Gettinger Scott
Section of Medical Oncology, Department of Internal Medicine, Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA.
Semin Respir Crit Care Med. 2008 Jun;29(3):291-301. doi: 10.1055/s-2008-1076749.
Molecularly targeted therapies have recently expanded the options available for patients with advanced non-small-cell lung cancer (NSCLC). Two cancer cell pathways in particular have been exploited, the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) pathway. The former has emerged as a key regulator of cancer cell proliferation and invasion, and several EGFR inhibitors have been developed. Erlotinib, a small-molecule inhibitor of the EGFR intracellular tyrosine kinase, has been found to improve survival compared with placebo in previously treated patients with advanced NSCLC and is Food and Drug Administration (FDA)-approved in this setting. Clinical and molecular predictors of response to erlotinib, such as a history of never smoking and EGFR gene mutation or amplification, are presently being evaluated to select patients for earlier therapy with erlotinib. Additional EGFR inhibitors are also being examined in randomized trials. The VEGF pathway, a key mediator of angiogenesis, has become an attractive target in multiple malignancies, including lung cancer. Bevacizumab, a monoclonal antibody to VEGF, received FDA approval for use in advanced non-squamous-cell NSCLC in 2006 after a phase III trial reported a significant survival advantage when bevacizumab was added to standard first-line chemotherapy. Small-molecule inhibitors of the VEGF receptor tyrosine kinase, such as sunitinib and sorafenib, have also shown promise in phase II trials and are being further investigated in phase III studies. Because preclinical data suggest a synergistic effect when VEGF and EGFR inhibitors are combined, the concurrent use of erlotinib and bevacizumab has additionally been evaluated in a phase II trial, with encouraging early results suggesting at least equivalent activity to standard salvage chemotherapy, with less toxicity. Several other novel agents are being examined, including inhibitors of histone deacteylases and the 26S proteosome. Research efforts are currently focusing on tailoring such therapies according to predictive clinical and molecular markers.
分子靶向治疗最近扩大了晚期非小细胞肺癌（NSCLC）患者可选择的治疗方案。尤其有两条癌细胞通路已被利用，即表皮生长因子受体（EGFR）通路和血管内皮生长因子（VEGF）通路。前者已成为癌细胞增殖和侵袭的关键调节因子，并且已开发出几种EGFR抑制剂。厄洛替尼是一种EGFR细胞内酪氨酸激酶的小分子抑制剂，已发现在先前接受治疗的晚期NSCLC患者中，与安慰剂相比可提高生存率，并且在这种情况下已获得美国食品药品监督管理局（FDA）的批准。目前正在评估对厄洛替尼反应的临床和分子预测指标，例如从不吸烟史以及EGFR基因突变或扩增，以便选择患者尽早使用厄洛替尼进行治疗。其他EGFR抑制剂也正在进行随机试验研究。VEGF通路是血管生成的关键介质，已成为包括肺癌在内的多种恶性肿瘤中一个有吸引力的靶点。贝伐单抗是一种VEGF单克隆抗体，在一项III期试验报告将其添加到标准一线化疗中具有显著生存优势后，于2006年获得FDA批准用于晚期非鳞状NSCLC。VEGF受体酪氨酸激酶的小分子抑制剂，如舒尼替尼和索拉非尼，在II期试验中也显示出前景，并且正在III期研究中进一步研究。因为临床前数据表明VEGF和EGFR抑制剂联合使用时有协同作用，所以在一项II期试验中还评估了厄洛替尼和贝伐单抗的同时使用，早期令人鼓舞的结果表明其活性至少与标准挽救化疗相当，且毒性更小。正在研究其他几种新型药物，包括组蛋白去乙酰化酶抑制剂和26S蛋白酶体抑制剂。目前的研究工作集中在根据预测性临床和分子标志物来调整此类治疗方法。
