Cotellic (cobimetinib) / Exelixis, Roche - LARVOL DELTA

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

Discovery of drug combinations with momelotinib to improve myelofibrosis outcomes (ASH 2025) - "The VAF screen identified numerous inhibitors of signaling pathways operating parallel to the JAK-STAT signaling pathway including SHP2 (migoprotafib), PI3K (copanlisib), MEK (cobimetinib), agents targeting BET (BMS-986158), and STAT transcriptional targets, including BCLxL (navitoclax). The hepcidin screen identified inhibitors that combined to further suppress expression of the HiBiT transgene including CDK4 (atirmociclib) and MDM2 (navtemadlin). Notably, selinexor, an XPO1 inhibitor, combined positively with momelotinib to both kill malignant cells and suppress hepcidin expression. These results highlight several promising drug combinations that could enhance outcomes for MF patients by effectively controlling anemia and halting disease progression. These discoveries provide the scientific justification to identify optimal combination regimens aimed at addressing the multifaceted challenges of myelofibrosis."

IO biomarker • Myelofibrosis • ACVR1 • BCL2L1 • BMP6 • CDK4 • JAK1

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

MAPK pathway-driven metabolic-inflammatory axis in AL amyloidosis (ASH 2025) - "Functional assays and lipidomic analysis wereconducted in ALMC1 cells using the FASN inhibitor TVB-2640 and the MEK inhibitor cobimetinib.ResultsLipidomic analysis of pre-treatment plasma samples revealed a significant increase in the lipogenesisindex in AL patients, indicating elevated FASN activity. This axissustains a pro-inflammatory environment that may contribute to disease pathogenesis. Thus, FASN andMAPK may represent promising metabolic-immunologic targets for therapeutic intervention in ALamyloidosis."

Amyloidosis • Hematological Malignancies • Metabolic Disorders • Multiple Myeloma • CCL2 • CCL3 • CXCL10 • CXCL8 • IFNG • IL13 • IL1B • SDC1

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

Targeting the MEK/ERK Pathway to Suppress P-Glycoprotein and Reverse Carfilzomib Resistance in Multiple Myeloma. (PubMed, Int J Mol Sci) - "Carfilzomib (CFZ) is a cornerstone in the treatment of relapsed multiple myeloma (MM). At the IC50 concentration, both inhibitors reduced P-gp expression. In conclusion, combining CFZ with MAPK pathway inhibitors like cobimetinib or ulixertinib represents a promising strategy to overcome P-gp-mediated resistance in MM."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology

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

Phase 1b Study of IDH Inhibition with Enasidenib and MEK Inhibition with Cobimetinib in Patients with Relapsed or Refractory Acute Myeloid Leukemia Who Have Co-Occurring IDH2 and RAS Signaling Gene Mutations (ASH 2024) - P1 | "Background : Targeting of methylation by mutant isocitrate dehydrogenase (IDH) has changed the therapeutic landscape of relapsed or refractory (R/R) AML, culminating in the approval of IDH inhibitors, enasidenib, ivosidenib, and olutasidenib. Concurrent RAS-signaling mutations represent a growing problem in the management of R/R IDH mutant AML, since they are associated with resistance to IDH inhibitors and other approved therapies such as venetoclax-based regimens...As enasidenib is a moderate CYP3A inducer, the protocol was amended to also allow concomitant use of the moderate CYP3A4 inhibiting antifungal, isavuconazonium sulfate (cresemba)...To date, four patients have enrolled with three patients completing at least 1 cycle of treatment. Enrollment is open at City of Hope and the Fred Hutchinson Cancer Center (NCT05441514)."

Clinical • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BRAF • IDH2 • KRAS • NF1 • NRAS • PTPN11 • RIT1 • TET2

XL888 + Vemurafenib + Cobimetinib for Unresectable BRAF Mutated Stage III/IV Melanoma (clinicaltrials.gov) - P1 | N=26 | Active, not recruiting | Sponsor: H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Nov 2025 ➔ Nov 2026

Trial completion date • Genetic Disorders • Melanoma • Oncology • Skin Cancer • Solid Tumor • BRAF • CDC37

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

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

Accuracy of Budget Impact Projections in Bulgarian Health Technology Assessment: A Five-Year Validation Study (2020-2025). (PubMed, Healthcare (Basel)) - "Large overshoots were observed for Avelumab, Risankizumab, and Guselkumab; Cobimetinib and Abemaciclib remained below forecast. Health Technology Assessment Budget Impact Analyses captured broad cost scaling but systematically missed product-specific uptake, with deviations largely volume-driven. Strengthening national registries and real-world data pipelines, and adopting dynamic, indication-responsive contracting and forecasting, could materially improve budget predictability while preserving access to innovation."

