Zelboraf (vemurafenib) / Daiichi Sankyo, 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

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

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

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

Long-term outcomes of patients with hairy cell leukemia treated with first-line cladribine in British Columbia (ASH 2025) - "Of these 65 pts, 45 (69%) were re-treated with PAalone (cladribine 40; fludarabine 5), 14 (22%) with a PA (14 of which received fludarabine) plus R, 2 withsingle-agent R, 1 with RCHOP, and 3 were observed. When comparing those re-treated with PA aloneversus PA plus R, median PFS2 was 8.6 y vs. not reached (P=0.03), and median OS2 was 23.7 y vs. notreached (P=0.62), respectively.During the follow-up period, 17/62 pts received 3L therapy including: re-treatment with cladribinemonotherapy in 3 pts, fludarabine plus R in 8, bendamustine plus R in 1, single-agent R in 4, and 1 patienteach received ibrutinib and vemurafenib with R. 5/17 pts went on to receive 4L therapy and 2/5 ptsreceived 5L therapy, primarily with alternate PAs and other novel agents such as anti-CD22 mAbs,Bruton's tyrosine kinase or BRAF inhibitors.A total of 74 pts (36% of the entire cohort) died...Our study suggests that combining a PA with an anti-CD20 mAb (mostcommonly fludarabine and R in this..."

Clinical • Gastrointestinal Disorder • Hairy Cell Leukemia • Hematological Malignancies • Indolent Lymphoma • Infectious Disease • Leukemia • Melanoma • Septic Shock • Solid Tumor

Hairy cell leukemia treatment strategies: A real-world multicenter experience (ASH 2025) - "The most frequent frontline therapies were cladribine (63%),cladribine with rituximab (12%), rituximab monotherapy (9.7%), vemurafenib-based regimens (7.7%),splenectomy with or without interferon (3.8%), interferon monotherapy (2.9%), and other (1.9%). Outcomes in later lines remainfavorable, particularly with re-treatment using purine analogs or combination regimens. These findingsunderscore the importance of individualized treatment planning and the continued need for real-worldevidence to inform care in rare hematologic malignancies."

Clinical • Real-world • Real-world evidence • Hairy Cell Leukemia • Hematological Malignancies • Indolent Lymphoma • Leukemia

Assessing patient risk, benefit, and outcomes in drug development: a decade of vemurafenib clinical trials. (PubMed, Melanoma Manag) - "Although vemurafenib showed efficacy in metastatic melanoma, off-label use resulted in limited benefit and increased adverse events. Unclear endpoints and underreported adverse events highlight the need for improved clinical trial design."

Journal • Colorectal Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Non-melanoma Skin Cancer • Rare Diseases • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • BRAF

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

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

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

Vemurafenib, cetuximab and camrelizumab in BRAF V600E-mutated/MSS metastatic colorectal cancer. (PubMed, J Transl Med) - P1 | "A combination of vemurafenib, cetuximab combined with camrelizumab exhibited manageable adverse reactions and efficacy in BRAF V600E-mutated/MSS patients with metastatic colorectal cancer who progressed after standard treatment. This is a pilot study and a larger phase II trials is planned to validate the findings. (ClinicalTrials.gov ID: NCT05019534)."

IO biomarker • Journal • Cardiovascular • Colorectal Cancer • Hematological Disorders • Oncology • Solid Tumor • Thrombocytopenia • BRAF • CD4 • CD8

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

Modulation of the tumor microenvironment through BMAL1-LHX8 axis augments the sensitivity of ameloblastoma to vemurafenib. (PubMed, J Adv Res) - "Our findings reveal the role of the BMAL1-LHX8 axis in underlying AMF-mediated drug resistance in AM, and propose that the molecular clock modulation in tumor-stroma crosstalk represents a potential therapeutic avenue for ameloblastoma."

Biomarker • Journal • Oncology • ARNTL • BMAL1

Real-Life Efficacy and Safety of Vemurafenib Plus Rituximab (V+R) in Relapsed or Refractory Hairy Cell Leukemia: A Multi-Center Retrospective Study (HCL-PG03R) (ASH 2023) - "Prior therapies (median 2; range 0-11) included chemotherapy with cladribine or pentostatin (94% of pts), interferon-alpha (29%), rituximab (31%), splenectomy (6%), BRAF inhibitor monotherapy (6%) and zanubrutinib (3%). Analysis of MRD by allele-specific PCR for BRAF-V600E in the bone marrow aspirate was performed in 30 pts and showed MRD clearance (<0.05% mutant alleles) at a high rate: 79% (22/28 CR pts; or 65%, 22/35 pts, by ITT), which raised to 82% (66% by ITT) when including 1 additional CR case untested by PCR which had negative bone marrow flow cytometry.At a median follow-up of 21 months after the end of treatment, RFS was high among the 31 responding pts, with just 1 relapse (3%) in the only case obtaining a PR post-therapy (Figure). CONCLUSIONSThis study validates in a real-life context the high efficacy and tolerability of the V+R chemo-free regimen delivered to R/R HCL pts, including the cost-saving use of biosimilar rituximab."

