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.
免疫检查点抑制剂（CPIs）和细胞疗法产品的应用，已彻底改变了多种实体瘤和血液恶性肿瘤的治疗格局。这些药物在不同临床情境中展现出前所未有的应答率与长期获益。这些临床进展同时表明，在药物研发的早期与晚期阶段，都需要采用新的或经过调整的试验设计及疗效与安全性评估方法。传统肿瘤学其他领域使用的一些统计方法和终点指标，在免疫肿瘤学中似乎已不太适用；相反，其他方法和终点指标则作为替代方案应运而生。本文重点围绕CPIs，探讨免疫肿瘤学药物研发早期及晚期阶段试验设计的相关问题。针对早期试验，我们回顾了与剂量递增相关的最突出问题、免疫治疗中肿瘤应答和进展标准的应用与局限、缓解持续时间本身作为终点的作用，以及在新疗法开发中尽早开展随机试验的必要性。对于晚期阶段，我们讨论了随机试验主要终点的选择，回顾了替代终点的现状，并探讨了与免疫治疗相关的特定统计问题，包括时间-事件终点评估中的非比例风险、在此类情境下Cox模型的替代方法，以及广义配对比较法——该方法能够提供以患者为中心的临床获益评估，并可用于设计随机试验。
Trial Design for Cancer Immunotherapy: A Methodological Toolkit
肿瘤(癌症)患者之家