^
    1d
    Agnostic Administration of Targeted Anticancer Drugs: Looking for a Balance between Hype and Caution. (PubMed, Int J Mol Sci)
    Several agnostic drug-target matches have already been approved for clinical use, e.g., immune therapy for tumors with microsatellite instability (MSI) and/or high tumor mutation burden (TMB), NTRK1-3 and RET inhibitors for cancers carrying rearrangements in these kinases, and dabrafenib plus trametinib for BRAF V600E mutated malignancies. The existing format of data dissemination may not be optimal for agnostic cancer medicine, as conventional scientific journals are understandably biased towards the publication of positive findings and usually discourage the submission of case reports. Despite all the limitations and concerns, histology-independent drug-target matching is certainly feasible and, therefore, will be increasingly utilized in the future.
    Review • Journal • Tumor mutational burden • BRCA Biomarker • PD(L)-1 Biomarker • IO biomarker
    |
    HER-2 (Human epidermal growth factor receptor 2) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • TMB (Tumor Mutational Burden) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • HRD (Homologous Recombination Deficiency)
    |
    PD-L1 expression • BRAF V600E • TMB-H • HER-2 overexpression • HER-2 amplification • BRAF V600 • HRD • RET mutation • ALK translocation • NTRK1 mutation • HER-2 amplification + PD-L1 expression
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib)
    3d
    A Study of Dabrafenib and/or Trametinib in Patients With Relapsed and/or Refractory Multiple Myeloma (clinicaltrials.gov)
    P1, N=30, Recruiting, Massachusetts General Hospital | N=60 --> 30 | Trial completion date: Sep 2022 --> Sep 2024 | Trial primary completion date: Sep 2022 --> Sep 2024
    Enrollment change • Trial completion date • Trial primary completion date
    |
    KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog)
    |
    KRAS mutation • BRAF mutation
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib)
    5d
    Combined therapy of dabrafenib and an anti-HER2 antibody-drug conjugate for advanced BRAF-mutant melanoma. (PubMed, Cell Mol Biol Lett)
    These findings establish a preclinical foundation for the combined use of an anti-HER2 drug conjugate and a BRAF inhibitor in the treatment of BRAF-mutant cutaneous melanoma.
    Journal • IO biomarker • Metastases
    |
    BRAF (B-raf proto-oncogene)
    |
    HER-2 positive • BRAF mutation • BRAF V600
    |
    Tafinlar (dabrafenib)
    7d
    Study of the Rechallenge Concept in Patients With BRAF-positive Anaplastic Thyroid Cancer After Progression on Anti-BRAF Therapy (clinicaltrials.gov)
    P2, N=10, Recruiting, Saint Petersburg State University, Russia
    New P2 trial
    |
    PD-L1 (Programmed death ligand 1)
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib)
    8d
    Intracranial hemorrhage caused by dabrafenib and trametinib therapy for metastatic melanoma. (PubMed, Melanoma Res)
    Physicians should be aware of this rare but life-threatening adverse event of B-rapidly accelerated fibrosarcoma (BRAF) and mitogen-activated protein kinase kinase (MEK). However, they should be careful about the bleeding origin, which can prove to be a new onset of melanoma metastasis or anticoagulation overdose, or even an uncontrolled arterial hypertension.
