, Gerrards Cross, UK.
Drug Saf. 2019 Feb;42(2):181-198. doi: 10.1007/s40264-018-0772-x.
Tyrosine kinase inhibitors (TKIs) that target epidermal growth factor receptor (EGFR) have dramatically improved progression-free survival in non-small-cell lung cancer (NSCLC) patients who carry sensitizing EGFR-activating mutations and in patients with breast and pancreatic cancers. However, EGFR-TKIs are associated with significant and disabling undesirable effects that adversely impact on quality of life and compliance. These effects include dermatological reactions, diarrhoea, hepatotoxicity, stomatitis, interstitial lung disease and ocular toxicity. Each individual EGFR-TKI is also associated with additional adverse effect(s) that are not shared widely by the other members of its class. Often, these effects call for dose reduction, treatment discontinuation or pharmacotherapeutic intervention. Since dermatological effects result from on-target effects on wild-type EGFR, rash is often considered to be a biomarker of efficacy. A number of studies have reported better outcomes in patients with skin reactions compared with those without. This has led to a 'dosing-to-rash' strategy to optimize therapeutic outcomes. Although conceptually attractive, there is currently insufficient evidence-based support for this strategy. While skin reactions following EGFR-TKIs are believed to result from an effect on wild-type EGFR, their efficacy is related to effects on mutant variants of EGFR. It is noteworthy that newer EGFR-TKIs that spare wild-type EGFR are associated with fewer dermatological reactions. Furthermore, secondary mutations such as T790M in exon 20 often lead to development of resistance to the clinical activity and efficacy of first- and second-generation EGFR-TKIs. This has stimulated the search for later-generations of EGFR-TKIs with the ability to overcome this resistance and with greater target selectivity to spare wild-type EGFR in expectations of an improved safety profile. However, available data reviewed herein indicate that not only are these newer agents associated with the aforementioned adverse effects typical of earlier agents, but they are also susceptible to resistance due to tertiary mutations, most frequently C797S. At least three later-generation EGFR-TKIs, canertinib, naquotinib and rociletinib, have been discontinued from further development in NSCLC following concerns about their safety and risk/benefit.
酪氨酸激酶抑制剂（TKI）针对表皮生长因子受体（EGFR），显著改善了携带敏感 EGFR 激活突变的非小细胞肺癌（NSCLC）患者以及乳腺癌和胰腺癌患者的无进展生存期。然而，EGFR-TKI 与显著且使人衰弱的不良影响相关，这些影响会对生活质量和依从性产生不利影响。这些影响包括皮肤反应、腹泻、肝毒性、口腔炎、间质性肺病和眼部毒性。每一种单独的 EGFR-TKI 也与其他成员不同的其他不良影响相关。通常，这些影响需要减少剂量、停止治疗或药物治疗干预。由于皮肤反应是由于对野生型 EGFR 的靶向作用，因此皮疹通常被认为是疗效的生物标志物。许多研究报告了皮肤反应患者的结果优于无皮肤反应患者。这导致了一种“剂量与皮疹”的策略来优化治疗效果。尽管从概念上讲很有吸引力，但目前这种策略缺乏基于证据的支持。虽然 EGFR-TKI 引起的皮肤反应被认为是由于对野生型 EGFR 的作用，但它们的疗效与 EGFR 突变型变体的作用有关。值得注意的是，对野生型 EGFR 影响较小的新型 EGFR-TKI 与较少的皮肤反应相关。此外，如外显子 20 中的 T790M 等二次突变常导致对第一代和第二代 EGFR-TKI 的临床活性和疗效产生耐药性。这刺激了寻找具有克服这种耐药性的能力和更大的目标选择性的新一代 EGFR-TKI，以期改善安全性。然而，本文综述的可用数据表明，这些新型药物不仅与早期药物典型的上述不良影响相关，而且由于三级突变，最常见的是 C797S，也容易产生耐药性。由于对安全性和风险/获益的担忧，至少三种新型 EGFR-TKI（canertinib、naquotinib 和 rociletinib）已在 NSCLC 中停止进一步开发。
