Kent Oncology Centre, Maidstone Hospital, Kent, UK.
South West Wales Cancer Centre, Swansea, UK.
Clin Lung Cancer. 2020 May;21(3):e216-e228. doi: 10.1016/j.cllc.2019.12.003. Epub 2019 Dec 20.
The availability of 3 generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with different pharmacologic characteristics and clinical profiles has provided oncologists with a potentially confusing choice for the treatment of EGFR mutation-positive non-small-cell lung cancer. Although recent head-to-head clinical trials have demonstrated improved efficacy with second-generation (ie, afatinib, dacomitinib) and third-generation (ie, osimertinib) TKIs compared with the first-generation TKIs (eg, erlotinib, gefitinib), acquired resistance has been inevitable, regardless of which agent has been chosen as first-line therapy. Thus, the potential availability of subsequent treatment options is an important consideration. Recent data have demonstrated that osimertinib confers an overall survival benefit compared with first-generation EGFR TKIs, and dacomitinib has shown an overall survival benefit compared with gefitinib in an exploratory analysis. However, the relative benefits of different sequential EGFR-TKI regimens, especially those involving second- and third-generation agents, have remained uncertain and require prospective evaluation. Few such data currently exist to inform treatment choices. In the present review, we examined the pharmacologic characteristics and current clinical data for EGFR TKIs, including emerging information on the molecular mechanisms of resistance across the different generations of TKIs. Given the uncertainties regarding the optimal treatment choice, we have focused on the factors that might help determine the treatment decisions, such as efficacy and safety in patient subgroups. We also discussed the emerging real-world data, which have provided some insights into the benefits of sequential regimens in everyday clinical practice.
三代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）具有不同的药理特性和临床特征，为肿瘤学家提供了治疗 EGFR 突变阳性非小细胞肺癌的潜在困惑选择。尽管最近的头对头临床试验表明，与第一代 TKI（如厄洛替尼、吉非替尼）相比，第二代（如阿法替尼、达可替尼）和第三代（如奥希替尼）TKI 的疗效有所提高，但无论选择哪种药物作为一线治疗，获得性耐药都是不可避免的。因此，后续治疗选择的潜力是一个重要的考虑因素。最近的数据表明，奥希替尼与第一代 EGFR TKI 相比具有总体生存获益，达可替尼与吉非替尼相比在探索性分析中具有总体生存获益。然而，不同顺序 EGFR-TKI 方案的相对获益，特别是涉及第二代和第三代药物的方案，仍然不确定，需要前瞻性评估。目前很少有此类数据可用于指导治疗选择。在本综述中，我们检查了 EGFR TKI 的药理特性和当前临床数据，包括不同代 TKI 耐药的分子机制的新信息。鉴于最佳治疗选择存在不确定性，我们重点关注可能有助于确定治疗决策的因素，例如患者亚组的疗效和安全性。我们还讨论了新兴的真实世界数据，这些数据为日常临床实践中序贯方案的益处提供了一些见解。