    Journal • Metastases
    |
    BRAF (B-raf proto-oncogene)
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib)
    9d
    Clinical Study To Further Evaluate The Efficacy Of Dabrafenib Plus Trametinib In Patients With Rare BRAF V600E Mutation-Positive Unresectable or Metastatic Solid Tumors (clinicaltrials.gov)
    P=N/A, N=40, Recruiting, Novartis Pharmaceuticals | Not yet recruiting --> Recruiting | Trial primary completion date: Oct 2027 --> Feb 2028
    Enrollment open • Trial primary completion date • Metastases
    |
    BRAF V600E • BRAF V600
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib)
    9d
    Effectiveness and Safety of Dabrafenib in Combination With Trametinib as Adjuvant Treatment for Chinese Patients With Stage III BRAF V600 Mutation-positive Melanoma After Complete Resection (clinicaltrials.gov)
    P=N/A, N=80, Recruiting, Novartis Pharmaceuticals | Trial completion date: Dec 2026 --> Jul 2029 | Trial primary completion date: Dec 2026 --> Jul 2029
    Trial completion date • Trial primary completion date • Combination therapy
    |
    BRAF mutation • BRAF V600
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib)
    10d
    COMBI-i: A Study of the Anti-PD1 Antibody PDR001, in Combination With Dabrafenib and Trametinib in Advanced Melanoma (clinicaltrials.gov)
    P3, N=569, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Mar 2024 --> Aug 2024
    Trial completion date • Combination therapy • IO biomarker • Metastases
    |
    PD-L1 (Programmed death ligand 1) • CD8 (cluster of differentiation 8)
    |
    PD-L1 expression • BRAF mutation • BRAF V600
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib) • spartalizumab (PDR001)
    14d
    Synergistic effects of the combination of trametinib and alpelisib in anaplastic thyroid cancer with BRAF and PI3KCA co-mutations. (PubMed, Heliyon)
    Anaplastic thyroid cancer (ATC), a rare and aggressive malignancy with a poor prognosis, has shown promise with the approved dabrafenib/trametinib combination for BRAFV600E mutation. The combination of trametinib and alpelisib showed promise as a strategy for treating ATC with co-mutations in BRAF and PI3KCA, both in vitro and in vivo. This combination offers insights into overcoming resistance to BRAF-targeted treatments in ATC with mutations in BRAF and PI3KCA.
    Journal
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF V600E • BRAF mutation • PIK3CA mutation • BRAF V600
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib) • Piqray (alpelisib)
    15d
    Dabrafenib plus trametinib versus anti-PD-1 monotherapy as adjuvant therapy in BRAF V600-mutant stage III melanoma after definitive surgery: a multicenter, retrospective cohort study. (PubMed, EClinicalMedicine)
    No abstract available
    Retrospective data • Journal • PD(L)-1 Biomarker • IO biomarker • Surgery
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF mutation • BRAF V600
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib)
    18d
    BRAF/MEK-targeted therapy in BRAF ex15 p.T599dup mutation-driven NSCLC: a case report. (PubMed, J Cancer Res Clin Oncol)
    However, the efficacy of dabrafenib + trametinib on non-V600E mutant NSCLC in clinical practice only exists in some case reports. Here, we report a case of NSCLC patient carrying BRAF ex15 p.T599dup, who showed a clinical response to the combined therapy of dabrafenib + trametinib.
    Review • Journal
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF V600E • BRAF mutation • BRAF T599
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib)
    18d
    Exploiting BRAF mutations in the therapeutic approach towards oral and maxillofacial tumors. (PubMed, J Stomatol Oral Maxillofac Surg)
    A recent neoadjuvant therapy targeting BRAF, involving the use of dabrafenib and trametinib, has showcased a promising, safe, and effective strategy for organ preservation in the treatment of mandibular ameloblastoma. This convergence of molecular insights and targeted therapies holds the key to managing BRAF-mutated oral and maxillofacial tumors effectively, promising improved patient outcomes.
    Journal
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF V600E • BRAF mutation • BRAF V600
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib)
    21d
    A Multi-center Retrospective Study With Secondary Use of Data of Tafinlar (Dabrafenib) Plus Mekinist (Trametinib) in Chinese Patients With BRAF V600 Mutation Positive Melanoma (clinicaltrials.gov)
    P=N/A, N=90, Completed, Novartis Pharmaceuticals
    New trial
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib)
    25d
    If it's a target, it's a pan-cancer target: Tissue is not the issue. (PubMed, Cancer Treat Rev)
    Hence, we now have multiple genomic biomarker-based, tissue-agnostic Food and Drug Administration approvals for both gene- and immune-targeted therapies (larotrectinib/entrectinib, for NTRK fusions; selpercatinib, RET fusions; dabrafenib plus trametinib, BRAFV600E mutations; pembrolizumab/dostarlimab, microsatellite instability; and pembrolizumab for high tumor mutational burden; pemigatinib is also approved for FGFR1-rearranged myeloid/lymphoid neoplasms). Resistance to biomarker-driven therapeutics is often due to secondary mutations or co-driver gene defects; studies are now addressing the need for customized drug combinations matched to the complex molecular alteration portfolio in each tumor. Future investigation should expand tissue-agnostic therapeutics to encompass both hematologic and solid malignancies and include biomarkers beyond those that are DNA-based.
