VS-6766 is a unique inhibitor of the RAS/RAF/MEK/ERK signaling pathway. In contrast to other MEK inhibitors in development, VS-6766 is a dual RAF/MEK inhibitor that blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK. MEK-only inhibitors (e.g. PD0325901) paradoxically induce MEK phosphorylation (pMEK) by relieving ERK-dependent feedback inhibition of RAF which may limit their efficacy. By inhibiting RAF-mediated phosphorylation of MEK, VS-6766 has the advantage of not inducing pMEK. This unique mechanism of VS-6766 enables more effective inhibition of ERK signaling and may confer enhanced therapeutic activity against ERK-dependent, RAS or BRAF mutant tumors.1

VS-6766 has been shown to inhibit signaling and proliferation of tumor cell lines with a variety of KRAS, HRAS, or BRAF mutations.1 VS-6766 has also been shown to synergize with G12C inhibitors in KRAS mutant NSCLC and CRC in preclinical models and enhances the anti-tumor effects of anti-PD-1 in KRAS mutant NSCLC mouse models.2

Clinical Development in Advanced Cancers

VS-6766 has been studied in over 200 patients. Initial signs of activity have been observed in clinical studies as a monotherapy in KRAS mt (mutant) NSCLC, endometrial and ovarian cancers, in BRAF mt ovarian cancer, and in RAS mt multiple myeloma.3 Additionally, initial signs of clinical activity have been observed with the combination of VS-6766 and defactinib in LGSOC and KRAS G12V mt NSCLC.4

Rationale for Clinical Investigation of VS-6766 Combinations

Combinations with Defactinib

Defactinib is an oral small molecule inhibitor of FAK and PYK2 that targets malignant cells both directly and through modulation of the tumor microenvironment. MEK inhibition has been shown to induce compensatory activation of phospho-FAK (pFAK) preclinically5 and clinically,4 making defactinib a promising candidate for combination with VS-6766.4

Preclinical research has shown that the combination of the dual RAF/MEK inhibitor VS-6766 with defactinib causes synergistic growth inhibition in a variety of KRAS mutant tumor cell lines by inhibiting signal transduction.6 A clinical trial to evaluate combination therapy of defactinib with VS-6766 in patients with KRAS mutant advanced solid tumors including low grade serous ovarian cancer (LGSOC) and non-small cell lung cancer (NSCLC) is in progress (NCT03875820).4

Ongoing VS-6766 Clinical Trials:

  1. Investigator-sponsored Phase 1b study with The Royal Marsden Hospital to evaluate combination therapy of VS-6766 with defactinib in patients with advanced solid tumors (NCT03875820).