Mektovi (binimetinib) / Ono Pharma, Pierre Fabre, Pfizer, Medison - LARVOL DELTA

Direct small molecule inhibition of RAS enhances JAK2 inhibitor therapy in preclinical models of myeloproliferative neoplasms (ASH 2025) - "While the MEK inhibitor binimetinib readily suppressed pERK levels, its GI50 was > 5μM in these cells, suggesting direct inhibition of RAS may more efficiently suppress signaling requisite forJAK2-driven growth. RMC-7977 treatment suppressed inflammatorycytokine levels including TNFα and IL-6, two cytokines implicated in MPN pathogenesis, among others.Importantly, treatment of healthy mice concurrently with RMC-7977 and ruxolitinib was well tolerated asevidenced by the absence of impact on hematologic parameters and body weight. Our results reveal thatdirect inhibition of RAS and JAK2 may represent a promising therapeutic strategy for MPN patients andprovide evidence RAS inhibition has potential beyond solid tumor indications."

Preclinical • Aplastic Anemia • Essential Thrombocythemia • Hematological Malignancies • Leukemia • Myelofibrosis • Myeloproliferative Neoplasm • Polycythemia Vera • Solid Tumor • Thrombocytosis • CALR • DUSP6 • IL6 • KRAS • TNFA

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

Antitumor Activity of Metformin in Combination with Binimetinib Against Melanoma Cells. (PubMed, Int J Mol Sci) - "The concomitant effect of both compounds depended on the concentrations used and was caused by the reduced proliferation and/or increased apoptosis of melanoma cancer cells. In conclusion, the combination of metformin and binimetinib may have potential anticancer effects on melanoma cells; however, more studies are needed to elucidate the exact mechanisms of their combined action."

Journal • Genetic Disorders • Melanoma • Oncology • Skin Cancer • 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

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

The safety and efficacy of encorafenib plus binimetinib for brain metastases: a systematic review and meta-analysis. (PubMed, Discov Oncol) - No abstract available

Journal • Retrospective data • Review • Oncology • Solid Tumor

Efficacy of Targeted Agents and Immune Checkpoint Inhibitors in Patients with Malignant Histiocytosis (ASH 2024) - "TAs included BRAF inhibitor (vemurafenib [1]), MEK inhibitors (binimetinib [1], cobimetinib [2], trametinib [2]) and others (dasatinib [1], pazopanib [1], pexidartinib [1]), while ICIs were exclusively pembrolizumab (5)...TAs included BRAF inhibitor only (vemurafenib [3], dabrafenib [3]), MEK inhibitor only (trametinib [5]), BRAF + MEK inhibitors (2), and others (apatinib, anlotimib, bevacizumab, daratumumab, dasatinib, imatinib, pazopanib, sorafenib, or combinations [9]), while ICIs included pembrolizumab (4), nivolumab (4), tislelizumab (1), and sintilimab (1)...Conclusion TAs and ICIs can be considered in the management of MH. The responses to ICI therapy may be associated with the degree of PDL1 expression"

Checkpoint inhibition • Clinical • IO biomarker • Hematological Malignancies • Oncology • Sarcoma • Solid Tumor • DOCK8 • MAP2K1 • PD-L1 • PTPN11

CA209-73R: Encorafenib and Binimetinib With or Without Nivolumab in Treating Patients With Metastatic Radioiodine Refractory BRAF V600 Mutant Thyroid Cancer (clinicaltrials.gov) - P2 | N=24 | Active, not recruiting | Sponsor: Providence Health & Services | Trial completion date: Oct 2027 ➔ Jan 2027 | Trial primary completion date: Oct 2025 ➔ Jan 2026

Trial completion date • Trial primary completion date • Oncology • Solid Tumor • Thyroid Gland Carcinoma • BRAF

BRAF V600E-MUTATED GASTROINTESTINAL STROMAL TUMORS: A CASE SERIES AND ANALYSIS OF IMMUNE TUMOR INFILTRATE (CTOS 2025) - "Patient A received vemurafenib for 21 months achieving an initial response, followed by gradual progression. He subsequently received dabrafenib/trametinib for 8 months with stable disease initially followed by slow progression. Ipilimumab/nivolumab was initiated and achieved a durable complete response, remaining disease-free for 6.5 years off therapy. Patient B received binimetinib/encorafenib for 26 months showing an initial mixed response with regression of the primary tumor but progression of hepatic metastases... BRAF mutant GISTs are rare with variable responses to BRAF/MEK inhibition. A durable complete response to ICI was observed in one patient. Preliminary immune profiling supports further investigation of immunotherapy in selected cases with immune-infiltrated microenvironments."

