Medical Oncology Department, Gustave Roussy, Villejuif, France.
Medical and Gastrointestinal Oncology Department, Hôpital Européen Georges Pompidou, Paris, France.
JAMA Oncol. 2018 Mar 1;4(3):351-357. doi: 10.1001/jamaoncol.2017.4771.
Derived neutrophils/(leukocytes minus neutrophils) ratio (dNLR) and lactate dehydrogenase (LDH) level have been correlated with immune checkpoint inhibitor (ICI) outcomes in patients with melanoma.
To determine whether pretreatment dNLR and LDH are associated with resistance to ICIs in patients with advanced non-small cell lung cancer (NSCLC).
DESIGN, SETTING, AND PARTICIPANTS: Multicenter retrospective study with a test (n = 161) and a validation set (n = 305) treated with programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors in 8 European centers, and a control cohort (n = 162) treated with chemotherapy only. Complete blood cell counts, LDH, and albumin levels were measured before ICI treatment. A lung immune prognostic index (LIPI) based on dNLR greater than 3 and LDH greater than upper limit of normal (ULN) was developed, characterizing 3 groups (good, 0 factors; intermediate, 1 factor; poor, 2 factors).
The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS) and disease control rate (DCR).
In the pooled ICI cohort (N = 466), 301 patients (65%) were male, 422 (90%) were current or former smokers, and 401 (87%) had performance status of 1 or less; median age at diagnosis was 62 (range, 29-86) years; 270 (58%) had adenocarcinoma and 159 (34%) had squamous histologic subtype. Among 129 patients with PD-L1 data, 96 (74%) had PD-L1 of at least 1% by immunohistochemical analysis, and 33 (26%) had negative results. In the test cohort, median PFS and OS were 3 (95% CI, 2-4) and 10 (95% CI, 8-13) months, respectively. A dNLR greater than 3 and LDH greater than ULN were independently associated with OS (hazard ratio [HR] 2.22; 95% CI, 1.23-4.01 and HR, 2.51; 95% CI, 1.32-4.76, respectively). Median OS for poor, intermediate, and good LIPI was 3 months (95% CI, 1 month to not reached [NR]), 10 months (95% CI, 8 months to NR), and 34 months (95% CI, 17 months to NR), respectively, and median PFS was 2.0 (95% CI, 1.7-4.0), 3.7 (95% CI, 3.0-4.8), and 6.3 (95% CI, 5.0-8.0) months (both P < .001). Disease control rate was also correlated with dNLR greater than 3 and LDH greater than ULN. Results were reproducible in the ICI validation cohort for OS, PFS, and DCR, but were nonsignificant in the chemotherapy cohort.
Pretreatment LIPI, combining dNLR greater than 3 and LDH greater than ULN, was correlated with worse outcomes for ICI, but not for chemotherapy, suggesting that LIPI can serve as a potentially useful tool when selecting ICI treatment, raising the hypothesis that the LIPI might be useful for identifying patients unlikely to benefit from treatment with an ICI.
衍生中性粒细胞/（白细胞-中性粒细胞）比值（dNLR）和乳酸脱氢酶（LDH）水平与黑色素瘤患者免疫检查点抑制剂（ICI）的疗效相关。
确定预处理 dNLR 和 LDH 是否与晚期非小细胞肺癌（NSCLC）患者对 ICI 的耐药性相关。
设计、地点和参与者：这是一项多中心回顾性研究，包括在 8 个欧洲中心接受程序性死亡 1/程序性死亡配体 1（PD-1/PD-L1）抑制剂治疗的 161 名患者的测试队列和 305 名患者的验证队列，以及在另外 162 名患者中接受化疗的对照组。在 ICI 治疗前测量全血细胞计数、LDH 和白蛋白水平。基于 dNLR 大于 3 和 LDH 大于正常值上限（ULN）的肺免疫预后指数（LIPI）被开发出来，将患者分为 3 组（良好，0 个因素；中等，1 个因素；差，2 个因素）。
主要终点是总生存期（OS）。次要终点是无进展生存期（PFS）和疾病控制率（DCR）。
在合并的 ICI 队列（N=466）中，301 名患者（65%）为男性，422 名（90%）为现吸烟者或曾经吸烟者，401 名（87%）的体能状态为 1 或以下；诊断时的中位年龄为 62（范围，29-86）岁；270 名（58%）为腺癌，159 名（34%）为鳞状组织学亚型。在 129 名有 PD-L1 数据的患者中，96 名（74%）的 PD-L1 免疫组化分析至少为 1%，33 名（26%）为阴性。在测试队列中，中位 PFS 和 OS 分别为 3（95%CI，2-4）和 10（95%CI，8-13）个月。dNLR 大于 3 和 LDH 大于 ULN 与 OS 独立相关（危险比[HR]，2.22；95%CI，1.23-4.01 和 HR，2.51；95%CI，1.32-4.76）。中位 OS 为差、中、好 LIPI 分别为 3 个月（95%CI，1 个月至未达到[NR]）、10 个月（95%CI，8 个月至 NR）和 34 个月（95%CI，17 个月至 NR），中位 PFS 分别为 2.0（95%CI，1.7-4.0）、3.7（95%CI，3.0-4.8）和 6.3（95%CI，5.0-8.0）个月（均 P<.001）。疾病控制率也与 dNLR 大于 3 和 LDH 大于 ULN 相关。在 ICI 验证队列中，OS、PFS 和 DCR 的结果具有重现性，但在化疗队列中无统计学意义。
预处理 LIPI，结合 dNLR 大于 3 和 LDH 大于 ULN，与 ICI 的不良预后相关，但与化疗无关，这表明 LIPI 可能是选择 ICI 治疗时的一个有用工具，这提出了 LIPI 可能有助于识别不太可能从 ICI 治疗中获益的患者的假设。
