In this review, we summarize the efficacy and safety of encorafenib plus binimetinib from the PHAROS study. In addition, we discuss strategies to manage adverse reactions with this combination therapy with the intent of minimizing unnecessary treatment discontinuations in these patients.

P1/2, N=53, Recruiting, University of Chicago | Trial completion date: Apr 2024 --> Aug 2025 | Trial primary completion date: Apr 2024 --> Aug 2025

P2, N=20, Recruiting, Memorial Sloan Kettering Cancer Center

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

Our finding demonstrate that single knockdown of Dsg2 or Dsc2 could promote proliferation, motility and invasion in triple-negative MDA-MB-231 and luminal MCF-7 cells. Nevertheless, the underlying mechanisms were cellular context-specific and distinct.

P3, N=921, Active, not recruiting, Pfizer | Trial completion date: Mar 2024 --> Jul 2024

Our study comprehensively analyzed metabolic gene expression and highlighted the importance of NOX4 in promoting CRC metastasis, suggesting that trametinib could be a potential therapeutic drugs of CRC clinical therapy targeting NOX4.

Our data demonstrate that Id1 expression is involved in the resistance to trametinib and in the synergistic effect of trametinib with anti-PD-1 therapy in KRAS-mutant LUAD tumors. These findings suggest a potential therapeutic approach for immunotherapy-refractory KRAS-mutant lung cancers.

P1, N=58, Active, not recruiting, AstraZeneca | Trial completion date: Dec 2023 --> Dec 2024

We identified potential therapeutic drugs, including the MEK inhibitor (PD-184352)...We identified a distinct LUAD GT gene signature, and these differentially expressed mRNAs could serve as valuable prognostic biomarkers and therapeutic targets. Furthermore, we experimentally validated their expression levels and identified potential therapeutic agents.

P1, N=33, Completed, Shanghai Chest Hospital | Recruiting --> Completed | Trial completion date: Aug 2023 --> Mar 2024 | Trial primary completion date: Jan 2023 --> Jul 2023

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.

P2, N=33, Not yet recruiting, M.D. Anderson Cancer Center

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

The RP2D binimetinib regimen had a safety profile similar to previous binimetinib studies or nivolumab and ipilimumab combination studies. There was a lack of clinical benefit with either drug combination. Therefore, these data do not support further development of binimetinib in combination with nivolumab or nivolumab and ipilimumab in RAS-mutated MSS mCRC.

We found that Trametinib has a lower IC50 than Gemcitabine in PDAC cell lines. The study shows Trametinib has a critical inhibitory effect on PDAC. Besides, the combination of Trametinib with Palbociclib can inhibit the proliferation of PDAC-resistant cells.

Furthermore, D-mannose treatment dramatically improves the therapeutic efficacy of MEK inhibitor (MEKi) trametinib in vivo. Our findings unveil a universally unrecognized anti-tumor mechanism of D-mannose by destabilizing PD-1 and provide strategies to enhance the efficacy of both immune checkpoint blockade (ICB) and MEKi -based therapies.

This work proves the usefulness of FRET imaging protocols on both live and fixed Teen ERK reporter fish to readily monitor and quantify pharmacologically- and genetically-induced ERK activity modulations in early embryos, representing a useful tool in pre-clinical applications targeting RAS-MAPK signaling.

Drug synergy was seen using trametinib and rapamycin in combination with entrectinib.

P2, N=10, Recruiting, Saint Petersburg State University, Russia

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.

The obtained results require validation on a larger group of patients. If the results are confirmed, the indicated lncRNAs may play an important role as diagnostic and prognostic markers.

P=N/A, N=150, Not yet recruiting, AstraZeneca

P2, N=15, Active, not recruiting, Region Skane | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Jul 2023 --> Jul 2024

P=N/A, N=40, Recruiting, Novartis Pharmaceuticals | Not yet recruiting --> Recruiting | Trial primary completion date: Oct 2027 --> Feb 2028

P=N/A, N=80, Recruiting, Novartis Pharmaceuticals | Trial completion date: Dec 2026 --> Jul 2029 | Trial primary completion date: Dec 2026 --> Jul 2029

P3, N=569, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Mar 2024 --> Aug 2024

P1, N=26, Completed, City of Hope Medical Center | Active, not recruiting --> Completed | Trial completion date: Dec 2023 --> Jul 2023 | Trial primary completion date: Dec 2023 --> Jul 2023

Treatment with N-acetyl-cysteine (antioxidant) or PD98059 (ERK inhibitor) partly reverted the CBD-induced autophagy/ferroptosis by decreasing the activation of ERK and the production of ROS. Overall, CBD induced autophagy and ferroptosis through the activation of ERK and generation of ROS in GBM cells.

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.

P2, N=53, Active, not recruiting, National Cancer Institute (NCI)

P2, N=35, Active, not recruiting, National Cancer Institute (NCI)

P2, N=60, Active, not recruiting, National Cancer Institute (NCI)

Here, we showed that CD9- BCP-ALL cells were preferentially resistant to prednisone and dexamethasone over other standard cytotoxic agents. Importantly, the MEK inhibitor trametinib exhibited higher synergy with GCs against CD9- than CD9+ lymphoblasts to reverse drug resistance in vitro and in vivo. Collectively, our results elucidate a previously unrecognized regulatory function of CD9 in GC sensitivity, and inform new strategies for management of children with resistant BCP-ALL.

No abstract available

P1/2, N=14, Completed, Great Ormond Street Hospital for Children NHS Foundation Trust | Recruiting --> Completed | N=30 --> 14 | Trial primary completion date: Aug 2023 --> Feb 2024

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.

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.

We tracked ERV activation to the early induction of the transcription factor ELF3, which extensively bound and activated nonsilenced retroelements and synergized with IRF1 (interferon regulatory factor 1) in the activation of IFNs and IFN-stimulated genes. Trametinib-induced viral mimicry in PDAC may be exploited in the rational design of combination therapies in immuno-oncology.

Adverse events of ALK and MEK inhibitors differ from the more common adverse events experienced with conventional treatment modalities used in pediatric oncology. It is important for nurses to include information regarding potential adverse events in patient/family education for children receiving these targeted agents.

P=N/A, N=90, Completed, Novartis Pharmaceuticals

Successful management involved tailored approaches, such as clindamycin for acneiform rash and topical agents for paronychia. AEs might indirectly determine pNF regrowth due to therapy suspension. We thus emphasize the pivotal role of addressing cutaneous reactions for effective selumetinib management in pediatric patients.