Tafinlar (dabrafenib)

P3, N=603, Active, not recruiting, Institut National de la Santé Et de la Recherche Médicale, France | Trial completion date: Oct 2025 --> Jan 2026

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.

At the time of drafting this report, the patient had achieved 8 months of PFS. This case suggests that dose-adjusted dabrafenib combined with trametinib might be a potentially effective treatment strategy for elderly patients with advanced pancreatic adenocarcinoma harboring BRAF V600E mutations.

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 enabling comprehensive molecular diagnostics and facilitating enrollment in international trials. This review summarizes current targeted therapies and ongoing studies and outlines practical considerations for integrating precision oncology into pediatric neuro-oncology in Japan.

The patient received combined dabrafenib, trametinib, and pembrolizumab with close safety monitoring, achieving rapid tumor control and complete remission by six months with manageable toxicity. This case suggests that early integration of PD-1 blockade with BRAF/MEK inhibition treatment may benefit selected patients and underscores the value of comprehensive molecular and immunohistochemical assessment to guide individualized therapy.

This PEITC effect could be demonstrated in two further dabrafenib-resistant cell lines, WM164D and 451LuP. These results suggest that the altered redox status is linked to compromised mitochondria and is associated with the development of BRAFi resistance, rendering cells exquisitely sensitive to the actions of selective ROS-inducing therapeutics.

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.

Preclinical studies show that pharmacological inducers, including vitamin C, tenacissoside H, neferine, curcumin, and shikonin, as well as targeted agents such as dabrafenib and anlotinib, can trigger or synergize with ferroptosis. Although systemic toxicity and resistance remain obstacles, biomarker-driven selection and drug repurposing offer promise. Ferroptosis represents a mechanistically distinct and clinically exploitable pathway for ATC.

Molecular events included the emergence of a BRAF V600E mutation responsive to dabrafenib plus trametinib and the acquisition of an EGFR exon 19 deletion responsive to Osimertinib. EVA/PCD identified activity for targeted agents and revealed synergy for vinorelbine plus Osimertinib not predicted by genomic profiling, which provided additional response. This case highlights clonal evolution in NSCLC and illustrates how serial tissue analyses correlating phenotypic and genomic events can offer therapeutic interventions to provide long-term survival. The integration of functional and genomic profiling may improve personalized treatment in NSCLC by interrogating tumor heterogeneity and clonal evolution to inform rational therapeutic selection.

In this single-center retrospective cohort, neoadjuvant-plus-adjuvant dabrafenib and trametinib was feasible, enabling timely surgery with manageable toxicities. Survival outcomes were comparable to adjuvant-only therapy, and pathological responses in the neoadjuvant cohort provide exploratory prognostic information.

The United States Food and Drug Administration (FDA) has approved pembrolizumab for MSI-high tumors or tumors with a high TMB. Larotrectinib and entrectinib have been approved for the treatment of NTRK gene fusion-positive tumors. Additionally, the combination of dabrafenib and trametinib has been approved for BRAF V600E mutations, and selpercatinib has been approved for RET fusion-positive cancers as of 2022. Positive responses to agnostic therapy, a significant milestone in cancer treatment, depend on the identification of new agnostic biomarkers. Ongoing research is focused on defining additional molecular changes, such as programmed death-ligand 1 (PD-L1), Kirsten rat sarcoma virus (KRAS), neuregulin 1 (NRG1), fibroblast growth factor receptor (FGFR), anaplastic lymphoma kinase (ALK), AKT serine/threonine kinase (AKT), human epidermal growth factor receptor 2 (HER2), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), and breast cancer gene (BRCA), as potential agnostic biomarkers in various cancer types.

Genetic test showed a positive BRAF V600E gene mutation. Treatment with dabrafenib and trametinib was initiated nine days after lenvatinib was discontinued.