Mekinist (trametinib)

Finally, the combination of trametinib with paclitaxel exhibited significant inhibition of tumor growth in several KRAS-mutant patient-derived xenograft mouse models. Our data provide evidence supporting clinical trials of trametinib with paclitaxel as a novel therapeutic option for patients with KRAS-mutated, metastatic CRC.

This is a case showing improvement of a craniopharyngioma after treatment with BRAF and MEK inhibitor combinations. The role of BRAF and MEK inhibitor combinations continues to evolve in this space.

P1/2, N=58, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Nov 2025 | Trial primary completion date: Dec 2024 --> Nov 2025

P1/2, N=325, Completed, Bristol-Myers Squibb | Active, not recruiting --> Completed

Gliomas are tumors arising in the central nervous system, frequently associated with Class I mutations and BRAF fusions. Further research into resistance mechanisms and long-term effects is necessary to optimize treatment strategies. Other therapies, such as everolimus and Selumetinib, also show potential and warrant further investigation.

P2, N=120, Recruiting, Sun Yat-sen University | Not yet recruiting --> Recruiting

No abstract available

P1, N=27, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Oct 2024 --> Jan 2025

P2/3, N=260, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2024 --> Oct 2025

To our knowledge, this is the largest retrospective cohort of BRAF-mutated patients reported. The findings confirmed the significant efficacy of D-T in combination with BRAF V600E-mutated metastatic NSCLC in pretreated and untreated patients. These results under real-world conditions are consistent with those of other registered studies.

P1/2, N=27, Recruiting, Ann & Robert H Lurie Children's Hospital of Chicago

P2, N=16, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting

Dabrafenib plus trametinib is associated with favorable outcomes in gliomas, especially among those with lower age, BRAF V600 mutation, longer dual blockage treatment duration, and history of prior resection. The co-administration of dabrafenib and trametinib was associated with more favorable outcomes among LGGs than HGGs.

The patient demonstrated significant improvement in chylothorax and left ventricular hypertrophy, though pulmonary stenosis persisted. This case further confirms trametinib's potential as a therapeutic option for severe Noonan syndrome complications, emphasizing the need for further clinical trials to optimize treatment protocols and evaluate long-term outcomes.

Finally, according to our model and computational drug sensitivity analysis, four small molecule compounds, BMS-754807, SB216763, Doramapimod, and Trametinib, were identified as potential therapeutic agents for patients with MCL. This study provides a prognostic model with ferroptosis-related gene signature for MCL. The results show that the model helps predict prognosis in MCL.

Combined administration with KRAS siRNA, MEK1/2 inhibitor trametinib, and NF-κB inhibitor dimethyl fumarate (DMF), suppressed L-OHP- and 5-FU-induced EMT. These results suggest that KRAS/ERK/NF-κB pathway activation is important for EMT induction by L-OHP and 5-FU treatment. Thus, MEK1/2 and NF-κB inhibitors may facilitate the resistance acquisition to L-OHP and 5-FU therapy in KRAS G13D-mutated colon cancer.

This review provides a comprehensive overview of the current state of BRAF-targeted therapies in melanoma, highlighting the efficacy and limitations of FDA-approved combinations of BRAF and MEK inhibitors such as vemurafenib, dabrafenib, trametinib, and cobimetinib...Recent studies on regorafenib, ERK5 signaling, and CD73 inhibition are highlighted as novel strategies to overcome resistance and improve treatment outcomes. The review also delves into the role of advanced therapeutic tools, such as mRNA vaccines and CRISPR-Cas9, in revolutionizing personalized oncology by targeting specific genetic mutations and enhancing immune responses against melanoma. The ongoing synergy between advancing research, targeted interventions, strategic treatment combinations, and cost-effectiveness evaluations offers a promising pathway to elevate patient outcomes in the persistent battle against melanoma significantly.

