Abstract B183: Targeting PI3K pathway dependent endometrial tumors with allosteric AKT inhibitors, ARQ 092 and ARQ 751
Authors: Eathiraj Sudharshan , Schwartz Brian , Yu Yi , Wick Michael J. , Hall Terence , Chai Feng , Sachdev Jasgit , Abbadessa Giovanni 
Published: May 2016

Abstract
Background: In endometrial cancer more frequently than in other tumors, abnormal activation of the AKT pathway drives tumorigenesis and can be induced by both PI3K and AKT alterations, being associated with aggressive disease and poor prognosis. ARQ 092 is a highly selective, allosteric, potent AKT inhibitor currently under clinical investigation, and ARQ 751 is the next generation AKT inhibitor, with different physical-chemical properties.
Methods: ARQ 092 and ARQ 751 were profiled using a Cell-TiterGlo® viability assay and the inhibition of AKT and downstream targets were measured by Western and immunohistochemistry analyses in an AN3CA endometrial cell line with activated PI3K (via PIK3R1 mutation). The efficacy and pharmacodynamics effect of ARQ 092 and ARQ 751 on phospho-AKT and phospho-pRAS40 were determined in AN3CA xenografts after repeated daily oral dosing. ARQ 092 was also tested against 23 endometrial patient-derived tumor models (PDX). Lastly, endometrial cancer patients are being enrolled in the expanded cohort of ARQ 092-101, a phase 1 study, at 2 schedules: intermittent (200mg once a day, 1 week on, 1 week off) or weekly (300mg twice daily, 1 day on, 6 days off).
Results: In AN3CA cell lines, ARQ 092, and more potently ARQ 751, inhibited AKT signaling including inhibition of phosphorylation of downstream targets in a dose dependent manner. Both inhibitors exhibited strong anti-proliferative activity. However, while ARQ 092 inhibited 6 out of 9 cell lines with GI50 below 1 μM, ARQ 751 inhibited all 5 cell lines with GI50 below the 150 nM range. Of the 22 tested PDX models, 12 responded (&gt;50% tumor control compared to placebo). Both ARQ 092 and ARQ 751 exhibited over 90% AKT inhibition after 6 hrs exposure to a 40 mg/kg dose in an AN3CA mouse xenograft. In this model, at the maximum tolerated dose of 120mg/Kg, ARQ 092 and ARQ 751 resulted in 79% and 92% tumor growth reduction, respectively. Additionally, for ARQ 092, plasma Cmax in mouse models at the 100 mg/kg dose was compared to the Phase I human results. Plasma Cmax in mice was 2.1 μM whereas in patients enrolled at the intermittent and weekly schedules Cmax were 1.3 and 1.5 μM, respectively. Of the 19 enrolled patients with endometrial cancer, only one was treated at full dose, had a PIK3CA mutation (H1047R), and obtained a durable partial response after 2 months on therapy.
Conclusions: Both ARQ 092 and ARQ 751 demonstrated potent inhibition of p-AKT and downstream pathway signaling. In addition, both compounds exhibited potent antitumor activity in human endometrial cancer cells in vitro and in vivo. Such preclinical observations were recapitulated in the clinic by the rapid objective response observed in the first endometrial patient with PIK3CA mutation enrolled at full dose in the expanded cohort of the ongoing ARQ 092-101 Phase I clinical trial. Overall, these data provide a strong mechanistic rationale for further evaluation of ARQ 092, and possibly ARQ 751, in patients with PI3K-driven endometrial malignancies.
Citation Format: Sudharshan Eathiraj, Brian Schwartz, Yi Yu, Michael J. Wick, Terence Hall, Feng Chai, Jasgit Sachdev, Giovanni Abbadessa. Targeting PI3K pathway dependent endometrial tumors with allosteric AKT inhibitors, ARQ 092 and ARQ 751. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B183.