    Review • Journal • Tumor mutational burden • BRCA Biomarker • PD(L)-1 Biomarker • Pan tumor
    |
    HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • RET (Ret Proto-Oncogene) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • FGFR1 (Fibroblast growth factor receptor 1) • NRG1 (Neuregulin 1) • BRCA (Breast cancer early onset) • NTRK (Neurotrophic receptor tyrosine kinase)
    |
    BRAF V600E • TMB-H • KRAS G12C • BRAF V600 • RET fusion • KRAS G12 • NTRK fusion
    |
    Keytruda (pembrolizumab) • Mekinist (trametinib) • Tafinlar (dabrafenib) • Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • Retevmo (selpercatinib) • Jemperli (dostarlimab-gxly) • Pemazyre (pemigatinib)
    29d
    Study of Efficacy and Safety of Dabrafenib Plus Trametinib in Previously Treated Patients With Locally Advanced or Metastatic, Radio-active Iodine Refractory BRAFV600E Mutation-positive Differentiated Thyroid Cancer (clinicaltrials.gov)
    P3, N=150, Recruiting, Novartis Pharmaceuticals | Trial completion date: Oct 2026 --> Aug 2024 | Trial primary completion date: Apr 2024 --> Jul 2024
    Trial completion date • Trial primary completion date • Metastases
    |
    BRAF V600E • BRAF V600
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib)
    29d
    Augmentation of Radioiodine Uptake by Pulmonary Metastasis of Papillary Thyroid Carcinoma Treated with Dabrafenib and Trametinib. (PubMed, Nucl Med Mol Imaging)
    Diffuse increased radioiodine uptake by pulmonary metastasis was visualized on post ablation whole body scan. Response to second radioiodine ablation was demonstrated by decrease in size of pulmonary nodules seen on chest CT, along with decrease of thyroglobulin level.
    Journal
    |
    TG (Thyroglobulin)
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib)
    1m
    Response to Dabrafenib Plus Trametinib in a Patient With an Uncommon Activating BRAF Mutation: A First in Non-Small Cell Lung Cancer. (PubMed, J Natl Compr Canc Netw)
    This report presents a case of a woman with metastatic NSCLC harboring a class II BRAF p.N486_P490del variant who had a sustained clinical response to combination therapy with dabrafenib and trametinib. This first report of the use of BRAF/MEK-targeted therapy for this variant in NSCLC supports consideration of such treatment for tumors with class II BRAF variants.
    Journal
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF V600E • BRAF mutation • BRAF V600
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib)
    1m
    Dabrafenib and trametinib-BRAF V600E mutated pediatric gliomas (PubMed, Bull Cancer)
    No abstract available
    Journal
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF V600E • BRAF V600
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib)
    1m
    Combination of Dabrafenib and Trametinib in Patients with Metastatic BRAFV600E-Mutated Thyroid Cancer. (PubMed, Cancer Res Treat)
    Dose reduction due to adverse events was required in 81.5% of the patients. Dabrafenib and trametinib demonstrated a high ORR with promising PFS; however, most patients with BRAFV600E-mutated metastatic PTC required a dose reduction.
    Journal • Metastases
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF V600E • BRAF V600
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib)
    1m
    NCI-2020-03273: Testing Trametinib and Dabrafenib as a Potential Targeted Treatment in Cancers With BRAF Genetic Changes (MATCH-Subprotocol H) (clinicaltrials.gov)
    P2, N=35, Active, not recruiting, National Cancer Institute (NCI)
    Trial completion date
    |
    BRAF V600E • BRAF V600 • BRAF V600K • BRAF V600R • BRAF V600D
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib)
    1m
    First NGS-based companion diagnostic to aid in the selection of targeted therapy for anaplastic thyroid cancer patients with BRAF V600E mutations (AACR 2024)
    On September 29, 2023, the FDA granted companion diagnostic approval to the Oncomineâ„¢ Dx Target Test (ODxT Test) as an aid in the selection of patients with BRAF V600E-mutated ATC who may be eligible for treatment with dabrafenib in combination with trametinib. The ODxT Test was shown to be effective in identifying BRAF V600E mutations in ATC patients through a clinical concordance study using specimens from patients enrolled in the ROAR trial and commercially-sourced samples. The results support the expanded indication to the ODxT Test and marks the first FDA-approved NGS-based companion diagnostic for patients with BRAF V600E-mutated ATC.
