BACKGROUND Pre-planned futility analyses are commonly used in oncology studies. The LUME-Lung 2 study (NCT00806819; 1199.14) was stopped early based on a pre-planned, non-binding futility analysis of investigator-assessed progression-free survival (PFS), although subsequent analysis showed that the primary endpoint of improvement in centrally reviewed PFS was met. Retrospective analyses were conducted to understand the discrepancy between interim futility and final analyses. MATERIALS AND METHODS LUME-Lung 2 investigated nintedanib in combination with pemetrexed versus placebo‒pemetrexed for the treatment of patients with advanced or recurrent non-squamous non-small cell lung cancer who had relapsed or failed one prior line of chemotherapy. Pre-planned futility analysis was carried out by the Data Monitoring Committee (DMC) after 50% of the events for the primary PFS analysis (713 events) had occurred; the threshold for futility was a conditional power of < 20%. Conditional/predictive powers and hazard ratios were calculated retrospectively after varying percentages of events had occurred for both investigator- and centrally reviewed PFS. RESULTS At the time of the pre-planned futility analysis, the conditional power was 10.3% and the predictive power was 18.5%; no safety issues were identified. Retrospective analysis showed that the conditional and predictive powers fluctuated considerably over time for both investigator- and centrally reviewed PFS and that the power only dropped by a notable amount, and below the futility threshold, at the time of the futility analysis. CONCLUSIONS Retrospective investigations suggest that, had the DMC analysis been carried out at another time point, or had centrally reviewed PFS data been used, the futility outcome may have been different and the trial may have been continued. The design of futility analyses requires careful consideration and confirming negative futility outcomes by second analysis may be appropriate. TRIAL NUMBER NCT00806819.

中文翻译：

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临床研究中的统计争议：肿瘤学课程中关于随机对照试验潜在陷阱的无效分析。

背景技术预先计划的无效分析通常用于肿瘤学研究。LUME-Lung 2 研究 (NCT00806819; 1199.14) 基于对研究者评估的无进展生存期 (PFS) 的预先计划的、非约束性的无效分析而提前停止，尽管随后的分析表明改善的主要终点集中在已达到审查的 PFS。进行回顾性分析以了解中期无用性和最终分析之间的差异。材料和方法 LUME-Lung 2 研究了尼达尼布联合培美曲塞对比安慰剂-培美曲塞治疗既往一线化疗复发或失败的晚期或复发性非鳞状非小细胞肺癌患者。在主要 PFS 分析的 50% 事件（713 起事件）发生后，数据监测委员会 (DMC) 进行了预先计划的无效分析；无用的阈值是< 20% 的条件功效。在调查员和集中审查的 PFS 发生不同百分比的事件后，回顾性计算条件/预测能力和风险比。结果在预先计划的无效性分析时，条件能力为10.3%，预测能力为18.5%；没有发现安全问题。回顾性分析表明，研究者和集中审查的 PFS 的条件和预测能力随时间波动很大，并且在无用分析时，能力仅下降了显着量，并且低于无用阈值。结论 回顾性调查表明，如果 DMC 分析是在另一个时间点进行的，或者使用了集中审查的 PFS 数据，则无效结果可能会有所不同，并且试验可能会继续进行。无效分析的设计需要仔细考虑，并通过第二次分析确认消极的无效结果可能是合适的。试用号 NCT00806819。