PD-L1 表达和其他变量与免疫检查点抑制在晚期胃食管癌中获益的关联 17 项 3 期随机临床试验的系统回顾和荟萃分析

SCI

13 September 2022

Association of PD-L1 Expression and Other Variables With Benefit From Immune Checkpoint Inhibition in Advanced Gastroesophageal Cancer: Systematic Review and Meta-analysis of 17 Phase 3 Randomized Clinical Trials

（JAMA Oncology；IF:33.006）

Benefit From Immune Checkpoint Inhibition in Advanced Gastroesophageal Cancer: Systematic Review and Meta-analysis of 17 Phase 3 Randomized Clinical Trials [published online ahead of print, 2022 Aug 25]. JAMA Oncol. 2022;

Importance 重要性

Approval by the US Food and Drug Administration of immune checkpoint inhibition (ICI) for advanced gastroesophageal cancer (aGEC) irrespective of PD-L1 status has generated controversy. Exploratory analyses from individual trials indicate a lack of meaningful benefit from ICI in patients with absent or low PD-L1 expression; however, analysis of a single variable while ignoring others may not consider the instability inherent in exploratory analyses.

美国食品药品监督管理局批准免疫检查点抑制 (ICI) 用于晚期胃食管癌 (aGEC)，不论患者的PD-L1表达情况。这一举措引起了争议。个别试验的探索性分析表明，在 PD-L1 表达缺失或低的患者中，ICI 缺乏有意义的获益。然而，在忽略其他变量的情况下分析单个变量可能会导致忽略探索性分析中固有的不稳定因素。

Objective 目的

To systematically examine the predictive value of tissue-based PD-L1 status compared with that of other variables for ICI benefit in aGEC to assess its stability.

通过系统性地检验基于组织的 PD-L1 状态与其他变量相比对 aGEC 中 ICI 获益的预测价值，以评估其稳定性。

Data sources 数据来源

MEDLINE, Embase, Scopus, Web of Science, Cochrane Central Register (2000-2022).

MEDLINE, Embase, Scopus, Web of Science, Cochrane Central Register

Study selection, data extraction, and synthesis 研究选择、数据提取以及综合分析

Randomized clinical trials (RCTs) were included of adults with aGEC (adenocarcinoma [AC] or squamous cell carcinoma [SCC]) randomized to anti-PD-1 or PD-L1-containing treatment vs standard of care (SOC). Study screening, data abstraction, and bias assessment were completed independently by 2 reviewers. Of 5752 records screened, 26 were assessed for eligibility; 17 trials were included in the analysis.

选取纳入成人 aGEC（腺癌 [AC] 或鳞状细胞癌 [SCC]）随机接受抗 PD-1 或 PD-L1 治疗与标准护理（SOC）的随机临床试验 (RCT)。研究筛选、数据提取和偏倚评估由 2 位评审员独立完成。在筛选的 5752 项研究中，有 26 项被评估为合格；分析中包括了 17 项试验。

Main outcomes and measures 主要结果和测量

The prespecified primary end point was overall survival. The mean hazard ratio (HR) for ICI vs SOC was calculated (random-effects model). Predictive values were quantified by calculating the ratio of mean HRs between 2 levels of each variable.

预先设定的主要终点是总生存期。计算了 ICI 与 SOC 的平均风险比 (HR)（随机效应模型）。通过计算每个变量的 2 个水平之间的平均 HR 比率来量化预测值。

Results 结果  

In all, 17 RCTs (9 first line, 8 after first line) at low risk of bias and 14 predictive variables were included, totaling 11 166 participants (5067 with SCC, 6099 with ACC; 77.6% were male and 22.4% were female; 59.5% of patients were younger than 65 years, 40.5% were 65 years or older). Among patients with SCCs, PD-L1 tumor proportion score (TPS) was the strongest predictor of ICI benefit (HR, 0.60 [95% CI, 0.53-0.68] for high TPS; and HR, 0.84 [95% CI, 0.75-0.95] for low TPS), yielding a predictive value of 41.0% favoring high TPS (vs ≤16.0% for other variables). Among patients with AC, PD-L1 combined positive score (CPS) was the strongest predictor (after microsatellite instability high status) of ICI benefit (HR, 0.73 [95% CI, 0.66-0.81] for high CPS; and HR, 0.95 [95% CI, 0.84-1.07] for low CPS), yielding a predictive value of 29.4% favoring CPS-high (vs ≤12.9% for other variables). Head-to-head analyses of trials containing both levels of a variable and/or having similar design generally yielded consistent results.

总共纳入了 17 项低偏倚风险的 RCT（9 项一线，8 项一线后）和 14 个预测变量，共有 11166 名参与者（5067 名 SCC，6099 名 ACC；77.6% 为男性，22.4% 为女性；59.5% 的患者年龄小于 65 岁，40.5% 的患者年龄在 65 岁或以上）。在 SCC 患者中，PD-L1 肿瘤比例评分 (TPS) 是 ICI 获益的最佳预测因子（高 TPS 的 HR，0.60 [95% CI，0.53-0.68]；低TPS的HR，0.84 [95% CI，0.75-0.95] ），高TPS有着41.0%的预测值（而其他变量为 16.0%）。在 AC 患者中，PD-L1 联合阳性评分 (CPS) 是 ICI 获益的最强预测因子（在微卫星不稳定性高状态后）（高 CPS 的 HR，0.73 [95% CI，0.66-0.81]；HR，0.95 [ 95% CI, 0.84-1.07] 用于低 CPS），高CPS有着 29.4% 的预测值（其他变量为 12.9%）。包含两个变量水平和/或具有相似设计的试验的头对头分析通常产生一致的结果。

Conclusion and relevance 结论和相关性

Tissue-based PD-L1 expression, more than any variable other than microsatellite instability-high, identified varying degrees of benefit from ICI-containing therapy vs SOC among patients with aGEC in 17 RCTs.

在17项随机对照试验中，基于组织的 PD-L1 表达比除微卫星不稳定性高以外的任何变量都更能确定 aGEC 患者从含 ICI 的治疗与 SOC 的不同程度的获益。

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