Oncology Unit, 3rd Department of Internal Medicine, National and Kapodistrian University of Athens, 152 Μesogeion Avenue, 11527, Athens, Greece.
Department of Pulmonary Medicine, 401 General Army Hospital, 1 Kanellopoulou Avenue, 11526, Athens, Greece.
BioDrugs. 2016 Oct;30(5):421-439. doi: 10.1007/s40259-016-0194-1.
Chemotherapy has reached a plateau in the efforts for survival improvement in non-small cell lung cancer (NSCLC). The growing knowledge of NSCLC molecular pathobiology has led to the development of new treatments that target specific tumor functions. Angiogenesis is a tumor function leading to the formation of new tumor vessels that are crucial for its survival. Although vascular endothelial growth factor (VEGF) plays a primary role in angiogenesis, the inhibition of the VEGF pathway with VEGF-receptor (VEGFR) tyrosine kinase inhibitors (TKIs) is associated with a modest survival benefit due to the development of resistance by the tumor that has been mainly attributed to the up-regulation of other stimulators of angiogenesis. Thus, the use of multitargeted antiangiogenesis TKIs (MATKIs) for simultaneous inhibition of multiple angiogenic pathways has been proposed. This review summarizes data about novel treatment strategies incorporating the inhibition of angiogenesis with MATKIs in NSCLC. The data from all relevant studies shows that MATKIs do not offer additional survival benefit to currently available chemotherapeutic options in unselected NSCLC patients. However, the diversity in disease response to MATKI-containing regimens implies that specific patient subgroups may benefit from or be harmed by these agents. In this context, most studies agree that the VEGFR-targeting MATKIs are harmful in squamous NSCLC while specific MATKIs (i.e., motesanib, vandetanib and nintedanib) are associated with improved progression free survival in non-squamous NSCLC. However, overall survival benefit was found only in adenocarcinoma and Asian non-squamous NSCLC patients with the use of nintedanib and motesanib, respectively.
化疗在提高非小细胞肺癌（NSCLC）患者生存率方面已达到瓶颈。随着对 NSCLC 分子病理生物学认识的不断深入，针对特定肿瘤功能的新疗法不断涌现。血管生成是肿瘤形成新血管的功能，这些新血管对肿瘤的存活至关重要。虽然血管内皮生长因子（VEGF）在血管生成中起主要作用，但由于肿瘤对 VEGF 通路的抑制产生了耐药性，从而导致 VEGFR 酪氨酸激酶抑制剂（TKI）抑制 VEGF 通路的疗效有限，而这种耐药性主要归因于其他血管生成刺激物的上调。因此，同时抑制多个血管生成途径的多靶点抗血管生成 TKI（MATKIs）的应用已被提出。这篇综述总结了将 MATKIs 抑制血管生成用于 NSCLC 的新型治疗策略的数据。所有相关研究的数据表明，MATKIs 并不能为 NSCLC 患者提供比现有化疗方案更好的生存获益。然而，由于对 MATKI 治疗方案的疾病反应存在多样性，这意味着特定的患者亚组可能受益于或受到这些药物的伤害。在这种情况下，大多数研究都认为 VEGFR 靶向的 MATKIs 在鳞状 NSCLC 中是有害的，而特定的 MATKIs（即 motesanib、vandetanib 和 nintedanib）与非鳞状 NSCLC 患者的无进展生存期改善相关。然而，只有在使用 nintedanib 和 motesanib 时，才能在腺癌和亚洲非鳞状 NSCLC 患者中观察到总生存期的获益。
