Abstract 5566: LYC-55716, a first-in-class RORγ agonist: Rationale and preclinical data to support clinical combinations with established immunotherapies

Abstract

Abstract The retinoic acid-related orphan receptor γt (RORγt) is a nuclear receptor transcription factor that acts as an immune cell master control switch driving the generation and function of Th17 (helper) and Tc17 (cytotoxic) T cells. Preclinical data show that synthetic RORγ agonists modulate immune cell gene expression to both increase immune activity and decrease immunosuppressive mechanisms in the tumor microenvironment. Because RORγ agonists impact multiple antitumor mechanisms, these compounds have the potential to combine with other agents to enhance tumor immunity. In addition to preclinical data supporting a biologic rationale, bioinformatic and machine learning approaches based on the RORγ pathway were undertaken to prioritize possible clinical combinations. This work highlighted other immuno-oncology agents as well as targeted therapies and more conventional treatments. Preclinical, syngeneic mouse cancer models were used to test some of the hypotheses. Based on the finding that RORγ agonists decrease PD-1 expression and that anti-CTLA4 induces ICOS, which stabilizes RORγ expression, anti-PD1 or anti-CTLA4 agents were combined with the RORγ agonist LYC-54143 in 12 syngeneic murine models. Compared with individual agents, combination treatments elicited superior tumor growth inhibition in 6 of the models (Table). RORγ agonist treatment was also able to augment antitumor activity of doxorubicin. In preclinical and phase 1 clinical testing, the first-in-class, investigational oral small-molecule RORγ agonist LYC-55716 has demonstrated a favorable safety profile supporting combination with other immuno-oncology agents. Ongoing clinical trials include a phase 2a trial of LYC-55716 in patients with select solid tumors (NCT02929862) and a phase 1b trial of LYC-55716 combined with pembrolizumab in patients with non-small cell lung cancer. Percentage of tumor growth inhibition induced in syngeneic murine models of cancer.Murine modelAnti-PD1 aloneAnti-CTLA4 aloneRORγ agonist aloneRORγ agonist + anti-PD1RORγ agonist + anti-CTLA4H22 (Liver)30-50%>50%*10-30%>50%*>50%*Pan02 (Pancreas)<10%10-30%<10%10-30%*10-30%*CT26 (Colon)10-30%<10%<10%<10%30-50%B16F10 (Melanoma)10-30%10%10-30%10-30%30-50%A230 (Lymphoma)<10%<10%10-30%30-50%10%Renca (Renal)<10%10-30%30-50%*30-50%*30-50%*P<.05 vs vehicle. Citation Format: Xiao Hu, Xikui Liu, Hongxiu Li, Garry Weems, Elizabeth Zawidzka, Yilin Gao, H. Jeffrey Wilkins, Laura Carter. LYC-55716, a first-in-class RORγ agonist: Rationale and preclinical data to support clinical combinations with established immunotherapies [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 5566.