    Clinical • Next-generation sequencing • Companion diagnostic
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF V600E • BRAF V600
    |
    THXID® BRAF Kit • Oncomine™ Dx Target Test
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib)
    1m
    Next-generation sequencing for pediatric CNS tumors: does it add value in a middle-income country setup? (PubMed, Front Oncol)
    Nine patients received targeted therapy; dabrafenib/trametinib (6), pembrolizumab (2), and entrectinib (1), mostly upon tumor progression (7). Outsourcing of NGS testing was feasible; however, criteria for case selection are needed. In addition, local capacity-building in conducting the test, interpretation of the results, and access to "new drugs" continue to be a challenge in LMICs.
    Journal • PD(L)-1 Biomarker • Next-generation sequencing
    |
    BRAF (B-raf proto-oncogene) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • NTRK (Neurotrophic receptor tyrosine kinase) • STAT6 (Signal transducer and activator of transcription 6) • NAB2 (NGFI-A Binding Protein 2)
    |
    BRAF mutation • BRAF K601E • BRAF G469A • BRAF K601
    |
    TruSight RNA Pan-Cancer Panel
    |
    Keytruda (pembrolizumab) • Mekinist (trametinib) • Tafinlar (dabrafenib) • Rozlytrek (entrectinib)
    2ms
    Serial Measurements of Molecular and Architectural Responses to Therapy (SMMART) PRIME Trial (clinicaltrials.gov)
    P1, N=2, Terminated, OHSU Knight Cancer Institute | Active, not recruiting --> Terminated; Low accrual
    Trial termination
    |
    Keytruda (pembrolizumab) • Opdivo (nivolumab) • Avastin (bevacizumab) • Venclexta (venetoclax) • Lynparza (olaparib) • Mekinist (trametinib) • erlotinib • Gilotrif (afatinib) • Yervoy (ipilimumab) • Ibrance (palbociclib) • dasatinib • Zelboraf (vemurafenib) • Tafinlar (dabrafenib) • carboplatin • Imfinzi (durvalumab) • sorafenib • Rozlytrek (entrectinib) • imatinib • Sutent (sunitinib) • everolimus • Nerlynx (neratinib) • Iclusig (ponatinib) • Kadcyla (ado-trastuzumab emtansine) • Cotellic (cobimetinib) • Lorbrena (lorlatinib) • Lenvima (lenvatinib) • bortezomib • doxorubicin hydrochloride • capecitabine • Verzenio (abemaciclib) • Xtandi (enzalutamide capsule) • Cabometyx (cabozantinib tablet) • albumin-bound paclitaxel • Stivarga (regorafenib) • abiraterone acetate • oxaliplatin • Aliqopa (copanlisib) • Vizimpro (dacomitinib) • Zydelig (idelalisib) • daunorubicin • Zolinza (vorinostat) • Idhifa (enasidenib) • Farydak (panobinostat) • Erivedge (vismodegib) • Nubeqa (darolutamide) • bicalutamide • leucovorin calcium • cabazitaxel • Vesanoid (tretinoin) • fluorouracil topical
    2ms
    Dabrafenib alters MDSC differentiation and function by activation of GCN2. (PubMed, Cancer Res Commun)
    In vivo, we observed a pronounced reduction in PMN-MDSCs in dabrafenib-treated tumor-bearing mice suggesting that dabrafenib impacts MDSC populations systemically and locally, in the tumor immune infiltrate. Thus, our data reveals transcriptional networks that govern MDSC developmental programs, and the impact of GCN2 stress signaling on the innate immune landscape in tumors, providing novel insight into potentially beneficial off target effects of dabrafenib.
