Institute for Experimental Oncology, University Hospital Bonn, Bonn, Germany.
Center for Integrated Oncology Cologne/Bonn, University Hospital Bonn, Bonn, Germany.
J Immunother Cancer. 2022 Mar;10(3). doi: 10.1136/jitc-2021-004024.
Biomarkers for predicting response to anti-programmed death-1 (PD-1) immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC) remain in demand. Since anti-tumor immune activation is a process, early dynamic changes of the acute-phase reactant C reactive protein (CRP) may serve as a predictive on-treatment biomarker. In a retrospective (N=105) and prospective (N=108) ICB-treated NSCLC cohort, early CRP kinetics were stratified after the start of immunotherapy until weeks 4, 6, and 12 as follows: an early doubling of baseline CRP followed by a drop below baseline (CRP flare-responder), a drop of at least 30% below baseline without prior flare (CRP responders), or those who remained as CRP non-responders. In our study, we observed characteristic longitudinal changes of serum CRP concentration after the initiation of ICB. In the prospective cohort, N=40 patients were defined as CRP non-responders, N=39 as CRP responders, and N=29 as CRP flare-responders with a median progression-free survival (PFS) of 2.4, 8.1, and 14.3 months, respectively, and overall survival (OS) of 6.6, 18.6, and 32.9 months (both log-rank p<0.001). Of note, CRP flare-responses, characterized by a sharp on-treatment CRP increase in the first weeks after therapy initiation, followed by a decrease of CRP serum level below baseline, predict ICB response as early as 4 weeks after therapy initiation. Of note, early CRP kinetics showed no predictive value for chemoimmunotherapy or when steroids were administered concurrently. On-treatment CRP kinetics had a predictive value for both major histological NSCLC subtypes, adenocarcinoma and squamous cell carcinoma. The results were verified in an independent retrospective cohort of 105 patients. In conclusion, CRP flare predicted anti-PD-1 monotherapy response and survival in two independent cohorts including a total of 213 patients with NSCLC, regardless of histology. Due to its wide clinical availability, early CRP kinetics could become an easily determined, cost-efficient, and non-invasive biomarker to predict response to checkpoint inhibitors in NSCLC within the first month.
用于预测非小细胞肺癌（NSCLC）抗程序性死亡-1（PD-1）免疫检查点阻断（ICB）反应的生物标志物仍有需求。由于抗肿瘤免疫激活是一个过程，急性期反应物 C 反应蛋白（CRP）的早期动态变化可能作为一种预测治疗中的生物标志物。在回顾性（N=105）和前瞻性（N=108）ICB 治疗 NSCLC 队列中，在免疫治疗开始后直至第 4、6 和 12 周，对 CRP 的早期动力学进行分层，如下所示：基线 CRP 的早期倍增，随后降至基线以下（CRP 爆发反应者），至少下降 30%而无前期爆发（CRP 反应者），或那些保持 CRP 无反应者。在我们的研究中，我们观察到 ICB 起始后血清 CRP 浓度的特征性纵向变化。在前瞻性队列中，N=40 例患者被定义为 CRP 无反应者，N=39 例为 CRP 反应者，N=29 例为 CRP 爆发反应者，中位无进展生存期（PFS）分别为 2.4、8.1 和 14.3 个月，总生存期（OS）分别为 6.6、18.6 和 32.9 个月（均 log-rank p<0.001）。值得注意的是，CRP 爆发反应者，在治疗开始后的前几周内 CRP 急剧增加，随后 CRP 血清水平降至基线以下，在治疗开始后 4 周即可预测 ICB 反应。值得注意的是，早期 CRP 动力学对化疗免疫治疗或同时给予皮质类固醇无预测价值。治疗中的 CRP 动力学对 NSCLC 的主要组织学亚型，腺癌和鳞状细胞癌均具有预测价值。在 105 例患者的独立回顾性队列中验证了这些结果。总之，CRP 爆发反应预测了抗 PD-1 单药治疗反应和生存，在包括 213 例 NSCLC 患者的两个独立队列中得到了验证，无论组织学如何。由于其广泛的临床可用性，早期 CRP 动力学可能成为一种易于确定、具有成本效益且非侵入性的生物标志物，可在第一个月内预测 NSCLC 对检查点抑制剂的反应。
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