Abstract 1179: Rational combinations with the dual RAF/MEK inhibitor VS-6766 for treatment of cutaneous melanoma harboring BRAF, NRAS, NF1 or CRAF mutations
Authors: Bacchiocchi Antonella , Coma Silvia , Chowdhury Sanjib , Sznol Mario , Halaban Ruth , Pachter Jonathan A. 
Published: June 2022

Abstract
VS-6766 is a unique dual RAF/MEK inhibitor which blocks MEK activity without the compensatory MEK activation that limits the efficacy of MEKi. VS-6766 produced clinical responses as a single agent in gynecological cancers and KRAS mutant non-small cell lung cancer (NSCLC) (Guo Lancet Oncology 2020). Clinical responses were also observed with VS-6766 in combination with the focal adhesion kinase (FAK) inhibitor defactinib in patients with low-grade serous ovarian cancer and KRAS mutant NSCLC. In patients with advanced cutaneous melanoma, mutations in the RAS/RAF/MEK/ERK (MAPK) pathway occur mainly in BRAF (41%), NRAS (27%), NF1 (25%) and CRAF (2.6%) (AACR Genie v10). Although several selective BRAFV600 inhibitors (BRAFi) are FDA-approved alone or in combination with MEK-only inhibitors (MEKi) for melanomas with BRAFV600E/K, there is still a need for agents to improve response rate, duration of response, and tolerability. There are no targeted therapy options for melanoma patients carrying NRAS or NF1 mutations following progression on immune checkpoint inhibitors. Using low passage cell lines derived from patients with metastatic melanoma and extensively profiled for genomic alterations together with commercially available immortalized human melanoma cell lines, all of which carried mutations in the MAPK pathway, we tested the activity of VS-6766 alone or in combination with other agents. In vitro proliferation assays showed that VS-6766 is as potent as BRAFi in BRAFV600E melanoma cell lines and is more potent than pan-RAF inhibitors in melanoma cell lines bearing NRAS, NF1 or CRAF mutations. We next tested rational combinations of VS-6766 with other agents in specific genetic backgrounds. In BRAFV600E melanoma cell lines, combination of VS-6766 with BRAFi (encorafenib, vemurafenib, dabrafenib) showed greater synergy than combination of MEKi (binimetinib, cobimetinib, trametinib) with BRAFi. Since ~65% of BRAF or NRAS mutant melanomas co-express mutations in the PI3K/AKT/mTOR pathway, we tested the combination of VS-6766 with the mTOR inhibitor everolimus. VS-6766 was synergistic with everolimus in reducing the viability of melanoma cells harboring BRAF or NRAS mutations. Because CDK4/6 pathway activation has been correlated with poor progression-free survival in melanoma patients treated with BRAFi combined with MEKi, we tested the combination of VS-6766 with the CDK4/6 inhibitor abemaciclib. We found that VS-6766 was synergistic with abemaciclib in reducing viability of melanoma cell lines. Additional combinations with VS-6766 are currently being tested and will be reported. These preclinical data support clinical testing of VS-6766 in rational combinations for treatment of cutaneous melanoma with BRAF, NRAS, NF1 or CRAF mutations. In clinical trials, a recommended phase 2 dose has been defined for the combination of VS-6766 with everolimus.
Citation Format: Antonella Bacchiocchi, Silvia Coma, Sanjib Chowdhury, Mario Sznol, Ruth Halaban, Jonathan A. Pachter. Rational combinations with the dual RAF/MEK inhibitor VS-6766 for treatment of cutaneous melanoma harboring BRAF, NRAS, NF1 or CRAF mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1179.