Immune checkpoint inhibitors across neoadjuvant, perioperative, and adjuvant settings for resectable non-small-cell lung cancer: a systematic review and meta-analysis of randomized trials.
完整摘要 · 中文译文
背景：可切除非小细胞肺癌中免疫检查点抑制的随机证据已从病理缓解进展至成熟的生存结局。我们考察了各终点之间探索性的方向一致性，并量化了临床获益、治疗负担以及围手术期治疗实施的程度。 方法：我们综合了来自12项母随机试验的20篇同行评审报告，包括8,197名唯一参与者和13项符合条件的随机治疗比较。以母试验为分析单位，对于每个至事件发生时间结局，最新兼容报告取代了较早的估计值。直接随机比较采用限制最大似然随机效应模型进行合并。我们重建了累积无事件生存（EFS）和总生存（OS）证据，估计了绝对差异，进行了探索性试验水平跨终点分析，并合并了试验组中开始术后研究治疗的患者比例。 结果：在七项试验中，术前开始治疗使EFS事件减少41%（HR，0.59；95% CI：0.53-0.66；I2 = 12%）。五项试验显示死亡减少32%（HR，0.68；95% CI：0.58-0.80；I2 = 0%）。每100名随机化患者中，术前开始治疗产生31例额外的主要病理缓解（95% CI：24-39）、22例额外的病理完全缓解（95% CI：16-27），以及4例额外的接受或尝试接受根治性意向手术的患者（95% CI：1-7）。≥3级治疗相关不良事件每100名患者增加约4例 nts（95% CI：0-8）。在探索性分析中，较大的pCR改善往往伴随较低的EFS HR（Spearman ρ = -0.67；p = 0.098；k = 7），且EFS与OS估计值在方向上一致（ρ = 0.95；p = 0.051；k = 4）。在六项围手术期试验中，69.7%（95% CI：65.5%-73.7%）随机分配至实验组的患者开始了术后研究治疗。 结论：在可切除非小细胞肺癌（NSCLC）中，术前启动的含免疫检查点抑制剂（ICI）策略改善了病理缓解、EFS和OS。约70%分配至围手术期实验组的患者开始了术后研究治疗；这一描述性治疗实施结果并不能确定术后ICI是否可安全省略。需要开展前瞻性、由缓解和残留风险引导的随机试验。
完整摘要 · 英文原文
BACKGROUND: Randomized evidence for immune checkpoint inhibition in resectable non-small-cell lung cancer has progressed from pathological response to mature survival outcomes. We examined exploratory directional alignment across endpoints and quantified clinical yield, treatment burden, and the extent of perioperative therapy delivery. METHODS: We synthesized 20 peer-reviewed reports from 12 parent randomized trials, including 8,197 unique participants and 13 eligible randomized treatment comparisons. The parent trial was the analysis unit, and the latest compatible report replaced earlier estimates for each time-to-event outcome. Direct randomized comparisons were pooled using restricted maximum-likelihood random-effects models. We reconstructed cumulative event-free survival (EFS) and overall survival (OS) evidence, estimated absolute differences, performed exploratory trial-level cross-endpoint analyses, and pooled the proportion of experimental-arm patients who started postoperative study treatment. RESULTS: Across seven trials, treatment initiated before surgery reduced EFS events by 41% (HR, 0.59; 95% CI: 0.53-0.66; I2 = 12%). Five trials showed a 32% reduction in death (HR, 0.68; 95% CI: 0.58-0.80; I2 = 0%). Per 100 randomized patients, preoperative-start therapy produced 31 additional major pathological responses (95% CI: 24-39), 22 additional pathological complete responses (95% CI: 16-27), and 4 additional patients who underwent or attempted curative-intent surgery (95% CI: 1-7). Grade ≥3 treatment-related adverse events increased by approximately 4 per 100 patients (95% CI: 0-8). In exploratory analyses, larger pCR improvements tended to accompany lower EFS HRs (Spearman ρ = -0.67; p = 0.098; k = 7), and EFS and OS estimates were directionally aligned (ρ = 0.95; p = 0.051; k = 4). In six perioperative trials, 69.7% (95% CI: 65.5%-73.7%) of randomized experimental-arm patients started postoperative study treatment. CONCLUSION: ICI-containing strategies initiated before surgery improve pathological response, EFS, and OS in resectable NSCLC. Approximately 70% of patients assigned to perioperative experimental arms started postoperative study treatment; this descriptive treatment-delivery finding does not establish whether postoperative ICI can be safely omitted. Prospective response- and residual-risk-guided randomized trials are required.
摘要 待译
BACKGROUND: Randomized evidence for immune checkpoint inhibition in resectable non-small-cell lung cancer has progressed from pathological response to mature survival outcomes. We examined exploratory directional alignment across endpoints and quantified clinical yield, treatment burden, and the extent of perioperative therapy delivery. METHODS: We synthesized 20 peer-reviewed reports from 12 parent randomized trials, including 8,197 unique participants and 13 eligible randomized treatment comparisons.…