Study Highlights Promising New Treatment Option for Patients With Treatment-Resistant Acute Myeloid Leukemia

The Clinical Leukemia Service at Roswell Park Comprehensive Cancer Center helped lead the first clinical trial of the experimental oral drug ziftomenib in patients with acute myeloid leukemia (AML). The results of the KOMET-001 study, published today in The Lancet Oncology, show that the drug — part of a class of targeted therapies known as menin inhibitors — produced a partial or complete response in about a third of patients, all of whom had received two or more prior therapies.

All 83 patients enrolled in the study experienced disease progression after receiving between 2 and 9 prior therapies. The most pronounced results were seen in patients with NPM1 mutations and KMT2A rearrangements — profiles associated with poorer clinical outcomes.

“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,” says study first author Eunice S. Wang, MD, Chief of the Leukemia/Benign Hematology Service and Leukemia Clinical Disease Team Leader at Roswell Park. The clinical trial was conducted by investigators at 22 hospitals in France, Italy, Spain and the U.S. from 2019-2022.

Ziftomenib, previously known as KO-539, works by blocking the interaction of two proteins — menin and KMT2A MLL — that enable certain leukemia cells to survive and multiply. It particularly benefited patients who had either a mutation in the nucleophosmin 1 (NPM1) gene or a lysine methyltransferase 2A (KMT2A) gene rearrangement, which occurs when the gene is in the wrong location in the genome.

NPM1 mutations occur in about 30% of all cases of AML, and KMT2A rearrangements occur in 5-10% of cases. Both are associated with very poor outcomes: While many patients with the NPM1 mutation tend to respond to initial treatment, those who relapse have a median survival of only 6.1 months. AML with a KMT2A gene rearrangement is highly resistant to initial treatment and tends to recur, with a five-year overall survival rate of less than 20%.

But in the clinical trial, when patients with an NPM1 mutation were treated with the recommended 600 mg. daily dose of ziftomenib, 35% (7 of 20) achieved complete remission. Based on study results, earlier this year the FDA granted Breakthrough Therapy designation to the drug, a recognition intended to speed its development and review for FDA approval.

The study results are important because currently more than half of AML patients do not have mutations for which targeted drugs are available, so they continue to be treated with cytotoxic, or cell-killing therapies, such as chemotherapy, which tend to produce subpar outcomes for this disease.

“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,” notes Dr. Wang.

“Roswell Park leukemia patients were among the first in the entire world to receive treatment with this menin inhibitor,” she adds. “That’s because the trial is part of the Early Phase Leukemia Clinical Trials program, funded by donations to the Roswell Park Alliance Foundation, which provides dedicated resources to bring the most promising and innovative experimental agents to leukemia patients here in Western and Central New York.”

Additional clinical trials of ziftomenib are now underway at Roswell Park, including the phase 2 portion of the KOMET-001 study, which will further evaluate its safety, tolerability and antileukemia 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) that will study the potential of combining ziftomenib with intensive and nonintensive chemotherapy and other targeted agents in AML patients with NPM1 mutations and KMT2A rearrangements. The first trial includes patients with newly diagnosed disease; the second will include newly diagnosed patients.