Karmanos Cancer Institute, Experimental Therapeutics Program, Wayne State University, 4100 John R, Detroit, MI 48201, USA.
Future Oncol. 2011 Aug;7(8):947-53. doi: 10.2217/fon.11.77.
Crizotinib is an oral small-molecule inhibitor of ALK and c-Met tyrosine kinases that is being developed by Pfizer. ALK mutations or gene rearrangements result in growth factor-independent ALK activation. Most of the available clinical data with crizotinib are in patients with tumors that have an activated ALK, and the drug has shown very promising clinical benefit in these patients. ALK gene rearrangement occurs in approximately 3-5% of non-small-cell lung cancer patients, most of whom are never- or light smokers and have adenocarcinoma histology. In these patients, crizotinib at a dose of 250 mg twice daily demonstrated a response rate of 56% and a disease control rate of 87% in previously treated patients. The drug is generally well tolerated, with the most common adverse events being nausea, vomiting and some minor visual disturbances that are fleeting. Grade 3/4 elevations in hepatic transaminases occurred in 6% of the patients, which in most patients resolved with dose reduction. Ongoing studies will define the true utility of this drug in ALK-rearranged non-small-cell lung cancer patients and in patients with other tumors that also have ALK activation. Preliminary data suggest that the drug may also be active in tumors with an activated c-Met pathway.
克唑替尼是辉瑞公司研发的一种针对 ALK 和 c-Met 酪氨酸激酶的口服小分子抑制剂。ALK 突变或基因重排导致生长因子非依赖性 ALK 激活。目前大多数关于克唑替尼的临床数据都来自于具有激活的 ALK 的肿瘤患者，该药在这些患者中显示出非常有前景的临床获益。ALK 基因重排在大约 3-5%的非小细胞肺癌患者中发生，这些患者大多从不吸烟或轻度吸烟，且组织学为腺癌。在这些患者中，每日两次 250mg 的克唑替尼在先前治疗的患者中显示出 56%的缓解率和 87%的疾病控制率。该药物通常具有良好的耐受性，最常见的不良反应为恶心、呕吐和一些短暂的轻微视觉障碍。6%的患者出现了 3/4 级肝转氨酶升高，大多数患者通过降低剂量得以缓解。正在进行的研究将确定该药物在具有 ALK 重排的非小细胞肺癌患者和具有 ALK 激活的其他肿瘤患者中的真正用途。初步数据表明，该药在激活的 c-Met 通路的肿瘤中也可能具有活性。
