cytotoxic agents and potentially supports combining ziftomenib with other agents in the future, Dr. Wang said.
Clinical Pearls for Ziftomenib
In KOMET-001, ziftomenib was associated with a risk of differentiation syndrome, predominantly during the first cycle. Patients should have a white blood cell count below 20,000 before initiating ziftomenib, and physicians should have hydroxyurea and dexamethasone available while monitoring in the first few weeks of therapy, said Dr. Wang.
Additionally, the FDA label for ziftomenib carries a warning for QTc prolongation. In the study, grade 3 or higher QTc prolongation was reported in about 9% of patients overall. Still, it occurred in only 3 patients in the phase 2 population, all of whom had electrolyte abnormalities or concomitant medications, according to Dr. Wang. She recommended weekly monitoring for any patients with baseline QTc prolongation.
As a final clinical pearl, Dr. Wang highlighted that ziftomenib can take a long time to work, with some patients taking up to 3 months to respond. “Give it for at least 2 months, or even longer, to see whether there might initially be stable disease; you might not get the responses until you continue,” she said.