Retrospective Analysis of Master Protocols in Tumor-Agnostic Drug Development: Evaluation of Application to Single-Agent Therapies With ORR as the Endpoint for Approval of Oncology Drugs

Abstract

The first global approval of a microsatellite instability-high solid tumors was a landmark in oncology, paving the way for targeted therapies approved globally. However, guidance remains limited regarding the biological and methodological conditions under which such designs, statistical borrowing, are most effective. We retrospectively evaluated the feasibility of tumor-agnostic development using Bayesian modeling based on the objective response rate (ORR) as the primary endpoint, focusing on single-agent molecular targeted therapy (MTT) in Japan. Using Pharmaceuticals and Medical Devices Agency (PMDA) approval documents, we identified MTTs approved for ≥ 3 cancer types in Japan between 2001 and 2023. We analyzed whether their ORR in treatment lines without standard therapy exceeded thresholds using the beta-binomial model (BBM) and hierarchical Bayesian model (HBM). Among 97 approved MTTs, 57 were for solid tumors or sarcomas, and 14 for ≥ 3 indications. Poly (ADP-ribose) polymerase (PARP) inhibitors and human epidermal growth factor receptor 2 antibody-drug conjugate (HER2 ADC) consistently exceeded thresholds in both models. In contrast, mechanistic target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF) inhibitors showed generally consistent results across both models, although some exceeded the threshold while others did not, indicating considerable variability. This study evaluates single-agent therapies using ORR as the primary endpoint; therefore, the findings may not apply to combination therapies or endpoints such as progression-free survival or overall survival. Nevertheless, integrating Bayesian models and biological understanding can clarify when statistical borrowing is appropriate, particularly in biologically similar tumor types and improve interpretability and the strategic feasibility of basket trials in tumor-agnostic development.