Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
Lung Cancer. 2013 Aug;81(2):155-61. doi: 10.1016/j.lungcan.2013.02.021. Epub 2013 May 10.
Reversible ATP-competitive inhibitors targeting the epidermal growth factor receptor (EGFR) have been established as the most effective treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring "activating" mutations in exons 19 and 21 of the EGFR gene. However, clinical activity is limited by acquired resistance which on average develops within 10 months of continued treatment. The mechanisms for acquired resistance include selection of the EGFR T790M mutation in approximately 50% of cases, and MET gene amplification, PIK3CA gene mutation, transdifferentiation into small-cell lung cancer and additional rare or unkown mechanisms. Afatinib is a small molecule covalently binding and inhibiting the EGFR, HER2 and HER4 receptor tyrosine kinases. In preclinical studies, afatinib not only inhibited the growth of models with common activating EGFR mutations, but was also active in lung cancer models harboring wild-type EGFR or the EGFR L858R/T790M double mutant. Clinical efficacy of afatinib has been extensively studied in the LUX-Lung study program. These trials showed promising efficacy in patients with EGFR-mutant NSCLC or enriched for clinical benefit from EGFR tyrosine kinase inhibitors gefitinib or erlotinib. Here we review the current status of clinical application of afatinib in NSCLC. We also discuss clinical aspects of resistance to afatinib and strategies for its circumvention.
针对表皮生长因子受体（EGFR）的可逆 ATP 竞争性抑制剂已被确立为治疗携带 EGFR 基因外显子 19 和 21“激活”突变的晚期非小细胞肺癌（NSCLC）患者最有效的方法。然而，临床疗效受到获得性耐药的限制，这种耐药平均在持续治疗 10 个月内出现。获得性耐药的机制包括约 50%的病例中出现 EGFR T790M 突变，以及 MET 基因扩增、PIK3CA 基因突变、向小细胞肺癌的转化以及其他罕见或未知的机制。阿法替尼是一种小分子，通过共价键结合并抑制 EGFR、HER2 和 HER4 受体酪氨酸激酶。在临床前研究中，阿法替尼不仅抑制了常见激活 EGFR 突变模型的生长，而且对野生型 EGFR 或 EGFR L858R/T790M 双突变模型也具有活性。阿法替尼的临床疗效已在 LUX-Lung 研究计划中进行了广泛研究。这些试验显示出阿法替尼在 EGFR 突变型 NSCLC 患者或从 EGFR 酪氨酸激酶抑制剂吉非替尼或厄洛替尼中获得临床获益的患者中具有良好的疗效。在这里，我们回顾了阿法替尼在 NSCLC 中的临床应用现状。我们还讨论了阿法替尼耐药的临床方面和规避策略。
