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

Research output: Contribution to journalArticle

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
Externally publishedYes

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Mitogen-Activated Protein Kinase Kinases
Acute Myeloid Leukemia
Extracellular Signal-Regulated MAP Kinases
Myelodysplastic Syndromes
Mitogens
Phosphotransferases
Therapeutics
Mitogen-Activated Protein Kinases
MEK162
Safety
Febrile Neutropenia
Proteins
Disease Resistance
Hypokalemia
Hypotension
Patient Selection
Neoplasms
Bone Marrow

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., ... 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

Phase II Trial of MEK Inhibitor Binimetinib (MEK162) in RAS-mutant Acute Myeloid Leukemia. / Maiti, Abhishek; Naqvi, Kiran; Kadia, Tapan M.; Borthakur, Gautam; Takahashi, Koichi; Bose, Prithviraj; Daver, Naval G.; Patel, Ami; Alvarado, Yesid; Ohanian, Maro; DiNardo, Courtney D.; Cortes, Jorge E.; Jabbour, Elias J.; Garcia-Manero, Guillermo; Kantarjian, Hagop M.; Ravandi, Farhad.

In: Clinical Lymphoma, Myeloma and Leukemia, Vol. 19, No. 3, 03.2019, p. 142-148.e1.

Research output: Contribution to journalArticle

Maiti, A, Naqvi, K, Kadia, TM, Borthakur, G, Takahashi, K, Bose, P, Daver, NG, Patel, A, Alvarado, Y, Ohanian, M, DiNardo, CD, Cortes, JE, Jabbour, EJ, Garcia-Manero, G, Kantarjian, HM & Ravandi, F 2019, 'Phase II Trial of MEK Inhibitor Binimetinib (MEK162) in RAS-mutant Acute Myeloid Leukemia', Clinical Lymphoma, Myeloma and Leukemia, vol. 19, no. 3, pp. 142-148.e1. https://doi.org/10.1016/j.clml.2018.12.009
Maiti, Abhishek ; Naqvi, Kiran ; Kadia, Tapan M. ; Borthakur, Gautam ; Takahashi, Koichi ; Bose, Prithviraj ; Daver, Naval G. ; Patel, Ami ; Alvarado, Yesid ; Ohanian, Maro ; DiNardo, Courtney D. ; Cortes, Jorge E. ; Jabbour, Elias J. ; Garcia-Manero, Guillermo ; Kantarjian, Hagop M. ; Ravandi, Farhad. / Phase II Trial of MEK Inhibitor Binimetinib (MEK162) in RAS-mutant Acute Myeloid Leukemia. In: Clinical Lymphoma, Myeloma and Leukemia. 2019 ; Vol. 19, No. 3. pp. 142-148.e1.
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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.",
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author = "Abhishek Maiti and Kiran Naqvi and Kadia, {Tapan M.} and Gautam Borthakur and Koichi Takahashi and Prithviraj Bose and Daver, {Naval G.} and Ami Patel and Yesid Alvarado and Maro Ohanian and DiNardo, {Courtney D.} and Cortes, {Jorge E.} and Jabbour, {Elias J.} and Guillermo Garcia-Manero and Kantarjian, {Hagop M.} and Farhad Ravandi",
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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

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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