Phase II Trial of MEK Inhibitor Binimetinib (MEK162) in RAS-mutant Acute Myeloid Leukemia

Abhishek Maiti, Kiran Naqvi, Tapan M. Kadia, Gautam Borthakur, Koichi Takahashi, Prithviraj Bose, Naval G. Daver, Ami Patel, Yesid Alvarado, Maro Ohanian, Courtney D. DiNardo, Jorge E. Cortes, Elias J. Jabbour, Guillermo Garcia-Manero, Hagop M. Kantarjian, Farhad Ravandi

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6 Scopus citations

Abstract

Background: Relapsed and refractory (R/R) acute myeloid leukemia (AML) continues to be a therapeutic challenge with poor outcomes. Dysregulation of the mitogen-activated protein (MAP) kinase/extracellular-signal regulated kinase (ERK) pathway frequently occurs in AML and myelodysplastic syndrome (MDS). Preclinical studies and early-phase trials have shown promise for MAP-ERK kinase (MEK) inhibition in AML. We evaluated the safety and efficacy of the MEK 1/2 inhibitor binimetinib in advanced myeloid malignancies. Patients and Methods: Nineteen patients with R/R AML and MDS, who were not candidates for intensive chemotherapy or with disease resistance or intolerance to standard treatment were enrolled in the present phase II study of binimetinib dosed twice daily continuously in 28-day cycles. Results: The median age of the cohort was 64 years (range, 31-85 years). These patients had received a median of 3 previous lines of therapy (range, 1-6). The median bone marrow blast percentage was 49% (range, 2%-94%), and 14 patients had RAS mutations. The patients received a median of 2 cycles (range, 1-4 cycles) of binimetinib and received treatment for a median duration of 1.2 months (range, 0.1-3.4 months). Sixteen patients (84%) received the 45-mg twice daily dose. The most common grade 3/4 treatment-emergent adverse events were hypokalemia (6%), hypotension (6%), lung infection (6%), and febrile neutropenia (6%). No treatment-related deaths occurred. One of the 13 evaluable patients (8%) achieved a complete response with incomplete blood count recovery lasting 2.1 months. The other 12 patients (92%) did not have a response. Six patients could not be evaluated. Conclusion: Binimetinib had tolerable safety profile with a minimal response in RAS-mutant AML. Future studies should focus on better patient selection and synergistic combination therapies involving MEK inhibition. Dysregulation of the mitogen-activated protein (MAP) kinase/extracellular-signal regulated kinase (ERK) pathway frequently occurs in acute myeloid leukemia and myelodysplastic syndrome. Nineteen patients with advanced myeloid malignancies were treated with the MAP-ERK kinase 1/2 inhibitor binimetinib. Minimal activity was noted, with 1 of 13 evaluable patients (8%) achieving a complete response with incomplete blood count recovery, 12 patients (92%) had no response, and 6 patients could not be evaluated. Future studies are needed to evaluate synergistic combination therapies involving MAP-ERK kinase inhibition.

Original languageEnglish (US)
Pages (from-to)142-148.e1
JournalClinical Lymphoma, Myeloma and Leukemia
Volume19
Issue number3
DOIs
StatePublished - Mar 2019

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Keywords

  • Acute myeloid leukemia
  • Binimetinib
  • KRAS
  • MEK
  • MEK162
  • NRAS
  • RAS

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Maiti, A., Naqvi, K., Kadia, T. M., Borthakur, G., Takahashi, K., Bose, P., Daver, N. G., Patel, A., Alvarado, Y., Ohanian, M., DiNardo, C. D., Cortes, J. E., Jabbour, E. J., Garcia-Manero, G., Kantarjian, H. M., & Ravandi, F. (2019). Phase II Trial of MEK Inhibitor Binimetinib (MEK162) in RAS-mutant Acute Myeloid Leukemia. Clinical Lymphoma, Myeloma and Leukemia, 19(3), 142-148.e1. https://doi.org/10.1016/j.clml.2018.12.009