Sumiyoshi Issei, Okabe Takahiro, Togo Shinsaku, Takagi Haruhi, Motomura Hiroaki, Ochi Yusuke, Shimada Naoko, Haraguchi Mizuki, Shibayama Rina, Fujimoto Yuichi, Watanabe Junko, Iwai Moe, Kadoya Kotaro, Iwakami Shin-Ichiro, Takahashi Kazuhisa
Division of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Leading Center for the Development and Research of Cancer Medicine, Juntendo University, Tokyo, Japan.
J Transl Med. 2021 Feb 28;19(1):92. doi: 10.1186/s12967-021-02761-1.
Regimens combining pemetrexed (PEM) and immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) or programmed death-ligand 1 (PD-L1) are widely used for the treatment of advanced non-squamous non-small-cell lung cancer (NSq-NSCLC). Recently, PEM was shown to induce immunogenic cell death (ICD) and to enhance immune-regulatory genes. Some patients demonstrate an extremely long-term response to PEM. It is possible that the continued response in these patients is dependent on not only the pharmacological induction of cytotoxic cell death but also antitumor immunity. However, factors that can predict outcomes associated with long-term PEM administration using blood test results have not yet been elucidated. We investigated the clinical characteristics and predictive factors in patients with advanced NSq-NSCLC who underwent long-term PEM maintenance therapy.
In total, 504 patients with advanced NSq-NSCLC who received PEM combination therapy/monotherapy (n = 414) or paclitaxel (PTX) combination therapy (n = 90) between January 2010 and November 2019 were recruited; 381 patients were retained for the final analysis. Patients treated with PEM (n = 301) were divided into subgroups according to the total cycles of PEM (≥ 17 [n = 25] for the long-term administration group and ≤ 16 [n = 276] for the intermediate/short-term group) and compared with another population (n = 80) treated with PTX combination regimen. We investigated clinical features and predictive biomarkers, focusing on immune-regulatory factors, absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), and PD-1 and PD-L1 expression, to predict long-term response to PEM.
The long-term PEM administration group exhibited a higher ALC and a lower NLR than the shorter-term group did. Both these markers displayed greater association with progression-free survival and overall survival in the PEM combination therapy group than in the PTX combination therapy group. Increased PD-1 lymphocytes were associated with the long-term PEM response group, as PD-L1 expression in tumors was associated with a high incidence of immune-related adverse effects following ICI administration.
ALC, NLR, and PD-1 expression are PEM-mediated predictive biomarkers that are indirectly related to tumor immunity and can provide useful predictive information on the long-term response to PEM in patients with NSq-NSCLC.
培美曲塞（PEM）与靶向程序性细胞死亡蛋白1（PD-1）或程序性死亡配体1（PD-L1）的免疫检查点抑制剂（ICI）联合方案广泛用于治疗晚期非鳞状非小细胞肺癌（NSq-NSCLC）。最近，研究显示PEM可诱导免疫原性细胞死亡（ICD）并增强免疫调节基因。一些患者对PEM表现出极其长期的反应。这些患者的持续反应可能不仅取决于细胞毒性细胞死亡的药理学诱导，还取决于抗肿瘤免疫力。然而，尚未阐明能够利用血液检测结果预测长期使用PEM相关预后的因素。我们调查了接受长期PEM维持治疗的晚期NSq-NSCLC患者的临床特征和预测因素。
总共招募了2010年1月至2019年11月期间接受PEM联合治疗/单药治疗（n = 414）或紫杉醇（PTX）联合治疗（n = 90）的504例晚期NSq-NSCLC患者；381例患者纳入最终分析。接受PEM治疗的患者（n = 301）根据PEM的总疗程分为亚组（长期给药组≥17个疗程[n = 25]，中期/短期组≤16个疗程[n = 276]），并与另一组接受PTX联合方案治疗的患者（n = 80）进行比较。我们研究了临床特征和预测生物标志物，重点关注免疫调节因子、绝对淋巴细胞计数（ALC）、中性粒细胞与淋巴细胞比值（NLR）以及PD-1和PD-L1表达，以预测对PEM的长期反应。
长期PEM给药组的ALC高于短期组，NLR低于短期组。在PEM联合治疗组中，这两个标志物与无进展生存期和总生存期的相关性均高于PTX联合治疗组。PD-1淋巴细胞增加与长期PEM反应组相关，因为肿瘤中的PD-L1表达与ICI给药后免疫相关不良反应的高发生率相关。
ALC、NLR和PD-1表达是PEM介导的预测生物标志物，与肿瘤免疫间接相关，可为NSq-NSCLC患者对PEM的长期反应提供有用的预测信息。
