Department of Medicine, Division of Solid Tumor Oncology, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering, New York, New York.
Clin Cancer Res. 2019 Feb 1;25(3):1063-1069. doi: 10.1158/1078-0432.CCR-18-1102. Epub 2018 Jul 25.
Tumor mutation burden (TMB) is a biomarker of response to immune checkpoint blockade (ICB). The impact of TMB on outcomes with targeted therapies has not been explored.
We identified all patients with metastatic exon19del or L858R-mutant lung cancers treated with first/second-generation EGFR tyrosine kinase inhibitors (TKIs) with pretreatment next-generation sequencing data (MSK-IMPACT assay). The effect of TMB on time-to-treatment discontinuation (TTD) and overall survival (OS) were evaluated in univariate and multivariate analyses. wild-type lung adenocarcinoma samples were used for comparison.
Among 153 patients with -mutant lung cancer, TMB was lower compared with EGFR wild-type ( = 1,849; median 3.77 vs. 6.12 mutations/Mb; < 0.0001) with a broad range (0.82-17.9 mutations/Mb). Patients with -mutant lung cancer whose tumors had TMB in the high tertile had shorter TTD (HR, 0.46; = 0.0008) and OS (HR, 0.40; = 0.006) compared with patients with low/intermediate TMB. Evaluating by median TMB, there was significantly shorter TTD and OS for patients with higher TMB (TTD, = 0.006; OS, = 0.03). In multivariate analysis, TTD and OS remained significantly longer in the low/intermediate tertile compared with high TMB (HR = 0.57, = 0.01; HR = 0.50, = 0.02, respectively). In paired pretreatment and postprogression samples, TMB was increased at resistance (median 3.42 vs. 6.56 mutations/Mb; = 0.008).
TMB is negatively associated with clinical outcomes in metastatic patients with -mutant lung cancer treated with EGFR-TKI. This relationship contrasts with that seen in lung cancers treated with immunotherapy..
肿瘤突变负荷（TMB）是免疫检查点阻断（ICB）反应的生物标志物。TMB 对靶向治疗结果的影响尚未得到探索。
我们确定了所有接受第一代/第二代 EGFR 酪氨酸激酶抑制剂（TKI）治疗的转移性外显子 19 缺失或 L858R 突变型肺癌患者，这些患者均有预处理的下一代测序数据（MSK-IMPACT 检测）。在单变量和多变量分析中评估 TMB 对治疗停药时间（TTD）和总生存期（OS）的影响。野生型肺腺癌样本用于比较。
在 153 名 - 突变型肺癌患者中，TMB 低于 EGFR 野生型（ = 1849；中位数 3.77 与 6.12 个突变/Mb； < 0.0001），且范围广泛（0.82-17.9 个突变/Mb）。肿瘤 TMB 处于高三分位的 - 突变型肺癌患者 TTD（HR，0.46； = 0.0008）和 OS（HR，0.40； = 0.006）均较短，与低/中 TMB 患者相比。按中位 TMB 评估，TMB 较高的患者 TTD（ = 0.006）和 OS（ = 0.03）明显更短。多变量分析显示，低/中三分位与高 TMB 相比，TTD 和 OS 明显更长（HR = 0.57， = 0.01；HR = 0.50， = 0.02）。在配对的预处理和进展后样本中，耐药时 TMB 增加（中位数 3.42 与 6.56 个突变/Mb； = 0.008）。
在接受 EGFR-TKI 治疗的转移性 - 突变型肺癌患者中，TMB 与临床结局呈负相关。这种关系与免疫治疗治疗的肺癌不同。
