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Cancer. 2016 Jun 15;122(12):1871-9. doi: 10.1002/cncr.29986. Epub 2016 Mar 18.

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

Author information

1
The University of Texas MD Anderson Cancer Center, Houston, Texas.
2
City of Hope Medical Center, Duarte, California.
3
University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
4
University of Alabama Hospital, Birmingham, Alabama.
5
Carl Gustav Carus University Hospital, Dresden, Germany.
6
Paoli-Calmettes Institute, Marseille, France.
7
Fred Hutchinson Cancer Research Center, Seattle, Washington.
8
University of California San Francisco, San Francisco, California.
9
Columbia University Medical Center, New York, New York.
10
Marien Hospital, Dusseldorf, Germany.
11
Mayo Clinic, Rochester, New York.
12
Quintiles, Durham, North Carolina.
13
Merck & Company, Incorporated, North Wales, Pennsylvania.
14
Pfizer Oncology, La Jolla, California.
15
GlaxoSmithKline, Collegeville, Pennsylvania.
16
Teva Pharmaceuticals, Frazier, Pennsylvania.
17
Pfizer, Incorporated, Collegeville, Pennsylvania.

Erratum in

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.

KEYWORDS:

KRAS; NRAS; acute myeloid leukemia; chronic myelomonocytic leukemia; myelodysplastic syndromes; trametinib

PMID:
26990290
PMCID:
PMC5779863
DOI:
10.1002/cncr.29986
[Indexed for MEDLINE]
Free PMC Article

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