Ziftomenib in Relapsed or Refractory NPM1-Mutated AML

Author(s): Eunice S. Wang, MD¹; Pau Montesinos, MD²; James Foran, MD³; Harry Erba, MD⁴; Eduardo Rodríguez-Arbolí, MD⁵; Kateryna Fedorov, MD⁶; Maël Heiblig, MD⁷; Florian H. Heidel, MD⁸; Jessica K. Altman, MD⁹; Maria R. Baer, MD¹⁰; Lionel Ades, MD¹¹; Kristen Pettit, MD¹²; Pierre Peterlin, MD¹³; Cristina Papayannidis, MD¹⁴; Céline Berthon, MD¹⁵; Roland B. Walter, MD¹⁶; Mithun V. Shah, MD, PhD¹⁷; Suresh Balasubramanian, MD¹⁸; Mohamad Khawandanah, MD¹⁹; Olga Salamero Garcia, MD²⁰; Julie Bergeron, MD²¹; Yazan F. Madanat, MD²²; Gail J. Roboz, MD²³; Matthew Ulrickson, MD²⁴; Robert L. Redner, MD²⁵; James McCloskey, MD²⁶; Arnaud Pigneux, MD²⁷; Adolfo de la Fuente Burguera, MD²⁸; Amitava Mitra, PhD²⁹; Harris S. Soifer, PhD²⁹; Marilyn Tabachri, BSN²⁹; Zijing Zhang, PhD²⁹; Marcie Riches, MD²⁹; Daniel Corum, PhD²⁹; Mollie Leoni, MD²⁹; Ghayas C. Issa, MD³⁰; Amir T. Fathi, MD³¹;

Source: DOI: 10.1200/JCO-25-01694

Dr. Anjan Patel's Thoughts

Ziftomenib 600 mg daily achieved a CR/CRh rate of 22% (61% MRD-negative among responders) and an overall response rate (ORR) of 33% in heavily pretreated R/R NPM1-mutated AML, with a median duration of response (DOR) of 4.6 months and median overall survival (OS) of 6.6 months (18.4 months in responders). Efficacy was consistent across subgroups, including prior venetoclax and FLT3/IDH co-mutations, and safety was manageable with on-target differentiation syndrome in 25% (15% grade 3; no grade 4–5), low myelosuppression, rare QTc prolongation (3%), and only 3% discontinuations for drug-related AEs. This non-cytotoxic, oral menin inhibitor offers meaningful activity in a high-risk population and is a practical option while we await combination data.

PURPOSE

Ziftomenib—a potent, highly selective, oral menin inhibitor—was well tolerated and demonstrated encouraging clinical activity as monotherapy for relapsed/refractory NPM1-mutated (NPM1-m) and KMT2A-rearranged AML in the KOMET-001 phase I trial.

METHODS

In the registration-enabling phase II part of KOMET-001, patients with relapsed/refractory NPM1-m AML received ziftomenib 600 mg once daily. The primary end point was the rate of complete remission with full hematologic recovery (CR)/CR with partial hematologic recovery (CRh).

RESULTS

From January 26, 2023, to May 13, 2024, 92 patients (median age, 69 years [range, 33-84]) were treated. The primary end point was met, with a CR/CRh rate of 22% (95% CI, 14 to 32; P = .0058); 61% were negative for measurable residual disease. Overall response rate was 33% (95% CI, 23 to 43), with a median duration of 4.6 months (95% CI, 2.8 to 7.4). Prespecified subgroup analyses showed comparable CR/CRh regardless of previous therapy, including venetoclax, or type of comutations. Median overall survival was 6.6 months (95% CI, 3.6 to 8.6). Common grade ≥3 treatment-emergent adverse events were febrile neutropenia (26%), anemia (20%), and thrombocytopenia (20%). Differentiation syndrome occurred in 25% of patients (15% grade 3; no grade 4-5) and was manageable with protocol-defined mitigation. Three patients (3%) discontinued treatment because of ziftomenib-related adverse events.

CONCLUSION

Ziftomenib demonstrated significant clinical benefit and deep responses in patients with heavily pretreated, relapsed/refractory NPM1-m AML. Ziftomenib was well tolerated with a safety profile consistent with previous studies, including manageable differentiation syndrome, lack of clinically significant QTc prolongation, and low rates of myelosuppression.

Author Affiliations

¹Roswell Park Comprehensive Cancer Center, Buffalo, NY; ²Hospital Universitari i Politècnic La Fe, Valencia, Spain; ³Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, FL; ⁴Duke Cancer Institute, Durham, NC; ⁵Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBiS/CSIC), University of Seville, Seville, Spain; ⁶Vanderbilt-Ingram Cancer Center, Nashville, TN; ⁷Centre Hospitalier Lyon Sud, Lyon, France; ⁸Hannover Medical School, Hannover, Germany; ⁹Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL; ¹⁰University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD; ¹¹Hôpital Saint-Louis, Paris, France; ¹²University of Michigan, Ann Arbor, MI; ¹³CHU de Nantes-Hôtel-Dieu, Nantes, France; ¹⁴IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli”, Bologna, Italy; ¹⁵CHU Lille, Lille, France; ¹⁶Fred Hutchinson Cancer Center, Seattle, WA; ¹⁷Mayo Clinic, Rochester, MN; ¹⁸Karmanos Cancer Institute, Wayne State University, Detroit, MI; ¹⁹University of Oklahoma Health Sciences Center, Stephenson Cancer Center, Oklahoma, OK; ²⁰Hospital Universitari Vall d'Hebron and Institute of Oncology (VHIO), Universitat Autonoma of Barcelona, Barcelona, Spain; ²¹Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada; ²²University of Texas Southwestern Medical Center, Dallas, TX; ²³Weill Medical College of Cornell University, New York, NY; ²⁴Banner MD Anderson Cancer Center, Gilbert, AZ; ²⁵University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA; ²⁶Hackensack University Medical Center, Hackensack, NJ; ²⁷Bordeaux Haut-Leveque University Hospital, Pessac, France; ²⁸MD Anderson Cancer Center Madrid, Madrid, Spain; ²⁹Kura Oncology, Inc, San Diego, CA; ³⁰The University of Texas MD Anderson Cancer Center, Houston, TX; ³¹Massachusetts General Hospital, Harvard Medical School, Boston, MA

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