    Journal
    |
    ZBTB7A (Zinc finger and BTB domain containing 7A)
    |
    Tafinlar (dabrafenib)
    2ms
    Special Drug Use-results Surveillance of Tafinlar/Mekinist (clinicaltrials.gov)
    P=N/A, N=90, Recruiting, Novartis Pharmaceuticals | Not yet recruiting --> Recruiting
    Enrollment open • Metastases
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib)
    2ms
    Exploration of Fenestration Decompression Combined With Dalafenib in the Treatment of BRAF Mutant Ameloblastoma (clinicaltrials.gov)
    P3, N=10, Not yet recruiting, Shandong University
    New P3 trial
    |
    Tafinlar (dabrafenib)
    2ms
    Special Drug Use-results Surveillance of Tafinlar/Mekinist (clinicaltrials.gov)
    P=N/A, N=90, Not yet recruiting, Novartis Pharmaceuticals
    New trial • Metastases
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib)
    2ms
    A Study of Select Drug Combinations in Adult Patients With Advanced/Metastatic BRAF V600 Colorectal Cancer (clinicaltrials.gov)
    P1, N=122, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: May 2024 --> Sep 2024 | Trial primary completion date: May 2024 --> Sep 2024
    Trial completion date • Trial primary completion date • Metastases
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF mutation • BRAF V600
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib) • Tevimbra (tislelizumab) • spartalizumab (PDR001) • naporafenib (ERAS-254) • batoprotafib (TNO155) • rineterkib (LTT462)
    2ms
    Clinical Trial of Phenformin in Combination With BRAF Inhibitor + MEK Inhibitor for Patients With BRAF-mutated Melanoma (clinicaltrials.gov)
    P1; Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025
    Combination therapy • Trial completion date • Trial primary completion date
    |
    BRAF V600E • BRAF V600 • BRAF V600K • BRAF V600E + BRAF V600K • BRAF exon 11 mutation • BRAF exon 15 mutation
    |
    MSK-IMPACT
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib) • phenformin
    2ms
    Combi-Neo: Dabrafenib and Trametinib Before and After Surgery in Treating Patients With Stage IIIB-C Melanoma With BRAF V600 Mutation (clinicaltrials.gov)
    P2, N=58, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Apr 2024 --> Apr 2025 | Trial primary completion date: Apr 2024 --> Apr 2025
    Trial completion date • Trial primary completion date • Surgery
    |
    BRAF V600E • BRAF V600K
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib)
    2ms
    JSI-1187-01 Monotherapy and in Combination With Dabrafenib for Advanced Solid Tumors With MAPK Pathway Mutations (clinicaltrials.gov)
    P1, N=71, Suspended, JS InnoPharm, LLC | N=124 --> 71 | Trial primary completion date: Dec 2023 --> Jun 2024
    Enrollment change • Trial primary completion date • Combination therapy • Metastases
    |
    MAP2K1 (Mitogen-activated protein kinase kinase 1) • NF1 (Neurofibromin 1) • RASA1 (RAS P21 Protein Activator 1)
    |
    BRAF V600E • BRAF V600K
    |
    Tafinlar (dabrafenib) • JSI-1187
    2ms
    The safety and efficacy of dabrafenib and trametinib in patients with glioma: A systematic review and meta-analysis. (PubMed, Eur J Clin Pharmacol)
    Dabrafenib and trametinib demonstrate promising anti-tumor efficacy in gliomas, particularly low-grade tumors, achieving durable disease stabilization in many patients. However, toxicity significantly limited tolerability. Additional research should further examine efficacy and refine safe administration protocols across glioma subtypes.
    Retrospective data • Review • Journal
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF mutation • BRAF V600
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib)
    2ms
    Dabrafenib and trametinib administration in patients with BRAF V600E/R or non-V600 BRAF mutated advanced solid tumours (BELIEVE, NCCH1901): a multicentre, open-label, and single-arm phase II trial. (PubMed, EClinicalMedicine)
    Dabrafenib and trametinib would offer a new therapeutic option for rare cancers, such as high-grade gliomas, biliary tract cancer, and thyroid cancer. This study was funded by the Japan Agency for Medical Research and Development (22ck0106622h0003) and a Health and Labour Sciences Research Grant (19EA1008).
