Abstract 1425: Synergistic antitumor efficacy of the dual RAF/MEK inhibitor VS-6766 with FAK inhibition for treatment of RAS-dependent solid tumors
Authors: Coma Silvia , Paradis Justine S. , Gutkind J Silvio , Pachter Jonathan A. 
Published: July 2021

Abstract
The RAS/RAF/MEK/ERK pathway is the most mutated oncogenic pathway in cancer, and RAS pathway mutations often present with an overall worse prognosis. Although RAF and MEK have been validated as anticancer targets and several BRAF and MEK inhibitors (MEKi) are FDA approved, acquired resistance develops in most patients. Preclinically, inhibition of RAF or MEK has been found to activate focal adhesion kinase (FAK) signaling which may bypass RAS pathway blockade by driving tumor growth through activation of downstream pathways such as RhoA and YAP. VS-6766 is a unique dual RAF/MEK inhibitor which allows VS-6766 to block MEK signaling without the compensatory MEK activation that limits the efficacy of other MEK inhibitors. Defactinib is a selective FAK inhibitor (FAKi). Clinical studies are ongoing evaluating VS-6766 and defactinib for the treatment of various solid tumors. In 3D proliferation assays in vitro, defactinib was synergistic with VS-6766 or trametinib (MEKi) in reducing viability of several human tumor cell lines, including KRAS mutant (mt) ovarian cancer (TOV-21G) and KRAS-G12V mt non-small cell lung cancer (NSCLC; H441). We next investigated whether FAKi augments the efficacy of VS-6766 in solid tumor models. Combination of a FAKi with VS-6766 in a KRAS mt ovarian xenograft model (TOV21G) induced &gt;30% tumor regression in 9/10 mice, whereas each agent alone induced mainly tumor stasis (&gt;30% tumor regression with FAKi monotherapy or VS-6766 monotherapy in 1/10 and 3/10 mice, respectively) following 11 days of treatment. Similar results were observed in KRAS mt NSCLC (H2122) and GNAQ mt uveal melanoma (92.1) models in which the combination of FAKi with VS-6766 or trametinib induced tumor regression. In several patients with KRAS mt tumors, sequential biopsies showed that treatment with VS-6766 induced FAK activation (pY397) as a potential resistance mechanism, and this increased FAK activation was reversed in the presence of the defactinib/VS-6766 combination. Accordingly, the combination of VS-6766 with defactinib showed clinical activity in low grade serous ovarian cancer (LGSOC; ORR = 56% in KRAS-G12 mt and ORR = 41% in all 17 LGSOC patients; 8/17/20 data cut off). Importantly, the combination of defactinib with VS-6766 also induced responses in patients who had progressed on previous MEK inhibitor regimens. VS-6766 with defactinib also showed clinical activity in KRAS-G12V mt NSCLC. Furthermore, this combination regimen of VS-6766 with defactinib exhibited a manageable safety profile with no patients discontinuing for adverse events (NCT03875820). These preclinical and clinical data support the recent initiation of two registration-directed studies evaluating VS-6766 ± defactinib for the treatment of recurrent LGSOC with or without a KRAS mutation (NCT04625270) and recurrent NSCLC with KRAS-G12V or other KRAS mutation (NCT04620330).
Citation Format: Silvia Coma, Justine S. Paradis, J Silvio Gutkind, Jonathan A. Pachter. Synergistic antitumor efficacy of the dual RAF/MEK inhibitor VS-6766 with FAK inhibition for treatment of RAS-dependent solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1425.