Zelboraf (vemurafenib)

P2, N=720, Recruiting, Canadian Cancer Trials Group | Trial primary completion date: Jan 2026 --> Dec 2026

The lack of clinical efficacy may be due to inadequate inhibition of RAS-to-ERK signaling as toxicities necessitated dose reduction. NCT05068752.

Therefore, this study aimed to examine the protein composition of the secretome of cells resistant to vemurafenib (a BRAF inhibitor) and cobimetinib (a MEK inhibitor) and to compare it with that of nonresistant cells. Proteins secreted by resistant melanoma cells can undoubtedly influence the surrounding microenvironment in a way that promotes the formation of a pro-tumor niche. Among the proteins secreted in significantly higher amounts by resistant cells (compared to the control group), which may be potential biomarkers or therapeutic targets in melanoma, plasminogen activator inhibitor 1, thymosin beta-4, clusterin, interleukin-6, superoxide dismutase, and selected matrix metalloproteinases can be distinguished.

P1, N=18, Not yet recruiting, Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

P2, N=30, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jan 2026 --> Jan 2027 | Trial primary completion date: Jan 2026 --> Jan 2027

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.

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.

P2, N=1376, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: May 2026 --> Jan 2027

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.

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.

In conclusion, our case highlights that the primary diagnostic clue for ECD may be a single yellowish plaque, which requires further investigation in relation to other systemic symptoms. Vemurafenib treatment may lead to regression of systemic symptoms and cutaneous yellowish plaques associated with ECD carrying a BRAF mutation.