avutometinib + defactinib + encorafenib

This combination therapy consists of **avutometinib** (a dual RAF/MEK inhibitor), **defactinib** (a focal adhesion kinase [FAK] inhibitor), and **encorafenib** (a BRAF inhibitor). It is being investigated in the Phase 1b/2 **DETERMINE** trial (NCT06194929) led by the University of Utah's Huntsman Cancer Institute in collaboration with Verastem Oncology. The regimen targets advanced cutaneous melanoma with brain metastases, particularly in patients who have progressed on immune checkpoint inhibitors. By simultaneously inhibiting the MAPK pathway (via RAF/MEK/BRAF) and FAK, the combination aims to overcome resistance mechanisms and improve intracranial efficacy. Avutometinib provides a unique dual blockade of RAF and MEK, while defactinib targets FAK signaling, which is often upregulated in resistant tumors and contributes to the survival of melanoma cells in the brain microenvironment.

Brand names

Braftovi

Other names

DETERMINE trial regimenRAF/MEK/FAK inhibitor combination