Ziftomenib Demonstrates Activity and Tolerability in Relapsed/Refractory AML

Ziftomenib monotherapy showed pronounced antileukemic activity and a tolerable toxicity profile in pretreated patients with relapsed/refractory acute myeloid leukemia.

According to updated data from a phase 1/2 trial (NCT04067336) presented at the 2022 American Society of Hematology (ASH) Annual Meeting, ziftomenib (KO-539) monotherapy had a tolerable toxicity profile and provided pronounced antileukemic activity when given at a 600-mg dose in heavily pretreated patients with relapsed or refractory acute myeloid leukemia (AML).1

When given at this dose in patients with NPM1-mutated disease enrolled to phase 1a and 1b of the trial (n = 20), the menin-KMT2A inhibitor elicited a complete remission (CR) rate of 30.0%. Notably, 2 of these patients had a concurrent IDH1/2 mutation, and 2 patients had both IDH1/2 and FLT3-ITD/TKD mutations. Of the 7 patients who had IDH1/2 comutations, 57% achieved a CR with ziftomenib.

In this population, the CR/CR with partial hematologic recovery (CRh) rate with the agent was 30.0% and the composite CR (CRc) rate was 35.0%. The minimal residual disease (MRD) negativity rate was 42.9%. Ziftomenib elicited an overall response rate (ORR) of 40.0% in those who harbored this mutation.

Activity was also observed in patients with KMT2A-rearranged disease who were enrolled to the phase 1a and 1b portions of the trial and received the agent at 600 mg (n = 18). In this group, the CR/CRh rate achieved with ziftomenib was 5.6%, and the CRc rate was 11.1%. The MRD-negativity rate achieved with the agent was 100.0%. Moreover, ziftomenib produced an ORR of 16.7% in this population.

“Optimal benefit-to-risk ratio was demonstrated at the 600-mg recommended phase 2 dose [RP2D], with pronounced activity and a 30% CR rate in the 20 NPM1-mutated patients, giving us confidence in the data,” Harry P. Erba, MD, PhD, lead study author and hematologic oncologist at Duke Cancer Institute, said in a presentation of the data. “The monotherapy data are supportive of future combination strategies with no predicted adverse drug-drug interactions. The activity of the KMT2A-rearranged population is clear, and therefore, optimization activities are underway to develop rational combination strategies and to maximize patients’ time on treatment.”

Ziftomenib is an oral investigational drug that was designed to be a highly potent and selective inhibitor of the menin/KMT2A interaction, leading to downregulation of HOXA9 and MEIS1, and increased differentiation, according to Erba.

The first-in-human, open-label, dose-escalation and -validation/expansion study enrolled patients with relapsed or refractory AML who were at least 18 years of age and who had an ECOG performance status of 0 to 2 and acceptable liver and kidney function.2 Those with acute promyelocytic leukemia, chronic myelogenous leukemia in blast crisis, or clinically active central nervous system leukemia were excluded.

In phase 1a, dose escalation of ziftomenib was evaluated in an all-comer population to determine the maximum-tolerated dose and/or the RP2D. Here, investigators evaluated the agent at doses escalating from 50 mg (n = 1) to 100 mg (n = 1) to 200 mg (n = 6) to 400 mg (n = 5) to 600 mg (n = 5) to 800 mg (n = 11) to 1000 mg (n = 1). They evaluated the safety, tolerability, pharmacokinetics (PK), and early evidence of antitumor activity.

A total of 30 patients were enrolled to the portion of the research. In this group, the median age was 65.5 years (range, 22-85); 56.7% were male and 63.3% had an ECOG performance status of 1. Moreover, 13.3% of patients had NPM1-mutated disease and 53.3% had non–KM2TA-rearranged/NPM1-mutated disease. The median number of previous therapies received was 3.5 (range, 1-9), with 73.3% of patients having received venetoclax (Venclexta) and 23.3% having undergone prior stem cell transplant.

“There were no patterns of toxicity by dose, and overall, events were consistent with the effects of the underlying disease,” Erba noted. No drug-induced QT/QTc prolongation was observed.

Two dose-limiting toxicities (DLTs) were reported with the agent; pneumonitis/post-aspiration pneumonia occurred in the cohort of patients who received the agent at 400 mg, and differentiation syndrome (DS) occurred in the 1000-mg cohort. In accordance with trial protocol, the DLT in the first patient at 1000 mg resulted in de-escalation of the drug to 800 mg.

