使用程序性细胞死亡1(PD-1)/PD-L1抑制剂的免疫检查点阻断在各种恶性肿瘤中有效,并且被认为是非小细胞肺癌(NSCLC)患者的标准治疗方式。然而,新出现的证据表明,PD-1/PD-L1阻断可导致高进行性疾病(HPD),肿瘤的生长与预后不佳有关。这项研究旨在评估HPD的发生率,并确定与PD-1/PD-L1阻断治疗的NSCLC患者HPD相关的决定因素。
我们招募了2014年4月至2018年11月期间接受PD-1/PD-L1抑制剂治疗的复发和/或转移性NSCLC患者。临床病理变量,肿瘤生长动力学,分析接受PD-1/PD-L1阻断的NSCLC患者的治疗结果.根据肿瘤生长动力学(TGK)定义HPD,肿瘤生长速率(TGR),治疗失败时间(TTF)。对外周血CD8+T淋巴细胞进行免疫分型,以探索HPD的潜在预测生物标志物。
共分析了263例患者。在55例(20.9%)中观察到HPD,54(20.5%),根据TGK,98名(37.3%)患者,TGR,和TTF。符合TGK和TGR标准的HPD与更差的无进展生存期[风险比(HR)4.619;95%置信区间(CI)2.868-7.440]和总生存期(HR,5.079;95%CI,3.136-8.226)比无HPD的进行性疾病。没有HPD特有的临床病理变量。在外周血CD8+T淋巴细胞的探索性生物标志物分析中,效应子/记忆亚群(总CD8+T细胞中的CCR7-CD45RA-T细胞)的频率较低,严重耗竭群体(PD-1+CD8+T细胞中的TIGIT+T细胞)的频率较高,与HPD和低生存率相关.
HPD在PD-1/PD-L1抑制剂治疗的NSCLC患者中很常见。从合理设计的分析中得出的生物标志物可以成功预测HPD和更糟糕的结果,值得HPD进一步调查。
Immune checkpoint blockade with Programmed cell death 1 (PD-1)/PD-L1 inhibitors has been effective in various malignancies and is considered as a standard treatment modality for patients with non-small-cell lung cancer (NSCLC). However, emerging evidence show that PD-1/PD-L1 blockade can lead to hyperprogressive disease (HPD), a flair-up of tumor growth linked to dismal prognosis. This study aimed to evaluate the incidence of HPD and identify the determinants associated with HPD in patients with NSCLC treated with PD-1/PD-L1 blockade.
We enrolled patients with recurrent and/or metastatic NSCLC treated with PD-1/PD-L1 inhibitors between April 2014 and November 2018. Clinicopathologic variables, dynamics of tumor growth, and treatment outcomes were analyzed in patients with NSCLC who received PD-1/PD-L1 blockade. HPD was defined according to tumor growth kinetics (TGK), tumor growth rate (TGR), and time to treatment failure (TTF). Immunophenotyping of peripheral blood CD8+ T lymphocytes was conducted to explore the potential predictive biomarkers of HPD.
A total of 263 patients were analyzed. HPD was observed in 55 (20.9%), 54 (20.5%), and 98 (37.3%) patients according to the TGK, TGR, and TTF. HPD meeting both TGK and TGR criteria was associated with worse progression-free survival [hazard ratio (HR) 4.619; 95% confidence interval (CI) 2.868-7.440] and overall survival (HR, 5.079; 95% CI, 3.136-8.226) than progressive disease without HPD. There were no clinicopathologic variables specific for HPD. In the exploratory biomarker analysis with peripheral blood CD8+ T lymphocytes, a lower frequency of effector/memory subsets (CCR7-CD45RA- T cells among the total CD8+ T cells) and a higher frequency of severely exhausted populations (TIGIT+ T cells among PD-1+CD8+ T cells) were associated with HPD and inferior survival rate.
HPD is common in NSCLC patients treated with PD-1/PD-L1 inhibitors. Biomarkers derived from rationally designed analysis may successfully predict HPD and worse outcomes, meriting further investigation of HPD.