Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.
Clinical Research Center, Kindai University Hospital, Osaka-Sayama, Osaka 589-8511, Japan.
Eur J Cancer. 2022 Jan;161:44-54. doi: 10.1016/j.ejca.2021.11.011. Epub 2021 Dec 15.
Tumour burden (TB) is implicated in resistance to programmed cell death-1/PD-L1 inhibitor (immune checkpoint inhibitor [ICI]) therapy. However, whether TB contributes to such resistance in non-small-cell lung cancer (NSCLC) has remained unknown.
A total of 260 treatment-naïve patients with advanced NSCLC who started ICI monotherapy (ICI cohort), platinum-doublet therapy (Chemo cohort) or ICI and platinum-doublet therapy (ICI+Chemo cohort) as first-line treatment were consecutively included. TB was estimated on the basis of the sum of the diameters of measurable target lesions as per Response Evaluation Criteria in Solid Tumours. Progression-free survival (PFS) in the ICI cohort was evaluated as per TB as a preplanned primary objective, with the analysis based on propensity score-weighted survival curves and estimation of restricted mean survival time (RMST). The Chemo cohort served as a control to determine whether TB is predictive of ICI treatment outcomes. The ICI+Chemo cohort was exploratory. The relation of TB to tumour immune status was assessed by immune-related gene expression profiling (irGEP) of pretreatment tumour tissue.
In the ICI cohort, patients with a low TB showed a significantly longer PFS than did those with a high TB (median, 17.9 vs 4.3 months; weighted hazard ratio, 0.32 [95% confidence interval, 0.19-0.53]). No such difference was apparent in the other cohorts. A significant difference in overall survival was also observed only in the ICI cohort. RMST-based analysis confirmed these results. The irGEP analysis implicated M2-type macrophages, angiogenesis and transforming growth factor-β as well as protumourigenic signalling pathways in ICI resistance conferred by a high TB.
A high TB was associated with a poor outcome of ICI therapy for advanced NSCLC as a result of immunosuppressive phenotypes. Development of combination or novel treatment strategies for such disease is thus warranted.
肿瘤负担（TB）与程序性细胞死亡-1/PD-L1 抑制剂（免疫检查点抑制剂[ICI]）治疗耐药有关。然而，TB 是否导致非小细胞肺癌（NSCLC）的这种耐药性仍不清楚。
共连续纳入 260 名初治晚期 NSCLC 患者，他们接受 ICI 单药治疗（ICI 队列）、铂类双药治疗（化疗队列）或 ICI 和铂类双药治疗（ICI+化疗队列）作为一线治疗。TB 根据实体瘤反应评估标准中可测量靶病灶的直径总和来估计。ICI 队列中 PFS 作为 TB 的一个预先计划的主要目标进行评估，分析基于倾向评分加权生存曲线和估计受限平均生存时间（RMST）。化疗队列作为对照，以确定 TB 是否预测 ICI 治疗结果。ICI+化疗队列为探索性。通过预处理肿瘤组织的免疫相关基因表达谱（irGEP）评估 TB 与肿瘤免疫状态的关系。
在 ICI 队列中，TB 低的患者 PFS 明显长于 TB 高的患者（中位 PFS，17.9 个月比 4.3 个月；加权风险比，0.32[95%置信区间，0.19-0.53]）。其他队列中没有明显差异。只有 ICI 队列观察到总生存的显著差异。RMST 分析证实了这些结果。irGEP 分析表明 M2 型巨噬细胞、血管生成和转化生长因子-β以及原肿瘤信号通路与 TB 高导致的 ICI 耐药有关。
TB 高与晚期 NSCLC 的 ICI 治疗结果不良有关，这是由于免疫抑制表型所致。因此，有必要为这种疾病开发联合或新型治疗策略。
