Advances in molecular-based personalized non-small-cell lung cancer therapy: targeting epidermal growth factor receptor and mechanisms of resistance.
Advances in molecular-based personalized non-small-cell lung cancer therapy: targeting epidermal growth factor receptor and mechanisms of resistance.
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DOI：
10.1002/cam4.506
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发表时间：
2015-11
期刊：
影响因子：
4
通讯作者：
Spigel DR
中科院分区：
文献类型：
--
作者：
Jotte RM;Spigel DR
针对特定肿瘤特征的分子靶向治疗为晚期非小细胞肺癌（NSCLC）的治疗提供了个性化方法。可逆性表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）吉非替尼和厄洛替尼经历了动荡的临床开发，直到发现这些药物对携带激活EGFR突变的NSCLC患者具有优先活性。此后，多项III期临床试验共同显示，EGFR-TKI单药治疗作为EGFR突变阳性晚期NSCLC的一线治疗比联合化疗更有效。治疗EGFR突变阳性晚期NSCLC的下一代EGFR靶向药物是针对EGFR和其他ErbB家族成员的不可逆TKI，包括最近获批的阿法替尼和目前正在III期试验中测试的dacomitinib。随着研究工作继续探索EGFR-TKI治疗获得性耐药的各种拟议机制，正在研究靶向EGFR下游信号通路的药物与EGFR TKI联合治疗分子选择的晚期NSCLC。总体而言，许多正在进行的涉及EGFR TKI的III期试验的结果将有助于确定晚期NSCLC的个性化治疗是否可以通过更新的药物和组合获得进一步的收益。这篇文章回顾了针对EGFR和相关通路的药物进行个性化NSCLC治疗的关键临床试验数据，特别是基于个体肿瘤的分子特征和耐药机制。
Molecularly targeted therapies, directed against the features of a given tumor, have allowed for a personalized approach to the treatment of advanced non-small-cell lung cancer (NSCLC). The reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib had undergone turbulent clinical development until it was discovered that these agents have preferential activity in patients with NSCLC harboring activating EGFR mutations. Since then, a number of phase 3 clinical trials have collectively shown that EGFR-TKI monotherapy is more effective than combination chemotherapy as first-line therapy for EGFR mutation-positive advanced NSCLC. The next generation of EGFR-directed agents for EGFR mutation-positive advanced NSCLC is irreversible TKIs against EGFR and other ErbB family members, including afatinib, which was recently approved, and dacomitinib, which is currently being tested in phase 3 trials. As research efforts continue to explore the various proposed mechanisms of acquired resistance to EGFR-TKI therapy, agents that target signaling pathways downstream of EGFR are being studied in combination with EGFR TKIs in molecularly selected advanced NSCLC. Overall, the results of numerous ongoing phase 3 trials involving the EGFR TKIs will be instrumental in determining whether further gains in personalized therapy for advanced NSCLC are attainable with newer agents and combinations. This article reviews key clinical trial data for personalized NSCLC therapy with agents that target the EGFR and related pathways, specifically based on molecular characteristics of individual tumors, and mechanisms of resistance.