Medical Oncology Department, Hospital Universitario 12 de Octubre, Avda de Córdoba s/n, 28041, Madrid, Spain.
Lung Cancer Group, Clinical Research Program, CNIO (Centro Nacional de Investigaciones Oncológicas) and Instituto de Investigación i+12, Madrid, Spain.
Drugs. 2018 Jun;78(9):893-911. doi: 10.1007/s40265-018-0916-4.
Lung cancer is the second most common malignant tumor and the leading cause of cancer death. Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is a distinct subtype of lung cancer comprising approximately 15-40% of non-squamous tumors. The development of first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) has been a significant step forward in the treatment of patients with EGFR-mutant tumors, and over the last few years has been the therapy of choice in the initial management of patients with activating mutations in EGFR, with some differences in efficacy and toxicity profile. Up to 50% of patients treated with first- and second-generation TKIs develop an EGFR exon 20 T790M mutation at the time of progression. In this context, osimertinib has shown a great benefit in terms of progression-free survival (PFS) in the second-line setting, including central nervous system metastasis control. The FLAURA trial, which compared osimertinib to first-generation inhibitors as first-line therapy, showed a clear PFS advantage for osimertinib and a trend towards an increased overall survival (OS) assessed by investigator review. Although T790M mutation is the most common mechanism of resistance to first- and second-generation EGFR TKIs, other EGFR-dependent and -independent mechanisms have been described, such as HER2 and MET amplifications or BRAF and MEK mutations. Some mechanisms of resistance to osimertinib and other third-generation TKIs have also been described. Several fourth-generation TKIs, targeted drug combinations and immunotherapy strategies are under investigation to overcome resistance to EGFR TKIs in order to improve EGFR-mutant NSCLC patient outcomes.
肺癌是第二大常见恶性肿瘤，也是癌症死亡的主要原因。表皮生长因子受体（EGFR）突变型非小细胞肺癌（NSCLC）是一种独特的肺癌亚型，约占非鳞状肿瘤的 15-40%。第一代和第二代 EGFR 酪氨酸激酶抑制剂（TKI）的发展是 EGFR 突变型肿瘤治疗的重大进展，在过去几年中，它已成为 EGFR 激活突变患者初始管理的首选治疗方法，在疗效和毒性特征方面存在一些差异。高达 50%接受第一代和第二代 TKI 治疗的患者在进展时会出现 EGFR 外显子 20 T790M 突变。在这种情况下，奥希替尼在二线治疗中在无进展生存期（PFS）方面显示出巨大的获益，包括对中枢神经系统转移的控制。FLAURA 试验比较了奥希替尼与第一代抑制剂作为一线治疗，奥希替尼在 PFS 方面具有明显优势，且研究者评估的总生存期（OS）有增加趋势。尽管 T790M 突变是对第一代和第二代 EGFR TKI 耐药的最常见机制，但已描述了其他 EGFR 依赖性和非依赖性机制，如 HER2 和 MET 扩增或 BRAF 和 MEK 突变。奥希替尼和其他第三代 TKI 的一些耐药机制也已被描述。为了改善 EGFR 突变型 NSCLC 患者的预后，正在研究几种第四代 TKI、靶向药物联合和免疫治疗策略，以克服对 EGFR TKI 的耐药性。
