Gomekli (mirdametinib) / EMD Serono - LARVOL DELTA

Testing the Effectiveness of the Anti-cancer Drug, Mirdametinib, in Treating Relapsed, Refractory Chronic Lymphocytic Leukemia (clinicaltrials.gov) - P2 | N=20 | Not yet recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2027 ➔ Feb 2030 | Trial primary completion date: Dec 2027 ➔ Feb 2030

Trial completion date • Trial primary completion date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

Testing the Effectiveness of the Anti-cancer Drug, Mirdametinib, in Treating Relapsed, Refractory Chronic Lymphocytic Leukemia (clinicaltrials.gov) - P2 | N=20 | Not yet recruiting | Sponsor: National Cancer Institute (NCI) | Initiation date: Oct 2025 ➔ Jan 2026

Trial initiation date • Chronic Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Small Lymphocytic Lymphoma

A case report of the first adult neurofibromatosis type 1 patient treated with mirdametinib (SNO 2025) - "Although there was an FDA-approved drug for pediatric populations with inoperable PNs (selumetinib), there were no FDA-approved drugs for adults until February 2025, when Mirdametinib, a highly selective, allosteric, central nervous system-penetrant, MEK 1/2 inhibitor, was approved. She developed an acneiform rash on her face and trunk shortly after beginning treatment, which resolved with doxycycline and topical corticosteroids. To ensure her safety, she is closely monitored with echocardiograms and ophthalmological evaluations every three months."

Case report • Clinical • Brain Cancer • Cardiovascular • Cognitive Disorders • Developmental Disorders • Genetic Disorders • Glioma • Heart Failure • Neurofibromatosis • Ophthalmology • Retinal Vein Occlusion • Solid Tumor • MAP2K1 • NF1

Systematic pan-cancer analysis reveals the prognostic and immunological roles of ectonucleoside triphosphate diphosphohydrolase 6. (PubMed, World J Clin Oncol) - "This pan-cancer study elucidates the pivotal role of ENTPD6 in tumor progression and establishes its potential as a therapeutic target for immunotherapeutic approaches in specific malignancies."

IO biomarker • Journal • Pan tumor • Tumor mutational burden • Colon Adenocarcinoma • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Microsatellite Instability • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Rectal Adenocarcinoma • Solid Tumor • MSI • TMB

Modeling and Translating Precision Therapies for NF1-Associated Tumors Across the Disease Spectrum (SNO 2025) - P1 | "Combining MEK and HDAC inhibitors (e.g., mirdametinib + vorinostat) led to durable tumor regression in vivo and supported our initiation of an early phase window of opportunity trial now open (NCT06693284). Two of our patient cases illustrate clinical potential: one with refractory, H3K27me3-negative MPNST had pain relief and reduced PET activity on selumetinib + vorinostat and remained alive more than two years after failure of all other therapies; another, an 11-year-old with NF1 and H3K27M-mutant spinal glioma, remained recurrence-free for over two years on the same combination. These integrated efforts advance several translational platforms to develop and implement targeted therapies across the NF1 tumor spectrum."

Brain Cancer • Genetic Disorders • Glioma • Neurofibromatosis • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor • CDKN2A • CDKN2B • NF1 • SUZ12

Real-World Use of Medications With Moderate-to-Strong Cytochrome P450 3A4 (CYP3A4) Induction/Inhibition or Potential to Increase the Risk for Bleeding in Children and Adults with Neurofibromatosis Type 1-Associated Plexiform Neurofibroma (NF1-PN): A United States (US) Claims Database Analysis (SNO 2025) - "The current analysis demonstrates the prevalent use of moderate-to-strong CYP3A4 inhibitors/inducers and medications that increase bleeding risk in children and adults with NF1-PN in the US. This highlights the importance of a thorough assessment of concomitant drugs prior to starting treatment with a MEK inhibitor. Mirdametinib and selumetinib (in children only) for NF1-PN treatment present with differentiated drug metabolism profiles."

