Royal Marsden NHS Foundation Trust, London, UK.
National University Health System, Singapore, Singapore.
Drugs. 2017 May;77(8):813-827. doi: 10.1007/s40265-017-0732-2.
Non-small-cell lung cancer (NSCLC) remains a significant global health challenge and the leading cause of cancer-related mortality. The traditional 'one-size-fits-all' treatment approach has now evolved into one that involves personalized strategies based on histological and molecular subtypes. The molecular era has revolutionized the treatment of patients harboring epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) and ROS1 gene aberrations. In the appropriately selected population, anti-tumor agents against these molecular targets can significantly improve progression-free survival. However, the emergence of acquired resistance is inevitable. Novel potent compounds with much improved and rational selectivity profiles, such as third-generation EGFR T790M resistance mutation-specific inhibitors, have been developed and added to the NSCLC armamentarium. To date, attempts to overcome resistance bypass pathways through downstream signaling blockade has had limited success. Furthermore, the majority of patients still do not harbor known driver genetic or epigenetic alterations and/or have no new available treatment options, with chemotherapy remaining their standard of care. Several potentially actionable driver aberrations have recently been identified, with the early clinical development of multiple inhibitors against these promising targets currently in progress. The advent of immune checkpoint inhibitors has led to significant benefit for advanced NSCLC patients with durable responses observed. Further interrogation of the underlying biology of NSCLC, coupled with modern clinical trial designs, is now required to develop novel targeted therapeutics rationally matched with predictive biomarkers of response, so as to further advance NSCLC therapeutics through the next decade.
非小细胞肺癌（NSCLC）仍然是一个重大的全球健康挑战，也是癌症相关死亡的主要原因。传统的“一刀切”治疗方法现在已经演变为基于组织学和分子亚型的个性化策略。分子时代彻底改变了对携带表皮生长因子受体（EGFR）、间变性淋巴瘤激酶（ALK）和 ROS1 基因异常的患者的治疗。在适当选择的人群中，针对这些分子靶标的抗肿瘤药物可以显著改善无进展生存期。然而，获得性耐药的出现是不可避免的。已经开发出了许多新型有效的化合物，这些化合物具有改善和合理的选择性特征，例如第三代 EGFR T790M 耐药突变特异性抑制剂，并已加入 NSCLC 的治疗手段中。迄今为止，通过下游信号阻断来克服耐药旁路的尝试取得的成功有限。此外，大多数患者仍然没有已知的驱动基因或表观遗传改变，并且/或者没有新的可用治疗选择，化疗仍然是他们的标准治疗方法。最近已经确定了一些潜在的可靶向驱动异常，目前针对这些有前途的靶点的多种抑制剂的早期临床开发正在进行中。免疫检查点抑制剂的出现为晚期 NSCLC 患者带来了显著的益处，观察到了持久的缓解。现在需要进一步研究 NSCLC 的生物学基础，并结合现代临床试验设计，合理地开发靶向治疗药物，并与反应预测生物标志物相匹配，以在未来十年内进一步推进 NSCLC 的治疗。
