本研究旨在评估将两种最新的 I 期荟萃分析方法应用于肿瘤学中开发的蛋白激酶抑制剂 (PKIs) 的可行性，并确定这些方法既可行又有用的情况。这项辅助研究使用了系统评价的数据，以确定 PKI 的剂量探索研究。选择进行荟萃分析的 PKI 需要至少进行五项涉及癌症患者的完整剂量探索研究，并提供可用结果，并以毒性评估为指导进行剂量递增。为了解释不同给药方案引起的异质性，一些研究被分为多个研究部分，在荟萃分析中被视为单独的实体。对于每个 PKI，应用两种贝叶斯随机效应荟萃分析方法来模拟推荐剂量的毒性概率分布并估计最大耐受剂量 (MTD)。对 20 个 PKI 进行了荟萃分析，其中包括 96 项研究，对应 115 个研究部分。对于 70% 的 PKI，毒性概率的中位后验概率低于 0.20 的毒性阈值，即使所得的可信区间非常宽。所有批准剂量均低于最小毒性阈值估计的 MTD，但批准剂量高于最大阈值估计 MTD 的剂量除外。 I 期荟萃分析方法的应用对于大多数 PKI 来说是可行的；然而，它们的实施需要多重条件。然而，荟萃分析导致的估计具有很大的不确定性，可能是由于有限的患者数量和/或研究之间的变异性。这引发了对推荐剂量可靠性的质疑。© 2024 作者。约翰·威利 (John Wiley) 出版的研究综合方法

This study aimed to assess the feasibility of applying two recent phase I meta-analyses methods to protein kinase inhibitors (PKIs) developed in oncology and to identify situations where these methods could be both feasible and useful. This ancillary study used data from a systematic review conducted to identify dose-finding studies for PKIs. PKIs selected for meta-analyses were required to have at least five completed dose-finding studies involving cancer patients, with available results, and dose escalation guided by toxicity assessment. To account for heterogeneity caused by various administration schedules, some studies were divided into study parts, considered as separate entities in the meta-analyses. For each PKI, two Bayesian random-effects meta-analysis methods were applied to model the toxicity probability distribution of the recommended dose and to estimate the maximum tolerated dose (MTD). Meta-analyses were performed for 20 PKIs including 96 studies corresponding to 115 study parts. The median posterior probability of toxicity probability was below the toxicity thresholds of 0.20 for 70% of the PKIs, even if the resulting credible intervals were very wide. All approved doses were below the MTD estimated for the minimum toxicity threshold, except for one, for which the approved dose was above the MTD estimated for the maximal threshold. The application of phase I meta-analysis methods has been feasible for the majority of PKI; nevertheless, their implementation requires multiple conditions. However, meta-analyses resulted in estimates with large uncertainty, probably due to limited patient numbers and/or between-study variability. This calls into question the reliability of the recommended doses.© 2024 The Author(s). Research Synthesis Methods published by John Wiley & Sons Ltd.