    P2 data • Journal • Metastases
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF V600E • BRAF V600R • BRAF G466A
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib)
    2ms
    Thyroid Cancer: A Review. (PubMed, JAMA)
    For metastatic disease, surgical resection or stereotactic body irradiation is favored over systemic therapy (eg, lenvatinib, dabrafenib). Antiangiogenic multikinase inhibitors (eg, sorafenib, lenvatinib, cabozantinib) are approved for thyroid cancer that does not respond to radioactive iodine, with response rates 12% to 65%. Targeted therapies such as dabrafenib and selpercatinib are directed to genetic mutations (BRAF, RET, NTRK, MEK) that give rise to thyroid cancer and are used in patients with advanced thyroid carcinoma...Radioactive iodine treatment after surgery improves overall survival in patients at high risk of recurrence. Antiangiogenic multikinase inhibitors and targeted therapies to genetic mutations that give rise to thyroid cancer are increasingly used in the treatment of metastatic disease.
    Review • Journal
    |
    BRAF (B-raf proto-oncogene) • NTRK (Neurotrophic receptor tyrosine kinase)
    |
    BRAF mutation • RET mutation
    |
    Tafinlar (dabrafenib) • sorafenib • Lenvima (lenvatinib) • Cabometyx (cabozantinib tablet) • Retevmo (selpercatinib)
    3ms
    LOGGIC/FIREFLY-2: a phase 3, randomized trial of tovorafenib vs. chemotherapy in pediatric and young adult patients with newly diagnosed low-grade glioma harboring an activating RAF alteration. (PubMed, BMC Cancer)
    The promising tovorafenib activity data, CNS-penetration properties, strong scientific rationale combined with the manageable tolerability and safety profile seen in patients with pLGG led to the SIOPe-BTG-LGG working group to nominate tovorafenib for comparison with SoC chemotherapy in this first-line phase 3 trial. The efficacy, safety, and functional response data generated from the trial may define a new SoC treatment for newly diagnosed pLGG.
    P3 data • Journal
    |
    KIAA1549
    |
    BRAF V600E • BRAF V600 • KIAA1549-BRAF fusion • BRAF fusion
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib) • tovorafenib (DAY101)
    3ms
    Design, Virtual Screening, Molecular Docking, ADME and Cytotoxicity Studies of 1,3,5-Triazine Containing Heterocyclic Scaffolds as Selective BRAF Monomeric, Homo and Heterodimeric Inhibitors. (PubMed, Comb Chem High Throughput Screen)
    It was identified that top-hit molecules had better binding and interaction activity than standard in all three classes of mutants.
    Journal
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF mutation
    |
    Zelboraf (vemurafenib) • Tafinlar (dabrafenib) • sorafenib • Braftovi (encorafenib)
    3ms
    BRAF - a tumour-agnostic drug target with lineage-specific dependencies. (PubMed, Nat Rev Clin Oncol)
    In June 2022, the FDA granted Accelerated Approval to the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib for the treatment of adult and paediatric patients (≥6 years of age) with unresectable or metastatic BRAF-mutant solid tumours, except for BRAF-mutant colorectal cancers. In this Review, we describe the biochemical basis for oncogenic BRAF-induced activation of MAPK signalling and pan-cancer and lineage-specific mechanisms of intrinsic, adaptive and acquired resistance to BRAF inhibitors. We also discuss novel RAF inhibitors and drug combinations designed to delay the emergence of treatment resistance and/or expand the population of patients with BRAF-mutant cancers who benefit from molecularly targeted therapies.
    Review • Journal • Pan tumor
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF mutation
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib)
    3ms
    Efficacy and safety of 'Second Adjuvant' therapy with BRAF/MEK inhibitors after local therapy for recurrent melanoma following adjuvant PD-1 based immunotherapy. (PubMed, Eur J Cancer)
    This is the first study examining outcomes of 'second adjuvant' targeted therapy for melanoma, after failure of adjuvant PD-1 based immunotherapy. Data suggest a short-term improvement in RFS, but at the cost of toxicity. Alternative strategies and more data on sequencing adjuvant therapies are required to improve outcomes.
