P1, N=104, Completed, Royal Marsden NHS Foundation Trust | Active, not recruiting --> Completed | Trial completion date: Jun 2025 --> Oct 2025 | Trial primary completion date: Jun 2025 --> Oct 2025

P2, N=40, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Mar 2026 --> Mar 2027 | Trial primary completion date: Mar 2026 --> Mar 2027

P1/2, N=16, Active, not recruiting, National Cancer Institute (NCI) | N=58 --> 16 | Trial completion date: Nov 2025 --> Jan 2027

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

Using a panel of BRAFV600E positive YUMM lines, we find that, following chronic vemurafenib treatment, SOX10 is lost whereas SOX9 is induced...Overall, our data show that the loss of SOX10 and SOX9 induction are critical to program drug resistance. Furthermore, we show that the YUMM cell lines represent a good murine model to investigate transitions to an acquired drug resistant state.

The oral drug combination was well tolerated with no dose-limiting toxicity or need for dose reduction over the 4 year period. The Avutometinib and Defactinib combination may represent a new standard treatment option for platinum-resistant and AI-resistant/recurrent LGSOC who have failed other MEKi.

Glioblastoma (GBM) is the most lethal brain tumor, characterized by strong resistance to conventional therapies. Furthermore, vemurafenib, which targets FOSL1, was identified as a potential therapeutic agent against TMZ-resistant GBM in a mouse model. These findings suggest that FOSL1 promotes TMZ chemoresistance by regulating IL-6-pSTAT3Tyr705-mediated stemness in GBM cells, making it a promising therapeutic target to overcome chemoresistance in GBM.

The greatest benefits of encorafenib plus binimetinib were observed in patients with evidence of high TMB and/or tumor immune infiltration, suggesting potential immune contributions to efficacy, which were not observed with vemurafenib. BRAF V600 detectability in ctDNA appears to have utility as a marker of prognosis and response in this population.

P1/2, N=75, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2025 --> Dec 2027 | Trial primary completion date: Dec 2025 --> Dec 2027

P1/2, N=153, Active, not recruiting, Verastem, Inc. | Recruiting --> Active, not recruiting | Trial primary completion date: Sep 2025 --> Jun 2026

These three compounds were also tested on the vemurafenib-resistant (A375R) and normal (HaCaT and MRC-5) cell lines, and compound 8 showed better cytotoxicity (IC50 = 8.84 ± 1.24 µM) and selectivity (>3.50) when compared to telmisartan (IC50 = 29.23 ± 3.88, selectivity > 2.40). All three compounds induced cell cycle arrest and disrupted mitochondrial morphology and membrane potential. These findings highlight their potential as non-antihypertensive telmisartan derivatives for melanoma therapy.

Data from this study provides provocative evidence that, while BRAF+/-MEK inhibitor therapy produces an increase in overall and clonal T cell infiltrates, there is limited evidence for generation of new or persistent tumor immunity. Thus, BRAFi/MEKi therapy may enable tumor-reactive T cells to infiltrate tumors but tumor control does not appear to depend on priming new immune responses.