在随机对照交叉设计试验中，总生存期（OS）治疗效应评估通常会受到对照组因疾病进展后接受治疗而获益的影响。我们通过考虑对照组交叉治疗以及疾病进展后继续接受Cemiplimab治疗的潜在影响，估计了EMPOWER-Lung 1（NCT03088540）中经过调整的 OS 治疗效应。患者被随机分配为 cemiplimab每3周350毫克（Q3W）或铂双药化疗1：1。在或化疗后疾病进展的患者可接受持续不超过108周的 cemiplimab 350毫克 Q3W治疗。在 cemiplimab 治疗进展的患者可在持续4个化疗周期的情况下继续接受 cemiplimab 350毫克 Q3W治疗，持续时间不超过108周。三种调整方法考虑了交叉和/或持续治疗：简化的两阶段校正（有或没有重新审查）、逆概率删除加权（IPCW）和保序结构失效时间模型（RPSFT；有或没有重新审查）。在 PD-L1≥50% 患者中（N=563；中位随访时间为10.8个月），38.2% 的患者（n=107/280）从化疗转为 cemiplimab 治疗（在经确认有进展的患者中，71.3% 的患者（n=107/150）实现传输），16.3%（n=46/283）在经组织学特异性化疗增加后进行了 Cemiplimab 治疗（在经确认有进展的患者中，38.7% 的患者（n=46/119）接受了治疗）。Cemiplimab 相对于化疗的非调整 OS 风险比（HR）为0.566（95% 置信区间[CI]：0.418,0.767）。根据已发布的指南和试验特点，简化的两阶段校正是最适合的方法，不用重新审查的 OS HR 为 0.490（95% CI：0.365，0.654）；有重新审查的 OS HR 为 0.493（95% CI：0.361，0.674）。IPCW 和 RPSFT 方法的估计与简化的两阶段校正相一致。在考虑了 EMP OWER-Lung 1 中观察到的治疗交叉和疾病进展后持续接受 histology-specifc 化疗和 cemiplimab 治疗的情况后，Cemiplimab 仍然表现出与原始分析一致的显著临床和统计学上的 OS 益处相对于化疗。版权所有2023年Feliciano，McLoone，Xu，Quek，Kuznik，Pouliot，Gullo，Rietschel，Guyot，Konidaris，Chan，Keeping，Wilson和Freemantle。

In randomized-controlled crossover design trials, overall survival (OS) treatment effect estimates are often confounded by the control group benefiting from treatment received post-progression. We estimated the adjusted OS treatment effect in EMPOWER-Lung 1 (NCT03088540) by accounting for the potential impact of crossover to cemiplimab among controls and continued cemiplimab treatment post-progression.Patients were randomly assigned 1:1 to cemiplimab 350 mg every 3 weeks (Q3W) or platinum-doublet chemotherapy. Patients with disease progression while on or after chemotherapy could receive cemiplimab 350 mg Q3W for ≤108 weeks. Those who experienced progression on cemiplimab could continue cemiplimab at 350 mg Q3W for ≤108 additional weeks with four chemotherapy cycles added. Three adjustment methods accounted for crossover and/or continued treatment: simplified two-stage correction (with or without recensoring), inverse probability of censoring weighting (IPCW), and rank-preserving structural failure time model (RPSFT; with or without recensoring).In the programmed cell death-ligand 1 ≥50% population (N=563; median 10.8-month follow-up), 38.2% (n=107/280) crossed over from chemotherapy to cemiplimab (71.3%, n=107/150, among those with confirmed progression) and 16.3% (n=46/283) received cemiplimab treatment after progression with the addition of histology-specific chemotherapy (38.7%, n=46/119, among those with confirmed progression). The unadjusted OS hazard ratio (HR) with cemiplimab versus chemotherapy was 0.566 (95% confidence interval [CI]: 0.418, 0.767). Simplified two-stage correction-the most suitable method based on published guidelines and trial characteristics-produced an OS HR of 0.490 (95% CI: 0.365, 0.654) without recensoring and 0.493 (95% CI: 0.361, 0.674) with recensoring. The IPCW and RPSFT methods produced estimates generally consistent with simplified two-stage correction.After adjusting for treatment crossover and continued cemiplimab treatment after progression with the addition of histology-specific chemotherapy observed in EMPOWER-Lung 1, cemiplimab continued to demonstrate a clinically important and statistically significant OS benefit versus chemotherapy, consistent with the primary analysis.Copyright © 2023 Feliciano, McLoone, Xu, Quek, Kuznik, Pouliot, Gullo, Rietschel, Guyot, Konidaris, Chan, Keeping, Wilson and Freemantle.