Claims database • Clinical • Real-world • Real-world evidence • Genetic Disorders • Neurofibromatosis • Solid Tumor • CYP3A4 • NF1

NCCN has published updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines), and the NCCN Drugs & Biologics Compendium (NCCN Compendium) for Central Nervous System Cancers, Version 3.2025. (NCCN)

NCCN guideline • Astrocytoma • CNS Lymphoma • Glioma • Oligodendroglioma

The Medicines and Healthcare products Regulatory Agency (MHRA) has today (11 December 2025) approved the medicine mirdametinib (Ezmekly) for the treatment of plexiform neurofibromas in adults and adolescents. (GOV.UK)

MHRA approval • Neurofibromatosis • Oncology

SpringWorks Therapeutics Receives Positive CHMP Opinion for Mirdametinib for the Treatment of Adult and Pediatric Patients with NF1-PN (GlobeNewswire) - "SpringWorks Therapeutics, Inc...announced today that the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion recommending the granting of a conditional marketing authorization for mirdametinib, a MEK inhibitor, for the treatment of symptomatic, inoperable plexiform neurofibromas (PN) in pediatric and adult patients with neurofibromatosis type 1 (NF1) aged 2 years and above. The European Commission (EC) will review the CHMP opinion and is expected to make a final decision regarding the approval in the third quarter of 2025. If approved, mirdametinib will be available in 1 and 2 mg capsules and in a 1 mg dispersible tablet, which dissolves easily in water....The MAA centered on the primary results from the Phase 2b ReNeu trial..."

CHMP • EMA approval • Neurofibromatosis • Oncology

Hidden-driver inference reveals synergistic brain-penetrant therapies for medulloblastoma. (PubMed, bioRxiv) - "The SINBA platform enables rapid identification of brain-penetrant, synergistic drug combinations by targeting hidden bottleneck drivers in high-risk tumors. SINBA-guided screening revealed that MEK inhibitors combined with regorafenib selectively eliminate the developmental cell-of-origin in G3 medulloblastoma and reprogram the tumor microenvironment, providing a clinically actionable precision oncology strategy."

Journal • Brain Cancer • Medulloblastoma • Oncology • Solid Tumor

Efficacy and tolerability of mirdametinib (PD-0325901) in children, adolescents, and young adults with recurrent/progressive low-grade glioma: update from the SJ901 (NCT04923126) phase 1/2 clinical trial (SNO 2025) - P1/2 | "Mirdametinib in patients with pLGG shows promising clinical activity and is well tolerated. Greater than one-third of patients treated at 3mg/m2/dose (declared RP2D) have already met efficacy criteria."

Clinical • P1/2 data • Brain Cancer • Glioma • Hematological Disorders • Solid Tumor • Thrombocytopenia • BRAF • FGFR1 • NF1

Update From the Long-Term Follow-Up (LTFU) Phase of ReNeu: A Pivotal Phase 2b Trial of Mirdametinib in Children and Adults With Neurofibromatosis Type 1 (NF1)-Associated Symptomatic Plexiform Neurofibroma (PN) (SNO 2025) - P2 | "Improved confirmed ORR was observed with longer duration of mirdametinib, with additional deep responses achieved in both adults and children. Mirdametinib continued to be well tolerated with a manageable safety profile and no new safety signals in the LTFU."

Clinical • P2b data • Dermatitis • Dermatology • Genetic Disorders • Immunology • Neurofibromatosis • Solid Tumor • NF1

Exploring the relationship between patient baseline characteristics with responses to mirdametinib in the ReNeu trial of children and adults with neurofibromatosis type 1 (NF1)-associated plexiform neurofibroma (PN) (SNO 2025) - P2 | "This analysis suggests mirdametinib provides clinical benefit across a broad range of patient and NF1-PN tumor characteristics; a relationship between analyzed baseline characteristics and confirmed objective response was not established. Mean PN volume was higher in non-responders, though CIs overlapped. Dose reductions and emergence of TRAEs did not appear to impact response to mirdametinib."

Clinical • Genetic Disorders • Neurofibromatosis • Solid Tumor • NF1

Understanding Commonly Reported (≥15%) Treatment-Related Adverse Events in the ReNeu Trial of Mirdametinib in Children and Adults With Neurofibromatosis Type 1 (NF1)-Associated Plexiform Neurofibroma (PN) (SNO 2025) - "Overall, common TRAEs arose before treatment benefits and were generally resoluble by DCO. Proactively managing TRAEs may improve treatment experience and adherence."

