Mekinist (trametinib)

P1, N=25, Terminated, University of Utah | Trial completion date: Mar 2029 --> Aug 2025 | Active, not recruiting --> Terminated; Lack of Funding

VT103 consistently synergized with inhibitors of MEK (trametinib and selumetinib), SHP2 (TNO155) and mTOR (everolimus). The highest synergy ZIP score, calculated using SynergyFinder, was ~65 in the NF2 -SWN cell line SC4, with lower magnitudes in an NF1 cell line.

This case illustrates the histological heterogeneity and hybrid nature of MH, where canonical dendritic LCH cells coexist with macrophage-rich ECD-like infiltrate. An integrated approach involving a multidisciplinary clinical team, thorough molecular genetic testing, and the application of targeted therapy is essential for improving prognosis and quality of life in young patients.

Commercial cell lines showed promising viability reduction similar to prior laboratory results with treatments, including 5-μM darovasertib, 700-nM selumetinib, 700-nM selumetinib + 1000-nM MK-2206, 500-nM sotrastaurin + 1000-nM alpelisib, and 100-nM trametinib, with overall viability reduced to 32.5% for all drugs. PDLs and PDOs may more accurately represent uveal melanoma clinical response. Demonstrating efficacy of novel therapeutics in these models could improve the likelihood of successful translation for future clinical trials, but future studies are needed to define clinically meaningful in-vitro response thresholds.

In contrast, macrophage-conditioned medium had little effect on regorafenib and increased sensitivity to dabrafenib, suggesting that resistance depends on the inhibitory profile of each drug. The multi-kinase inhibitor masitinib-which targets several kinases along this resistance network-strongly restored sensitivity to trametinib and RMC-6236. Together, these data define a macrophage-driven resistance network in KRAS-mutant colorectal cancer organoids and support combined inhibition of RAS-pathway and tyrosine kinase signalling.

P1/2, N=30, Active, not recruiting, Medical Center - University Of Freiburg | Recruiting --> Active, not recruiting

Given her advanced age and frailty, she was treated with a first-line combination of pembrolizumab, dabrafenib, and trametinib. She achieved a radiographic complete response (CR) and has remained progression-free for over 26 months. This case highlights the potential synergy between MAPK pathway inhibition and immunotherapy, suggesting that even short-course targeted therapy may favorably remodel the tumor microenvironment to enable durable disease control in high-risk MSI-H/BRAF-mutant mCRC.

P4, N=165, Recruiting, Novartis Pharmaceuticals | Active, not recruiting --> Recruiting

Treatment with combined BRAF and MEK inhibition (dabrafenib and trametinib) resulted in a clinical response. In addition to this index case, a literature review identified multiple additional SS harboring BRAF V600E, supporting its role as a recurrent, potentially targetable alteration in a small subset of SS. These findings highlight the value of comprehensive genomic profiling in SS, particularly in advanced or refractory cases, to identify rare but actionable molecular events that may expand therapeutic options.

Here, we present two patients with BRAF p.V600E-mutant PCP who achieved exceptional tumor volume reductions of 95% and 98% following targeted therapy with dabrafenib and trametinib. Notably, Case 1 maintained the negative mutation status and did not experience recurrence during the 9-month follow-up period. These findings demonstrate that digital polymerase chain reaction-based monitoring of CSF-derived cfDNA is a sensitive and objective tool for assessing molecular response in PCP, reflecting the real-time efficacy of targeted treatment and providing a framework for individualized management and early detection of recurrence in precision neurooncology.

In this small single-center retrospective cohort, trametinib was associated with favorable short-term outcomes in all patients, and serial HistioTrak testing appeared feasible in selected patients. Prospective studies are needed before routine diagnostic or monitoring use can be recommended.

This study identified uric acid-related genes as potential independent indicators of clinical outcomes in glioblastoma progression. A novel prognostic UARG-associated signature was developed and validated, which showed potential in predicting GBM patient outcomes.