Trametinib May Be Active in RAS-mutated Myeloid Malignancies
Single-agent trametinib has therapeutic potential for RAS-mutated myeloid malignancies.
Single-agent trametinib has therapeutic potential for RAS-mutated myeloid malignancies, a study published in the journal Cancer has shown.1
Preclinical trials have demonstrated that trametinib, a mitogen-activated protein kinase 1 (MEK1)/MEK2 inhibitor, has activity against multiple myeloid cell lines at low concentrations. Because RAS/RAF/mitogen-activated protein kinase activation is common in myeloid malignancies, researchers sought to evaluate the safety and clinical activity of trametinib in patients with different leukemias.
For the phase 1/2 study, researchers enrolled 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) who harbor a RAS wild-type mutation or an unknown mutation status (cohort 2); and patients with CMML with an NRAS or KRAS mutation (cohort 3).
In the phase 1 portion, patients received varying dose of trametinib. The 2 mg dose given orally daily was recommended for the phase 2 portion.
Results showed that the most commonly reported treatment-emergent adverse events were diarrhea, rash, nausea, and increased alanine aminotransferase levels.
Researchers found that repeated cycles of trametinib were well tolerated and toxicities were manageable or reversible.
In terms of activity, the overall response rate in patients with relapsed/refractory AML or high-risk MDS with NRAS or KRAS mutations was 20% and 27% in patients with CMML with a NRAS or KRAS mutation.
However, in patients with AML, MDS, or CMML with a RAS wild-type mutation or an unknown mutation status had a response rate of only 3%.
Researchers expect combination regimens to further improve the response rate achieved with trametinib in these patient populations.
REFERENCE1. Borthakur G, Popplewell L, Boyiadzis M, et al. Activity of the oral mitogen-activated protein kinase kinase inhibitor trametinib in RAS-mutant relapsed or refractory myeloid malignancies [published online ahead of print March 18, 2016]. Cancer. doi:10.1002/cncr.29986.