Adverse events • Clinical • Dermatitis • Dermatology • Genetic Disorders • Immunology • Neurofibromatosis • Solid Tumor • NF1

Enhancing 5-ALA Photodynamic Therapy with MEK Inhibition for Targeted Treatment of H3K27-Mutant Diffuse Midline Glioma (SNO 2025) - "We assessed the potential utility of combining 5-ALA-PDT and MEK inhibition as a novel treatment strategy for DMG to show that the anticancer activity of 5-ALA-PDT can be improved with MEK inhibitors trametinib (TRAM) (in vitro) and mirdametinib (in vivo). Enhanced cell death was observed in both models following treatment, along with increased neural stem differentiation, initiated T-cells infiltration and extended survival in the immunocompetent mice. These results demonstrate that combining 5-ALA-PDT with MEK inhibition can produce antitumor effects, offering proof of concept for the potential clinical application of this combination therapy."

Brain Cancer • Diffuse Midline Glioma • Glioma • High Grade Glioma • Solid Tumor • CDC37 • HSP90AA1 • PDGFRA

Efficacy and tolerability of mirdametinib (PD-0325901) in children, adolescents, and young adults with recurrent/progressive low-grade glioma: update from the SJ901 (NCT04923126) phase 1/2 clinical trial (SNO 2025) - P1/2 | "Mirdametinib in patients with pLGG shows promising clinical activity and is well tolerated. Greater than one-third of patients treated at 3mg/m2/dose (declared RP2D) have already met efficacy criteria."

Clinical • P1/2 data • Brain Cancer • Glioma • Hematological Disorders • Solid Tumor • Thrombocytopenia • BRAF • FGFR1 • NF1

Modeling and Translating Precision Therapies for NF1-Associated Tumors Across the Disease Spectrum (WFNOS 2025) - P1 | "Combining MEK and HDAC inhibitors (e.g., mirdametinib + vorinostat) led to durable tumor regression in vivo and supported our initiation of an early phase window of opportunity trial now open (NCT06693284). Two of our patient cases illustrate clinical potential: one with refractory, H3K27me3-negative MPNST had pain relief and reduced PET activity on selumetinib + vorinostat and remained alive more than two years after failure of all other therapies; another, an 11-year-old with NF1 and H3K27M-mutant spinal glioma, remained recurrence-free for over two years on the same combination. These integrated efforts advance several translational platforms to develop and implement targeted therapies across the NF1 tumor spectrum."

Brain Cancer • Genetic Disorders • Glioma • Neurofibromatosis • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor • CDKN2A • CDKN2B • NF1 • SUZ12

PRECLINICAL ACTIVITY OF MEK INHIBITION IN COMBINATION WITH CHEMOTHERAPY IN MALIGNANT PERIPHERAL NERVE SHEATH TUMOR (CTOS 2025) - "We evaluated the preclinical activity of mirdametinib in combination with chemotherapy in MPNST patient-derived xenografts (PDXs). Clinically relevant dosing of mirdametinib monotherapy (0.5 mg/kg PO BID x 21 days) and in combination with conventional soft tissue sarcoma-based chemotherapy (ifosfamide/doxorubicin) were administered to nude mice to assess tolerability. MEK inhibition in combination with chemotherapy results in superior tumor volume control and PFS in preclinical models of MPNST and supports future investigation of this combination strategy in patients with MPNST."

Combination therapy • Preclinical • Brain Cancer • Neurofibrosarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • NF1

Real-World Use of Medications With Moderate-to-Strong Cytochrome P450 3A4 (CYP3A4) Induction/Inhibition or Potential to Increase the Risk for Bleeding in Children and Adults with Neurofibromatosis Type 1-Associated Plexiform Neurofibroma (NF1-PN): A United States (US) Claims Database Analysis (WFNOS 2025) - "The current analysis demonstrates the prevalent use of moderate-to-strong CYP3A4 inhibitors/inducers and medications that increase bleeding risk in children and adults with NF1-PN in the US. This highlights the importance of a thorough assessment of concomitant drugs prior to starting treatment with a MEK inhibitor. Mirdametinib and selumetinib (in children only) for NF1-PN treatment present with differentiated drug metabolism profiles."

