NEJM：克唑替尼治疗ALK阳性的晚期肺癌疗效优于标准化疗

既往单组研究显示，间变性淋巴瘤激酶(ALK)基因的染色体重排与口服酪氨酸激酶抑制剂ALK靶向药物克唑替尼（crizotinib）明显的临床应答相关。然而克唑替尼的疗效是否优于标准化疗方案尚未明确。美国波士顿 Mas -sachusetts 总医院癌症中心的 Shaw医生等人进行了深入研究，他们发现，对于那些经既往治疗的、ALK基因发生重排的晚期非小细胞肺癌患者，克唑替尼治疗效果优于标准化疗方案。相关论文发表于国际权威杂志NEJM2013年6月在线版上。

研究人员开展了一项3期、开放标签试验，在347例接受过一次基于铂方案治疗的局部晚期或转移性ALK阳性肺癌患者中比较了克唑替尼VS化疗的疗效。患者经随机分组，分别接受口服克唑替尼(250 mg)每天两次或每3周接受培美曲塞（500 mg 每平米体表）或多西他奇（75 mg 每平米体表）静脉化疗。化疗组患者出现进展后则交叉进入克唑替尼治疗组，并作为独立研究的一部分。试验主要终点为无进展生存期。

结果显示，克唑替尼治疗组和化疗组的中位无进展生存期分别为7.7月和3.0个月（克唑替尼组进展或死亡危险比为0.49; 95% 置信区间[CI], 0.37 至0.64; P<0.001)。克唑替尼治疗组应答率为65% (95% CI, 58 to 72)，与之相比化疗组则为20% (95% CI, 14 to 26) (P<0.001)。总生存率中期分析显示，无组间显著差异（克唑替尼组危险比，1.02; 95% CI, 0.68 to 1.54; P=0.54)。克唑替尼组常见不良反应为视觉障碍，胃肠副作用，肝转氨酶水平升高，而化疗组的常见不良反应则为疲劳，脱发，呼吸困难。患者报道与化疗组相比，克唑替尼组患者肺癌症状得到更多缓解，个人生活总质量也得到改善。

研究人员由此得出结论，对于那些经既往治疗的、ALK基因发生重排的晚期非小细胞肺癌患者，克唑替尼治疗优于标准化疗方案。

点评：

辉瑞公司的XALKORI (crizotinib)胶囊获得美国食品药品管理局(FDA)批准，这是第一个对间变性淋巴瘤激酶(ALK)进行靶向治疗的药品，用于治疗通过FDA批准的检测方法诊断为ALK阳性的局部晚期或转移的非小细胞肺癌(NSCLC)。克唑替尼是ALK和c-MET基因或其变异体的双重阻断剂。两项多中心单臂临床试验显示，对于ALK阳性的NSCLC患者，克唑替尼具有显着的治疗活性。

2012版NCCN指南推荐对于ALK阳性的NSCLC患者一线治疗可选择克唑替尼。2011年8月美国FDA批准克唑替尼用于局部晚期或转移性ALK阳性NSCLC的一线治疗。

近年来，EML4-ALK已成为靶向治疗研究的新宠。在NSCLC患者中，ALK重排的阳性率大约为3%～5%，在腺癌、从未吸烟或少量吸烟的患者中EML4-ALK 融合的几率高，且与ALK阴性的NSCLC患者相比，ALK阳性患者年龄较轻，但预后较差。

克唑替尼是否可用于二线治疗？目前一项正在进行的随机Ⅲ期临床研究（PROFILE1007）对克唑替尼与其他二线治疗方案进行了比较，我们也期待结果的发表。

克唑替尼加入一线治疗无疑是NSCLC患者靶向治疗的一项重大突破，但是尽管有效率比较高（>80%），但克唑替尼治疗有效的患者通常在用药1年后就会发生耐药，所以探明克唑替尼耐药机制及如何克服耐药仍有待进一步研究探索。

Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer
Background
In single-group studies, chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) have been associated with marked clinical responses to crizotinib, an oral tyrosine kinase inhibitor targeting ALK. Whether crizotinib is superior to standard chemotherapy with respect to efficacy is unknown.
Methods
We conducted a phase 3, open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen. Patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival.
Results
The median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group (hazard ratio for progression or death with crizotinib, 0.49; 95% confidence interval [CI], 0.37 to 0.64; P<0.001). The response rates were 65% (95% CI, 58 to 72) with crizotinib, as compared with 20% (95% CI, 14 to 26) with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, 0.68 to 1.54; P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy.
Conclusions
Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non–small-cell lung cancer with ALK rearrangement. (Funded by Pfizer; ClinicalTrials.gov number, NCT00932893.)