Abstract 666: Activity of the MEK inhibitor Binimetinib (MEK162) in combination with paclitaxel in patient-derived xenograft models of high-grade serous ovarian carcinoma
Authors: Winski Shannon L. , Bouhana Karyn , Rhodes Susan , Cable LouAnn , Anderson Deborah , Williams Lance , Tunquest Brian , Logan Tiffany , Vigers Guy , Lee Patrice 
Published: August 2015

Abstract
High-grade serous ovarian carcinoma (HGSOC) has the poorest prognosis amongst all gynecological cancers with a median survival of approximately 5 years. While most patients (pts) initially respond to therapy, few achieve long-term remission or cure; thus, new treatment strategies are needed. Paclitaxel (Pac), an agent commonly used in the treatment of HGSOC, induces the Ras/Raf/MEK/ERK pathway and resistance may be partially mediated through activation of MEK/ERK, suggesting a rationale for combining a MEK inhibitor with Pac. Binimetinib (MEK162) is an oral, potent, selective, allosteric small-molecule MEK1/2 inhibitor. The combination of binimetinib and Pac was studied in a panel of in vivo ovarian carcinoma xenograft models derived from either cell lines (A2780, SK-OV-3) or primary patient tumor resections pathologically confirmed to be HGSOC (OVC38B1, OVC604, OVC629, OVC104) and propagated solely in mice (pt-derived xenograft [PDX]). Three of these PDX models were from newly diagnosed pts, while 1 (OVC38B1) was from a pt who had relapsed following a prior response to a platinum/taxane regimen. All models were sequenced for cancer-specific genes by next-generation sequencing; no mutations were found in Ras, Raf, MEK or ERK. To evaluate single-agent and combination activity, tumor-bearing mice received 25 mg/kg Pac IP (days 1,5,9) and/or 30 mg/kg binimetinib PO (days 2-15). Single-agent binimetinib was modestly effective in 3/6 models (tumor growth inhibition [TGI] ≥ 50%), which is consistent with the lack of MAPK pathway mutations in these models. Single-agent Pac was highly effective in 3/6 models (TGI ≥ 90%) including OVC38B1 and 2 PDX models from newly diagnosed pts; the remaining models were taxane-resistant. This is consistent with expected high rates of response in the setting of newly diagnosed pts and/or prior responders. Binimetinib plus Pac had superior efficacy to either agent alone in 4/6 models including all taxane-resistant models. In 2 PDX models from newly diagnosed pts, combination activity was not improved, but Pac was highly effective as a single agent (72-82% regression) leaving little room for enhancement. Encouragingly, the combination induced tumor regressions in 2 taxane-resistant models in which no single-agent regressions were observed. In conclusion, in vivo drug sensitivity studies with binimetinib and Pac recapitulate the response expected in HGSOC based on stage, genetic background and clinical history. In models of taxane-resistant disease, combination with binimetinib had improved activity over taxane alone warranting further study of this approach in HGSOC.
Citation Format: Shannon L. Winski, Karyn Bouhana, Susan Rhodes, LouAnn Cable, Deborah Anderson, Lance Williams, Brian Tunquest, Tiffany Logan, Guy Vigers, Patrice Lee. Activity of the MEK inhibitor Binimetinib (MEK162) in combination with paclitaxel in patient-derived xenograft models of high-grade serous ovarian carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 666. doi:10.1158/1538-7445.AM2015-666