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

Gautam Borthakur, Leslie Popplewell, Michael Boyiadzis, James Foran, Uwe Platzbecker, Norbert Vey, Roland B. Walter, Rebecca Olin, Azra Raza, Aristoteles Giagounidis, Aref Al-Kali, Elias Jabbour, Tapan Kadia, Guillermo Garcia-Manero, John W. Bauman, Yuehui Wu, Yuan Liu, Dan Schramek, Donna S. Cox, Paul WisselHagop Kantarjian

Research output: Contribution to journalArticle

54 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1871-1879
Number of pages9
JournalCancer
Volume122
Issue number12
DOIs
StatePublished - Jun 15 2016

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Borthakur, G., Popplewell, L., Boyiadzis, M., Foran, J., Platzbecker, U., Vey, N., Walter, R. B., Olin, R., Raza, A., Giagounidis, A., Al-Kali, A., Jabbour, E., Kadia, T., Garcia-Manero, G., Bauman, J. W., Wu, Y., Liu, Y., Schramek, D., Cox, D. S., ... Kantarjian, H. (2016). Activity of the oral mitogen-activated protein kinase kinase inhibitor trametinib in RAS-mutant relapsed or refractory myeloid malignancies. Cancer, 122(12), 1871-1879. https://doi.org/10.1002/cncr.29986