第三代 EGFR 酪氨酸激酶抑制剂 (TKI) 彻底改变了携带 EGFR 激活突变的非小细胞肺癌 (NSCLC) 患者的治疗格局，与第一代 TKI 相比，其长期疗效得到改善。然而，疾病进展不可避免地发生，限制了奥希替尼的长期疗效。事实上，一线奥希替尼获得性耐药的分子生物学是多方面的，包括出现靶标和脱靶改变。 EGFR-C797S 突变代表最常见的靶向耐药机制，并阻碍药物与靶位点的结合。 EGFR 独立耐药性包括替代信号通路的激活，例如 MET 扩增和 HER2 突变以及组织学转化。在这种情况下，化疗是当前的治疗选择，但临床效果有限。因此，开发新的治疗策略来克服对奥希替尼的耐药性是一个重大挑战。在这种情况下，第四代 TKI 正在成为克服靶向耐药性的一种有趣的治疗选择。临床前药物开发导致了噻唑酰胺抑制剂的发现，其活性是通过 EGFR 的变构抑制介导的，从而对突变型 EGFR 具有高度特异性。早期 1/2 期临床试验正在进行中，以阐明它们在临床环境中的活性。本次审查的目的是对第四代 EGFR-TKI 的临床前开发提供最先进的分析，并提供有前景的初步临床数据。版权所有 © 2024 Elsevier Ltd。保留所有权利。

Third-generation EGFR tyrosine kinase inhibitor (TKIs) have revolutionized the treatment landscape for patients with non-small cell lung cancer (NSCLC) harboring EGFR activating mutations, with improved long-term outcomes compared to first-generation TKIs. Nevertheless, disease progression inevitably occurs, limiting osimertinib long-term efficacy. Indeed, the molecular biology underlying acquired resistance to first-line osimertinib is multifaceted and includes the emergence of on-target and off-target alterations. EGFR-C797S mutation represents the most frequent mechanism of on-target resistance and hinders drug binding to the target site. EGFR-independent resistance includes the activation of alternative signaling pathways, such as MET amplification and HER2 mutations, and histological transformation. In this setting, chemotherapy is the current therapeutic option, with modest clinical outcomes. Therefore, the development of novel therapeutic strategies to overcome resistance to osimertinib is a major challenge. In this setting, fourth-generation TKIs are emerging as an interesting therapeutic option to overcome on-target resistance. Preclinical drug development has led to the discovery of thiazole-amid inhibitors, which activity is mediated by the allosteric inhibition of EGFR, resulting in high specificity towards mutant-EGFR. Early phase 1/2 clinical trials are ongoing to elucidate their activity also in the clinical setting. Aim of this review is to provide a state-of-the-art analysis on preclinical development of fourth-generation EGFR-TKIs and promising preliminary clinical data.Copyright © 2024 Elsevier Ltd. All rights reserved.