Ziftomenib Induces Clinical Activity in NPM1-mutant R/R AML


The KMT2A inhibitor appeared safe and led to clinical activity in the treatment of patients with NPM1-mutated, relapsed/refractory acute myeloid leukemia, according to the phase 1 KOMET-001 trial.

Amir Fathi, MD

Amir Fathi, MD

Treatment with ziftomenib, a menin-MLL (KMT2A) inhibitor, appeared to be safe and effective in treating in heavily pretreated and co-mutated patients with NPM1-mutated, relapsed/refractory acute myeloid leukemia (AML), according to phase 1 data from the KOMET-001 trial (NCT04067336) presented at the 2023 EHA Congress.

Treatment emergent adverse events (TEAEs) of any grade occurred in 19 patients (95%), which included diarrhea (n = 9; 45%), hypokalemia (n = 8; 40%), nausea (n = 6; 30%), anemia (n = 6; 30%), back pain (n = 6; 30%), and epistaxis (n = 5; 25%). Seventeen patients (85%) experienced a grade 3 or higher TEAE, including anemia (25%) and thrombocytopenia (20%).

In addition, 12 patients (60%) reported with any-graded treatment-related AEs (TRAEs), which included nausea (20%) and differentiation syndrome (20%). Six patients had grade 3 or higher TRAEs (30%).

“We know that differentiation syndrome is an adverse event of particular interest with this class of agents. Among these 20 patients, there was only 1 report of a grade 3 differentiation syndrome. And that particular case was managed successfully with appropriate mitigation, including with steroids,” Amir Fathi, MD, associate professor of medicine, Harvard Medical School, program director, Center for Leukemia, Massachusetts General Hospital, explained, adding that there were also no reports of drug-induced QTc prolongation.

“This is similar to previous reports, and we did not find any new safety signals to report here today,” he added.

Further, the complete remission (CR) rate was 35%, with a composite CR (CRc) rate of 40% and an overall response rate (ORR) of 45%. Patients with co-mutations of FLT3 and IDH demonstrated CR rates of 33% and 50%, respectively.

“I would like to also note that a patient with complete remission and incomplete hematologic recovery went to transplant and is currently in remission following stem cell transplant,” Fahti said. “The patients with [morphologic leukemia-free state], unfortunately, prior to achieving count recovery, died from complications of COVID infection.”

The median time to first response to ziftomenib was 51 days (range, 26-225).

According to the swim plot presented, 1 patient with a CR at the 200-mg dose has an ongoing duration of response (DOR) of 36 cycles. Median DOR for those with CRc was 8.2 months (95% CI, 1.0–not evaluable).

Two patients went on to undergo stem cell transplant, including 1 patient who remains in CR on ziftomenib for post-stem cell transplant maintenance and 1 remains in CR.

Four of 6 patients (67%) who achieved CRc were MRD negative.

“So in theory, we feel that this agent does retain activity against several of these resistance mutations,” Fahti said.

Lastly, following reports of MEN1 resistance mutations with another menin inhibitor, an analysis of the trial identified 1 patient (3.4%) with the resistance mutation that was acquired while on ziftomenib treatment. Further, the MEN1 resistance mutation was not detected in 13 other patients who received 2 or more cycles of ziftomenib, with best responses of stable and progressive disease, “suggesting that progression or lack of response in these subjects is not due to MEN1 mutations,” Fahti added.

Study Background

While the prognosis for those with AML can be favorable, Fathi noted, “however, the nuance to that: patients who are older, patients with certain concurrent mutations, and certainly those with relapsed or refractory disease have a much more suboptimal outcome. As of yet, there is no FDA-approved NPM1 mutation-specific targeted therapy that exists today for AML.”

Therefore, in the global, open-label phase 1/2 KOMET-001 trial, Fahti and colleagues evaluated ziftomenib as treatment for adult patients with relapsed/refractory AML. At the 2023 Congress, Fahti discussed the phase 1 dose escalation and randomized dose expansion portion of the trial in patients with KMT2A rearrangements or NPM1 mutations.

In the phase 1b expansion trial, 20 patients received a dose of 600 mg ziftomenib orally, once daily, in 28-day cycles until relapse, progression, or unacceptable toxicity.

The main objectives were safety and tolerability, pharmacokinetics, and clinical activity.

Median age was 70.5 years (range, 22-86), while only 6 patients were male (30%). The majority of patients had an ECOG performance status of 1 (70%). The median number of lines of prior therapy was 3 (range, 1-10), with most receiving prior venetoclax (Venclexta; 65%) and previous stem cell transplant (20%).

Thirty percent of patients also had an FLT3 mutation, 40% had an IDH1/2 mutation, and20% had a combination of both co-mutations.

Seven patients were still in follow-up (35%). Reasons for treatment discontinuation were AEs not related to the study drug (25%), death (5%), disease progression (45%), and other reasons (25%). Thirteen patients discontinued from the study as a result of death (65%).

Data cutoff was April 12, 2023.

Next Steps

The pivotal KOMET-001 trial is currently recruiting patients with NPM1-mutated relapsed/refractory AML.

In addition, the phase 1 KOMET-007 trial (NCT05735184) is open for enrollment, with the aim to evaluate ziftomenib in combination with existing intensive and non-intensive chemotherapy standards of care in newly diagnosed and relapsed/refractory NPM1-mutant or KMT2A-rearranged AML.

“There is also an ongoing phase 2 registration-enabling study with a primary end point of CR and CRh [complete remission with partial hematologic recovery],” Fahti added.


Fathi A, Wang E, Issa G, et al. Activity, tolerability, and resistance profile of the menin inhibitor ziftomenib in adults with relapsed/refractory NPM1-mutated AML. Presented at: 2023 EHA Congress; June 8-11, 2023; Frankfurt, Germany. Abstract LB2713.

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