TY - JOUR
T1 - Phase II Trial of MEK Inhibitor Binimetinib (MEK162) in RAS-mutant Acute Myeloid Leukemia
AU - Maiti, Abhishek
AU - Naqvi, Kiran
AU - Kadia, Tapan M.
AU - Borthakur, Gautam
AU - Takahashi, Koichi
AU - Bose, Prithviraj
AU - Daver, Naval G.
AU - Patel, Ami
AU - Alvarado, Yesid
AU - Ohanian, Maro
AU - DiNardo, Courtney D.
AU - Cortes, Jorge E.
AU - Jabbour, Elias J.
AU - Garcia-Manero, Guillermo
AU - Kantarjian, Hagop M.
AU - Ravandi, Farhad
N1 - Funding Information:
A.M. has received research funding from Celgene Corporation. K.T. has reported a consultancy with Symbio Pharmaceuticals. P.B. has received honoraria from Incyte Corporation and Celgene Corporation and research funding from Incyte Corporation, Celgene Corporation, CTI BioPharma, Constellation Pharmaceuticals, Blueprint Medicines Corporation, Astellas Pharmaceuticals, and Pfizer. N.G.D. has reported a consultancy with, and research funding from, Sunesis Pharmaceuticals, Inc, Karyopharm, Pfizer Inc, and Bristol-Myers Squibb Company; research funding from Immunogen, Daiichi-Sankyo, and Kiromic; honoraria and research funding from Incyte Corporation; and a consultancy with Novartis Pharmaceuticals Corporation, Otsuka America Pharmaceutical, Inc, and Jazz. C.D.D. has received honoraria and research funding from AbbVie, Agios, Novartis, Celgene, and Daiichi-Sankyo. J.E.C. has received research funding from Ambit BioSciences, ARIAD, Arog, Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Celator, Celgene, Novartis, Pfizer, Sanofi, Sun Pharma, and Teva and has been a consultant to Ambit BioSciences, ARIAD, Astellas Pharma, BiolineRx, Bristol-Myers Squibb, Novartis, and Pfizer. E.J.J. has received research funding from Amgen, Novartis, and Pfizer. H.M.K. has received research funding from Amgen, ARIAD, Bristol-Myers Squibb, Delta-Fly Pharma, Novartis, and Pfizer. F.R. has received research funding from Amgen, Bristol-Myers Squibb, Merck, Seattle Genetics, and Sunesis Pharmaceuticals, honoraria from Amgen, Pfizer, Seattle Genetics, and Sunesis Pharmaceuticals, and has served in a consulting or advisory role for Amgen, Seattle Genetics, and Sunesis Pharmaceuticals. The remaining authors have stated that they have no conflicts of interest.The present study was conducted in collaboration with Array BioPharma and supported in part by the MD Anderson Cancer Center (support grant CA016672) from the National Cancer Institute. We thank the patients and their families, coinvestigators, and members of the study team involved in the present trial.
Funding Information:
The present study was conducted in collaboration with Array BioPharma and supported in part by the MD Anderson Cancer Center (support grant CA016672) from the National Cancer Institute . We thank the patients and their families, coinvestigators, and members of the study team involved in the present trial.
Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2019/3
Y1 - 2019/3
N2 - 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.
AB - 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.
KW - Acute myeloid leukemia
KW - Binimetinib
KW - KRAS
KW - MEK
KW - MEK162
KW - NRAS
KW - RAS
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U2 - 10.1016/j.clml.2018.12.009
DO - 10.1016/j.clml.2018.12.009
M3 - Article
C2 - 30635233
AN - SCOPUS:85059586000
SN - 2152-2650
VL - 19
SP - 142-148.e1
JO - Clinical Lymphoma, Myeloma and Leukemia
JF - Clinical Lymphoma, Myeloma and Leukemia
IS - 3
ER -