Furthermore, this model can serve as a valuable tool for guiding the use of trametinib. In summary, this study provides a comprehensive understanding of the interplay between M2 macrophages and cancer cells in glioma; utilizes a cross-talk gene signature to develop a predictive model that can predict the differentiation of patient prognosis, recurrence instances, and microenvironment characteristics; and aids in optimizing the application of trametinib in glioma patients.

Over 80% of patients remained relapse- and metastasis-free at 12 months after 2L dab/tram initiation, with only 2 deaths observed. Dab/tram appears to have activity in the 2L adjuvant setting, although more follow-up is required.

By using the novel PDX platform, the results presented in this study demonstrate that the treatments with Palbociclib or Dabrafenib/Trametinib significantly reduced tumor size. In conclusion, PDX models offer a deeper understanding of eGBM at the genomic level and facilitate the identification of potential therapeutic targets. Further translational studies of this novel PDX model hold promise for advancing the diagnosis and treatment of this specific subtype of glioblastoma.

P3, N=264, Recruiting, ECOG-ACRIN Cancer Research Group | Not yet recruiting --> Recruiting

Next, we used clinically available signal inhibitors (MEK inhibitor trametinib, JAK inhibitor ruxolitinib, and JNK inhibitor SP600125), and found that ruxolitinib inhibits AMIGO2 expression more stably. Using the MKN45 gastric cancer cells, we confirmed that ruxolitinib could prevent liver metastasis of human cancer cells. These results demonstrate that pharmacological inhibition of AMIGO2 expression in tumor cells is a promising novel strategy to prevent and control liver metastasis.

The cytotoxicity of trametinib (MEK inhibitor), DT2216 (BCL-xL degrader) and afatinib (pan-EGFR inhibitor) and their combination was tested in patient-derived, primary PDAC cells using a live cell imaging system. Pathway analysis revealed the addition of afatinib in triplet regimen further inhibited PI3K/AKT effectors of p90RSK, p70S6K, and GSK3α/β along with a secondary pathway of P38 MAPK. Our study identifies an important contribution of EGFR inhibition to elevate the response of PDAC, supporting a clinical assessment of this triplet combination in patients.

In addition, the high expression of model gene produced drug resistance to trametinib, selumetinib and RDEA119 (refametinib). The prognostic risk model based on six prognostic related DEGs is an independent prognostic factor of HCC, which can effectively predict the survival and prognosis of HCC patients.

P1/2, N=75, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

P1/2, N=74, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Jun 2025 --> Dec 2025 | Trial primary completion date: Apr 2025 --> Nov 2025

Interestingly, C2 was less effective in suppressing A375 and B16-F10 cell lines (LD50 C2 < LD50 Dabrafenib/control), with its LD50 value nearly matching that of the Trametinib control in B16-F10 cell lines. Consequently, GSCRE, especially C2 or Caulersin, shows promise as a new molecule for developing functional foods to combat aging and human melanoma. However, further in vivo studies and clinical trials are necessary to confirm these findings.

In addition, a PDX model with acquired resistance to osimertinib was induced, and the overactivation of RAS mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) signaling pathway caused by the dual-specificity phosphatase 6 (DUSP6) M62I mutation was found to play a key role in the development of osimertinib resistance. Trametinib, a specific inhibitor of the MAPK-ERK pathway significantly slowed down the tumor growth in osimertinib-resistant PDX models, providing an alternative treatment in patients after osimertinib failure.

Dabrafenib plus trametinib, as the first tumor-agnostic therapy, has been approved by the US Food and Drug Administration for the treatment of adult and pediatric patients aged 6 years and older harboring a BRAF V600E mutation with unresectable or metastatic solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. Therefore, we have established a universal and systematic strategy for diagnosing and treating solid tumors with BRAF mutations. In this expert consensus, we (1) summarize the epidemiology and clinical characteristics of BRAF mutations in different solid tumors, (2) provide recommendations for the selection of genetic testing methods and platforms, and (3) establish a universal strategy for the diagnosis and treatment of patients with solid tumors harboring BRAF mutations.

