Joanne Lager

Abstract 4638: Anti-tumor activity of pimasertib in combination with SAR245409 or SAR245408 in human primary colorectal cancer xenograft models bearing PI3K/KRas and KRas mutations.

The PI3K/AKT/mTOR and Ras/Raf/MEK/ERK are interlinked growth and survival signaling pathways that are often constitutively activated in human tumors as a result of amplifications and/or mutations in PIK3CA, RAS and BRAF genes. In the present work, we have investigated the anti-tumor activity and documented the steady state pharmacodynamic impact of combinations between 2 selective pan PI3K Class I inhibitors, SAR245408 (XL147) and SAR245409 (XL765) with the selective allosteric inhibitor of MEK1/2, pimasertib (AS703026; MSC1936369B) against several different patient derived colorectal cancer (CRC) xenograft models harboring either KRAS mutations, dual KRAS and BRAF mutations or dual KRAS and PIK3CA mutations. In the BRAF driven CRC model, effects of the combinations were not significantly different from that of single agent treatment of pimasertib alone. In the G12V KRAS or G12D KRAS mutant CRC models, both combinations led to significantly greater anti-tumor activity than that of single agent treatment. In the dual PIK3CA/KRAS mutant tumors, combination therapies lead to a potent inhibition of both TORC1 and TORC2 pathways, in addition to inhibition of the MAPK pathway in contrast to single agent treatments. Overall, pimasertib combined with either SAR245409 or SAR245408 showed a significantly greater anti-tumor activity as compared to single agent treatment alone in primary models bearing KRAS mutations or dual PIK3CA/KRAS mutations. The combination of pimasertib and SAR245409 is currently being investigated in patients with PIK3CA/KRAS mutant colorectal cancer as part of an ongoing Phase Ib dose escalation trial of oral combination therapy with pimasertib (MSC1936369B) and SAR245409 in subjects with locally advanced or metastatic solid tumors. Citation Format: Sukhvinder S. Sidhu, Coumaran Egile, Marc Malfilatre, Celine Lefranc, Yvette Ruffin, Jianguo Ma, Karl Hsu, Joanne Lager, Stephane Marzabal, Janet A. Ogden, Loic Vincent. Anti-tumor activity of pimasertib in combination with SAR245409 or SAR245408 in human primary colorectal cancer xenograft models bearing PI3K/KRas and KRas mutations. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4638. doi:10.1158/1538-7445.AM2013-4638

Abstract P3-04-05: Identification of SAR439859, an orally bioavailable selective estrogen receptor degrader (SERD) that has strong antitumor activity in wild-type and mutant ER+ breast cancer models

Nearly 70% or more of newly diagnosed cases of breast cancer (BC) are estrogen receptor positive (ER+) where endocrine therapy is a primary treatment. However, substantial evidence describes a continued role of ER signaling in tumor progression, where approximately 40% of patients on endocrine therapy develop resistance that include mutations in the ER that drive a constitutively active receptor. Fulvestrant, an estrogen receptor degrader, is effective at shutting down ER signaling. However, fulvestrant efficacy studies report insufficient blockade of ER signaling in patients that may be a consequence of poor pharmaceutical properties. Here we describe the discovery of SAR439859, a novel, orally bioavailable SERD with potent antagonist and degradative properties against ER both in vitro and in vivo. SAR439859 has robust inhibition of ER signaling activity in multiple ER+ breast cancer cell lines including tamoxifen resistant lines harboring ER mutations. Across a large panel of ER+ cells, SAR439859 demonstrated broad and superior ER degradation activity as compared to other SERDs including improved inhibition of ER signaling and inhibition of cell growth. Similarly, in vivo treatment with SAR439859 demonstrated significant tumor regression in ER+ BC models including MCF7-ESR1 mutant-Y537S model and endocrine therapy resistant patient-derived xenograft tumor transplantation. Collectively, these results showed that SAR439859 is an oral, nonsteroidal, selective estrogen receptor antagonist and degrader that could provide therapeutic benefit to ER+ breast cancer patients. SAR439859 is currently being evaluated in a phase I clinical trial. Citation Format: Maysoun Shomali, Youssef El-Ahmad, Frank Halley, Jane Cheng, Michael Weinstein, Muchun Wang, Fangxian Sun, Natalia Malkova, Mikhail Levit, Malvika Koundinya, Zhuyan Gou, Andrew Hebert, Jessica McManus, Dietmar Hoffman, Hui Cao, Joonil Jung, Jack Pollard, Sylvie Vincent, Timothy Ackerson, Francisco Adrian, Chris Winter, Victoria Richon, Hong Chen, Karl Hsu, Joanne Lager, Albane Courjaud, Rosalia Arrebola, Laurent Besret, Pierre-Yves Abecassis, Laurent Schio, Gary McCort, Michel Tabart, Victor Certal, Fabienne Thompson, Bruno Filoche-Romme, Laurent Debussche, Patrick Cohen, Carlos Garcia-Echeverria, Monsif Bouaboula. Identification of SAR439859, an orally bioavailable selective estrogen receptor degrader (SERD) that has strong anti-tumor activity in wild-type and mutant ER+ breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5775.

