Koselugo (selumetinib) / Merck (MSD), AstraZeneca, Pfizer - LARVOL DELTA

Pharmacokinetic-Based Dose Adjustment of Selumetinib in 2 Young Children With Neurofibroma. (PubMed, Pediatr Neurol) - No abstract available

Journal • PK/PD data • Genetic Disorders • Neurofibromatosis • Solid Tumor

Remission instead of eradication? MEK inhibition in primary refractory childhood LCH (ASH 2025) - "Patient and Methods We report on a 9-month-old infant with multisystemic LCH (thymus and cervical lymph nodes) who progressed under vinblastin/prednisone and did not respond to second-line cytarabine/vincristine therapy...This class confers resistance to first-and second generation BRAF inhibitors (e.g., Vemurafenib, Dabrafenib), which preferentially target monomeric BRAFV600E but not dimer-dependent BRAF. Functional ex vivo drug sensitivity profiling demonstarted superior tumor cell cytotoxicity of cobimetinib compared to other tested agents, including BRAF inhibitors and alternative MEK1/2 inhibitors, such as trametinib and selumetinib...However, the risk of clonal persistence underscores the need for integrated strategies. Future studies should investigate rational combinations of MEK inhibitors with senolytics and/or mTOR blockade to target both MAPK signaling and senescent cell survival, thereby suppressing SASP-related inflammation, aiming for durable molecular..."

Clinical • Hematological Malignancies • Langerhans Cell Histiocytosis • ARAF

Haematological toxicities with targeted drugs in tumors: A systematic review and network meta-analysis of randomized controlled trials (ASH 2025) - "1 patient treated with sorafenib plus chemotherapy was reported to have died as a result of pancytopenia and 1 patient treated with chemotherapy (gemcitabine plus cisplatin) died due to anemia. Our study confirmed that chemotherapy with or without a placebo, one targeted drug with chemotherapy was associated with more severe hematologic toxicities compared with the use of one targeted drug, tepotinib plus gefitinib, tivantinib plus erlotinib. In the targeted drug monotherapy category, for the primary outcome, we found that alectinib and gefitinib had a higher risk of all-grade (grade 1-5) and severe-grade (grade 3-5) anemia, respectively...Ganitumab plus chemotherapy had the highest risk of grade 1-5 anemia and thrombocytopenia. Afatinib plus chemotherapy had the highest risk of grade 3-5 anemia and thrombocytopenia. Ramucirumab plus chemotherapy had the highest risk of grade 1-5 and 3-5 neutropenia. Veliparib plus chemotherapy had the highest risk of grade 1-5 and 3-5..."

Retrospective data • Review • Febrile Neutropenia • Leukopenia • Lung Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thrombocytopenia

Underexplored mutations in plasma cell myeloma (ASH 2025) - "Many FDA-approved therapies exist in other cancers (such as sotorasib, selumetinib,vemurafenib, enasidenib, midostaurin, ruxolitinib, crizotinib, erlotinib), though these remain largelyunexplored in PCM. CHIP mutation burden in MM / PCM was 40%, Our analysis identified several potentially targetablemutations in pts with PCM, including KRAS, NRAS, BRAF, IDH2, FLT3, JAK2, ALK, and EGFR. Clonalhematopoiesis (CH/CHIP) mutations, such as DNMT3A, TET2, ASXL1, and SRSF2, were also observed.Although the lineage origin of several targetable mutations remains unclear, the likely high plasma cellburden in PCM cases suggests that many may originate within the malignant plasma cell clone. Thishypothesis warrants systematic investigation in future studies."

Tumor mutational burden • Hematological Malignancies • Multiple Myeloma • ALK • ASXL1 • BCOR • BRAF • CALR • CREBBP • CSF3R • DNMT3A • EGFR • FLT3 • GNAS • IDH2 • JAK2 • KRAS • NRAS • PHF6 • PPM1D • PRPF8 • SRSF2 • SUZ12 • TET2 • TMB • TP53

A perturb-seq map of a differentiation hub reveals synergistic vulnerabilities in KMT2A-rearranged AML (ASH 2025) - "Finally, we established the Myeloid Program as a predictive biomarker whose low activity scoreidentifies a vulnerable, undifferentiated state with unique sensitivity to PI3K/AKT/mTOR pathwayinhibitors (e.g., Selumetinib, r = -0.37, p = 2.2e-16; MK-2206, r = -0.31, p = 1.2e-11; Rapamycin (r = -0.34, p = 8.44e-14). Our work establishes circuit-level epigenetic compensation as a core mechanism ofresistance in KMT2A-r AML. We identify the Myeloid Program as a central regulatory node, a dual-purpose biomarker, and a key therapeutic objective. These findings provide a data-driven rationale fortwo distinct precision strategies: 1) collapsing the compensatory repressive circuit with synergistic co-inhibition of its core components, or 2) exploiting the emergent vulnerability of the undifferentiatedstate by combining differentiation agents with PI3K/mTOR pathway inhibitors."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • DOT1L • KAT6A • KMT2A

