Gao Xin, Le Xiuning, Costa Daniel B
a Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center , Harvard Medical School , Boston , MA , USA.
Expert Rev Anticancer Ther. 2016;16(4):383-90. doi: 10.1586/14737140.2016.1162103. Epub 2016 Mar 21.
First- and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the evidence-based first-line treatment for metastatic non-small-cell lung cancers (NSCLCs) that harbor sensitizing EGFR mutations (i.e. exon 19 deletions or L858R). However, acquired resistance to EGFR TKI monotherapy occurs invariably within a median time frame of one year. The most common form of biological resistance is through the selection of tumor clones harboring the EGFR T790M mutation, present in >50% of repeat biopsies. The presence of the EGFR T790M mutation negates the inhibitory activity of gefitinib, erlotinib, and afatinib. A novel class of third-generation EGFR TKIs has been identified by probing a series of covalent pyrimidine EGFR inhibitors that bind to amino-acid residue C797 of EGFR and preferentially inhibit mutant forms of EGFR versus the wild-type receptor. We review the rapid clinical development and approval of the third-generation EGFR TKI osimertinib for treatment of NSCLCs with EGFR-T790M.
第一代和第二代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKIs）是针对携带敏感EGFR突变（即19号外显子缺失或L858R）的转移性非小细胞肺癌（NSCLCs）的循证一线治疗方法。然而，对EGFR TKI单药治疗的获得性耐药通常在一年的中位时间内出现。最常见的生物学耐药形式是通过选择携带EGFR T790M突变的肿瘤克隆，该突变存在于超过50%的重复活检中。EGFR T790M突变的存在使吉非替尼、厄洛替尼和阿法替尼的抑制活性失效。通过探究一系列与EGFR的氨基酸残基C797结合并优先抑制EGFR突变形式而非野生型受体的共价嘧啶EGFR抑制剂，已鉴定出一类新型的第三代EGFR TKIs。我们综述了第三代EGFR TKI奥希替尼用于治疗伴有EGFR-T790M的NSCLCs的快速临床开发和批准情况。
