Mekinist (trametinib) / Japan Tobacco, Novartis, BeOne Medicines - LARVOL DELTA

Identification of high-risk signatures and therapeutic targets through molecular characterization and immune profiling of TP53-mutant breast cancer. (PubMed, J Genet Eng Biotechnol) - "Our findings underscore the prognostic value of the identified genes and the immunosuppressive TME in TP53-mutant breast cancer. The identification of drug candidates with strong binding affinities to key proteins provides promising avenues for targeted therapy in this high-risk patient population."

Journal • Breast Cancer • Oncology • Solid Tumor • AGR3 • CA9 • CTSC • ER • FGFR4 • PSAT1 • S100P • TFF1 • TP53

The molecular landscape of patients with malignant histiocytosis (ASH 2025) - "Responders received a range of agents matched to their mutations: trametinib ( BRAFV600E, MAP2K1F53I, KRASQ16H/PTEND24G/EPHB1R327C, MAP2K1F53I/BCL2/CDKN1B/KIT, and CALR), dabrafenib + trametinib( BRAFG596R/KRASQ61H) , imatinib ( MAP2K1C121S/METG28881T/DUSP2G137D/HIST1H3BC97Y/GRIN2AS1216C and PTPN11/STK11/GNA11/JAK2) , chidamide + sintilimab( IDH2G515A/RHOAG50T/TET23344delC), sirolimus( PTEN/FGFR3/SETD2) and sorafenib ( BRAFD594G/KRASK117N/TP53). Despite this complexity, durable clinical responses to targeted agents are achievable, even in heavily mutated cases. These findings support the use of comprehensive genomic profiling in MH to identify therapeutic targets and guide precision treatment strategies."

Clinical • IO biomarker • Sarcoma • Solid Tumor • ADGRG6 • BCL2 • BCL6 • BRAF • CALR • CDK1 • CDKN1A • CDKN1B • CDKN2A • CDKN2B • CREBBP • CYTOR • DNMT3A • EGFR • FGFR3 • GNA11 • JAK2 • KRAS • MAP2K1 • NF1 • NRAS • NRF1 • PTEN • PTPN11 • SETD2 • STK11 • TET2 • TP53

Consolidation of dual MAPK inhibitor therapy by allograft in histiocytic sarcoma: A report of two cases (ASH 2025) - "Transplant proceeded using fludarabine 150mg/m 2 and melphalan 140mg/m 2 with post-grafting cyclophosphamide, mycophenolate mofetil and tacrolimus for graft-versus-host disease (GvHD) prophylaxis...He remains well on dabrafenib and trametinib in CMR at 16-months post-transplant...To consolidate this response, allograft from a haploidentical donor was performed using fludarabine 150mg/m 2 and melphalan 140mg/m 2 with post-grafting cyclophosphamide and ciclosporin for GvHD prophylaxis... These 2 cases suggest that allograft is feasible on dual MAPK inhibitor therapy and may have potential efficacy as consolidation for high-risk visceral HS. Withdrawal of inhibitors and longer follow up are required to determine the durability of remission with this approach."

Clinical • Cough • Gastroenterology • Gastrointestinal Disorder • Graft versus Host Disease • Immunology • Infectious Disease • Respiratory Diseases • Sarcoma • Solid Tumor • Tuberculosis • BCL6 • CCND1 • CD14 • CD163 • CD1a • KRAS • MAP2K1

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

KRAS mutations in histiocytic neoplasms: Mutation spectrum and response to MEK inhibition (ASH 2025) - "Regarding treatment, 57% (13/23) received MEKi, all initially cobimetinib, with 1 patient switched to trametinib due to progression. Of the 10 patients who did not receive MEKi, 1 was treated with vemurafenib for a concurrent BRAF p.V600E mutation; 3 remained on observation; 2 underwent surgery without recurrence; 3 received other systemic therapies including corticosteroid, methotrexate, rituximab, lenalidomide, or sirolimus; and 1 developed diffuse large B-cell lymphoma, treated with R-CHOP...A retrospective cohort described an ECD patient with p.K117N achieving PR on dabrafenib and trametinib with a concurrent BRAF mutation and another with p.G12A achieving PR on trametinib...As MEKi acts downstream, efficacy likely depends on the level of pathway activation conferred by specific KRAS variants. Larger studies are needed to confirm these observations and identify mutation-specific predictors to guide personalized treatment."

