在 PACIFIC 试验中，度伐利尤单抗用于不可切除的 III 期非小细胞肺癌患者时，按肿瘤 PD-L1 表达情况的疗效。
Outcomes with durvalumab by tumour PD-L1 expression in unresectable, stage III non-small-cell lung cancer in the PACIFIC trial.
作者信息
Paz-Ares L, Spira A, Raben D, Planchard D, Cho B C, Özgüroğlu M, Daniel D, Villegas A, Vicente D, Hui R, Murakami S, Spigel D, Senan S, Langer C J, Perez B A, Boothman A-M, Broadhurst H, Wadsworth C, Dennis P A, Antonia S J, Faivre-Finn C
机构信息
Hospital Universitario 12 de Octubre, Lung Cancer Unit CNIO-H12o, CiberOnc and Universidad Complutense, Madrid, Spain.
Virginia Health Specialists, Fairfax, USA.
出版信息
Ann Oncol. 2020 Jun;31(6):798-806. doi: 10.1016/j.annonc.2020.03.287. Epub 2020 Mar 21.
BACKGROUND
In the PACIFIC trial, durvalumab significantly improved progression-free and overall survival (PFS/OS) versus placebo, with manageable safety, in unresectable, stage III non-small-cell lung cancer (NSCLC) patients without progression after chemoradiotherapy (CRT). We report exploratory analyses of outcomes by tumour cell (TC) programmed death-ligand 1 (PD-L1) expression.
PATIENTS AND METHODS
Patients were randomly assigned (2:1) to intravenous durvalumab 10 mg/kg every 2 weeks or placebo ≤12 months, stratified by age, sex, and smoking history, but not PD-L1 status. Where available, pre-CRT samples were tested for PD-L1 expression (immunohistochemistry) and scored at pre-specified (25%) and post hoc (1%) TC cut-offs. Treatment-effect hazard ratios (HRs) were estimated from unstratified Cox proportional hazards models (Kaplan-Meier-estimated medians).
RESULTS
In total, 713 patients were randomly assigned, 709 of whom received at least 1 dose of study treatment durvalumab (n = 473) or placebo (n = 236). Some 451 (63%) were PD-L1-assessable: 35%, 65%, 67%, 33%, and 32% had TC ≥25%, <25%, ≥1%, <1%, and 1%-24%, respectively. As of 31 January 2019, median follow-up was 33.3 months. Durvalumab improved PFS versus placebo (primary-analysis data cut-off, 13 February 2017) across all subgroups [HR, 95% confidence interval (CI); medians]: TC ≥25% (0.41, 0.26-0.65; 17.8 versus 3.7 months), <25% (0.59, 0.43-0.82; 16.9 versus 6.9 months), ≥1% (0.46, 0.33-0.64; 17.8 versus 5.6 months), <1% (0.73, 0.48-1.11; 10.7 versus 5.6 months), 1%-24% [0.49, 0.30-0.80; not reached (NR) versus 9.0 months], and unknown (0.59, 0.42-0.83; 14.0 versus 6.4 months). Durvalumab improved OS across most subgroups (31 January 2019 data cut-off; HR, 95% CI; medians): TC ≥ 25% (0.50, 0.30-0.83; NR versus 21.1 months), <25% (0.89, 0.63-1.25; 39.7 versus 37.4 months), ≥1% (0.59, 0.41-0.83; NR versus 29.6 months), 1%-24% (0.67, 0.41-1.10; 43.3 versus 30.5 months), and unknown (0.60, 0.43-0.84; 44.2 versus 23.5 months), but not <1% (1.14, 0.71-1.84; 33.1 versus 45.6 months). Safety was similar across subgroups.
CONCLUSIONS
PFS benefit with durvalumab was observed across all subgroups, and OS benefit across all but TC <1%, for which limitations and wide HR CI preclude robust conclusions.
背景
在 PACIFIC 试验中，对于接受放化疗（CRT）后未进展的不可切除 III 期非小细胞肺癌（NSCLC）患者，度伐利尤单抗对比安慰剂显著改善了无进展生存期和总生存期（PFS/OS），且安全性可控。我们报告了按肿瘤细胞（TC）程序性死亡配体 1（PD-L1）表达进行的结局探索性分析。
患者和方法
患者按 2:1 随机分配，每 2 周静脉注射 10 mg/kg 度伐利尤单抗或安慰剂≤12 个月，按年龄、性别和吸烟史分层，但不按 PD-L1 状态分层。如有可用的 CRT 前样本，检测其 PD-L1 表达（免疫组织化学），并在预先指定的（25%）和事后（1%）TC 临界值处评分。治疗效应风险比（HR）由未分层的 Cox 比例风险模型（Kaplan-Meier 估计中位数）估计。
结果
总共 713 例患者被随机分配，其中 709 例接受了至少 1 剂研究治疗，度伐利尤单抗组（n = 473）或安慰剂组（n = 236）。约 451 例（63%）可评估 PD-L1：分别有 35%、65%、67%、33%和 32%的患者 TC≥25%、<25%、≥1%、<1%和 1%-24%。截至 2019 年 1 月 31 日，中位随访时间为 33.3 个月。在所有亚组中，度伐利尤单抗对比安慰剂均改善了 PFS（主要分析数据截止日期为 2017 年 2 月 13 日）[HR，95%置信区间（CI）；中位数]：TC≥25%（0.41，0.26 - 0.65；17.8 个月对 3.7 个月），<25%（0.59，0.43 - 0.82；16.9 个月对 6.9 个月），≥1%（0.46，0.33 - 0.64；17.8 个月对 5.6 个月），<1%（0.73，0.48 - 1.11；10.7 个月对 5.6 个月），1%-24%[0.49，0.30 - 0.80；未达到（NR）对 9.0 个月]，以及未知（0.59，0.42 - 0.83；14.0 个月对 6.4 个月）。在大多数亚组中，度伐利尤单抗改善了 OS（数据截止日期为 2019 年 1 月 31 日；HR，95%CI；中位数）：TC≥25%（0.50，0.30 - 0.83；NR 对 21.1 个月），<25%（0.89，0.63 - 1.25；39.7 个月对 37.4 个月），≥1%（0.59，0.41 - 0.83；NR 对 29.6 个月），1%-24%（0.67，0.41 - 1.10；43.3 个月对 30.5 个月），以及未知（0.60，0.43 - 0.84；44.2 个月对 23.5 个月），但 TC<1%亚组未改善（1.14，0.71 - 1.84；33.1 个月对 45.6 个月）。各亚组的安全性相似。
结论
在所有亚组中均观察到度伐利尤单抗对 PFS 的获益，除 TC<1%亚组外，在所有亚组中均观察到对 OS 的获益，该亚组存在局限性且 HR 的置信区间较宽，无法得出确凿结论。
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