Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon; Division of Medical Oncology, Department of Internal Medicine.
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon; Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul.
Ann Oncol. 2019 Jul 1;30(7):1104-1113. doi: 10.1093/annonc/mdz123.
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.
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均有效，被认为是治疗非小细胞肺癌（NSCLC）患者的标准治疗方法。然而，新出现的证据表明，PD-1/PD-L1 阻断会导致超进展性疾病（HPD），即与预后不良相关的肿瘤生长加剧。本研究旨在评估 NSCLC 患者接受 PD-1/PD-L1 阻断治疗后 HPD 的发生率，并确定与 HPD 相关的决定因素。
我们纳入了 2014 年 4 月至 2018 年 11 月期间接受 PD-1/PD-L1 抑制剂治疗的复发性和/或转移性 NSCLC 患者。对接受 PD-1/PD-L1 抑制剂治疗的 NSCLC 患者的临床病理变量、肿瘤生长动力学、治疗结果进行分析。根据肿瘤生长动力学（TGK）、肿瘤生长率（TGR）和治疗失败时间（TTF）定义 HPD。对外周血 CD8+T 淋巴细胞进行免疫表型分析，以探讨 HPD 的潜在预测生物标志物。
共分析了 263 例患者。根据 TGK、TGR 和 TTF，55 例（20.9%）、54 例（20.5%）和 98 例（37.3%）患者出现 HPD。同时符合 TGK 和 TGR 标准的 HPD 与无 HPD 的进展性疾病相比，无进展生存期（HR 4.619；95%CI 2.868-7.440）和总生存期（HR 5.079；95%CI 3.136-8.226）更差。没有特定于 HPD 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/记忆亚群（总 CD8+T 细胞中 CCR7-CD45RA-T 细胞）频率较低，严重耗尽人群（PD-1+CD8+T 细胞中 TIGIT+T 细胞）频率较高与 HPD 和较低的生存率相关。
PD-1/PD-L1 抑制剂治疗的 NSCLC 患者中 HPD 很常见。从合理设计的分析中得出的生物标志物可成功预测 HPD 和更差的结局，值得进一步研究 HPD。
