Ziftomenib with venetoclax and azacitidine in relapsed/refractory NPM1-mutated acute myeloid leukemia
Abstract
Ziftomenib - a potent, selective, oral menin inhibitor - is approved as monotherapy for adults with relapsed/refractory (R/R) NPM1-mutated acute myeloid leukemia (NPM1-m AML). The KOMET-007 phase 1 trial investigated clinical activity and tolerability of ziftomenib in combination with standard therapies for R/R and newly diagnosed AML. Here, we report outcomes of adults with R/R NPM1-m AML treated with ziftomenib plus venetoclax/azacitidine. In phase 1a, patients received ziftomenib 200, 400, or 600 mg once daily with standard doses of venetoclax/azacitidine. In phase 1b, ziftomenib 600 mg was selected for expansion. Sixty-seven patients were treated (27 phase 1a; 40 phase 1b). Median age was 66 years, and 55% were men. Median number of prior therapies was 1 (range 1-8); 55% received prior venetoclax and 22% had prior transplantation. Most common (≥20%) grade ≥3 treatment-emergent adverse events were leukopenia (34%), thrombocytopenia (28%), febrile neutropenia and neutropenia (25% each). Six patients developed QTc prolongation (1 ziftomenib-related; grade 1), and 2 experienced differentiation syndrome (grade 3); all events were successfully managed. In patients receiving ziftomenib 600 mg, composite complete remission (CRc) rate was 46% (22/48), with 67% (12/18) achieving central measurable residual disease (MRD) negativity (<0.01% threshold). In venetoclax-naïve and -exposed patients, CRc rates were 70% (16/23) and 24% (6/25), with MRD-negativity rates of 75% (9/12) and 50% (3/6), respectively. Median duration of response was 8.6 months, and median overall survival was not reached. The combination of ziftomenib 600 mg with venetoclax/azacitidine was well tolerated with deep and durable clinical activity in R/R NPM1-m AML. This trial was registered at www.ClinicalTrials.gov as #NCT05735184.
Article Details
Authors (36)
Eunice S. Wang
30Roswell Park Cancer Institute, Buffalo, NY
Harry P. Erba
Duke University, Durham, North Carolina, United States
Amer M. Zeidan
Gail J. Roboz
Weill Cornell Medicine, New York Presbyterian Hospital, New York
Jessica K. Altman
Division of Hematology/Oncology Department of Medicine Robert H. Lurie Comprehensive Cancer Center Northwestern University Chicago Illinois USA
Anjali S. Advani
Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio, United States
Tara L. Lin
University of Kansas, Fairway, Kansas, United States
Stephen A. Strickland
32Sarah Cannon Transplant and Cellular Therapy Network, Nashville, TN
Mark B. Juckett
University of Minnesota, Minneapolis, Minnesota, United States
Keith W. Pratz
University of Pennsylvania, Philadelphia, Pennsylvania, United States
James K. Mangan
University of California, San Diego, La Jolla, California, United States
Christine M. McMahon
University of Colorado, Aurora, Colorado, United States
Leonard Clarkson Alsfeld
Ochsner Health, New Orleans, Louisiana, United States
Suresh Kumar Balasubramanian
Karmanos Cancer Institute, Detroit, Michigan, United States
Guru Subramanian Guru Murthy
Medical College of Wisconsin, Milwaukee, Wisconsin, United States
Marcello Rotta
Colorado Blood Cancer Institute, Denver, Colorado, United States
Neil Palmisiano
Rutgers Cancer Institute, New Brunswick, New Jersey, United States
James McCloskey
John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, New Jersey, United States
Antoine N Saliba
Mayo Clinic, Rochester, Minnesota, United States
Mohamad Khawandanah
Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
Yazan F. Madanat
UT Southwestern Medical Center, Dallas, Texas, United States
Kiran Naqvi
Chao Family Comprehensive Cancer Center, University of California Irvine Health, Orange, California, United States
Ayman H. Qasrawi
University of Kentucky College of Medicine, Lexington, Kentucky, United States
Gary J. Schiller
David Geffen School of Medicine at UCLA, Los Angeles, California, United States
Talha Badar
Mayo Clinic, Jacksonville, Florida, United States
Ivana Gojo
Johns Hopkins University, Baltimore, Maryland, United States
George Yaghmour
University of Southern California, Los Angeles, California, United States
Diaa Osman
Texas Oncology, Austin, Texas, United States
Hongling Zhang
Ying Tian
Harris S. Soifer
Kura Oncology Inc., San Diego, California, United States
Marcie Riches
Kura Oncology Inc., San Diego, California, United States
Daniel Corum
Kura Oncology Inc., San Diego, California, United States
Mollie Leoni
Kura Oncology, Inc., Boston, Massachusetts, United States
Amir T. Fathi
Massachusetts General Hospital Cancer Center–Harvard Medical School, Boston
Ghayas C. Issa