Tuebingen Center for Academic Drug Discovery & Development, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Tübingen, Germany.
Expert Opin Drug Discov. 2021 Oct;16(10):1091-1103. doi: 10.1080/17460441.2021.1936496. Epub 2021 Jun 20.
: Osimertinib is currently the only FDA- and EMA-approved third-generation small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). It was initially indicated for second-line treatment of patients with metastatic T790M mutation-positive non-small cell lung cancer (NSCLC) and got approved for first-line treatment of activation mutation-positive metastatic NSCLC in 2018. Most recently, the FDA granted approval for the adjuvant treatment of patients with early-stage mutated NSCLC after tumor resection.: This drug discovery case history focuses on the key studies that led to the preclinical discovery and development of osimertinib. The authors focus on published preclinical studies by scientists from AstraZeneca and highlight key events in the clinical development.: Although eventually compromised by the cellular plasticity of the tumor and the inevitable acquisition of drug resistance through the use of osimertinib, its key role in the treatment of NSCLC with specific mutations will be maintained in the near future. As the genome of EGFR is highly labile and since the rapid development of new mutants remains an issue, there is still room for improvement for the next generation of inhibitors.
奥希替尼是目前唯一获得美国食品药品监督管理局（FDA）和欧洲药品管理局（EMA）批准的第三代小分子表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）。它最初被批准用于治疗转移性 T790M 突变阳性非小细胞肺癌（NSCLC）患者的二线治疗，并于 2018 年获得批准用于治疗激活突变阳性转移性 NSCLC 的一线治疗。最近，FDA 批准奥希替尼用于经肿瘤切除的早期突变型 NSCLC 患者的辅助治疗。
本文重点介绍了导致奥希替尼在临床前发现和开发的关键研究。作者关注了阿斯利康科学家发表的临床前研究，并强调了临床开发中的关键事件。
尽管肿瘤的细胞可塑性最终会对其产生影响，而且不可避免地会通过使用奥希替尼产生耐药性，但它在治疗特定突变的 NSCLC 方面的关键作用在不久的将来仍将保持不变。由于 EGFR 的基因组高度不稳定，而且新突变体的快速发展仍然是一个问题，因此下一代抑制剂仍有改进的空间。