HEOR • Journal • Oncology

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

Real World Outcomes in Adult Histiocytosis: 23-Year Canadian Single Center Analysis (ASH 2024) - "Twenty (33%) LCH patients required subsequent lines of therapies with four patients receiving targeted therapies (Cobimetinib-3; vemurafenib-1); all these patients attained at least a partial response. Various first line systemic therapies given in ECD were cladribine (n=1), interferon alfa (n=5), anakinra (n=3), vemurafenib (n=1) with ORR of 40%. Eight patients (72%) required subsequent therapies with cladribine in 4, vemurafenib in 2 and dabrafenib and trametinib combination in 2 patients...High incidence of second hematological malignancies in our small cohort warrants more efforts to establish the association between the two entities. Prospective, multicenter studies with molecular discoveries are needed in adult counterpart of this orphan disease."

Clinical • Real-world • Real-world evidence • Acute Myelogenous Leukemia • Ataxia • Chronic Lymphocytic Leukemia • Fibrosis • Hairy Cell Leukemia • Hematological Malignancies • Immunology • Langerhans Cell Histiocytosis • Leukemia • Metabolic Disorders • Movement Disorders • Myeloproliferative Neoplasm • Oncology • Ophthalmology • Pediatrics • Rare Diseases • Tobacco Cessation • BRAF • CALR • JAK2

Tumor-intrinsic MHC-II activation in pancreatic ductal adenocarcinoma enhances immune response and treatment efficacy. (PubMed, bioRxiv) - "In the KPC mouse model of PDAC, pharmacologic induction of MHC-II expression by cobimetinib treatment in malignant epithelial cells significantly enhanced the therapeutic response to immune checkpoint blockade (ICB)...Our results position MHC-II as a promising prognostic biomarker and therapeutic target in PDAC, paving the way for novel immunomodulatory strategies. Single-cell and spatial transcriptomic analyses reveal that elevated MHC-II expression in malignant PDAC cells correlates with increased infiltration of CD4⁺ and CD8⁺ T cells.Stimulating MHC-II expression in tumors effectively enhances immunotherapeutic responses to ICB in the PDAC KPC mouse model, including PDAC tumors previously resistant to therapeutic interventions.MHC-II serves as a prognostic biomarker and a promising target for immunotherapy in PDAC."

IO biomarker • Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CD4 • CD8 • HLA-DRB1

Efficacy of Belvarafenib with and without Cobimetinib in Preclinical Models of Ras Pathway-Mutant AML (ASH 2023) - "Mechanistically, we identified distinct biochemical and transcriptional effects of RAF dimer and MEK inhibition in AML cells. We are characterizing these further and pursuing causes of resistance in primary Nras- and ­Kras-mutant mouse AMLs that relapsed after an initial response to treatment."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • Solid Tumor • BRAF • KRAS • NF1 • NRAS • SPRY2

Efficacy and Tolerability of Trametinib in Adults with Histiocytic Neoplasms (ASH 2024) - "BRAFV600E is the most common mutation but in approximately 50% of patients, a range of other mutations involving MAP2K (MEK), CSF1R, NRAS, KRAS and gene fusions are observed, which may be susceptible to treatment with MEK inhibitors such as Cobimetinib or Trametinib...Patients over 18 years who commenced Trametinib as monotherapy or in combination with Dabrafenib before 31st December 2023 were included in the study...Further studies are required to define optimal patient eligibility, Trametinib dosing and modes of response assessment. Note : the use of Trametinib to treat histiocytic neoplasms is off-label."

Clinical • Cardiovascular • CNS Disorders • Gastroenterology • Gastrointestinal Disorder • Hematological Malignancies • Hypertension • Immunology • Langerhans Cell Histiocytosis • Oncology • Rare Diseases • Sarcoma • Solid Tumor • CSF1R • KRAS • NRAS

CONCERTO: Cobimetinib in Newly Diagnosed or HMA-treated CMML Patients With RAS Pathway Mutations (clinicaltrials.gov) - P2 | N=29 | Recruiting | Sponsor: University of Utah | Trial primary completion date: Aug 2025 ➔ Jan 2026

Trial primary completion date • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • BRAF • FLT3 • JAK2 • KRAS • NF1 • NRAS • PTPN11

Belvarafenib Inhibits the Growth of RAS-Mutant Acute Myeloid Leukemia Cell Lines in Vitro and Drives Adaptive Resistance In Vivo (ASH 2024) - "OCI-AML3 cells were lentivirally transduced with doxycycline-inducible vectors containing constitutively active MEK-DD, a MEK mutation that confers resistance to allosteric MEK inhibitors (L115P), or candidate MEK resistance mutations and cell viability was determined by CellTiter-Glo...NRAS-mutant OCI-AML3 cells expressing MEK-DD were resistant to belvarafenib and sensitive to cobimetinib...We are characterizing candidate resistance mutations in addition to Mapk21 K57T that emerged during belvarafenib treatment. Altogether, our data support further investigation of belvarafenib monotherapy and rational drug combinations in AML."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • BRAF • EIF4EBP1 • KRAS • MAP2K1 • MAPK1 • NRAS

Alliance A071601: Phase II trial of BRAF/MEK inhibition in recurrent papillary craniopharyngiomas (SNO 2025) - P2 | "Vemurafenib/cobimetinib resulted in an objective response in all patients with previously treated PCP. The study met primary endpoint, similar to that reported for previously untreated PCP. Thus, BRAF/MEK inhibitors could be an effective tool for previously treated PCP and warrants further evaluation."