Clinical • IO biomarker • Stroma • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Hepatocellular Cancer • Oncology • Sarcoma • BRAF • CD20 • CD8 • EP300 • FLT4 • JAK3 • LAG3 • NF1 • PD-1 • PD-L1 • RB1 • TSC2

Successful response in advanced leptomeningeal disease from pleomorphic xanthoastrocytoma with BRAF/MEK inhibitors: a case report. (PubMed, Front Oncol) - "In here we report a case of a female patient who developed LMD from a Pleomorphic Xanthoastrocytoma (PXA), BRAFV600-mutated, who has shown successful response to treatment with BRAF/MEKi (Encorafinib/Binimetinib) for over 3 years since initial LMD diagnosis. The effectiveness of therapy in this patient was initially observed as stable disease, with radiographic progression when BRAF/MEKi were withheld, and immediate tumor control achieved when reinstated. Despite being just one case, this hopefully could serve as proof-of-concept for use of targeted therapy for BRAF V600E-mutated tumors with LMD progression, sparing patients from alternative tumor control options such as radiation therapy."

Journal • Astrocytoma • Brain Cancer • CNS Tumor • Oncology • Pleomorphic Xanthoastrocytoma • BRAF

Intracranial antitumor efficacy of combination treatment with encorafenib plus binimetinib in BRAF V600E-mutated anaplastic thyroid carcinoma. (PubMed, Auris Nasus Larynx) - "The patient was initially diagnosed with T4bN1bM1 and experienced disease progression following surgery and lenvatinib treatment. This possibility is supported by reliable evidence for the use of BRAF plus MEK inhibitor for brain metastasis from BRAF-mutated malignant melanoma. We conclude that encorafenib plus binimetinib treatment for brain metastasis from BRAF-mutated thyroid cancer is a safe and effective treatment choice."

Journal • Infectious Disease • Melanoma • Novel Coronavirus Disease • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • BRAF

Study of Binimetinib in Combination With Pembrolizumab in Advanced Non-Small Cell Lung Cancer (clinicaltrials.gov) - P1 | N=40 | Recruiting | Sponsor: University Health Network, Toronto | Trial primary completion date: Dec 2025 ➔ Aug 2026

Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • BRAF • EGFR • KRAS • PD-L1 • STK11

Developments of MEK inhibitors as future cancer therapies: what have we learned from preclinical and clinical studies? (PubMed, Expert Opin Investig Drugs) - "This is a descriptive review. While MEK inhibitors in combination with BRAF inhibitors obtained one of the first tumor-agnostic FDA approvals for BRAF V600E/K mutated tumors, additional indications for MEK inhibitors alone have been received in very selected diseases for which molecular characterization is crucial."

Journal • Preclinical • Review • Genetic Disorders • Lung Cancer • Melanoma • Neurofibromatosis • Oncology • Solid Tumor • Thyroid Gland Carcinoma

GIST Trial 13-162: MEK162 in Combination With Imatinib Mesylate in Patients With Untreated Advanced Gastrointestinal Stromal Tumor (GIST) (clinicaltrials.gov) - P1/2 | N=75 | Active, not recruiting | Sponsor: Memorial Sloan Kettering Cancer Center | Trial completion date: Nov 2025 ➔ Nov 2026 | Trial primary completion date: Nov 2025 ➔ Nov 2026

Trial completion date • Trial primary completion date • Gastrointestinal Stromal Tumor • Oncology • Sarcoma

Aberrant KIF11 induction is a potential driver of aggressiveness in ER-a positive positive breast cancer (SABCS 2025) - "Pharmacological inhibition of MEK1/2 using binimetinib significantly reduced KIF11 expression, whereas overexpression of constitutively active MEK1 (CA-MEK1) increased its expression. As expected, ispinesib induced G2/M phase arrest and completely inhibited cell growth in ER+ breast cancer cells. These findings support KIF11 as a prognostic marker and potential therapeutic target in ER+ breast cancer, regulated at least in part by the MAPK signaling pathway."

Breast Cancer • Estrogen Receptor Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • KIF11 • MAPK1 • STAT3

Mutations in PIK3R1 Activate Multiple Pathways in Triple Negative Breast Cancer (SABCS 2025) - "We previously showed that PIK3R1 knock-out causes increased phosphorylation of MEK and enhanced sensitivity to MEK inhibitors, trametinib and binimetinib...This study tested binimetinib, alpelisib, and their combination in PDX models with PIK3R1MUT. Four TNBC PDX models were studied (Table 1)... Mutations in PIK3R1 sensitize TNBCs to combined MEK and PI3K pathway inhibition. Co-mutations in PIK3R1 wt PDX models may also sensitize TNBC to MEK and PI3K inhibitors. These findings suggest that combining inhibitors of MEK and PIK3CA could inhibit growth of TNBCs.Disclaimer: AA is employed by AstraZeneca but contributed to this publication in his own capacity."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • PIK3CA • PIK3R1

Turning the Tables: How Encorafenib and Binimetinib are Reshaping NSCLC Treatment. (PubMed, Cancer Invest) - No abstract available

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

ENCEFALO (GEM2301) clinical trial: Encorafenib and binimetinib followed by cemiplimab and fianlimab in BRAF-mutant melanoma and symptomatic brain metastases (ESMO-IO 2025) - P2 | "If among the first 18 pts, ≥4 had icPD at 6m or sooner, the study will stop. Accrual started in May 2025 and five patients were included by Sep 2025.Clinical trial identification EudraCT: 2024-513375-40-00; NCT06887088.Legal entity responsible for the study Grupo Español Multidisciplinar de Melanoma (GEM)."