B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Langerhans Cell Histiocytosis • Lymphoma • Non-Hodgkin’s Lymphoma • Rare Diseases • ARAF • KRAS • MAP2K1 • NRAS • PIK3CA

Phase 2 trial of encorafenib plus binimetinib for patients with BRAF V600 mutated relapsed/refractory hairy cell leukemia (ASH 2025) - "Background : Hairy cell leukemia (HCL) is an indolent B-cell leukemia characterized by durable completeremissions to purine analogs cladribine or pentostatin, but repeated relapses and cumulative toxicity torepeated purine analog courses...Vemurafenib was combined with rituximab,achieving 57% MRD-free CRs... Encorafenib-binimetinib is highly effective in relapsed/refractory HCL and was well toleratedwhen dose reductions occurred as needed. Compared to dabrafenib-trametinib, the lower incidence offever (11% vs 58%, p<0.0001) is a major advantage. The CR rate of 93% without rituximab isunprecedented for BRAF inhibition in HCL."

Clinical • P2 data • Hairy Cell Leukemia • Hematological Malignancies • Leukemia • Melanoma • Musculoskeletal Pain • Pancreatitis • Retinal Disorders • Solid Tumor • BRAF

PI3Kδ inhibition enhances trametinib efficacy by suppressing feedback-activated PI3K/AKT signaling in PTPN11-mutant JMML (ASH 2025) - "These data collectively support thenotion that MEK inhibition relieves feedback inhibition on RAS, resulting in its hyperactivation anddiversion of signaling through bypass pathways such as PI3K/AKT.To counteract compensatory PI3K/AKT activation under MEK inhibition, we tested Trametinib combinedwith Idelalisib, a selective PI3Kδ inhibitor. This dual blockade strategy provides a mechanistic rationale andpreclinical proof-of-concept for combination therapy in PTPN11-mutant JMML, which is historicallyresistant to single-agent MEK inhibitors. These results support future clinical investigation of MEK andPI3Kδ co-inhibition to improve treatment outcomes in this high-risk JMML subgroup."

Clinical • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Juvenile Myelomonocytic Leukemia • Leukemia • Thrombocytopenia • PIK3CD • PTPN11

Boosting anti-tumor immunity in NRAS; ASXL1-driven Acute Myeloid Leukemia through combined inhibition of MEK and HDACs. (ASH 2025) - "Targeting hyperactive RAS/MEK signaling viatrametinib (Tra, a MEK inhibitor) attenuated T cell exhaustion and prolonged the survival of NA-AML mice,cementing the role of T cells in modulating AML treatment outcomes...We identified and validated inhibition ofMEK/ERK signaling via Tra and histone deacetylases (HDACs) via quisinostat (Qui, a 2nd generation ofHDAC inhibitor) as an effective combo therapy against mouse and human primary NA-AML cells and non-NA human AML cell lines in vitro...Our results suggest that we must seek additionalMHC-independent anti-cancer mechanisms to further improve the therapeutic effects of TQ. We arecurrently evaluating the effects of combining TQ with anti-TIGIT immune checkpoint blockade to activateendogenous non-MHC restricted natural killer cells in NA-AML mice."

IO biomarker • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • ASXL1 • CD4 • CD8 • CIITA • IL2 • NRAS • TIGIT

The transition from myelodysplastic neoplasm to secondary acute myeloid leukemia is revealed by molecular analysis, while functional drug screening demonstrates novel sensitivity patterns with clinical implication (ASH 2025) - "There are only a limited number of agentsthat are FDA approved for treatment of MDS including BCL2 and IDH inhibitors, hypomethylating agents(HMAs), ESAs, luspatercept and imetelstat...For MDS patients, weidentified the most effective agents with the proportion of sensitive samples noted in parentheses:mitoxantrone (100%), olutasidenib (78%), venetoclax (67%), dinaciclib (67%), trametinib (67%), olaparib(56%), GSK3368715 (56%), pacritinib (44%), lenalidomide (44%), fludarabine (55%), tasquinimod (44%),veliparib (44%). For sAML patients, we identified lenalidomide, olutasidenib, GSK3368715 have high DSSsin all tested samples, while fludarabine, fedratinib, tasquinimod, trametinib, veliparib, mitoxantrone andolaparib have high DSSs in 75% of the AML samples...Cancer Research 2024), and our samples included SF3B1 and U2AF1 mutations.Summary This study of the transition of MDS to sAML highlights molecular changes and reveals new drugsensitivity with agents that could be..."