    Journal • PD(L)-1 Biomarker • IO biomarker
    |
    BRAF (B-raf proto-oncogene)
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib)
    3ms
    Dabrafenib plus Trametinib: A breakthrough in pediatric low-grade glioma therapy. (PubMed, Health Sci Rep)
    A multicenter Phase I/II trial demonstrated the superior efficacy of dabrafenib plus trametinib (D+T) compared to carboplatin plus vincristine (C+T), with higher overall response rates, clinical benefit rates, and longer progression-free survival. The safety profile of dabrafenib plus trametinib (D+T) was favorable, with fewer discontinuations and adverse events compared to the control group. The introduction of D+T as a targeted therapy represents a significant advancement in the management of pLGG, necessitating further investigations to understand its long-term consequences and optimize patient care.
    Journal
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF V600E • BRAF V600
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib) • carboplatin • vincristine
    3ms
    Tyrosine Kinase Inhibitors for Radioactive Iodine Refractory Differentiated Thyroid Cancer. (PubMed, Life (Basel))
    Currently, Lenvatinib and Sorafenib, multitargeted TKIs, represent the standard first-line systemic treatment options for RAIR thyroid carcinoma, while Cabozantinib is the standard second-line treatment option. Furthermore, targeted therapies for patients with specific targetable molecular abnormalities include Latrectinib or Entrectinib for patients with NTRK gene fusions and Selpercatinib or Pralsetinib for patients with RET gene fusions. Dabrafenib plus Trametinib currently only have tumor agnostic approval in the USA for patients with BRAF V600E mutations, including thyroid cancer. Redifferentiation therapy is an area of active research, with promising initial results, while immunotherapy studies with checkpoint inhibitors in combination with tyrosine kinase inhibitors are underway.
    Review • Journal • IO biomarker
    |
    BRAF (B-raf proto-oncogene) • RET (Ret Proto-Oncogene) • NTRK (Neurotrophic receptor tyrosine kinase)
    |
    BRAF V600E • BRAF V600 • RET fusion • NTRK fusion
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib) • sorafenib • Rozlytrek (entrectinib) • Lenvima (lenvatinib) • Cabometyx (cabozantinib tablet) • Retevmo (selpercatinib) • Gavreto (pralsetinib)
    3ms
    Metabolic Imaging Biomarkers of Response to Signaling Inhibition Therapy in Melanoma. (PubMed, Cancers (Basel))
    Notably, our noninvasive assessment of the metabolic status of the human melanoma xenografts by H/P MRS demonstrated early metabolite changes preceding therapy response (i.e., tumor shrinkage). Therefore, this noninvasive methodology could be translated to assess in vivo predictive metabolic biomarkers of response in melanoma patients under dabrafenib and probably other signaling inhibition therapies.
    Journal
    |
    BRAF (B-raf proto-oncogene)
    |
    BRAF mutation
    |
    Tafinlar (dabrafenib)
    3ms
    Significant and Various Effects of ML329-Induced MITF Suppression in the Melanoma Cell Line. (PubMed, Cancers (Basel))
    To study the inhibitory effects on microphthalmia-associated transcription factor (MITF)-related biological aspects in malignant melanomas (MMs) in the presence or absence of the low-molecular MITF specific inhibitor ML329, cell viability, cellular metabolic functions, and three-dimensional (3D) spheroid formation efficacy were compared among MM cell lines including SK-mel-24, A375, dabrafenib- and trametinib-resistant A375 (A375DT), and WM266-4. Furthermore, the mRNA expression levels of selected genes, including STAT3 as a possible regulator of 3D spheroid formation, KRAS and SOX2 as oncogenic-signaling-related factors, PCG1a as the main regulator of mitochondrial biogenesis, and HIF1a as a major hypoxia transcriptional regulator, fluctuated among the MM cell lines, possibly supporting the diverse ML329 effects mentioned above. The findings of diverse ML329 effects on various MM cell lines suggest that MITF-associated biological activities are different among various types of MM.
    Preclinical • Journal
    |
    KRAS (KRAS proto-oncogene GTPase) • HIF1A (Hypoxia inducible factor 1, alpha subunit) • STAT3 (Signal Transducer And Activator Of Transcription 3) • SOX2 • MITF (Melanocyte Inducing Transcription Factor)
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib)