Abstract 4866: BI 907828: A novel, potent MDM2 inhibitor that induces antitumor immunologic memory and acts synergistically with an anti-PD-1 antibody in syngeneic mouse models of cancer

Abstract

Abstract MDM2 inhibitors block the interaction between the Tumor Protein p53 (TP53) and MDM2, its key negative regulator, and represent a new therapeutic concept in cancer therapy. MDM2 inhibitors are designed to restore p53 activity in TP53 wild-type tumors. Several MDM2 inhibitors are currently being evaluated in early clinical development. While the tumor targeting activity of MDM2 inhibitors has been well documented, recent preclinical data with the tool compound Nutlin-3 have shown that p53 activation by local, intra-tumoral injections induces anti-tumor immunity (Cancer Res 2017, 77(9) 2292-2305). Here we present data on BI 907828, a novel and potent MDM2 inhibitor with optimized drug-like properties that is suitable for intermittent dose schedules in syngeneic mouse models of cancer. Our data show that immune modulation contributes to efficacy of BI 907828 after oral administration in a Colon-26 syngeneic mouse model. Responding mice develop anti-tumor immunity that can control the tumor growth of a secondary tumor without any further treatment in a re-challenge study. A T cell depletion study shows a contribution of CD8+ T cells but not of CD4+ T cells to single-agent efficacy with BI 907828. Moreover, preclinical data in a Colon-26 syngeneic mouse model of cancer show synergistic efficacy for the combination of a PD-1 checkpoint inhibitor with BI 907828. In summary, BI 907828 is a novel, potent, orally bioavailable MDM2 inhibitor that shows synergistic efficacy in combination with a PD-1 checkpoint inhibitor in syngeneic mouse models of cancer. Citation Format: Dorothea Rudolph, Markus Reschke, Sophia Blake, Jörg Rinnenthal, Andreas Wernitznig, Ulrike Weyer-Czernilofsky, Andreas Gollner, Christian Haslinger, Pilar Garin-Chesa, Jens Quant, Darryl B. McConnell, Kraut Norbert, Jürgen Moll. BI 907828: A novel, potent MDM2 inhibitor that induces antitumor immunologic memory and acts synergistically with an anti-PD-1 antibody in syngeneic mouse models of cancer [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 4866.