Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations.
Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations.
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DOI：
10.1158/2159-8290.cd-14-0326
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发表时间：
2014-09
期刊：
影响因子：
28.2
通讯作者：
Pao W
中科院分区：
文献类型：
--
作者：
Janjigian YY;Smit EF;Groen HJ;Horn L;Gettinger S;Camidge DR;Riely GJ;Wang B;Fu Y;Chand VK;Miller VA;Pao W
对可逆性表皮生长因子受体（EGFR）抑制剂（吉非替尼/厄洛替尼）有反应的EGFR突变型肺癌会产生获得性耐药，在超过50%的病例中是由EGFR第二位点T790M突变介导的。在临床前研究中，阿法替尼（不可逆的ErbB家族阻滞剂）联合西妥昔单抗（抗EGFR单克隆抗体）可克服T790M介导的耐药性。这项将阿法替尼和西妥昔单抗联合使用的Ib期研究纳入了经过大量前期治疗的晚期EGFR突变型肺癌患者，这些患者对厄洛替尼/吉非替尼产生了获得性耐药。患者提供获得性耐药后的肿瘤样本用于分析EGFR突变情况。在126名患者中，客观缓解率（总体为29%）在T790M阳性和T790M阴性肿瘤中相当（32%对25%；P = 0.341）。中位无进展生存期为4.7个月（95%置信区间，4.3 - 6.4）；确认的客观缓解中位持续时间为5.7个月（范围，1.8 - 24.4）。44%/2%的患者发生了与治疗相关的3/4级不良事件。阿法替尼/西妥昔单抗在对吉非替尼或厄洛替尼产生获得性耐药的EGFR突变型肺癌中，无论是否存在T790M突变，均显示出良好的临床活性和可控的安全性，值得进一步研究。
EGFR-mutant lung cancers responsive to reversible EGFR inhibitors (gefitinib/erlotinib) develop acquired resistance, mediated by second-site EGFR T790M mutation in >50% cases. Preclinically, afatinib (irreversible ErbB family blocker) plus cetuximab (anti-EGFR monoclonal antibody) overcomes T790M-mediated resistance. This phase Ib study combining afatinib and cetuximab enrolled heavily pretreated patients with advanced EGFR-mutant lung cancer and acquired resistance to erlotinib/gefitinib. Patients provided post-acquired-resistance tumor samples for profiling EGFR mutations. Among 126 patients, objective response rate (overall 29%) was comparable in T790M-positive and T790M-negative tumors (32% vs. 25%; P = 0.341). Median progression-free survival was 4.7 months (95% confidence interval, 4.3–6.4); median duration of confirmed objective response was 5.7 months (range, 1.8–24.4). Therapy-related grade 3/4 adverse events occurred in 44%/2% of patients. Afatinib/cetuximab demonstrated robust clinical activity and a manageable safety profile in EGFR-mutant lung cancers with acquired resistance to gefitinib or erlotinib, both with and without T790M mutations, warranting further investigation.