Abstract 2943: In vivo combination of miransertib (ARQ 092) with anti-PD-1 antibody, trametinib, lapatinib, trastuzumab and paclitaxel

Abstract

Abstract Dysregulation of the PI3K-AKT signaling pathway has been implicated as a key driver in cancer initiation and progression. AKT is a serine/threonine kinase and a critical component mediating the PI3K-AKT signaling axis. Although AKT inhibitors have been extensively studied, clinical outcome has not been impressive. Interestingly, it has been shown that PI3K/AKT pathway has been involved in resistance to conventional chemotherapy, and inhibition of AKT enhances targeted therapy and sensitizes radiation therapy. Miransertib is a potent and selective pan-AKT inhibitor and currently in early clinical studies. In this study, we assessed combined effect of Miransertib with immune checkpoint inhibitor, anti-MEK and anti-HER2 agents, and a chemotherapeutic agent in vivo. Miransertib at doses of range from 20mg/kg to 120mg/kg was tested in combination with anti-PD-1 antibody, trametinib, lapatinib, trastuzumab, or paclitaxel. Anti-tumor efficacy was assessed in syngeneic mouse CT-26 colon and 4T1 breast tumor models and xenografts models with endometrial (AN3CA) and breast (HCC1954, KPL-4, ZR-75-1) tumors, two patient-derived (PDX) models of endometrial cancer (with PIK3CAH1047R and R93W+D350G mutations) and in one vemurafenib-resistant melanoma PDX (with BRAFV600E and PIK3CA H1047R mutations). Combinability and efficacy of Miransertib and anti-PD-1 antibody was assessed in syngeneic mouse CT-26 colon tumor model. Miransertib at 60 mg/kg and anti-PD-1 antibody at 10mg/kg were combinable. Combined dosing of Miransertib with Anti-PD-1 antibody exerted superior anti-tumor activity in comparison to the single agents (TGI: 65% for combination, 50% for Miransertib and 55% for anti-PD-1 antibody after dosing for 9 days and more significant difference after 12 day dosing). In 4T1 breast tumor model, combination of Miransertib and anti-PD-1 antibody showed a very modest anti-tumor activity whereas there is no effect as single agents. In one of the endometrial PDX models, the combination of Miransertib with trametinib enhanced anti-tumor activity of each drug alone, reducing tumor growth by 67% compared to single-agent tumor reductions by 43% for either Miransertib or trametinib. In a vemurafenib-resistant melanoma PDX model, tumor growth was reduced by 73% when Miransertib was combined with trametinib, while trametinib alone only reduced tumor growth by 26% for trametinib and by 16% by Miransertib. Miransertib enhanced efficacy of in combination with trastuzumab, lapatinib, or paclitaxel, by reducing tumor growth as much as 92%, 73% and 85% respectively, while single agent comparators reduced tumors by less than 50%. Miransertib is combinable with anti-PD-1 antibody, trametinib, lapatinib, trastuzumab, and paclitaxel and exhibits enhanced anti-tumor activity. These results provide us rationale for the combination study of Miransertib in a clinical setting. Citation Format: Yi Yu, Terence Hall, Sudharshan Eathiraj, Ron E. Savage, Brian Schwartz. In vivo combination of miransertib (ARQ 092) with anti-PD-1 antibody, trametinib, lapatinib, trastuzumab and paclitaxel [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 2943.