Hyperprogressive Disease in Patients With Advanced Non-Small Cell Lung Cancer Treated With PD-1/PD-L1 Inhibitors or With Single-Agent Chemotherapy
Hyperprogressive Disease in Patients With Advanced Non-Small Cell Lung Cancer Treated With PD-1/PD-L1 Inhibitors or With Single-Agent Chemotherapy
复制标题
PD-1/PD-L1抑制剂或单药化疗治疗晚期非小细胞肺癌患者的疾病进展
DOI：
10.1001/jamaoncol.2018.3676
复制
发表时间：
2018-11-01
期刊：
影响因子：
28.4
通讯作者：
Caramella, Caroline
中科院分区：
文献类型：
--
作者：
Ferrara, Roberto;Mezquita, Laura;Caramella, Caroline
超进展性疾病（HPD）是最近在接受程序性细胞死亡1 （PD-1）和程序性细胞死亡配体1 （PD-L1）抑制剂治疗的癌症患者中发现的一种新的进展模式。HPD在晚期非小细胞肺癌（NSCLC）中的发病率和预后尚不清楚。目的探讨与单药化疗相比，PD-1/PD-L1抑制剂治疗的晚期NSCLC患者是否观察到HPD，以及治疗与HPD之间是否存在关联。在这项多中心回顾性研究中，纳入了2011年8月4日至2017年4月5日期间接受治疗的患者，研究环境是在法国接受PD-1/PD-L1抑制剂（8家机构）或单药化疗（4家机构）的晚期非小细胞肺癌患者。治疗前至少2次计算机断层扫描，治疗期间至少1次计算机断层扫描，根据实体瘤反应评价标准（RECIST 1.1版）定义的可测量疾病。计算治疗前和治疗期间的肿瘤生长率（TGR）和每月变化量（Delta TGR）。超进展性疾病定义为首次评估时疾病进展且Delta TGR超过50%。主要结局和测量主要终点是评估接受IO或化疗的患者的HPD率。结果在406例接受PD-1/PD-L1抑制剂治疗的患者中（63.8%为男性），46.3%（n = 188）年龄在65岁及以上，72.4%（n = 294）为非鳞状组织，92.9%（n = 377）在二线或之后接受了PD-1抑制剂的单一治疗。中位随访期为12.1个月（95% CI, 10.1-13.8个月），中位总生存期（OS）为13.4个月（95% CI, 10.2-17.0个月）。56例（13.8%）患者被归类为HPD。在4.7%（n = 19）的人群中观察到假进展。与非hpd相比，在使用PD-1/PD-L1抑制剂前，超进展性疾病与2个以上转移部位显著相关（62.5%[56人中35人]vs 42.6%[350人中149人]；P = 0.006）。在PD-1/PD-L1抑制剂治疗的前6周内发生HPD的患者与疾病进展的患者相比，生存期显著降低（中位生存期，3.4个月[95% CI， 2.8-7.5个月]vs 6.2个月[95% CI， 5.3-7.9个月]；风险比，2.18 [95% CI, 1.29-3.69]; P = 0.003）。在59例接受化疗的符合条件的患者中，3例（5.1%）被分类为HPD。结论和相关性我们的研究表明，与化疗相比，PD-1/PD-L1抑制剂治疗的非小细胞肺癌患者中HPD更常见，并且在PD-1/PD-L1抑制剂治疗的患者中，HPD也与高转移负担和不良预后相关。需要进一步的研究来确定HPD的分子机制。
IMPORTANCE Hyperprogressive disease (HPD) is a new pattern of progression recently described in patients with cancer treated with programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors. The rate and outcome of HPD in advanced non-small cell lung cancer (NSCLC) are unknown.OBJECTIVES To investigate whether HPD is observed in patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors compared with single-agent chemotherapy and whether there is an association between treatment and HPD.DESIGN, SETTING, AND PARTICIPANTS In this multicenter retrospective study that included patients treated between August 4, 2011, and April 5, 2017, the setting was pretreated patients with advanced NSCLC who received PD-1/PD-L1 inhibitors (8 institutions) or single-agent chemotherapy (4 institutions) in France. Measurable disease defined by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) on at least 2 computed tomographic scans before treatment and 1 computed tomographic scan during treatment was required.INTERVENTIONS The tumor growth rate (TGR) before and during treatment and variation per month (Delta TGR) were calculated. Hyperprogressive disease was defined as disease progression at the first evaluation with Delta TGR exceeding 50%.MAIN OUTCOMES AND MEASURES The primary end point was assessment of the HPD rate in patients treated with IO or chemotherapy.RESULTS Among 406 eligible patients treated with PD-1/PD-L1 inhibitors (63.8% male), 46.3%(n = 188) were 65 years or older, 72.4%(n = 294) had nonsquamous histology, and 92.9%(n = 377) received a PD-1 inhibitor as monotherapy in second-line therapy or later. The median follow-up was 12.1 months (95% CI, 10.1-13.8 months), and the median overall survival (OS) was 13.4 months (95% CI, 10.2-17.0 months). Fifty-six patients (13.8%) were classified as having HPD. Pseudoprogression was observed in 4.7%(n = 19) of the population. Hyperprogressive disease was significantly associated with more than 2 metastatic sites before PD-1/PD-L1 inhibitors compared with non-HPD (62.5%[35 of 56] vs 42.6%[149 of 350]; P =.006). Patients experiencing HPD within the first 6 weeks of PD-1/PD-L1 inhibitor treatment had significantly lower OS compared with patients with progressive disease (median OS, 3.4 months [95% CI, 2.8-7.5 months] vs 6.2 months [95% CI, 5.3-7.9 months]; hazard ratio, 2.18 [95% CI, 1.29-3.69]; P =.003). Among 59 eligible patients treated with chemotherapy, 3 (5.1%) were classified as having HPD.CONCLUSIONS AND RELEVANCE Our study suggests that HPD is more common with PD-1/PD-L1 inhibitors compared with chemotherapy in pretreated patients with NSCLC and is also associated with high metastatic burden and poor prognosis in patients treated with PD-1/PD-L1 inhibitors. Additional studies are needed to determine the molecular mechanisms involved in HPD.