TY - JOUR
T1 - Activity of the oral mitogen-activated protein kinase kinase inhibitor trametinib in RAS-mutant relapsed or refractory myeloid malignancies
AU - Borthakur, Gautam
AU - Popplewell, Leslie
AU - Boyiadzis, Michael
AU - Foran, James
AU - Platzbecker, Uwe
AU - Vey, Norbert
AU - Walter, Roland B.
AU - Olin, Rebecca
AU - Raza, Azra
AU - Giagounidis, Aristoteles
AU - Al-Kali, Aref
AU - Jabbour, Elias
AU - Kadia, Tapan
AU - Garcia-Manero, Guillermo
AU - Bauman, John W.
AU - Wu, Yuehui
AU - Liu, Yuan
AU - Schramek, Dan
AU - Cox, Donna S.
AU - Wissel, Paul
AU - Kantarjian, Hagop
N1 - Publisher Copyright:
© 2016 American Cancer Society.
PY - 2016/6/15
Y1 - 2016/6/15
N2 - BACKGROUND RAS/RAF/mitogen-activated protein kinase activation is common in myeloid malignancies. Trametinib, a mitogen-activated protein kinase kinase 1 (MEK1)/MEK2 inhibitor with activity against multiple myeloid cell lines at low nanomolar concentrations, was evaluated for safety and clinical activity in patients with relapsed/refractory leukemias. METHODS This phase 1/2 study accrued patients with any relapsed/refractory leukemia in phase 1. In phase 2, this study accrued patients with relapsed/refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) with NRAS or KRAS mutations (cohort 1); patients with AML, MDS, or chronic myelomonocytic leukemia (CMML) with a RAS wild-type mutation or an unknown mutation status (cohort 2); and patients with CMML with an NRAS or KRAS mutation (cohorts 3). RESULTS The most commonly reported treatment-related adverse events were diarrhea, rash, nausea, and increased alanine aminotransferase levels. The phase 2 recommended dose for Trametinib was 2 mg orally daily. The overall response rates were 20%, 3%, and 27% for cohorts 1, 2, and 3, respectively, and this indicated preferential activity among RAS-mutated myeloid malignancies. Repeated cycles of trametinib were well tolerated with manageable or reversible toxicities; these results were similar to those of other trametinib studies. CONCLUSIONS The selective, single-agent activity of trametinib against RAS-mutated myeloid malignancies validates its therapeutic potential. Combination strategies based on a better understanding of the hierarchical role of mutations and signaling in myeloid malignancies are likely to improve the response rate and duration.
AB - BACKGROUND RAS/RAF/mitogen-activated protein kinase activation is common in myeloid malignancies. Trametinib, a mitogen-activated protein kinase kinase 1 (MEK1)/MEK2 inhibitor with activity against multiple myeloid cell lines at low nanomolar concentrations, was evaluated for safety and clinical activity in patients with relapsed/refractory leukemias. METHODS This phase 1/2 study accrued patients with any relapsed/refractory leukemia in phase 1. In phase 2, this study accrued patients with relapsed/refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) with NRAS or KRAS mutations (cohort 1); patients with AML, MDS, or chronic myelomonocytic leukemia (CMML) with a RAS wild-type mutation or an unknown mutation status (cohort 2); and patients with CMML with an NRAS or KRAS mutation (cohorts 3). RESULTS The most commonly reported treatment-related adverse events were diarrhea, rash, nausea, and increased alanine aminotransferase levels. The phase 2 recommended dose for Trametinib was 2 mg orally daily. The overall response rates were 20%, 3%, and 27% for cohorts 1, 2, and 3, respectively, and this indicated preferential activity among RAS-mutated myeloid malignancies. Repeated cycles of trametinib were well tolerated with manageable or reversible toxicities; these results were similar to those of other trametinib studies. CONCLUSIONS The selective, single-agent activity of trametinib against RAS-mutated myeloid malignancies validates its therapeutic potential. Combination strategies based on a better understanding of the hierarchical role of mutations and signaling in myeloid malignancies are likely to improve the response rate and duration.
KW - KRAS
KW - NRAS
KW - acute myeloid leukemia
KW - chronic myelomonocytic leukemia
KW - myelodysplastic syndromes
KW - trametinib
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U2 - 10.1002/cncr.29986
DO - 10.1002/cncr.29986
M3 - Article
C2 - 26990290
AN - SCOPUS:84961282550
SN - 0008-543X
VL - 122
SP - 1871
EP - 1879
JO - Cancer
JF - Cancer
IS - 12
ER -