Tumor Mutation Burden and Efficacy of EGFR-Tyrosine Kinase Inhibitors in Patients with EGFR-Mutant Lung Cancers.
Tumor Mutation Burden and Efficacy of EGFR-Tyrosine Kinase Inhibitors in Patients with EGFR-Mutant Lung Cancers.
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DOI：
10.1158/1078-0432.ccr-18-1102
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发表时间：
2019-02-01
期刊：
影响因子：
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通讯作者：
Hellmann MD
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作者：
Offin M;Rizvi H;Tenet M;Ni A;Sanchez-Vega F;Li BT;Drilon A;Kris MG;Rudin CM;Schultz N;Arcila ME;Ladanyi M;Riely GJ;Yu H;Hellmann MD
肿瘤突变负荷（TMB）是对免疫检查点阻断（ICB）反应的生物标志物。尚未探讨TMB对靶向治疗结局的影响。我们使用治疗前大样本组下一代测序数据（MSK-IMPACT测定）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EGFR外显子19 del或L 858 R突变型肺癌患者。在单变量和多变量分析中评估TMB对治疗终止时间（TTD）和总生存期（OS）的影响。EGFR野生型（WT）肺腺癌样品用于比较。在153例EGFR突变型肺癌患者中，TMB低于EGFR野生型（n=1849）（中位数3.77 vs. 6.12突变/Mb，p<0.0001），范围较宽（0.82-17.9）。与低/中等TMB患者相比，肿瘤TMB在上三分位数的EGFR突变肺癌患者的TTD（HR=0.46，p=0.0008）和OS（HR=0.40，p=0.006）较短。通过中位TMB评估，TMB较高的患者的TTD和OS显著较短（TTD p=0.006，OS p=0.03）。在多变量分析中，与高TMB组相比，低/中三分位数组的TTD和OS显著更长（分别为HR=0.57，p=0.01; HR=0.50，p=0.02）。在配对的治疗前和进展后样本中，TMB在耐药时增加（中位数6.56 vs 3.42突变/Mb，p=0.008）。在接受EGFR-TKI治疗的转移性EGFR突变型肺癌患者中，TMB与临床结局呈负相关。这种关系与用免疫疗法治疗的肺癌形成对比。
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 EGFR exon19del or L858R mutant lung cancers treated with first/second generation EGFR tyrosine kinase inhibitors (TKIs) with pre-treatment large panel 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. EGFR wild-type (WT) lung adenocarcinoma samples were used for comparison. Among 153 patients with EGFR mutant lung cancer, TMB was lower compared to EGFR wild-type (n=1849) (median 3.77 vs. 6.12 mutations/Mb, p<0.0001) with a broad range (0.82–17.9). EGFR mutant lung cancer patients whose tumors had TMB in the upper tertile had shorter TTD (HR=0.46, p=0.0008) and OS (HR=0.40, p=0.006) compared to patients with low/intermediate TMB. Evaluating by median TMB, there was significantly shorter TTD and OS for patients with higher TMB (TTD p=0.006, OS p=0.03). In multivariate analysis, TTD and OS remained significantly longer in the low/intermediate tertile compared to high TMB (HR=0.57, p=0.01; HR=0.50, p=0.02, respectively). In paired pre-treatment and post-progression samples, TMB was increased at resistance (median 6.56 vs 3.42 mutations/Mb, p=0.008). TMB is negatively associated with clinical outcomes in metastatic EGFR mutant lung cancer patients treated with EGFR-TKI. This relationship contrasts with that seen in lung cancers treated with immunotherapy.