A Nonparametric Population Pharmacokinetic Model of Selumetinib in Pediatric Patients Diagnosed With Neurofibromatosis-I or Plexiform Neurofibromas. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "The nonparametric population model provides efficient priors for making individual predictions of SLT concentrations. The simulation did not reveal any disadvantages of q6h or q8h dosing."

Journal • PK/PD data • Genetic Disorders • Neurofibromatosis • Oncology • Pediatrics • Solid Tumor

Development of selumetinib-loaded solid dispersion based on low molecular weight methylcellulose for the enhanced solubility, stability, dissolution, and bioavailability. (PubMed, Int J Biol Macromol) - "Furthermore, F3 enhanced oral absorption (1.96-fold in Cmax and 1.69-fold in AUCinf) in rats compared with the raw SEL suspension group, and this improvement was further supported by its nearly 100 % absolute bioavailability. In conclusion, F3 suggested in this work was a potential novel SD formulation for SEL, offering enhanced solubility, dissolution, physical stability, and bioavailability."

Journal • Oncology

Effect of selumetinib treatment on long-term pain medication utilization in pediatric patients: a retrospective study of a US claims database (SNO 2025) - "Overall, 26 patients were receiving gabapentin in the 12 months prior to selumetinib initiation; 50% (n=13) discontinued use within 12 months of selumetinib initiation. For patients who continued gabapentin (n=13), the average dose declined from 802 mg/day (before selumetinib) to 675 mg/day (after selumetinib).Selumetinib was associated with a consistent and durable reduction in PMU over a follow-up period of up to ~3 years, adding to the long-term and the real-world data supporting its clinical benefits in pediatric patients with neurofibromatosis type 1-related plexiform neurofibroma."

Claims database • Retrospective data • Genetic Disorders • Neurofibromatosis • Pain • Pediatrics • Solid Tumor

Selective Enhancement of Sonodynamic Therapy by Trametinib Through Modulation of PpIX Accumulation in Glioma (SNO 2025) - "Among the MEK inhibitors tested, only Trametinib effectively enhances 5-ALA-mediated sonodynamic therapy by increasing PpIX accumulation and improving tumor suppression in glioma models. These findings suggest Trametinib as a promising adjuvant to SDT for glioma treatment and highlight the importance of in vivo validation when selecting combination strategies."

Brain Cancer • Glioma • High Grade Glioma • Solid Tumor

Selumetinib in NF1-associated high-grade astrocytoma with piloid features (SNO 2025) - "Of prior HGAP cases, none received selumetinib, though one was treated with trametinib, another MEK inhibitor, with 8.5 months survival. These cases suggest MEK inhibitors may offer therapeutic benefit. Collaborative research is needed to better understand the disease's molecular profile and optimize treatment strategies."

Astrocytoma • Brain Cancer • Breast Cancer • Genetic Disorders • Glioblastoma • Glioma • Hematological Malignancies • Infectious Disease • Leukemia • Neurofibromatosis • Oncology • Pilocytic Astrocytoma • Pneumonia • Respiratory Diseases • Solid Tumor • ATRX • CDKN2A • NF1

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

Targeted blood-nerve-barrier opening for the delivery of MEK inhibitor selumetinib in peripheral nerve sheath tumours using focused ultrasound. (SNO 2025) - "This suggests this technique may be feasible. Future work will be to perform FUS in a tumour model with and without drug."

Brain Cancer • Genetic Disorders • Neurofibromatosis • Oncology • Solid Tumor • 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

Combinatorial targeting of avapritinib-driven MAPK activation in pediatric high-grade glioma (SNO 2025) - "Combinatorial treatment of pHGG models with MEK (selumetinib, trametinib), ERK (ulixertinib) and integrated stress/ERK inhibitors (ONC201, ONC206) in vitro eradicated pERK activity. A patient with an un-resected PDGFRα-mutant pHGG treated with avapritinib and selumetinib prior to progression demonstrated complete and ongoing tumor regression (12 months+). Considering sustained MAPK activation identified in our study, dual avapritinib-MAPK targeted treatment may be an effective approach for PDGFRΑ-driven pHGG."