P2 data • Brain Cancer • CNS Tumor

The Contribution of Oncogenic RAS Mutations in Obesity-Associated Multiple Myeloma (ASH 2024) - "Additionally, hyperactivation of the RAS signaling pathway by BMAs altered the sensitivity to FDA-approved drugs targeting the RAS signaling cascade (Cobimetinib, Sorafenib, Dabrafenib, and Cabozantinib), further implicating RAS signaling in therapeutic response...This study demonstrates a novel interaction between genetic factors (RAS mutations) and the tumor microenvironment (adipocyte secreted factors) to drive MM clonal expansion. Findings from this study will be critical for understanding the role of oncogenic RAS in obesity-associated MM and illuminate novel therapeutic targets or modifiable risk factors to combat disease progression and chemoresistance in MM."

Genetic Disorders • Hematological Malignancies • Lung Cancer • Multiple Myeloma • Obesity • Oncology • Pancreatic Cancer • Solid Tumor • IL6 • KRAS • RAS

Alliance A071601: Phase II trial of BRAF/MEK inhibition in recurrent papillary craniopharyngiomas (WFNOS 2025) - P2 | "Vemurafenib/cobimetinib resulted in an objective response in all patients with previously treated PCP. The study met primary endpoint, similar to that reported for previously untreated PCP. Thus, BRAF/MEK inhibitors could be an effective tool for previously treated PCP and warrants further evaluation."

P2 data • Brain Cancer • Solid Tumor

Mixed histiocytosis of the thoracic dura: a rare presentation of Mixed Erdheim-Chester Disease and Rosai-Dorfman Disease mimicking IgG4-Related Disease (SNO 2025) - "He received high dose prednisone and etanercept without radiographic or clinical improvement...He was treated with radiation therapy targeting the dural lesion with temporarily worsening symptoms improved with steroids and started on cobimetinib. A 50-year-old man presented for evaluation of spastic paraparesis in the context of a thoracic dural lesion. Two years prior he developed an inflammatory monoarthritis concerning for rheumatoid arthritis unresponsive to methotrexate. Six months prior he developed leg spasms, gait spasticity, and urinary incontinence."

CNS Disorders • Fibrosis • Genetic Disorders • Immunology • Inflammation • Inflammatory Arthritis • Movement Disorders • Otorhinolaryngology • Rare Diseases • Rheumatoid Arthritis • Rheumatology • Urinary Incontinence • Urology • BRAF • CCND1 • CD163 • CD1a • F13A1 • MAP2K1

Mixed Erdheim-Chester disease with thoraco-abdominal involvement. (PubMed, Acta Radiol Open) - "The patient was started on targeted therapy with cobimetinib, a MEK inhibitor...We present a rare case of mixed ECD-LCH with thoraco-abdominal and pulmonary involvement. Comprehensive diagnostic workup including histopathology and molecular profiling is crucial for accurate diagnosis and initiation of targeted therapy."

Journal • Chronic Myelomonocytic Leukemia • Diabetes • Hematological Malignancies • Langerhans Cell Histiocytosis • Leukemia • Metabolic Disorders • Oncology • Rare Diseases • Type 2 Diabetes Mellitus

Mixed histiocytosis of the thoracic dura: a rare presentation of Mixed Erdheim-Chester Disease and Rosai-Dorfman Disease mimicking IgG4-Related Disease (WFNOS 2025) - "He received high dose prednisone and etanercept without radiographic or clinical improvement...He was treated with radiation therapy targeting the dural lesion with temporarily worsening symptoms improved with steroids and started on cobimetinib. A 50-year-old man presented for evaluation of spastic paraparesis in the context of a thoracic dural lesion. Two years prior he developed an inflammatory monoarthritis concerning for rheumatoid arthritis unresponsive to methotrexate. Six months prior he developed leg spasms, gait spasticity, and urinary incontinence."

CNS Disorders • Fibrosis • Genetic Disorders • Immunology • Inflammation • Inflammatory Arthritis • Movement Disorders • Otorhinolaryngology • Rare Diseases • Rheumatoid Arthritis • Rheumatology • Urinary Incontinence • Urology • BRAF • CCND1 • CD163 • CD1a • F13A1 • MAP2K1