Stieglitz E, Lee AG, Angus SP, Davis C, Barkauskas DA, Hall D, Kogan SC, Meyer J, Rhodes SD, Tasian SK, Xuei X, Shannon K, Loh ML, Fox E, Weigel BJ. Efficacy of the Allosteric MEK Inhibitor Trametinib in Relapsed and Refractory Juvenile Myelomonocytic Leukemia: a Report from the Children’s Oncology Group. Cancer Discov. 2024 Sep 4;14(9):1590-1598. doi: 10.1158/2159-8290.CD-23-1376. PMID: 38867349; PMCID: PMC11374478.
Study ID Citation
Abstract
Juvenile myelomonocytic leukemia (JMML) is a hematologic malignancy of young children caused by mutations that increase Ras signaling output. Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment but patients with relapsed or refractory (advanced) disease have dismal outcomes. This phase 2 trial evaluated the safety and efficacy of trametinib, an oral MEK1/2 inhibitor, in patients with advanced JMML. Ten infants and children were enrolled and the objective response rate was 50%. Four patients with refractory disease proceeded to HSCT after receiving trametinib. Three additional patients completed all 12 cycles permitted on study and continue to receive off-protocol trametinib without HSCT. The remaining three patients had progressive disease with two demonstrating molecular evolution by the end of cycle 2. Transcriptomic and proteomic analyses provided novel insights into the mechanisms of response and resistance to trametinib in JMML. ClinicalTrials.gov Identifier: NCT03190915.