Clinical • IO biomarker • Melanoma • Oncology • Solid Tumor • BRAF

Trends of adverse event reports associated with BRAF and MEK inhibitors and combinations: a retrospective disproportionality analysis using the FDA adverse event reporting system database from 2012 to 2021. (PubMed, Melanoma Res) - "Study drugs included BRAF/MEK inhibitors (dabrafenib, trametinib, vemurafenib, cobimetinib, encorafenib, and binimetinib). AE reports associated with melanoma therapies are sizable and significant. Healthcare professionals should be aware of the AE profiles attributable to the melanoma treatment and management."

Adverse events • Journal • Retrospective data • Fatigue • Melanoma • Musculoskeletal Pain • Oncology • Solid Tumor

Successful response in advanced leptomeningeal disease from pleomorphic xanthoastrocytoma with BRAF / MEK inhibitors: A case report and review of the literature. (SNO 2025) - "In here we report a case of a female patient who developed LMD from a Pleomorphic Xanthoastrocytoma (PXA), BRAFV600-mutated, who has shown successful response to treatment with BRAF/MEKi (Encorafinib/Binimetinib) for almost four years since initial LMD diagnosis...Despite being just one case, this hopefully could serve as proof-of-concept for use of targeted therapy for BRAF V600E-mutated tumors with LMD progression. Patient is well up to date and to our knowledge, this is the first case reported in the literature of a PXA with LMD with successful response to targeted therapy."

Case report • Clinical • Metastases • Review • Astrocytoma • Brain Cancer • Oncology • Pleomorphic Xanthoastrocytoma • BRAF

Rapid response to encorafenib and binimetinib (Enc/Bini) in a patient with recurrent ganglioglioma with leptomeningeal spread (SNO 2025) - "Initial treatment included surgical resection, followed by concurrent radiation and temozolomide (TMZ). She initiated anti-BRAFV600E therapy with dabrafenib and trametinib but was intolerant due to intractable flu-like symptoms including fever, rash and fatigue...Ocular and generalized seizures resolved with targeted treatment and transition to lacosamide...Prior studies in patients with primary CNS tumors and brain metastases have demonstrated encouraging responses and overall tolerability with this regimen. To our knowledge, this represents the first documented case of a rapid and durable (four months to date) clinical and radiographic response to systemic BRAF-targeted therapy in a patient with recurrent-AGG and leptomeningeal spread."

Clinical • Brain Cancer • CNS Disorders • CNS Tumor • Epilepsy • Ganglioglioma • Glioma • Mood Disorders • Ophthalmology • Otorhinolaryngology • Solid Tumor • APC • CDKN2A • CDKN2B

A phase II clinical trial of regorafenib (REGO) combined with BRAF-/MEK-inhibitors in advanced pretreated BRAFV600-mutant (mut) melanoma (RegoMel) (ESMO 2025) - P2 | "REGO was added to encorafenib/binimetinib (E/B) and dabrafenib/trametinib (D/T) in 10 and 8 pts respectively. Conclusions This phase 2 trial of REGO + BRAF/MEKi in BRAF V600 mut melanoma pts progressing on BRAF/MEKi failed to meet its predefined primary efficacy endpoint but demonstrated activity (incl. in the brain) in a subset of patients, with manageable toxicity."

Clinical • Metastases • P2 data • Melanoma • Oncology • Solid Tumor

Selective Enhancement of Sonodynamic Therapy by Trametinib Through Modulation of PpIX Accumulation in Glioma (WFNOS 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 • Solid Tumor

Rapid response to encorafenib and binimetinib (Enc/Bini) in a patient with recurrent ganglioglioma with leptomeningeal spread (WFNOS 2025) - "Initial treatment included surgical resection, followed by concurrent radiation and temozolomide (TMZ). She initiated anti-BRAFV600E therapy with dabrafenib and trametinib but was intolerant due to intractable flu-like symptoms including fever, rash and fatigue...Ocular and generalized seizures resolved with targeted treatment and transition to lacosamide...Prior studies in patients with primary CNS tumors and brain metastases have demonstrated encouraging responses and overall tolerability with this regimen. To our knowledge, this represents the first documented case of a rapid and durable (four months to date) clinical and radiographic response to systemic BRAF-targeted therapy in a patient with recurrent-AGG and leptomeningeal spread."

Clinical • Brain Cancer • CNS Disorders • Epilepsy • Ganglioglioma • Glioma • Mood Disorders • Oncology • Ophthalmology • Otorhinolaryngology • Psychiatry • Solid Tumor • APC • CDKN2A • CDKN2B

Myasthenia gravis induced by encorafenib and binimetinib for metastatic melanoma. (PubMed, Ann Dermatol Venereol) - No abstract available

Journal • CNS Disorders • Melanoma • Myasthenia Gravis • Oncology • Solid Tumor