Retrospective data • Dermatology • Hairy Cell Leukemia • Hematological Disorders • Hematological Malignancies • Human Immunodeficiency Virus • Infectious Disease • Leukemia • Musculoskeletal Pain • Oncology • Respiratory Diseases • Tuberculosis

A Single Arm Phase II Pilot Study of Low Dose Vemurafenib Plus Rituximab in the Front-Line and Relapsed/Refractory Treatment of Hairy Cell Leukemia (ASH 2023) - "Interim results to-date suggest that rituximab and low-dose vemurafenib (240 mg twice daily) have efficacy and good tolerability in patients with untreated or relapsed HCL. With accruing patient data and further enrollment on study, more information will guide the durability, efficacy and tolerability of this treatment approach."

Clinical • P2 data • Hairy Cell Leukemia • Hematological Malignancies • Infectious Disease • Leukemia • Oncology • BRAF

Serum Soluble Interleukin-2 Receptor Levels in Hairy Cell Leukemia As a Marker of Tumor Burden with Prognostic Value and As a Tool for Disease Monitoring (ASH 2023) - "Among treated patients, 47/54 (87%) received cladribine and 7/54 (13%) pentostatin...A similar decrease in sIL-2R levels after therapy was observed in 4 relapsed patients treated with rituximab-vemurafenib (median pre-therapy sIL-2R 11.460 vs. 467 kU/L after treatment, p = 0.03; median reduction 10.848 kU/L)...While more data is required to validate its use in clinical routine, sIL-2R could be used as an effective marker for disease monitoring. Moreover, given the prognostic significance of post-therapy levels, sIL-2R may represent a prognostic factor alongside MRD to identify those patients that are more likely to develop early relapse."

IO biomarker • Hairy Cell Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CD38 • IL2

Efficacy and Safety of Obinutuzumab in Relapsed or Refractory Hairy Cell Leukemia (R/R HCL): An Italian Multicenter Phase-2 Academic Trial (HCL-PG04) (ASH 2023) - "NEJM 2015), especially when added to rituximab (Tiacci et al. The 13 non-CR pts (minor response 7; no response 3; progression 3) were effectively salvaged with another course of OBI combined with vemurafenib, which will be presented at the meeting. CONCLUSIONS OBI frequently produced deep and durable responses in R/R HCL, to an extent apparently greater than RTX, thus qualifying as an active and safe chemotherapy-free strategy in this setting."

Clinical • P2 data • Chronic Lymphocytic Leukemia • Follicular Lymphoma • Hairy Cell Leukemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Lymphoma • Neutropenia • Oncology • Pneumonia • Respiratory Diseases • Thrombocytopenia

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

Targeting centromere protein M represses cell growth and mobility via inactivating AKT pathway but less affects BRAF inhibitor sensitivity in cutaneous melanoma. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "Cutaneous melanoma cell lines (A375 and SK-MEL-28) were transfected by CENPM siRNA (si-CENPM), followed by detections and treatment of various concentrations of dabrafenib and vemurafenib. Clinically, GEPIA database revealed that CENPM was upregulated and correlated with worse overall survival in cutaneous melanoma patients. Targeting CENPM suppresses cutaneous melanoma growth and mobility by inactivating AKT pathway, indicating its potential as a treatment target."

Journal • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • CENPM

Development of a biomimetic thyroid acellular scaffold as a 3D platform for modeling thyroid cancer aggressiveness and drug resistance. (PubMed, Front Bioeng Biotechnol) - "Critically, the 3D microenvironment induced a more aggressive phenotype, characterized by upregulated expression of the BRAF V600E oncogene and the induction of epithelial-mesenchymal transition (EMT), and conferred significantly increased resistance to both cisplatin and vemurafenib. These findings indicate that our tissue-specific, TAS-based 3D model successfully recapitulates key pathophysiological hallmarks of thyroid cancer, representing a more clinically relevant and predictive platform for investigating tumor mechanisms and for the preclinical evaluation of novel therapeutic agents."

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

Real-life efficacy and safety of vemurafenib plus rituximab in relapsed or refractory hairy-cell leukemia: A multicenter Italian retrospective study (HCL-PG03R). (PubMed, Hemasphere) - No abstract available

Journal • Retrospective data • Hairy Cell Leukemia • Hematological Malignancies • Leukemia • Oncology