Phase II Trial of MEK Inhibitor Binimetinib (MEK162) in RAS-mutant Acute Myeloid Leukemia.
Acute myeloid leukemia
Binimetinib
KRAS
MEK
MEK162
NRAS
RAS
Journal
Clinical lymphoma, myeloma & leukemia
ISSN: 2152-2669
Titre abrégé: Clin Lymphoma Myeloma Leuk
Pays: United States
ID NLM: 101525386
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
23
06
2018
revised:
17
11
2018
accepted:
12
12
2018
pubmed:
13
1
2019
medline:
4
6
2020
entrez:
13
1
2019
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 30635233
pii: S2152-2650(18)30679-7
doi: 10.1016/j.clml.2018.12.009
pii:
doi:
Substances chimiques
Benzimidazoles
0
binimetinib
181R97MR71
Types de publication
Clinical Trial, Phase II
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
142-148.e1Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Informations de copyright
Copyright © 2018 Elsevier Inc. All rights reserved.