Claims database • Clinical • Real-world • Real-world evidence • Genetic Disorders • Neurofibromatosis • Oncology • Solid Tumor • CYP3A4 • NF1

Modeling and Translating Precision Therapies for NF1-Associated Tumors Across the Disease Spectrum (WFNOS 2025) - P1 | "Combining MEK and HDAC inhibitors (e.g., mirdametinib + vorinostat) led to durable tumor regression in vivo and supported our initiation of an early phase window of opportunity trial now open (NCT06693284). Two of our patient cases illustrate clinical potential: one with refractory, H3K27me3-negative MPNST had pain relief and reduced PET activity on selumetinib + vorinostat and remained alive more than two years after failure of all other therapies; another, an 11-year-old with NF1 and H3K27M-mutant spinal glioma, remained recurrence-free for over two years on the same combination. These integrated efforts advance several translational platforms to develop and implement targeted therapies across the NF1 tumor spectrum."

Brain Cancer • Genetic Disorders • Glioma • Neurofibromatosis • Neurofibrosarcoma • Sarcoma • Solid Tumor • CDKN2A • CDKN2B • NF1 • SUZ12

Acute Myeloid Leukemia Relapse after Bromodomain Inhibitor Treatment or Chemotherapy is Characterized by Myc-Ras Transcriptional Remodeling. (PubMed, bioRxiv) - "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."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • MYC • NRAS

A case report of the first adult neurofibromatosis type 1 patient treated with mirdametinib (WFNOS 2025) - "Although there was an FDA-approved drug for pediatric populations with inoperable PNs (selumetinib), there were no FDA-approved drugs for adults until February 2025, when Mirdametinib, a highly selective, allosteric, central nervous system-penetrant, MEK 1/2 inhibitor, was approved. She developed an acneiform rash on her face and trunk shortly after beginning treatment, which resolved with doxycycline and topical corticosteroids. To ensure her safety, she is closely monitored with echocardiograms and ophthalmological evaluations every three months."

Case report • Clinical • Brain Cancer • Cardiovascular • Cognitive Disorders • Developmental Disorders • Genetic Disorders • Glioma • Heart Failure • Neurofibromatosis • Ophthalmology • Retinal Vein Occlusion • Solid Tumor • MAP2K1 • NF1

Restoration of Spermatogenesis is Dependent on Activation of a SPRY4-ERK Checkpoint Following Germline Stem Cell Damage. (PubMed, bioRxiv) - "Here, we demonstrate that following alkylating agent busulfan (BU)-induced injury, germline-specific Spry4 gene deletion ( Spry4 G-KO ) reduces stem cell regeneration but promotes differentiation with rapidly enhanced nuclear ERK1/2 activity in undifferentiated (A undiff ) spermatogonia (including SSCs) in adult mice...Furthermore, the MEK1/2 inhibitor PD0325901, but not mTORC1 inhibitor Rapamycin, was sufficient to promote spermatogonial proliferation in Spry4 G-KO testis 10 days post-BU treatment...In summary, germline-specific deletion of Spry4 results in hyper-activation of the MAPK/ERK pathway in A undiff spermatogonia, unleashing excessive spermatogenesis after germline damage, and ultimately impairing germline regeneration in adult males. Our study indicates an essential role for SPRY4-ERK signaling as a molecular checkpoint in securing SSC recovery upon chemotherapy drug-induced germline damage, revealing how stem cells normally withstand environmental stress."

Journal • Infertility • Sexual Disorders • CXCL12

Mirdametinib in Patients With Advanced NF1-mutant Melanoma (clinicaltrials.gov) - P2 | N=10 | Recruiting | Sponsor: Kevin Kim, MD

IO biomarker • New P2 trial • Melanoma • Oncology • Solid Tumor

Update From the Long-Term Follow-Up (LTFU) Phase of ReNeu: A Pivotal Phase 2b Trial of Mirdametinib in Children and Adults With Neurofibromatosis Type 1 (NF1)-Associated Symptomatic Plexiform Neurofibroma (PN) (WFNOS 2025) - P2 | "Improved confirmed ORR was observed with longer duration of mirdametinib, with additional deep responses achieved in both adults and children. Mirdametinib continued to be well tolerated with a manageable safety profile and no new safety signals in the LTFU."

Clinical • P2b data • Dermatitis • Dermatology • Genetic Disorders • Immunology • Neurofibromatosis • Oncology • Solid Tumor • NF1