Department of Pathology, Division of Diagnostic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Department of Thoracic Oncology, Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
PLoS One. 2024 Jul 31;19(7):e0293707. doi: 10.1371/journal.pone.0293707. eCollection 2024.
The efficacy of PD-1 blocking agents in advanced NSCLC has shown prolonged effectiveness, but only in a minority of patients. Multiple biomarkers have been explored to predict treatment benefit, yet their combined performance remains inadequately examined. In this study, we assessed the combined predictive performance of multiple biomarkers in NSCLC patients treated with nivolumab.
Pretreatment samples from 135 patients receiving nivolumab were used to evaluate the predictive performance of CD8 tumor-infiltrating lymphocytes (TILs), intratumoral (IT) localization of CD8 TILs, PD-1 high expressing TILs (PD1T TILs), CD3 TILs, CD20 B-cells, tertiary lymphoid structures (TLS), PD-L1 tumor proportion score (TPS) and the Tumor Inflammation score (TIS). Patients were randomly assigned to a training (n = 55) and validation cohort (n = 80). The primary outcome measure was Disease Control at 6 months (DC 6m) and the secondary outcome measure was DC at 12 months (DC 12m).
In the validation cohort, the two best performing composite biomarkers (i.e. CD8+IT-CD8 and CD3+IT-CD8) demonstrated similar or lower sensitivity (64% and 83%) and NPV (76% and 85%) compared to individual biomarkers PD-1T TILs and TIS (sensitivity: 72% and 83%, NPV: 86% and 84%) for DC 6m, respectively. Additionally, at 12 months, both selected composite biomarkers (CD8+IT-CD8 and CD8+TIS) demonstrated inferior predictive performance compared to PD-1T TILs and TIS alone. PD-1T TILs and TIS showed high sensitivity (86% and 100%) and NPV (95% and 100%) for DC 12m. PD-1T TILs could more accurately discriminate patients with no long-term benefit, as specificity was substantially higher compared to TIS (74% versus 39%).
Composite biomarkers did not show improved predictive performance compared to PD-1T TILs and TIS alone for both the 6- and 12-month endpoints. PD-1T TILs and TIS identified patients with DC 12m with high sensitivity. Patients with no long-term benefit to PD-1 blockade were most accurately identified by PD-1T TILs.
PD-1 阻断剂在晚期 NSCLC 中的疗效显示出延长的有效性，但仅在少数患者中。已经探索了多种生物标志物来预测治疗益处，但它们的综合性能仍未得到充分检验。在这项研究中，我们评估了接受nivolumab 治疗的 NSCLC 患者中多种生物标志物的联合预测性能。
使用 135 名接受 nivolumab 治疗的患者的预处理样本，评估 CD8 肿瘤浸润淋巴细胞 (TIL)、肿瘤内 (IT) CD8 TIL 定位、PD-1 高表达 TILs (PD1T TILs)、CD3 TILs、CD20 B 细胞、三级淋巴结构 (TLS)、PD-L1 肿瘤比例评分 (TPS) 和肿瘤炎症评分 (TIS) 的预测性能。患者被随机分配到训练 (n = 55) 和验证队列 (n = 80)。主要观察指标为 6 个月时的疾病控制 (DC 6m)，次要观察指标为 12 个月时的疾病控制 (DC 12m)。
在验证队列中，两种表现最佳的组合生物标志物 (即 CD8+IT-CD8 和 CD3+IT-CD8) 与单独的生物标志物 PD-1T TILs 和 TIS 相比，敏感性 (64%和 83%) 和阴性预测值 (76%和 85%) 相似或更低，用于 DC 6m。此外，在 12 个月时，与 PD-1T TILs 和 TIS 相比，两种选定的组合生物标志物 (CD8+IT-CD8 和 CD8+TIS) 的预测性能均较差。PD-1T TILs 和 TIS 对 DC 12m 具有高敏感性 (86%和 100%) 和阴性预测值 (95%和 100%)。PD-1T TILs 对无长期获益的患者具有较高的特异性，特异性明显高于 TIS (74%比 39%)。
与 PD-1T TILs 和 TIS 相比，组合生物标志物在 6 个月和 12 个月的终点均未显示出更好的预测性能。PD-1T TILs 和 TIS 以高敏感性识别出 12 个月时疾病控制的患者。PD-1 阻断无长期获益的患者通过 PD-1T TILs 最准确地识别。
