Introduction: The use of ALK (anaplastic lymphoma kinase) and ROS1 (ROS1 protoncogene) inhibitors are the standard of care in advanced non-small-cell lung cancer (NSCLC) patients withALKorROS1gene rearrangements (approximately 5.5% of patients). Three generations of inhibitors are available, but there is no direct comparison of their efficacy in homogeneous Caucasian populations in real-world practice. In this retrospective study, we compare the efficacy of crizotinib, brigatinib, and alectinib in NSCLC patients with different clinical courses of the disease.Materials and Methods: One hundred four NSCLC patients withALKorROS1gene rearrangement were enrolled for first-line therapy with ALK inhibitors (crizotinib in 25 patients, brigatinib in 22 patients, and alectinib in 41 patients) or the ROS1 inhibitor (crizotinib in 16 patients) as part of daily clinical practice in two Polish cancer centers. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared according to treatment methods and clinical data.Results: InALK-rearranged patients, ORR was insignificantly higher in patients treated with second-generation ALK inhibitors than in patients receiving crizotinib (68.25% vs. 48% of patients,p= 0.0547). Median PFS in the crizotinib group was 8 months, and in the group that received second-generation ALK inhibitors this was not reached (HR = 5.2182, 95% CI: 2.6163–10.4079,p< 0.0001). Similarly, median OS was significantly lower in patients treated with crizotinib than in patients receiving second-generation ALK inhibitors (26 vs. not reached, HR = 3.529, 95% CI: 1.5559–7.2258,p= 0.002). The efficacy of crizotinib in patients withROS1andALKgene rearrangement did not differ significantly (ORR—37.5 vs. 48%, median PFS—6 vs. 7 months, median OS—8 vs. 26 months, respectively). InALK-rearranged patients, multivariate analysis showed that the only factor significantly increasing the risk of progression was liver metastases (HR = 2.1917,p= 0.0418). The risk of death was significantly higher in patients treated with crizotinib (HR = 2.4823,p= 0.0359) and in patients with liver metastases (HR = 3.1266,p= 0.0104).Conclusions: Second-generation ALK inhibitors are more effective than crizotinib inALK-rearranged patients. Liver metastases, but not brain metastases, are the main clinical factors shortening PFS and OS in NSCLC patients treated with ALK inhibitors.
引言：对于携带ALK（间变性淋巴瘤激酶）或ROS1（ROS1原癌基因）基因重排（约占患者总数的5.5%）的晚期非小细胞肺癌（NSCLC）患者，使用ALK和ROS1抑制剂已成为标准治疗方案。目前已有三代抑制剂可供选择，但在真实世界临床实践中，尚未有研究对它们在同质高加索人群中的疗效进行直接比较。本回顾性研究旨在比较克唑替尼、布加替尼和阿来替尼在不同临床病程的NSCLC患者中的疗效。 材料与方法：研究纳入104例携带ALK或ROS1基因重排的NSCLC患者，这些患者来自波兰两家癌症中心，在日常临床实践中接受一线治疗：其中ALK抑制剂治疗组（克唑替尼25例、布加替尼22例、阿来替尼41例）及ROS1抑制剂治疗组（克唑替尼16例）。根据治疗方法及临床数据，比较各组的总缓解率（ORR）、无进展生存期（PFS）和总生存期（OS）。 结果：在ALK基因重排患者中，接受第二代ALK抑制剂治疗的患者ORR（68.25%）较克唑替尼组（48%）有升高趋势但未达统计学显著差异（p=0.0547）。克唑替尼组中位PFS为8个月，而第二代ALK抑制剂组尚未达到（HR=5.2182，95% CI：2.6163–10.4079，p<0.0001）。同样，克唑替尼组中位OS（26个月）显著低于第二代ALK抑制剂组（未达到）（HR=3.529，95% CI：1.5559–7.2258，p=0.002）。克唑替尼在ROS1与ALK基因重排患者中的疗效无显著差异（ORR分别为37.5% vs 48%，中位PFS为6 vs 7个月，中位OS为8 vs 26个月）。在ALK重排患者的多变量分析中，唯一显著增加疾病进展风险的因素是肝转移（HR=2.1917，p=0.0418）。接受克唑替尼治疗（HR=2.4823，p=0.0359）及存在肝转移（HR=3.1266，p=0.0104）的患者死亡风险显著增高。 结论：对于ALK基因重排患者，第二代ALK抑制剂疗效优于克唑替尼。在接受ALK抑制剂治疗的NSCLC患者中，肝转移（而非脑转移）是缩短PFS和OS的主要临床因素。
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