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.

• Authors: 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 Wissel, Hagop Kantarjian
• Journal: Cancer (Cancer) Vol. 122 Issue 12 Pg. 1871-9 (06 15 2016) ISSN: 1097-0142 [Electronic] United States
• PMID: 26990290 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 American Cancer Society.

Chemical References

• KRAS protein, human
• Protein Kinase Inhibitors
• Pyridones
• Pyrimidinones
• trametinib
• Proto-Oncogene Proteins p21(ras)

Topics

• Adult
• Aged
• Aged, 80 and over
• Dose-Response Relationship, Drug
• Humans
• Kaplan-Meier Estimate
• Leukemia (blood, drug therapy, enzymology)
• Leukemia, Myeloid, Acute (blood, drug therapy, enzymology, genetics)
• MAP Kinase Signaling System (drug effects)
• Middle Aged
• Mutation
• Myelodysplastic Syndromes (blood, drug therapy, enzymology, genetics)
• Protein Kinase Inhibitors (administration & dosage, adverse effects, blood)
• Proto-Oncogene Proteins p21(ras) (genetics)
• Pyridones (administration & dosage, adverse effects, blood)
• Pyrimidinones (administration & dosage, adverse effects, blood)
• Recurrence
• Young Adult