Abstract P036: Trial in progress: Combination of the dual RAF/MEK inhibitor VS-6766 with the mTOR inhibitor everolimus with expansion in patients with KRAS mutant NSCLC
Authors: Manickavasagar Thubeena , Stavraka Chara , Anam Kaiser , Coma Silvia , Chowdhury Sanjib , Pachter Jonathan A. , Parker Tom , Parmar Mona , Finneran Laura , Hall Emma , Spicer James , Minchom Anna , Banerji Udai 
Published: December 2021

Abstract
The RAS/RAF/MEK/ERK (MAPK) pathway is a frequently deregulated oncogenic pathway in cancer driven by RAS and RAF mutations as well as being a key signaling pathway downstream of deregulated receptor tyrosine kinases. Although RAF and MEK have been validated as anticancer targets and several BRAF and MEK inhibitors are FDA approved, acquired resistance develops in most patients. Preclinically, inhibition of RAF or MEK has been found to activate AKT/mTOR signaling as a potential resistance mechanism, and combination of MEK inhibition with an inhibitor of the AKT/mTOR pathway yields improved anti-tumor activity. However, combined inhibition of MEK with an AKT or mTOR inhibitor has typically shown poor clinical tolerability. VS-6766 is a unique dual RAF/MEK inhibitor which blocks MEK activity without the compensatory MEK activation that limits the efficacy of other MEK inhibitors. VS-6766 has shown clinical responses as a single agent in gynecological cancers and KRAS mutant non-small cell lung cancer (NSCLC) (Guo Lancet Oncology 2020), and has shown clinical responses in combination with the focal adhesion kinase (FAK) inhibitor defactinib in patients with low-grade serous ovarian cancer and KRAS mutated NSCLC. To explore the combination of VS-6766 with blockade of the AKT/mTOR pathway, we tested the combination of VS-6766 with the mTOR inhibitor everolimus for potential synergy across a variety of RAS pathway mutations and tumor types in preclinical experiments. In 3D proliferation assays in vitro, VS-6766 was synergistic with everolimus in reducing viability of cell lines representing multiple MAPK pathway alterations, including KRAS (G12C, G12D, G12V and G13D), BRAF V600E, NRAS and NF1 mutations. Synergy of VS-6766 with everolimus was observed in 8/9 NSCLC, 16/20 colorectal cancer, 7/10 melanoma and 5/7 pancreatic cancer cell lines tested. These preclinical data support testing the combination of VS-6766 with everolimus in patients with KRAS mutant NSCLC as well as in numerous other cancer indications with various MAPK pathway alterations. A phase I study is ongoing to assess the combination of VS-6766 with everolimus with an intermittent dosing schedule. The clinical trial uses a rule-based design of 3+3 dose escalation cohorts, initially with once weekly dosing of VS-6766 in combination with everolimus. If this was found to be tolerable, the combination of twice weekly dosing of both compounds was to be explored. Following establishment of the recommended phase 2 dose (RP2D) for the combination, an expansion cohort (n = 10) in patients with KRAS mutant NSCLC was planned. The trial is currently recruiting into an expansion cohort of patients with KRAS mutated NSCLC ;NCT02407509, (Trial in Progress).
Citation Format: Thubeena Manickavasagar, Chara Stavraka, Kaiser Anam, Silvia Coma, Sanjib Chowdhury, Jonathan A. Pachter, Tom Parker, Mona Parmar, Laura Finneran, Emma Hall, James Spicer, Anna Minchom, Udai Banerji. Trial in progress: Combination of the dual RAF/MEK inhibitor VS-6766 with the mTOR inhibitor everolimus with expansion in patients with KRAS mutant NSCLC [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 P036.