Gomekli (mirdametinib)

Here we show that the BET inhibitor PLX51107 potently suppresses the growth of NRAS -mutant AML cell lines, and that these activities are enhanced by co-treatment with the MEK inhibitor PD0325901. AMLs that relapsed after frontline chemotherapy showed similar transcriptional remodeling. These studies demonstrate transcriptional plasticity in primary AMLs that relapse following in vivo treatment with either targeted agents or chemotherapy, and support evaluating BET inhibition in leukemias with monocytic differentiation and RAS mutations.

Drug sensitivity analysis identified four promising therapeutic compounds-PD-0325901, Bryostatin-1, ATRA, and Roscovitine-with potential clinical utility for ESCC treatment. The findings of this study offer clinically relevant insights for prognostic stratification and characterization of the immune microenvironment in ESCC patients. Moreover, these results provide novel perspectives that may contribute to the development of more effective prognostic tools and targeted therapeutic strategies for ESCC management.

Clinically, low GCKR expression predicted poorer survival and reduced immunotherapy benefit, while higher expression indicated selective sensitivity to MEK inhibitors including refametinib and PD0325901. These findings define GCKR as both a mutation- and expression-driven biomarker that connects metabolic regulation with immune remodeling, offering translational value for prognosis and precision therapy in gastric cancer.

In vivo studies further validated these findings, showing that the combination treatment inhibited tumor growth and significantly prolonged survival in mouse models bearing patient-derived NRAS-mutated melanoma tumors. Given the tolerability of this combination in vivo, our results suggest that brimarafenib and mirdametinib represent a promising therapeutic strategy for patients with NRAS-mutated melanomas and potentially other RAS-mutated solid tumors.

Our findings indicate that the combination of AZD5438 and PD0325901 holds therapeutic potential for the treatment of HPV (-) HNSCC, particularly in tumors with a high mutational burden. By targeting complementary pathways, this combination may improve treatment outcomes in this aggressive cancer subtype.

PN, often progressive and disfiguring, significantly impairs quality of life (QOL), and it can transform into malignant peripheral nerve sheath tumors (MPNST). In February 2025, mirdametinib was FDA-approved under the brand name GOMEKLI for pediatric and adult patients with inoperable PNs.

P1/2, N=50, Not yet recruiting, St. Justine's Hospital | Trial completion date: Apr 2035 --> Apr 2033 | Initiation date: Apr 2025 --> Dec 2025

Currently, MEK inhibitors selumetinib and mirdametinib are the only FDA-approved targeted therapies for NF1-related symptomatic or progressive, inoperable plexiform neurofibromas. Several additional MEK inhibitors are being investigated in clinical trials for the treatment of plexiform neurofibromas. Additional therapies are currently under investigation for the treatment of malignant peripheral nerve sheath tumors, low-grade gliomas, skeletal manifestations, cutaneous neurofibromas, and other NF1-related complications.

Mirdametinib offers an effective, targeted, and orally available treatment for NF1-associated plexiform neurofibromas, with the added advantage of CNS penetration and durable clinical benefit. However, resistance and toxicity remain challenges, and future research should focus on optimizing patient selection and developing combination strategies to further expand its role in NF1-PN management.

Additionally, fibroblasts showed higher resistance to selumetinib and mirdametinib than pNF1 tumor structures, likely due to elevated P-glycoprotein levels. This study is the first to define precise roles of fibroblasts in pNF1 drug resistance, emphasizing the potential of fibroblast-targeted therapies as a promising approach to improve pNF1 treatment outcomes.

P2, N=114, Active, not recruiting, SpringWorks Therapeutics, Inc. | Trial completion date: May 2025 --> Dec 2028

MEK inhibitors, including selumetinib and mirdametinib, have recently changed the treatment paradigm for these tumors. Selumetinib was well tolerated in our patient, with an asymptomatic Grade 3 CPK elevation that subsequently improved with a dose reduction. Our case adds to the growing body of evidence suggesting that selumetinib is effective and well tolerated in adult patients with NF1-associated PNs.