Drug Development Unit, Royal Marsden Hospital and Institute of Cancer Research, Sutton, United Kingdom.
Drug Development Unit, Royal Marsden Hospital and Institute of Cancer Research, Sutton, United Kingdom.
Crit Rev Oncol Hematol. 2021 Mar;159:103225. doi: 10.1016/j.critrevonc.2021.103225. Epub 2021 Jan 20.
Epidermal Growth Factor Receptor (EGFR) mutations are the most common targetable oncogenic driver mutation in metastatic non-small lung cancer (NSCLC). There have been significant advances in the management of metastatic EGFR-mutant NSCLC from the advent of first and second generation EGFR inhibitors to, more recently, the third-generation inhibitor osimertinib. Osimeritinib is now established as first-line therapy on the basis of improved outcomes compared to first and second generation agents. However, despite excellent initial response rates, responses may not be durable due to the development of acquired resistance. Understanding these mechanisms of resistance is critical to the development of rational drug and drug combinations capable of circumventing them. We discuss the major mechanisms of resistance to first, second and third generation EGFR TKIs. The potential of drug combinations utilising chemotherapy, immunotherapy and anti-angiogenic drugs are explored. We examine strategies to aid drug development, including circulating tumour DNA and novel trial designs.
表皮生长因子受体 (EGFR) 突变是转移性非小细胞肺癌 (NSCLC) 中最常见的可靶向致癌驱动突变。从第一代和第二代 EGFR 抑制剂的出现，到最近的第三代抑制剂奥希替尼，转移性 EGFR 突变型 NSCLC 的治疗取得了重大进展。与第一代和第二代药物相比，奥希替尼具有更好的疗效，现已确立为一线治疗药物。然而，尽管初始缓解率很高，但由于获得性耐药的发展，缓解可能不会持久。了解这些耐药机制对于开发能够规避这些机制的合理药物和药物组合至关重要。我们讨论了第一代、第二代和第三代 EGFR TKI 耐药的主要机制。探讨了利用化疗、免疫疗法和抗血管生成药物的药物组合的潜力。我们研究了有助于药物开发的策略，包括循环肿瘤 DNA 和新的试验设计。
