Abstract P121: Dual RAF/MEK inhibitor VS-6766 for treatment of solid tumors with diverse MAPK pathway alterations
Authors: Coma Silvia , Chowdhury Sanjib , Musteanu Monica , Barbacid Mariano , Pachter Jonathan A. 
Published: December 2021

Abstract
The RAS/RAF/MEK/ERK (MAPK) pathway shows frequent mutations in cancer which often confer worse prognosis. Whereas KRAS mutations (mt) are prevalent in pancreatic cancer (PDAC; 98%), colorectal cancer (CRC; 45%) and non-small cell lung cancer (NSCLC; 31%), melanoma shows frequent mutations in BRAF (60%) and NRAS (28%). Although several BRAF and MEK inhibitors (MEKi) are FDA approved, there is still a need for agents with improved response rate, duration of response, and tolerability. VS-6766 is a unique dual RAF/MEK inhibitor. In contrast to MEKi, VS-6766 is a potent allosteric inhibitor of MEK kinase activity, which promotes a dominant negative RAF/MEK complex preventing phosphorylation of MEK by wildtype BRAF, BRAF V600E and CRAF. This unique mechanism allows VS-6766 to block MEK signaling without the compensatory activation of MEK that appears to limit the efficacy of MEKi. In 3D proliferation assays in vitro, VS-6766 inhibited cell proliferation across multiple MAPK pathway alterations, including KRAS (G12C, G12D, G12V, G13D and Q61K), BRAF (V600E and class 2), NRAS and NF1 mt. Cell lines with KRAS G12V mt (n = 10; IC50 = 10 - 400 nM, average = 120 nM) were generally more sensitive than cell lines with KRAS G12D mt (n = 9; IC50 = 150 – 12,000 nM; average = 2.4 mM). Cell lines with NRAS mt also appeared to be especially sensitive to VS-6766 (average IC50 = 80 nM). Overall, VS-6766 inhibited proliferation of cell lines representing multiple cancers including NSCLC, PDAC, CRC and melanoma. VS-6766 effectively suppressed RAS pathway signaling (pMEK, pERK, DUSP4, pEphA2) throughout a 48-hour period among a panel of KRAS mt NSCLC cell lines. In a genetically engineered mouse tumor model of KRAS G12V mt/Trp53 KO NSCLC, which has previously been shown to be CRAF-dependent (Sanclemente et al., 2018), VS-6766 (0.1 mg/kg QD) induced regression of all tumors, whereas the MEKi trametinib at the same dose did not induce significant tumor growth inhibition. In KRAS mt NSCLC (H358) and ovarian cancer (TOV21G) xenograft models, VS-6766 significantly inhibited tumor growth (tumor growth inhibition, TGI = 70% and 69%, respectively), whereas the equivalent dose of trametinib was much less effective in inhibiting tumor growth (TGI = 13% and 29%, respectively). Clinically, intermittent dosing of VS-6766 as monotherapy has shown partial responses in patients with KRAS or BRAF mt gynecological malignancies (3/5) and KRAS mt NSCLC (3/10) (Guo, 2020). Interestingly, in NSCLC, responses occurred especially in patients with KRAS G12V mt tumors, which correlates with the greater anti-proliferative potency of VS-6766 observed across KRAS G12V mt NSCLC, CRC and PDAC cell lines. These data support the recent initiation of two registration-directed studies evaluating VS-6766 ± defactinib (FAK inhibitor) for the treatment of recurrent low-grade serous ovarian cancer (NCT04625270) and recurrent NSCLC with KRAS G12V or other KRAS mutation (NCT04620330), and suggest potential utility of VS-6766 for treatment of additional tumor types and oncogenic mutations in the MAPK pathway.
Citation Format: Silvia Coma, Sanjib Chowdhury, Monica Musteanu, Mariano Barbacid, Jonathan A. Pachter. Dual RAF/MEK inhibitor VS-6766 for treatment of solid tumors with diverse MAPK pathway alterations [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P121.