Trial Design for Cancer Immunotherapy: A Methodological Toolkit

SIMPLE SUMMARY: Immunotherapy has become a very important treatment against several types of cancer. The clinical trials of immunotherapy have shown that these treatments present us with some novel challenges in terms of the methodology required to assess their efficacy and safety. In this article, we discuss what we consider to be the most important among those challenges and provide some suggestions to address them in the design and analysis of clinical trials of immunotherapy, especially with the class of treatments named “checkpoint inhibitors”. In summary, the methodological aspects discussed in this article refer to definitions and implementation of efficacy endpoints, the evaluation of safety, and specific statistical issues that may require special attention in these trials. ABSTRACT: Immunotherapy with checkpoint inhibitors (CPIs) and cell-based products has revolutionized the treatment of various solid tumors and hematologic malignancies. These agents have shown unprecedented response rates and long-term benefits in various settings. These clinical advances have also pointed to the need for new or adapted approaches to trial design and assessment of efficacy and safety, both in the early and late phases of drug development. Some of the conventional statistical methods and endpoints used in other areas of oncology appear to be less appropriate in immuno-oncology. Conversely, other methods and endpoints have emerged as alternatives. In this article, we discuss issues related to trial design in the early and late phases of drug development in immuno-oncology, with a focus on CPIs. For early trials, we review the most salient issues related to dose escalation, use and limitations of tumor response and progression criteria for immunotherapy, the role of duration of response as an endpoint in and of itself, and the need to conduct randomized trials as early as possible in the development of new therapies. For late phases, we discuss the choice of primary endpoints for randomized trials, review the current status of surrogate endpoints, and discuss specific statistical issues related to immunotherapy, including non-proportional hazards in the assessment of time-to-event endpoints, alternatives to the Cox model in these settings, and the method of generalized pairwise comparisons, which can provide a patient-centric assessment of clinical benefit and be used to design randomized trials.