Abstract 213: VS-5584 a dual mTORC1/2 and PI3K inhibitor has anti-tumor activity in multiple in vivo xenograft tumor models and enhanced efficacy in combination with cisplatin or docetaxel

Abstract

Abstract Verastem is developing VS-5584, a potent and selective dual inhibitor of the mammalian target of rapamycin complexes 1 and 2 (mTOR) and Class I phosphatidylinositide 3-kinases (PI3K), for the treatment of advanced cancer. The PI3K/mTOR signaling pathway is a key regulator in cancer progression and in the survival of cancer stem cells (CSCs). VS-5584 has been shown to be an equipotent inhibitor of all four human Class I PI3K isoforms and the mTOR kinase, and PI3K signaling has been implicated in the maintenance of CSCs in solid tumors. In multiple orthogonal in vitro assays, VS-5584 has been shown to preferentially target CSCs and exhibited significant antiproliferative activity across multiple cancer cell lines. Furthermore, oral administration of VS-5584 has been shown to reduce CSCs in xenograft models. The in vivo antitumor efficacy of once daily and intermittent oral administration of VS-5584 was evaluated in multiple xenograft tumor models representing small cell (SCLC) and non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC) and mesothelioma. Once daily (QD) treatment with VS-5584 demonstrated potent anti-tumor activity, with mean percentage tumor growth inhibition (TGI) ranging from 40% to 97% (P < 0.05). In these models, TGI was dose-dependent with dosages at and above 15 mg/kg showing good antitumor activity (P < 0.05). Interestingly, tumor regression was observed in 33% (3/9) of mice bearing H69 (SCLC) tumors, 60% (6/10) of mice bearing MDA-MB-468 (TNBC) tumors and 50% (5/10) of mice bearing NCI-H226 mesothelioma tumors. This significant antitumor activity was generally observed at well-tolerated dosages. In studies exploring intermittent dosing schedules, efficacy and tolerability were similar or better with a QD 5 days on/2 days off or Monday, Wednesday, Friday schedule compared to continuous daily dosing. We also explored the efficacy of VS-5584 in combination with either cisplatin or docetaxel. In these studies, VS-5584 plus either cisplatin or docetaxel showed significant TGI compared to cisplatin alone in H69 SCLC and docetaxel alone in A549 NSCLC xenograft models (P < 0.05). This potent in vivo anti-tumor activity in xenograft models of NSCLC, SCLC, TNBC and mesothelioma suggests that VS-5584 has the potential for anticancer activity across a variety of cancer types. Intermittent dosing with VS-5584 was sufficient to achieve good efficacy while minimizing side effects, thus allowing a broader therapeutic window compared to QD dosing. VS-5584 in combination with either cisplatin or docetaxel had enhanced anti-tumor activity compared to either chemotherapeutic agent or VS-5584 alone in two in vivo models of lung cancer. VS-5584 is being evaluated in a Phase 1 clinical trial assessing intermittent dosing in subjects with advanced non-hematologic malignancies or lymphoma. Citation Format: Anthony F. Trombino, Vihren N. Kolev, Quentin G. Wright, Qunli Xu, Mahesh V. Padval. VS-5584 a dual mTORC1/2 and PI3K inhibitor has anti-tumor activity in multiple in vivo xenograft tumor models and enhanced efficacy in combination with cisplatin or docetaxel. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 213. doi:10.1158/1538-7445.AM2014-213