Gomekli (mirdametinib)

Mouse embryonic stem cells (mESCs) derived from protein kinase C inhibition (PKCi) exhibit self-renewal and pluripotency comparable to those ESCs captured by the classical 2iL (CHIR99021, PD0325901, and leukemia inhibitory factor) system...Thus, EZH2, a core subunit of PRC2, exhibits the distinct regulatory functions orchestrating mESCs at a poised state between self-renewal and differentiation under PKC inhibition. EZH2 exerts histone H3 methyltransferase activity to regulate Nanog expression as one of its key targets, thereby modulating the transcriptional regulatory network that maintains pluripotency and lineage specification in mESCs.

P2, N=20, Recruiting, National Cancer Institute (NCI) | Initiation date: Sep 2026 --> May 2026

While the mitogen-activated protein kinase kinase (MEK) inhibitors, selumetinib and mirdametinib, can reduce tumor volume, surgical resection remains the primary treatment for immediate debulking and symptom relief. These results provide the first evidence that ECM stiffening, including that plausibly associated with postsurgical remodeling, may contribute to pNF1 growth and reduced sensitivity to selumetinib in this 3D pNF1 culture model. Our findings highlight mechanobiology as a key regulator of tumor behavior and support further investigation of ECM-targeted strategies to improve outcomes in neurofibromatosis type 1 (NF1).

MEK inhibitor therapy is associated with significant improvements in patient-reported pain outcomes in NF1-associated PN, including reductions in pain intensity and interference, as well as a high proportion of patients achieving clinically meaningful improvement. While the average reduction in pain intensity did not reach the threshold for clinically meaningful change at the population level, responder analyses demonstrate substantial benefit in a significant subset of patients. These findings support the role of MEK inhibitors as a disease-modifying therapy with meaningful symptomatic benefit.

In vivo treatment with CB-5083 in Nf1fl/fl;DhhCre PNF mice significantly inhibited cell proliferation, increased cell apoptosis and reduced PNF volume. The combination with a MEK inhibitor did not increase efficacy compared to the single agent, supporting the hypothesis that VCP functions in parallel to, and may be modulated by, RAS-MAPK signaling under stress or oncogenic conditions. The significant effects of VCP inhibition in this pre-clinical study suggest a potential novel therapy for patients with PNFs.

P2, N=50, Recruiting, Murdoch Childrens Research Institute | Trial completion date: Dec 2026 --> May 2027 | Trial primary completion date: Aug 2026 --> Jan 2027

P1/2, N=26, Recruiting, Memorial Sloan Kettering Cancer Center

P2, N=55, Not yet recruiting, University of Alabama at Birmingham

Mirdametinib and abemaciclib combined to extend survival of mice bearing orthotopic ATRT xenografts. In conclusion, mirdametinib has single agent activity against ATRT and combines with abemaciclib to decrease proliferation and extend survival in orthotopic xenograft models of ATRT.

P1, N=36, Completed, SpringWorks Therapeutics, Inc. | Not yet recruiting --> Completed | Trial completion date: Oct 2026 --> Feb 2026

P1/2, N=54, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

FDA-approved mitogen-activated protein kinase kinase (MEK) inhibitors, selumetinib and mirdametinib, have shown ~30% tumor shrinkage in 70% and 42% pNF1 patients, respectively. This response was also observed in MPNST cell lines treated with MEK inhibitors. These findings suggest that adaptive activation of upstream and parallel survival pathways may counteract the intended effects of MEK inhibition and support the rationale for combination strategies to improve therapeutic outcomes in NF1-associated tumors.