Phase Ib/II oncology trials, despite their small sample sizes, aim to provide information for optimal internal company decision-making concerning novel drug development. Hybrid controls (a combination of the current control arm and controls from one or more sources of historical trial data [HTD]) can be used to increase the statistical precision. Here we assess combining two sources of Roche HTD to construct a hybrid control in targeted therapy for decision-making via an extensive simulation study. Our simulations are based on the real data of one of the experimental arms and the control arm of the MORPHEUS-UC Phase Ib/II study and two Roche HTD for atezolizumab monotherapy. We consider potential complications such as model misspecification, unmeasured confounding, different sample sizes of current treatment groups, and heterogeneity among the three trials. We evaluate two frequentist methods (with both Cox and Weibull accelerated failure time [AFT] models) and three different priors in Bayesian dynamic borrowing (with a Weibull AFT model), and modifications within each of those, when estimating the effect of treatment on survival outcomes and measures of effect such as marginal hazard ratios. We assess the performance of these methods in different settings and potential of generalizations to supplement decisions in early-phase oncology trials. The results show that the proposed joint frequentist methods and noninformative priors within Bayesian dynamic borrowing with no adjustment on covariates are preferred, especially when treatment effects across the three trials are heterogeneous. For generalization of hybrid control methods in such settings we recommend more simulation studies.

翻译：Ib/II期肿瘤试验虽然样本量较小，但旨在为新型药物开发提供最佳内部决策信息。混合对照（即当前对照组与一个或多个历史试验数据源的对照组合）可用于提高统计精度。本研究通过广泛模拟评估了结合罗氏两项历史试验数据构建混合对照，以支持靶向治疗决策的可行性。我们的模拟基于MORPHEUS-UC Ib/II期研究中一个试验组与对照组以及两项阿替利珠单抗单药治疗罗氏历史试验的真实数据。我们考虑了模型误设、未测量混杂因素、当前治疗组样本量差异及三项试验间异质性等潜在问题。在评估治疗对生存结局及边际风险比等效应指标的影响时，我们比较了两种频率学派方法（分别采用Cox模型和韦布尔加速失效时间模型）以及贝叶斯动态借用中的三种不同先验（采用韦布尔AFT模型），并针对每种方法探索了变体形式。我们评估了这些方法在不同场景下的性能及其推广至早期肿瘤试验决策支持的潜力。结果显示，联合频率学派方法与无协变量调整的贝叶斯动态借用非信息先验更优，尤其在治疗效应存在试验间异质性时表现突出。针对此类场景下混合对照方法的推广，我们建议开展更多模拟研究。