Soon Yu Yang, Sjoquist Katrin, Marschner Ian C, Schou I Manjula, Pavlakis Nick, Goldstein David, Shitara Kohei, Stockler Martin R, Simes John, Martin Andrew J
NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia.
Department of Radiation Oncology, National University Cancer Institute, Singapore, Singapore.
JNCI Cancer Spectr. 2025 Jul 1;9(4). doi: 10.1093/jncics/pkaf053.
The INTEGRATE phase 3 trial in advanced gastric and esophagogastric junction cancer involved pooling overall survival data with its preceding phase 2 trial, raising concerns about misalignment due to treatment switching in phase 2, or the "winner's curse." We evaluated phase 2 results, adjusted for these opposing effects, against phase 3 according to the prespecified statistical analysis plan.
Overall survival estimates were adjusted for treatment switching using the rank-preserving structural failure time model (RPSFTM) and inverse probability of censoring weights (IPCW) method. A novel shrinkage approach mitigated overestimation from the winner's curse, and Bayesian prediction methods predicted phase 3 outcomes from phase 2 estimates. A simulation study modeled 10 000 seamless phase 2/3 trials to quantify bias in the pooled estimate.
The observed phase 3 hazard ratio (HR = 0.71, 95% CI = 0.54 to 0.93) for overall survival was more conservative than the adjusted phase 2 estimates (RPSFTM and novel shrinkage approach: HR = 0.61, 95% CI = 0.29 to 1.29; RPSFTM and Bayesian prediction: HR = 0.59, 95% CI = 0.48 to 0.73; IPCW and novel shrinkage approach: HR = 0.55, 95% CI = 0.31 to 0.99; IPCW and Bayesian prediction: HR = 0.58, 95% CI = 0.46 to 0.72). Simulations indicated negligible bias in the pooled log hazard ratio of ‒0.011 and 0.005 under the null and alternative hypotheses, respectively.
Adjusting phase 2 estimates for both treatment switching and the winner's curse produced point estimates similar to the unadjusted phase 3 results. A prospective plan to pool trial data under a closed testing procedure may be a reasonable strategy when a recruitment shortfall in phase 3 is anticipated, provided that potential sources of misalignment are thoroughly assessed.
ACTRN12612000239864 (INTEGRATE I)NCT02773524 (INTEGRATE IIA).
在晚期胃癌和食管胃交界癌中开展的INTEGRATE 3期试验涉及将总生存数据与其之前的2期试验数据合并，这引发了对因2期治疗方案切换或“胜者诅咒”导致数据不一致的担忧。我们根据预先指定的统计分析计划，评估了针对这些相反效应进行调整后的2期结果与3期结果。
使用秩保持结构失效时间模型（RPSFTM）和删失权重逆概率（IPCW）方法对治疗方案切换进行总生存估计调整。一种新颖的收缩方法减轻了胜者诅咒带来的高估，贝叶斯预测方法根据2期估计预测3期结果。一项模拟研究对10000个无缝2/3期试验进行建模，以量化合并估计中的偏差。
观察到的3期总生存风险比（HR = 0.71，95%CI = 0.54至0.93）比调整后的2期估计更为保守（RPSFTM和新颖收缩方法：HR = 0.61，95%CI = 0.29至1.29；RPSFTM和贝叶斯预测：HR = 0.59，95%CI = 0.48至0.73；IPCW和新颖收缩方法：HR = 0.55，95%CI = 0.31至0.99；IPCW和贝叶斯预测：HR = 0.58，95%CI = 0.46至0.72）。模拟表明，在零假设和备择假设下，合并对数风险比的偏差分别可忽略不计，为-0.011和0.005。
针对治疗方案切换和胜者诅咒对2期估计进行调整后，得到的点估计与未调整的3期结果相似。当预计3期招募不足时，在封闭检验程序下合并试验数据的前瞻性计划可能是一种合理策略，前提是对潜在的不一致来源进行全面评估。
ACTRN12612000239864（INTEGRATE I）；NCT02773524（INTEGRATE IIA）