Clinical • Brain Cancer • CNS Tumor • Glioma • High Grade Glioma • Pediatrics • Solid Tumor • MCL1 • PDGFRA

Effect of selumetinib treatment on long-term pain medication utilization in pediatric patients: a retrospective study of a US claims database (SNO 2025) - "Overall, 26 patients were receiving gabapentin in the 12 months prior to selumetinib initiation; 50% (n=13) discontinued use within 12 months of selumetinib initiation. For patients who continued gabapentin (n=13), the average dose declined from 802 mg/day (before selumetinib) to 675 mg/day (after selumetinib).Selumetinib was associated with a consistent and durable reduction in PMU over a follow-up period of up to ~3 years, adding to the long-term and the real-world data supporting its clinical benefits in pediatric patients with neurofibromatosis type 1-related plexiform neurofibroma."

Claims database • Retrospective data • Genetic Disorders • Neurofibromatosis • Pain • Pediatrics • Solid Tumor

Potential of MEK Inhibition to overcome Trastuzumab deruxtecan Resistance in MAPK-Activated Triple-Negative Breast Cancer PDX Models (SABCS 2025) - "Proteomic profiling implicates MAPK pathway activation as a key mechanism of T-DXd resistance in TNBC. MEK inhibition with selumetinib restored T-DXd sensitivity in resistant PDX models, supporting MAPK blockade as a rational strategy to overcome ADC resistance. These findings provide preclinical justification for evaluating T-DXd and selumetinib in HER2-low TNBC."

Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • LRIG1 • MAPK3 • PMS1 • TUBB

Emerging Targeted Therapies and Ongoing Clinical Trials in Pediatric Brain Tumors (PubMed, No Shinkei Geka) - "Dabrafenib plus trametinib has shown superiority over chemotherapy in pediatric low-grade gliomas and activity against high-grade diseases. Larotrectinib and entrectinib provide tumor-agnostic options for NTRK-fusion-positive tumors with central nervous system penetration. Selumetinib offers clinical benefits in NF1-associated plexiform neurofibromas and shows promise for treating NF1-related low-grade gliomas. Tovorafenib, a type II RAF inhibitor active in BRAF-altered tumors (including BRAFKIAA1549 fusion), achieved robust responses, thereby leading to FDA approval. ONC201 (dordaviprone) has received accelerated approval for the treatment of H3 K27M-mutant diffuse midline gliomas, with Japanese trials and patient-initiated programs expanding access. Abemaciclib, a CDK4/6 inhibitor, is under phase II evaluation for pediatric high-grade glioma and diffuse midline glioma, including sites in Japan. Neurosurgeons play a pivotal role in securing high-quality biopsies, thus..."

Journal • Review • Brain Cancer • CNS Tumor • Diffuse Midline Glioma • Glioma • High Grade Glioma • Neurofibromatosis • Oncology • Pediatrics • Solid Tumor • BRAF • KIAA1549 • NF1 • NTRK

Precision Medicine in Pediatric Neuro-Oncology-Experience from a tertiary care center in Canada. (SNO 2025) - "Monotherapy with MEK inhibitors (Trametinib, Selumetinib, N=30/50, 60%) was the most common regime; 12 different combinations of TT were used; most common being Dabrafenib and Trametinib. Our study confirms existing data in the literature regarding precision medicine in pediatric cancer with high CBR along with good quality of life and minimal toxicities."

Clinical • Brain Cancer • Glioma • Pediatrics • Solid Tumor

Response to selumetinib in a neurofibromatosis 1 patient with high-grade astrocytoma with piloid features complicated by leptomeningeal dissemination (SNO 2025) - "Management typically follows glioblastoma treatment guidelines, including maximal safe surgical resection followed by concurrent chemoradiotherapy with temozolomide. Four months later, follow-up magnetic resonance imaging showed interval stability or slight reduction in disease burden. This case highlights the potential therapeutic relevance of MAPK pathway inhibition in NF-1-associated HGAP with leptomeningeal dissemination and supports further exploration of MEK inhibition in this setting."

