Tyrosine kinase inhibitors (TKIs) revolutionized the treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC) harboring most driver gene alterations. Starting from the first generation, research rapidly moved to the development of newer, more selective generations of TKIs, obtaining improved results in terms of disease control and survival. However, the use of novel generations of TKIs is not without limitations. We reviewed the main results obtained, as well as the ongoing clinical trials with TKIs in oncogene-addicted NSCLC, together with the biology underlying their potential strengths and limitations. Across driver gene alterations, novel generations of TKIs allowed delayed resistance, prolonged survival, and improved brain penetration compared to previous generations, although with different toxicity profiles, that generally moved their use from further lines to the front-line treatment. However, the anticipated positioning of novel generation TKIs leads to abolishing the possibility of TKI treatment sequencing and any role of previous generations. In addition, under the selective pressure of such more potent drugs, resistant clones emerge harboring more complex and hard-to-target resistance mechanisms. Deeper knowledge of tumor biology and drug properties will help identify new strategies, including combinatorial treatments, to continue improving results in patients with oncogene-addicted NSCLC.
酪氨酸激酶抑制剂（TKI）彻底改变了携带多数驱动基因变异的晚期或转移性非小细胞肺癌（NSCLC）患者的治疗格局。从第一代药物开始，研究迅速推进至开发更新、更具选择性的新一代TKI，在疾病控制和生存期方面取得了更优成果。然而，新一代TKI的应用并非没有局限性。我们系统回顾了TKI在致癌基因依赖型NSCLC治疗中取得的主要成果及正在进行的临床试验，并探讨了其潜在优势与局限性的生物学基础。针对不同驱动基因变异，新一代TKI相较于前代药物能够延缓耐药、延长生存期并改善脑部渗透性，尽管其毒性特征存在差异，这一进步通常使其从后线治疗前移至一线治疗。然而，新一代TKI的提前应用也导致TKI序贯治疗的可能性消失，前代药物因此失去治疗地位。此外，在此类强效药物的选择压力下，耐药克隆往往会产生更复杂且难以靶向的耐药机制。深化对肿瘤生物学和药物特性的理解，将有助于开发包括联合治疗在内的新策略，持续改善致癌基因依赖型NSCLC患者的治疗效果。
肿瘤(癌症)患者之家