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Activity of the oral mitogen-activated protein kinase kinase inhibitor trametinib in RAS-mutant relapsed or refractory myeloid malignancies.

Abstract：

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. Cancer 2016;122:1871-9. © 2016 American Cancer Society.

journal_name

Cancer

journal_title

Cancer

authors

Borthakur G,Popplewell L,Boyiadzis M,Foran J,Platzbecker U,Vey N,Walter RB,Olin R,Raza A,Giagounidis A,Al-Kali A,Jabbour E,Kadia T,Garcia-Manero G,Bauman JW,Wu Y,Liu Y,Schramek D,Cox DS,Wissel P,Kantarjian H

doi

10.1002/cncr.29986

subject

Has Abstract

pub_date

2016-06-15 00:00:00

pages

1871-9

issue

eissn

0008-543X

issn

1097-0142

journal_volume

122

pub_type

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Activity of the oral mitogen-activated protein kinase kinase inhibitor trametinib in RAS-mutant relapsed or refractory myeloid malignancies.