Tomohiro Sasaki1, Christina Friedrich2, Krishnakant Dasika2, Vincent Hurez2, Renee Meyers2, Lesley Benyon2, Miyuki Yuasa3, Emiri Takaki4, Kazuhide Nakamura4, Yosuke Kawai1
1Office of Clinical Pharmacology, Department of Biometrics, Headquarters of Clinical Development, Otsuka Pharmaceutical Co., Ltd., 2Rosa & Co, LLC, 3Department of Clinical Science 2 Group 1, Headquarters of Clinical Development, Otsuka Pharmaceutical Co., Ltd., 4Department of Medical Innovations, Osaka Research Center for Drug Discovery, Otsuka Pharmaceutical Co., Ltd.
Introduction/Objectives: Gastrointestinal stromal tumor (GIST), the most common mesenchymal tumor having KIT or platelet-derived growth factor receptor A activating mutations, is typically treated with tyrosine kinase inhibitors (TKIs), such as imatinib [1]. However, in advanced GISTs, resistance to TKIs due to secondary mutations is common [2]. OPB-171775 (OPB) is a first-in-class anti-tumor agent that selectively kills phosphodiesterase 3A (PDE3A)/Schlafen 12 (SLFN12) double-positive cancer cells [3]. OPB appears to induce OPB–PDE3A–SLFN12 complex formation, leading to the downregulation of anti-apoptotic proteins and increased cancer cell death. GIST cells express high levels of SLFN12 and PDE3A, making them particularly sensitive to OPB-induced tumor growth inhibition. Here, QSP modeling characterized OPB’s anti-tumor effects on GISTs and predicted its clinical efficacy to aid in OPB’s therapeutic development. Methods: The QSP model was developed to characterize the anti-tumor effects of OPB. The model includes the intracellular binding of OPB to PDE3A and the consequent recruitment of the SLFN12 protein to form a OPB–PDE3A–SLFN12 complex that affects ribosomal activity, as well as relevant cell death and cell cycling pathways. The model was tested to confirm that it produced the expected cell-level behaviors in response to various OPB doses. The in vivo response was calibrated using data from patient-derived xenografts. Then, the model was expanded to address GIST patient-related clinical research questions. This model includes calculations of tumor size and volume, and both OPB and imatinib PK and PD effects as estimated for GIST patients. Then, GIST virtual patients (VPs) were created that represented in vivo GIST growth, and the VPs’ range of clinical responses to imatinib were calibrated to match literature data [4]. To reproduce the slow reduction in imatinib efficacy over time in ‘imatinib-resistant’ GIST patients, a new reference VP, having a progressive increase in the imatinib IC50 for the KIT-dependent tumor growth inhibition, was created. A simulation was conducted to explore the clinical efficacy of OPB at different doses/regimens. To test the impacts of target expression on OPB efficacy, PDE3A and SLFN12 expression levels were varied between 0.1× and 10× of reference VP values. Results: A range of OPB doses were simulated in the reference GIST VP with or without imatinib resistance. The reference GIST VP achieved the RECIST-defined partial response (>30% reduction in sum of longest diameters) under several of the protocols of interest. Additionally, the simulation suggested that the response to OPB was correlated with binding target expression. Conclusions: OPB is efficacious in GIST patients with or without imatinib resistance. Under reasonable assumptions, clinical OPB dosing protocols, ranging from 0.1 mg QD to 2 mg Q2W, are expected to achieve at least partial responses, and PDE3A and SLFN12 expression levels are predictive of the OPB response. Conclusions: OPB is efficacious in GIST patients with or without imatinib resistance. Under reasonable assumptions, clinical OPB dosing protocols, ranging from 0.1 mg QD to 2 mg Q2W, are expected to achieve at least partial responses, and PDE3A and SLFN12 expression levels are predictive of the OPB response. References: [1] Joensuu H , Hohenberger P , Corless CL . Gastrointestinal stromal tumour. Lancet 2013;382:973–83. [2] Demetri GD , van Oosterom AT , Garrett CR , Blackstein ME , Shah MH , Verweij J , et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006;368:1329–38. [3] Takaki EO, Kiyono K, Obuchi Y, Yamauchi T, Watanabe T, Matsumoto H, et al. A PDE3A-SLFN12 molecular glue exhibits significant antitumor activity in TKI-resistant gastrointestinal stromal tumors. Clin Cancer Res. 2024;30:3603–3621. [4] Tang S., Y Yin, C Shen, J Chen, X Yin, B Zhang, et al. Preoperative imatinib mesylate (IM) for huge gastrointestinal stromal tumors (GIST). World J Surg Oncol 2017:15:79.
[1] Joensuu H , Hohenberger P , Corless CL . Gastrointestinal stromal tumour. Lancet 2013;382:973–83. [2] Demetri GD , van Oosterom AT , Garrett CR , Blackstein ME , Shah MH , Verweij J , et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006;368:1329–38. [3] Takaki EO, Kiyono K, Obuchi Y, Yamauchi T, Watanabe T, Matsumoto H, et al. A PDE3A-SLFN12 molecular glue exhibits significant antitumor activity in TKI-resistant gastrointestinal stromal tumors. Clin Cancer Res. 2024;30:3603–3621. [4] Tang S., Y Yin, C Shen, J Chen, X Yin, B Zhang, et al. Preoperative imatinib mesylate (IM) for huge gastrointestinal stromal tumors (GIST). World J Surg Oncol 2017:15:79.
Reference: PAGE 33 (2025) Abstr 11667 [www.page-meeting.org/?abstract=11667]
Poster: Drug/Disease Modelling - Oncology