Abstract 2077: Activity of DHODH inhibitor BAY2402234 in subcutaneous and intracranial models of SCLC

Abstract

Abstract Introduction: BAY2402234 is a potent and specific orally administered inhibitor of dihydroorotate dehydrogenase (DHODH) which showed anti-tumor activity in preclinical models of AML and is under clinical evaluation in myeloid malignancies (NCT03404726). Small cell lung cancer (SCLC) is a highly metastatic malignancy (the brain being a frequent metastatic site), which carries a dismal clinical prognosis. Previous preclinical research indicated that SCLC was particularly sensitive to DHODH inhibition, and in the current investigation the activity of BAY2402234 in this tumor indication was evaluated. Experimental Procedures: A variety of in vivo models derived from human SCLC samples were evaluated: (1) cell-line derived xenograft (CDX) subcutaneous models; (2) a CDX intracranial model; and (3) patient-derived xenograft (PDX) subcutaneous models. As is typical for SCLC, most of these models harbored mutations in both p53 and Rb1. BAY2402234 was administered orally either once daily or on an intermittent schedule (4 days on/3 days off). Standard-of-care (SoC) therapies were included in some experiments. Tumor tissue and plasma were collected for pharmacodynamic analyses. Results: In subcutaneous CDX models, BAY2402234 exhibited robust anti-tumor activity, including tumor regressions in some models. Strong anti-tumor activity was also observed in various subcutaneous PDX models, including activity in a model resistant to SoC therapy. In an intracranial tumor model, BAY2402234 significantly enhanced survival compared to the vehicle-treated cohort. Both dosing schedules tested were well-tolerated and highly active. Pharmacodynamic analyses to quantify the level of target inhibition observed in the various models are ongoing. Conclusions: The results of this investigation confirm and extend previous preclinical results and indicate that BAY2402234 may represent a novel treatment for SCLC, including patients with brain metastases. RESTRICTED Citation Format: Stefan Kaulfuss, Andreas Janzer, Gerhard Siemeister, Renan Borowicz, Katrin Jaensch, Katrin Gutberlet, Ricarda Schlenz, Andrea Triller, Ashley Eheim, Michael Jeffers, Sven Christian. Activity of DHODH inhibitor BAY2402234 in subcutaneous and intracranial models of SCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2077.