The experimental oral drug ziftomenib is showing promise in patients with acute myeloid leukemia (AML) who have developed resistance to multiple prior therapies. Results from the KOMET-001 study, published in The Lancet Oncology, indicate that ziftomenib, a menin inhibitor, induced partial or complete responses in approximately one-third of patients who had received two or more prior treatments.
The multi-center clinical trial, conducted across 22 hospitals in France, Italy, Spain, and the U.S. between 2019 and 2022, enrolled 83 patients with relapsed or refractory AML. All participants had experienced disease progression after undergoing between two and nine previous therapies. The most notable responses were observed in patients harboring NPM1 mutations and KMT2A rearrangements, genetic profiles typically associated with poorer clinical outcomes.
Mechanism of Action
Ziftomenib, previously known as KO-539, functions by selectively blocking the interaction between menin and KMT2A (lysine methyltransferase 2A, also known as MLL) proteins. This interaction is crucial for the survival and proliferation of leukemia cells carrying either NPM1 mutations or KMT2A rearrangements. NPM1 mutations are present in approximately 30% of AML cases, while KMT2A rearrangements occur in 5-10% of cases. Both are linked to unfavorable prognoses; patients with relapsed NPM1-mutated AML have a median survival of just 6.1 months, and those with KMT2A-rearranged AML have a five-year overall survival rate below 20%.
Clinical Trial Results
In the KOMET-001 clinical trial, 35% (7 out of 20) of patients with NPM1 mutations achieved complete remission when treated with the recommended daily dose of 600 mg of ziftomenib. These results led the FDA to grant Breakthrough Therapy designation to the drug earlier this year, a decision intended to accelerate its development and regulatory review.
Impact on AML Treatment
Currently, more than half of AML patients lack actionable mutations for which targeted therapies are available, leaving them reliant on cytotoxic chemotherapies that often yield suboptimal outcomes. According to Dr. Eunice S. Wang, Chief of the Leukemia/Benign Hematology Service and Leukemia Clinical Disease Team Leader at Roswell Park Comprehensive Cancer Center and first author of the study, "Ziftomenib represents a huge step forward for the treatment of patients with these aggressive subtypes of acute leukemia, who currently have no other treatment options."
Dr. Wang further noted, "The clinical activity of ziftomenib in NPM1-mutant AML in particular is among the highest reported for this type of AML and provides support for ziftomenib — and other menin inhibitors — to be the next approved targeted leukemia drug for these patients."
Ongoing Research
Additional clinical trials are underway to further evaluate ziftomenib. These include the phase 2 portion of the KOMET-001 study, which will assess the drug's safety, tolerability, and antileukemic activity in patients with NPM1-mutant AML. The Early Phase Leukemia Clinical Trials Program at Roswell Park is also recruiting patients for two phase 1 trials (NCT06001788 and NCT05735184) to investigate the potential of combining ziftomenib with chemotherapy and other targeted agents in AML patients with NPM1 mutations and KMT2A rearrangements.