“In the phase 1a, 30% of the relapsed/refractory AML patients remained on treatment for at least 4 cycles with decreasing blast counts observed across dose levels,” Erba said. “At the 600- and 800-mg doses, KMT2A-rearranged patients experienced stable diseases of significant durations in the context of decreasing blast counts and improved performance status. In the NMP1-mutated patients treated at the 200-mg dose, 1 patient achieved a MRD CR that is still ongoing for over 2 years at the time of the data cutoff. Another [patient] with concomitant FLT3-ITD mutation achieved a morphologic leukemia-free state.”

In the phase 1b portion of KOMET-001, patients were randomized to the lowest doses of ziftomenib that demonstrated evidence of clinical activity; these doses were 200 mg (cohort 1) and 600 mg (cohort 2).

The key objective of this phase of the research was to enroll 2 genetically enriched cohorts to identify the optimal RP2D in line with the FDA’s Project Optimus, which acknowledges that targeted therapies may reach maximal activity before reaching a maximally tolerated dose, Erba explained. Here, investigators examined ziftomenib’s safety and tolerability, PK, and antitumor efficacy.

A total of 53 patients were included in the phase 1b portion of the trial; 17 patients received ziftomenib at 200 mg and 36 received the agent at 600 mg. The median age in the 200-mg and 600-mg cohorts was 49.0 years (range, 30-79) and 54.5 years (range, 18-86). Just under half of patients were male (41.2% vs 41.7%).

“The overall median ECOG performance status was 1. While most patients treated at 200 mg were KMT2A-rearranged, there was a more even distribution at the 600-mg dose,” Erba noted.

The median number of prior therapies received in both cohorts was 3 (range, 1-11), and more than half of patients in both arms previously received venetoclax. One-third previously underwent at least 1 stem cell transplant, Erba said. “IDH and FLT3 mutations predominantly occurred in the NPM1-mutated patients,” he added.

At a data cutoff date of October 24, 2022, 27.8% of those who received the agent at 600 mg were still on treatment vs no patients who received the 200-mg dose. The most common reasons for treatment discontinuation in the 200-mg and 600-mg cohorts were toxicity (11.8% vs 11.1%, respectively), death (23.5% vs 8.3%), and disease progression (29.4% vs 30.6%). Death was the reason for study discontinuation in 82.4% of those in the 200-mg cohort and 38.9% of those in the 600-mg cohort.

No grade 3 or higher treatment-emergent adverse effects (AEs) were reported in the patients harboring NPM1 mutations, at either dose level. Of those with KMT2A-rearranged disease who received the agent at 200 mg (n = 13), 30.8% experienced DS. Of those with KMT2A-rearranged disease who were given the agent at 600 mg (n = 16), 25.0% had DS and 12.5% had febrile neutropenia.

Twenty percent of patients with NPM1-mutated disease treated at the 600-mg dose experienced DS; 5.0% of these cases were grade 3 or higher in severity. Moreover, 38.5% and 37.5% of those with KMT2A-rearranged disease treated at the 200-mg and 600-mg doses, respectively, experienced DS; this was grade 3 or higher in 30.8% and 25.0% of cases, respectively.

“We believe that the difference in the rates of DS is due to a greater risk of extramedullary disease in the KMT2A-rearranged AML population, coupled with the high tissue penetration of ziftomenib, leading to atypical presentations of DS in these patients,” Erba explained. “The severity of DS has decreased since the issuance and evolution of guidance that allows the better identification and earlier intervention for DS.”

DS was associated with a response in 75% of the NMP1-mutated population and 16.7% of the KMT2A-rearranged population.

The FDA has selected 600 mg as the RP2D for patients with NPM1-mutated AML.


  1. Erba HP, Fathi AT, Issa GC, et al. Update on a phase 1/2 first-in-human study of the menin-KMT2A (MLL) inhibitor ziftomenib (KO-539) in patients with relapsed or refractory acute myeloid leukemia. Blood. 2022;140(suppl 1):153-156. doi:10.1182/blood-2022-167412
  2. First in human study of KO-539 in relapsed or refractory acute myeloid leukemia. ClinicalTrials.gov. Updated May 2, 2022. Accessed December 10, 2022. https://clinicaltrials.gov/ct2/show/NCT04067336