Abstract
BACKGROUND: With numerous and fast approvals of different agents including immune checkpoint inhibitors, monoclonal antibodies, or chimeric antigen receptor (CAR) T-cell therapy, immunotherapy is now an established form of cancer treatment. These agents have demonstrated impressive clinical activity across many tumor types, but also revealed different toxicity profiles and mechanisms of action. The classic assumptions imposed by cytotoxic agents may no longer be applicable, requiring new strategies for dose selection and trial design. DESCRIPTION: This main goal of this article is to summarize and highlight main challenges of early-phase study design of immunotherapies from a statistical perspective. We compared the underlying toxicity and efficacy assumptions of cytotoxic versus immune-oncology agents, proposed novel endpoints to be included in the dose-selection process, and reviewed design considerations to be considered for early-phase trials. When available, references to software and/or web-based applications were also provided to ease the implementation. Throughout the paper, concrete examples from completed (pembrolizumab, nivolumab) or ongoing trials were used to motivate the main ideas including recommendation of alternative designs. CONCLUSION: Further advances in the effectiveness of cancer immunotherapies will require new approaches that include redefining the optimal dose to be carried forward in later phases, incorporating additional endpoints in the dose selection process (PK, PD, immune-based biomarkers), developing personalized biomarker profiles, or testing drug combination therapies to improve efficacy and reduce toxicity.