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

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][1]), 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. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01390818&atom=%2Fclincanres%2F19%2F19_Supplement%2FA48.atom

Abstract LB-208: Hijacking the PI3K/mTor and KRas/MEK/ERK signaling pathways with a therapeutic assault results in robust antitumor activity in PI3K/KRas and KRas mutant tumors

The PI3K/AKT/mTOR and Ras/Raf/MEK/ERK are interlinked growth and survival signaling pathways both involving regulation by Ras and often constitutively activated in human tumors as a result of frequent mutations in p1 10α, Ras and BRaf. Here, we have assessed the antitumor activity of the oral, potent and selective allosteric inhibitor of MEK1/2, MSC1936369 (formerly known as AS703026), in combination with SAR245408 (pan-PI3K formerly named XL147) or SAR245409 (dual panPI3K/mTOR formerly named XL765) in cellular in vitro and in vivo xenograft settings. In vitro, the anti-proliferative effects of MSC1936369 in combination with SAR245409 were evaluated in a panel of 81 tumor cell lines (17 indications). Potent combination effects were seen in colorectal, pancreatic, breast and NSCL cancers when compared to each agent alone. Across indications, tumor cells harboring mutations in KRas, p1 10α, BRaf and both p1 10α and KRas were identified as those more sensitive to the combination. In vivo, suboptimal therapeutic doses of MSC1936369, SAR245408 and SAR245409 were tested PO daily as single agents and in combination in human tumor xenograft models: MiaPaCa-2 pancreatic carcinoma (KRas mut), HCT116 colorectal adenocarcinoma (KRas/PIKC3A mut). In animals bearing MiaPaCa-2 xenografts, tumor growth inhibition was observed in all of the treatment groups, to varying degrees, compared to vehicle (p Overall, the combination treatment of the MEK inhibitor MSC1936369 and the dual panPI3K/mTOR inhibitor SAR245409 showed enhanced tumor inhibition both in a large battery of tumor-derived cell lines as well as in xenograft models of human cancer (KRas mut and dual PI3K/KRas mut). In addition, combination therapy with the panPI3K inhibitor SAR245408 demonstrated a robust gain of antitumor activity, particularly in the dual PI3K/KRas mutant tumors. The available preclinical pharmacological data support the use of these combinations in clinical settings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-208. doi:10.1158/1538-7445.AM2011-LB-208

Abstract LB-295: Combination of PI3K (SAR245408 and SAR245409) and MEK (MSC1936369B) inhibitors induce tumor apoptosis in vivo: fluorescence molecular tomography study in a human colon carcinoma xenograft model

The Merck-Serono MEK1/2 allosteric inhibitor MSC1936369B (formerly known as AS703026) was combined with the sanofi-aventis pan-PI3K inhibitor SAR245408 (also known as XL147) or the pan-PI3K/mTOR inhibitor SAR24540 (also know as XL765) in mice bearing colon carcinoma HCT116 xenograft tumors. These tumors harbor both KRAS (G13D) and PIK3CA (H1047R) mutations. Apoptosis induction was monitored non-invasively in vivo using fluorescence molecular tomography (FMT) after injection of fluorescent Annexin-V. Ex vivo apoptosis was assessed on tumor lysates using assays for cleaved caspase-3 and cleaved PARP detection. Suboptimal doses of SAR245408, SAR245409, and MSC1936369B were administered orally on a daily schedule as single agents or in combination. Single agent treatments showed marginal or no activity on HCT116 tumor growth inhibition. In contrast, robust enhanced anti-tumor activity was observed with the combination treatments, resulting in sustained tumor stasis and regression for both SAR245408/MSC1936369B (p in vivo by FMT was induced for the SAR245408/MSC1936369B combination, with p=0.005 and p In conclusion, the combination between the MEK1/2 inhibitor MSC1936369B with the pan-PI3K inhibitor SAR245408 or the pan-PI3K/mTOR SAR245409 resulted in significantly enhanced anti-tumor activity in a KRAS/PIK3CA mutated tumor xenograft model, with synergistic induction of tumor apoptosis as demonstrated ex vivo for both combinations and in vivo using longitudinal FMT imaging for the SAR245408/MSC1936369B combination. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-295. doi:10.1158/1538-7445.AM2011-LB-295