Abstract

Immunotherapy has transformed cancer treatment, providing durable responses and long-term survival benefits across a broad spectrum of malignancies. However, designing clinical trials for immunotherapeutic agents presents unique challenges distinct from those encountered with conventional chemotherapy and radiotherapy. These include atypical and delayed response patterns, low rates of dose-limiting toxicities, immune-related adverse events, and the critical role of immune biomarkers. As a result, traditional trial designs and endpoints may fall short in accurately evaluating immunotherapy. In response, a range of innovative trial designs have emerged to better capture the complex dynamics of immunotherapeutic agents. This review summarizes the evolving landscape of early-phase clinical trial design in immuneoncology, with a focus on toxicity assessment, endpoint selection, dose optimization, and biomarker integration. By addressing key methodological challenges and highlighting recent advances, we aim to guide researchers, clinicians, and trialists in the development of more efficient and informative trials that accelerate the safe and effective translation of immunotherapies into clinical practice. We conclude by discussing current limitations and outlining future directions for advancing immunotherapy trial design.

Keywords:Bayesian adaptive design; Biomarker; Immune response; Immunotherapy; Low-grade toxicities; Progression-free survival