The combined application of ERK inhibitors, U0126 or trametinib, with the VEGFR inhibitor Apatinib, additively suppresses angiogenesis and tumor growth of HCC1806 in nude mice. These findings provide new therapeutic strategies for TNBC.

Finally, 4 KGs-guided repositioning candidate drugs (ZSTK474, GSK2126458, Masitinib, and Trametinib) were proposed. The stability of three top-ranked drug-target interactions (CAV1 vs. ZSTK474, CAV1 vs. GSK2126458, and ASPM vs. Trametinib) were investigated by computing their binding free energies for 140 ns MD-simulation based on MM-PBSA approach. Therefore, the findings of this computational study may be useful for early prognosis, diagnosis and therapies of NSCLC.

P1, N=122, Terminated, Novartis Pharmaceuticals | Trial completion date: Jan 2025 --> Sep 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Jan 2025 --> Sep 2024; The decision of early termination was made due to business reasons, and was not based on any safety concerns for any of the treatment combinations.

P1, N=46, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Nov 2024 --> Nov 2025

P1/2, N=27, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2024 --> Oct 2025

The tumor growth inhibitory rate was 99.36% for dabrafenib, trametinib, and osimertinib; 99.25% for osimertinib plus vemurafenib; 98.92% for osimertinib, encorafenib, and cetuximab; and 62.83% for pemetrexed plus carboplatin. NGS analysis identified major resistance mechanisms following the triple-targeted therapy, including the EGFR-dependent pathway, EGFR and BRAF V600E-dependent pathway, and an off-target mechanism. EGFR/BRAF/MEK triple-targeted therapy is an effective and safe approach for treating EGFR-mutated NSCLC patients resistant to EGFR-TKIs with acquired BRAF V600E mutations.

We selected 108 CLL patient samples with genetic annotation and exposed them ex-vivo to small-molecule inhibitors used clinically (ibrutinib/BTKi, duvelisib/PI3Ki, trametinib/MEKi, everolimus/mTORi, selinexor/XPO1i) or targeting key signaling pathways (compound 26/TLRi, MK2206/AKTi, nutlin-3a/MDM2i, IBET872/BETi) for 48h. In conclusion, the addition of targeted pathway perturbations to the GEP of primary CLL samples can greatly enhance the potential for molecular and functional classification of disease and subgroups. Our study provides a blueprint to use perturbed omics profiling and interaction testing to link disease drivers to pathway activation and function.

P3, N=300, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Jun 2025 | Trial primary completion date: Dec 2024 --> Jun 2025

Additionally, the transcriptomes of these cells were reprogrammed to become highly responsive to chemotherapy (cisplatin), targeted therapy (trametinib), and epigenetic therapy (vorinostat). SCARA5 and AOX1 DNA promoters were hypermethylated in NSCLC, and SCARA5 methylation was identified as an epigenetic biomarker in tumors and liquid biopsies from NSCLC patients. Thus, we demonstrate that co-targeting G9a/DNMT1 is a promising strategy to enhance the efficacy of cancer drugs, and SCARA5 methylation could serve as a non-invasive biomarker to monitor tumor progression.

They are increasingly important as targets for therapeutic intervention such as capivasertib-fulvestrant for HR+HER2- BC with PIK3CA/AKT1/PTEN alterations, or dabrafenib–trametinib for solid tumors with the BRAF V600E mutation. More than half of BC tumor samples had potentially actionable genomic alterations affecting either the PI3K/AKT or MAPK pathways. In HR+HER2- BC, actionable alterations in PIK3CA, AKT1, and PTEN were generally present independently rather than co-occurring. These findings support a comprehensive testing approach that interrogates a large number of genes to maximize the number of patients identified who might benefit from targeted therapies.

P2, N=20, Terminated, University of Zurich | Recruiting --> Terminated; too few patients could be included

P2, N=4, Terminated, M.D. Anderson Cancer Center | Completed --> Terminated; Study stopped due to slow enrollment

P2, N=10, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Oct 2025