P1, N=36, Not yet recruiting, SpringWorks Therapeutics, Inc.

Trametinib is useful in NRAS-driven leptomeningeal melanoma in children, but not sufficient to prevent relapse, and can be helpful in NRAS-driven leptomeningeal dysplasia. It is very helpful symptomatically in BRAF fusion-driven cutaneous disease, where a reduced dose after initial response appears to sustain efficacy and reduce adverse effects.

P2, N=20, Not yet recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2027 --> Feb 2030 | Trial primary completion date: Dec 2027 --> Feb 2030

This exploratory analysis suggests pERK expression and mutation of KRAS/BRAF/NRAS are candidate biomarkers of improved PFS and response to trametinib, respectively.

The cooperative GOG 281/LOGS trial showed that trametinib, an MEK inhibitor (MEKi), was significantly more effective than standard-of-care options (including chemotherapy or hormonal therapy) in increasing progression-free survival (median PFS 13.0 months vs. 7.2 months; hazard ratio 0.48, p < 0.001)...Genomic and multi-omic profiling have revealed actionable vulnerabilities and precision oncology approaches. The advent of biomarker-directed trials, molecular subtyping incorporation, and innovative computational strategies is likely to gradually ameliorate therapy selection and, thereby, finally improve long-term outcomes for patients with this complex disease.

The proteasome inhibitor MG132 confirmed that fisetin accelerates β-catenin and MITF degradation. Additionally, inhibition of the PI3K/AKT pathway by LY294002 or the ERK pathway by PD98059 reversed fisetin's reduction of tyrosinase activity and melanin synthesis, further verifying the participation of these pathways. Computational docking integrated with deep learning-based CNN scoring revealed that fisetin interacts with PKCα, β-catenin, tyrosinase, and TYRP1. Collectively, these findings suggest that fisetin exerts multi-targeted inhibitory effects on melanogenesis, highlighting its potential as a therapeutic and cosmetic agent for hyperpigmentation.

MEK inhibition with trametinib resulted in similar, yet more pronounced effects. Thus, our findings provide novel insights into NRAS-mediated signaling through nanoscale clusters and underscore their potential as therapeutic targets.

P2, N=20, Not yet recruiting, National Cancer Institute (NCI) | Initiation date: Oct 2025 --> Jan 2026

P2, N=200, Completed, Melanoma Institute Australia | Active, not recruiting --> Completed | N=1000 --> 200 | Trial completion date: Dec 2028 --> Dec 2025

In here we report a case of a female patient who developed LMD from a Pleomorphic Xanthoastrocytoma (PXA), BRAFV600-mutated, who has shown successful response to treatment with BRAF/MEKi (Encorafinib/Binimetinib) for over 3 years since initial LMD diagnosis. The effectiveness of therapy in this patient was initially observed as stable disease, with radiographic progression when BRAF/MEKi were withheld, and immediate tumor control achieved when reinstated. Despite being just one case, this hopefully could serve as proof-of-concept for use of targeted therapy for BRAF V600E-mutated tumors with LMD progression, sparing patients from alternative tumor control options such as radiation therapy.

This pan-cancer study elucidates the pivotal role of ENTPD6 in tumor progression and establishes its potential as a therapeutic target for immunotherapeutic approaches in specific malignancies.

The patient was initially diagnosed with T4bN1bM1 and experienced disease progression following surgery and lenvatinib treatment. This possibility is supported by reliable evidence for the use of BRAF plus MEK inhibitor for brain metastasis from BRAF-mutated malignant melanoma. We conclude that encorafenib plus binimetinib treatment for brain metastasis from BRAF-mutated thyroid cancer is a safe and effective treatment choice.