Biomarker • Clinical • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • CD34 • FLT3 • JAK2 • NRAS • PTPN11 • SF3B1 • U2AF1

NRAS mutation drives excessive netosis and differentiation syndrome in acute promyelocytic leukemia (ASH 2025) - "Background Acute promyelocytic leukemia (APL) is highly curable with all-trans retinoic acid (ATRA) and arsenictrioxide (ATO)...Inhibitors targeting CXCR1/2 (Reparixin), NE(Sivelestat), MEK(Trametinib), PAD4(GSK484), and JAK1/2 (Ruxolitinib) were applied to evaluate their inhibitory effects onNETosis and differentiation...Targeting this pathway with reparixin or sivelestatattenuates NET formation without compromising cell differentiation, offering a promising therapeuticstrategy to mitigate DS-induced tissue damage while preserving anti-leukemic efficacy. These findingsprovide mechanistic insights into NRAS-driven inflammation in APL and support NETs-targeted therapyfor prophylaxis of DS."

Acute Promyelocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Thrombosis • ANXA5 • CXCL8 • CXCR1 • ICAM1 • ITGAM • JAK1 • JAK2 • NRAS • VCAM1

Discontinuation of targeted therapy in histiocytic neoplasms with durable response: A multicenter retrospective study (ASH 2025) - "Targeted therapies include BRAFi (n=5, 19.2%; 2 dabrafenib, 3 vemurafenib), MEKi(n=17, 65.4%; 14 cobimetinib, 3 trametinib), and BRAF/MEKi (n=4, 15.4%; 3 dabrafenib/trametinib, 1vemurafenib/cobimetinib). In patients with histiocytic neoplasm and prior durable response to targeted therapy, ~40%experienced disease progression after treatment discontinuation. BRAF V600E mutation and CNS diseaseare associated with inferior PFS, suggesting these subgroups may not be appropriate for limited durationof treatment. Novel approaches are needed in these high-risk patients."

Retrospective data • CNS Disorders • Langerhans Cell Histiocytosis • Rare Diseases • ASXL1 • MAP2K1 • NRAS • SRSF2

HEM-ismart: An international proof-of-concept therapeutic stratification trial of molecular anomalies in relapsed or refractory hematological malignancies in children (ASH 2025) - "Evaluation of potential and enrolled patients, safety,toxicity and response data from on-study subjects are reviewed each week at the coordinating teammeetings to ensure sponsor oversight.Current subtrials include:Subtrial B: dasatinib, venetoclax (VEN) and dexamethasone (DEX) with cyclophosphamide (CP) andcytarabine (CA) for ABL1 fusion-driven disease (approved, will be activated in Q3 2025)Subtrial C: ruxolitinib, VEN and DEX with CP and CA for IL7R-mutant and JAK/STAT pathway-drivendisease(approved, will be activated in Q3 2025)Subtrial D: trametinib and DEX with CP and CA for Ras/MAPK pathway-driven disease (recruiting)Subtrial E: capivasertib, VEN and DEX for molecularly unselected patients (generic) andPI3K/AKT/mTOR-driven disease (in process of regulatory submission)To date, 2 subjects with R/R B-ALL and 1 with R/R T-ALL were enrolled in subtrial D.ConclusionHEM-iSMART is an international, academic, collaborative, precision-medicine, multi-arm platform trial..."

Clinical • IO biomarker • Acute Lymphocytic Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Lymphoblastic Lymphoma • Lymphoma • Oncology • T Acute Lymphoblastic Leukemia • ABL1 • BCL2 • CD22 • IL7R

Clonal persistence of BRAFV600E under MEK inhibition in histiocytosis (ASH 2025) - P=N/A | "Ten CD34⁺ samples were profiled using the TAPESTRI platform for single-cell DNA and protein analysis and/or PromethION Nanopore long-read sequencing.In parallel, we used a conditional BRAFV600Ehet-SclCre+ murine model induced by tamoxifen (200mg/kg/day for 4 days) and treated with trametinib (0.3 mg/kg/day) for one month. Residualdisease persists in hematopoietic progenitors and displays a therapy-induced shift from monocytes to Bcells, suggesting lineage plasticity and identifying B cells as a potential reservoir. Our BRAFV600E murinemodel faithfully recapitulates clonal persistence under MEKi, underscoring the need for combinatorialstrategies to achieve complete molecular remission."

Langerhans Cell Histiocytosis • Rare Diseases • Solid Tumor • CD1C • CD34 • MME • TET2

PA03 Trametinib therapy for congenital melanocytic naevi. (PubMed, Br J Dermatol) - "Trametinib is useful in NRAS-driven leptomeningeal melanoma in children, but not sufficient to prevent relapse, and can be helpful in NRAS-driven leptomeningeal dysplasia. It is very helpful symptomatically in BRAF fusion-driven cutaneous disease, where a reduced dose after initial response appears to sustain efficacy and reduce adverse effects."

