Dr Erba on the Initial Safety and Activity of Ziftomenib in AML

Harry Paul Erba, MD, PhD, instructor, clinical investigator, Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University School of Medicine, member, Duke Cancer Institute, director, Leukemia Program and Phase I Development in Hematologic Malignancies, Duke Health, discusses the safety profile and preliminary activity of the investigational menin inhibitor ziftomenib in acute myeloid leukemia (AML).

Ziftomenib is an oral, potent, and selective small molecule inhibitor of the menin-KMT2A complex, which is a known mediator of leukemia cell proliferation. Menin inhibitors work to increase the differentiation of leukemic blasts and reduce uncontrolled proliferation by downregulating the expression of HOXA9 and NICE1 genes.

The agent is currently being investigated in the phase 1/2 KOMET-001 trial (NCT04067336) as a monotherapy for patients with relapsed/refractory AML, Erba begins.

According to previously reported data from the phase 1 portion of this trial, ziftomenib produced a signal of activity in patients with either NPM1-mutant or KMT2A-rearranged AML, Erba reports. At the data cutoff of October 24, 2022, patients with NPM1-mutant disease given ziftomenib at the 600 mg dose experienced an overall response rate (ORR) of 40.0%. This percentage was 33.3% at the 200 mg dose. The ORR in patients with KMT2A-rearranged disease was 16.7% at the 600 mg dose. However, no responses were seen in patients with this rearrangement who were given the 200 mg dose.

Regarding safety, ziftomenib demonstrated a favorable safety profile and was not associated with QTc prolongation, Erba continues. The primary toxicity observed with ziftomenib was differentiation syndrome, which was expected given the drug class, Erba details. Additionally, most adverse effects (AEs) were related to disease biology and pathology, or complications from neutropenia and thrombocytopenia, he adds. Notably, no grade 3 or higher treatment-emergent AEs occurred in patients harboring NPM1 mutations. The agent also displayed tolerable gastrointestinal toxicities, Erba notes. Although these initial safety findings are promising, more research on potential drug-drug interactions with ziftomenib is necessary for the development of future combination strategies, Erba emphasizes.

Updated findings from the phase 1 trial, which were presented at the 2023 EHA Congress confirmed the clinical activity and tolerable safety profile of the agent. No new safety signals were reported.

Editor’s Note: This interview was conducted prior to the 2023 EHA Congress.