Abstract A48: Anti-tumor activity of the MEK inhibitor pimasertib in combination with the PI3K/mTOR inhibitor SAR245409 in low-grade serous ovarian cancer

Abstract

Abstract Low-grade serous ovarian carcinoma is a distinct neoplasm from high-grade serous ovarian carcinoma and is chemo-resistant, both in the first line setting as well as in subsequent lines of therapy. Serous ovarian tumors of low malignant potential and low grade serous ovarian cancer (LGSOC) appear to be dependent, in part, on the activation of the mitogen-activated protein kinase (MAPK) survival signaling pathway, and furthermore display significantly higher prevalence of KRAS or BRAF mutations in contrast to high-grade serous carcinomas. The PI3K/AKT/mTOR and Ras/Raf/MEK/ERK (MAPK) survival pathways are interlinked survival signaling pathways, where compensatory activation of one of the pathways in response to the inhibition of the other has been observed. Given their ability to cross-talk, simultaneous inhibition of the MAPK and PI3K/PTEN signaling cascades may significantly enhance anti-tumor activity as compared with inhibition of either cascade alone. Preclinical studies have shown that the combination of MEK and PI3K inhibitors, both in vitro and in vivo, enhanced anti-tumor effects and induced apoptosis in cell lines and primary patient-derived models across a range of cancer types. In the present series of studies, we report: 1- the anti-tumor activity of the combination of two investigational drugs, a phosphatidylinositol 3-kinase (PI3K) and mTOR inhibitor, SAR245409 (XL765) with the selective allosteric inhibitor of MEK1/2, pimasertib (AS703026; MSC1936369B) against patient-derived ovarian cancer xenograft models harboring KRAS mutations from low, intermediate and high grade ovarian tumors), and 2- the preliminary clinical activity of the combination in ovarian patients. In patient-derived xenografts of low and intermediate grade ovarian cancer, the combination led to significantly greater antitumor activity than that of single agent treatments. In the high grade model of ovarian cancer, no additive effects on antitumor activity were observed in the combination as compared to pimasertib as a single agent. The combination of pimasertib and SAR245409 is currently being investigated in patients with refractory solid tumors in an ongoing Phase Ib Trial (EMR200066-006; NCT01390818), where objective responses have been reported in 2 out of 4 evaluable patients with low-grade serous ovarian carcinoma. A phase 2 study (EMR200066-012, EudraCT Number 2013-000902-40) will investigate the activity of the combination pimasertib and SAR245409 in subjects with recurrent or metastatic low grade ovarian cancer, a patient population which has a high unmet medical need. Citation Format: Sukhvinder S. Sidhu, Frank Campana, Coumaran Egile, Karl Hsu, Samantha Goodstal, Ekaterine Asatiani, Lars Damstrup, Joanne Lager, Janet Ogden, Loic Vincent. Anti-tumor activity of the MEK inhibitor pimasertib in combination with the PI3K/mTOR inhibitor SAR245409 in low-grade serous ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A48.