Clinical • Anaplastic Astrocytoma • Astrocytoma • Brain Cancer • CNS Tumor • Genetic Disorders • Glioblastoma • Glioma • Neurofibromatosis • Oncology • Solid Tumor • mTOR • NF1

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

Efficacy of Small Molecule Kinase Inhibitors in Histiocytic Neoplasms with Non-BRAFV600E Mutations: Concordance of Pre-Clinical Predictions to Clinical Responses (ASH 2024) - "Preclinical studies suggest class I, but not classes II-III, BRAF mutations are sensitive to RAF monomer inhibitors (dabrafenib, encorafenib, vemurafenib) while classes I-II, but not class III, BRAF mutations are sensitive to MEK inhibitors (Yaeger R, Cancer Discovery 2019). In contrast, RAF-regulated MAP2K1 mutants have variable sensitivities to allosteric MEK inhibitors (binimetinib, cobimetinib, selumetinib, trametinib) while RAF-dependent and RAF-independent MAP2K1 mutations are resistant...Among those with BRAF class II mutations, 2 received vemurafenib and had NR, while 9 received MEK inhibitors (binimetinib, cobimetinib, trametinib) and most responded (3 CRs, 5 PRs)...There was concordance of efficacy in the setting of BRAF classes I-III and MAP2K1 RAF-regulated mutations. However, we found discordant findings in patients harboring RAF-dependent and RAF-independent MAP2K1 mutations as well as KRAS mutations as most responded to allosteric MEK inhibitors."

Discordant • Preclinical • Langerhans Cell Histiocytosis • Rare Diseases • BRAF • KRAS • MAP2K1 • NRAS

Bitopic inhibitors of mTORC1 cooperate with inhibitors of mitogen-activated protein kinase kinase to drive cytotoxicity in glioblastoma. (SNO 2025) - "We previously described RapaLink-1, a bisteric mTORC1 inhibitor that links the allosteric mTORC1 inhibitor rapamycin to the mTOR kinase inhibitor sapanisertib...Like trametinib, the MEK inhibitor selumetinib similarly cooperated with RMC-6272 to block proliferation and increase apoptosis in isogenic T98G glioblastoma lines knocked-down for NF1 compared to NF1 wild-type T98G cells...Combining RMC-6272, trametinib and the autophagy ULK1 tool inhibitor MRT68921 augmented apoptosis compared to RMC-6272 and trametinib alone...We conclude that bitopic inhibitors of mTORC1 cooperate with inhibitors of MEK to drive cytotoxicity in both NF1WT and NF1MT glioblastoma. Combining RMC-5552 and trametinib represents a translatable strategy to improve survival in patients with glioblastoma."

Brain Cancer • Glioblastoma • Solid Tumor • NF1

Beyond DNA: Two Pediatric Glioma Cases Highlight the Diagnostic and Therapeutic Impact of RNA Sequencing (SNO 2025) - "By then, the patient had already started selumetinib with a positive clinical response...This guided treatment with larotrectinib, which has been well tolerated and has led to sustained disease control for over two years without recurrence...Early integration of RNA testing alongside DNA profiling should be standard in pediatric neuro-oncology workflows to expand therapeutic options and enhance treatment precision. Larger cohort studies are underway to validate these findings and optimize RNA-driven decision-making in pediatric CNS tumors."

Clinical • Astrocytoma • Brain Cancer • CNS Tumor • Gene Therapies • Glioma • Pediatrics • Pilocytic Astrocytoma • Pleomorphic Xanthoastrocytoma • Solid Tumor • BRAF • CDKN2A • CDKN2B • KANK1 • KIAA1549 • MTAP • NTRK2

BRAF V600E in Thyroid Cancer: Navigating Prognostic Uncertainty and Therapeutic Innovation. (PubMed, Eur Thyroid J) - "Selective BRAF and MEK inhibitors-including vemurafenib, dabrafenib, and selumetinib-have demonstrated efficacy in advanced thyroid cancers. The combination of dabrafenib and trametinib is FDA-approved for BRAF V600E-mutant anaplastic thyroid carcinoma (ATC) based on its significant survival benefits...Additionally, redifferentiation strategies using MAPK inhibitors to restore RAI avidity have shown promise, particularly in selected patients. These advances highlight the need to contextualize BRAF mutation status within a broader molecular and clinical framework to guide personalized, effective treatment strategies."

Journal • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • BRAF

Assessment of pharmacodynamic interactions of two-drug combinations of five selected cytostatics in an in vitro model of human melanoma: an isobolographic analysis. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "The experiments were conducted on four human malignant melanoma cell lines (A375, SK-MEL28, FM55M2, FM55P) and studied all possible (ten) pairs of combinations of five standard cancer chemotherapy drugs (based on the MTT test): cisplatin, mitoxantrone, docetaxel, vemurafenib, and selumetinib. Monotherapy for melanoma does not produce good results, so the best drug combinations are sought, which would improve long-term, durable patient response and overcome drug resistance. It would also be good if the combination used caused fewer side effects than monotherapy, and this could be achieved in the case of using synergistic combinations."

Journal • PK/PD data • Preclinical • Melanoma • Oncology • Solid Tumor