Journal • Retrospective data • Cardiomyopathy • Cardiovascular • Dermatitis • Dermatology • Herpes Simplex • Immunology • Melanoma • Oncology • Pruritus • Solid Tumor • BRAF

Safety profile of dabrafenib plus trametinib (D+T) in previously treated Chinese Mainland subgroup (CMS) population with radioactive iodine (RAI)–refractory BRAF V600E mutation–positive differentiated thyroid cancer (DTC) (ESMO Asia 2025) - P3 | "D+T therapy was tolerable in CMS pts with RAI-refractory BRAF V600E mutation-positive DTC, who received prior VEGFR targeted-therapy, with safety profile consistent with global studies of other indications."

Clinical • Brain Cancer • Glioma • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • BRAF

Retrospective study of dabrafenib and trametinib in advanced BRAF V600E-mutant thyroid cancer: Efficacy in neoadjuvant and RAIR settings (ESMO Asia 2025) - "DabTram exhibits significant activity in downsizing tumors and enabling organ-sparing surgery in advanced PTC. First-line use in RAIR patients shows promising tumor responses, warranting further investigation for long-term survival benefits. Larger prospective studies are needed to validate these findings."

Metastases • Retrospective data • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • BRAF

Redifferentiation of radioiodine-refractory metastatic differentiated thyroid carcinoma with BRAFV600E mutation by dabrafenib in combination with trametinib (ESMO Asia 2025) - P=N/A | "Dabrafenib combined with trametinib can induce redifferentiation by stimulating radioiodine uptake in patients with BRAF V600E -mutant radioactive iodine-refractory metastatic papillary thyroid carcinoma, suggesting an optional therapeutic strategy for this patient population."

Combination therapy • Metastases • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • BRAF • TG

MULTISARC: Molecular Profiling of Advanced Soft-tissue Sarcomas (clinicaltrials.gov) - P3 | N=603 | Active, not recruiting | Sponsor: Institut National de la Santé Et de la Recherche Médicale, France | Trial completion date: Oct 2025 ➔ Jan 2026

IO biomarker • Trial completion date • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Molecular profiling and tumour biomarker analysis of GOG281/LOGS: a positive late-phase trial of trametinib for recurrent/persistent low grade-serous ovarian cancer. (PubMed, Clin Cancer Res) - P2/3 | "This exploratory analysis suggests pERK expression and mutation of KRAS/BRAF/NRAS are candidate biomarkers of improved PFS and response to trametinib, respectively."

Biomarker • Journal • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • BRAF • KRAS • NRAS

NRas Nanoclusters Mediate Crosstalk Between BRAF/ERK and PI3K/AKT Signaling in Melanoma Cells. (PubMed, Int J Mol Sci) - "MEK inhibition with trametinib resulted in similar, yet more pronounced effects. Thus, our findings provide novel insights into NRAS-mediated signaling through nanoscale clusters and underscore their potential as therapeutic targets."

Journal • Melanoma • Oncology • Solid Tumor • BRAF • NRAS

Genomic Analysis of Low-Grade Serous Ovarian Cancer: Clinical and Biological Insights. (PubMed, Cureus) - "The cooperative GOG 281/LOGS trial showed that trametinib, an MEK inhibitor (MEKi), was significantly more effective than standard-of-care options (including chemotherapy or hormonal therapy) in increasing progression-free survival (median PFS 13.0 months vs. 7.2 months; hazard ratio 0.48, p < 0.001)...Genomic and multi-omic profiling have revealed actionable vulnerabilities and precision oncology approaches. The advent of biomarker-directed trials, molecular subtyping incorporation, and innovative computational strategies is likely to gradually ameliorate therapy selection and, thereby, finally improve long-term outcomes for patients with this complex disease."

IO biomarker • Journal • Review • Tumor mutational burden • Epithelial Ovarian Cancer • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • BRAF • CDH1 • CDKN2A • CDKN2B • ER • HER-2 • KRAS • MAP2K1 • MIR7 • NF1 • NRAS • RASSF1 • TMB • TP53

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

Advances in Tissue-Agnostic Targeting in Cancer Therapeutics: Current Approvals, Challenges, and Future Directions. (PubMed, Oncol Res) - "The purpose of this review is to explore the impact, safety, and challenges of tissue-agnostic therapies including pembrolizumab, dostarlimab, larotrectinib, entrectinib, repotrectinib, dabrafenib plus trametinib, selpercatinib, and trastuzumab deruxtecan. We discuss emergence of pan-histological biomarkers, such as neoantigen burden, current updates on trials as well as trial outlining strategies to refining patient selection, while also supporting broader access to biomarker testing. Collectively, these insights underscore the transformative role of tissue-agnostic therapies in precision oncology while emphasizing the ongoing need for research to optimize their application and overcome current barriers."

Biomarker • Journal • Pan tumor • Review • Oncology

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