Cardiovascular Research Methods Centre, University of Ottawa Heart Institute, Ottawa, Canada.
Independent Information Specialist, Ottawa, Canada.
PLoS One. 2020 Feb 19;15(2):e0229179. doi: 10.1371/journal.pone.0229179. eCollection 2020.
We sought to assess the relative effects of individual anaplastic lymphoma kinase (ALK) inhibitors for the treatment of non-small cell lung cancer (NSCLC).
We searched MEDLINE, Embase, Cochrane CENTRAL, and grey literature (July 23, 2019) for randomized controlled trials (RCTs) that included participants with ALK- or ROS1-positive NSCLC who received any ALK inhibitor compared with placebo, another ALK inhibitor, or the same ALK inhibitor at a different dose. The primary outcome was treatment-related death. Secondary outcomes were overall survival (OS), progression-free survival (PFS), and serious adverse events. Data were pooled via meta-analysis and network meta-analysis, and risk of bias was assessed. PROSPERO: CRD42017077046.
Thirteen RCTs reporting outcomes of interest among participants with ALK-positive NSCLC were identified. Treatment-related deaths were rare, with 10 deaths attributed to crizotinib (risk difference v. chemotherapy: 0.49, 95% credible interval [CrI] -0.16 to 1.46; odds ratio 2.58 (0.76-11.37). All ALK inhibitors improved PSF relative to chemotherapy (hazard ratio [95% CrI]: crizotinib 0.46 [0.39-0.54]; ceritinib 0.52 [0.42-0.64]; alectinib 300 BID 0.16 [0.08-0.33]; alectinib 600 BID 0.23 [0.17-0.30]; brigatinib 0.23 [0.15-0.35]), while alectinib and brigatinib improved PFS over crizotinib and ceritinib (alectinib v. crizotinib 0.34 [0.17-0.70]; alectinib v. ceritinib 0.30 [0.14-0.64]; brigatinib v. crizotinib 0.49 [0.33-0.73]; brigatinib v. ceritinib 0.43 [0.27-0.70]). OS was improved with alectinib compared with chemotherapy (HR 0.57 [95% CrI 0.39-0.83]) and crizotinib (0.68 [0.48-0.96]). Use of crizotinib (odds ratio 2.08 [95% CrI 1.56-2.79]) and alectinib (1.60 [1.00-2.58]) but not ceritinib (1.25 [0.90-1.74), increased the risk of serious adverse events compared with chemotherapy. Results were generally consistent among treatment-experienced or naïve participants.
CONCLUSION(S): Treatment-related deaths were infrequent among ALK-positive NSCLC. PFS may be improved by alectinib and brigatinib relative to other ALK inhibitors; however, the assessment of OS is likely confounded by treatment crossover and should be interpreted with caution.
我们旨在评估针对非小细胞肺癌（NSCLC）的个体间变性淋巴瘤激酶（ALK）抑制剂的相对疗效。
我们检索了 MEDLINE、Embase、Cochrane 中心数据库和灰色文献（2019 年 7 月 23 日），以纳入接受任何 ALK 抑制剂治疗的 ALK-或 ROS1 阳性 NSCLC 患者的随机对照试验（RCT），并将其与安慰剂、另一种 ALK 抑制剂或相同 ALK 抑制剂的不同剂量进行比较。主要结局是治疗相关死亡。次要结局是总生存期（OS）、无进展生存期（PFS）和严重不良事件。通过荟萃分析和网络荟萃分析对数据进行了汇总，并评估了偏倚风险。PROSPERO：CRD42017077046。
共确定了 13 项 RCT，报告了 ALK 阳性 NSCLC 患者的结局。治疗相关死亡较为罕见，10 例死亡归因于克唑替尼（与化疗相比，差异风险为 0.49，95%可信区间[CrI]为 0.16-1.46；比值比 2.58（0.76-11.37））。所有 ALK 抑制剂均改善了与化疗相比的 PFS（风险比[95% CrI]：克唑替尼 0.46 [0.39-0.54]；塞瑞替尼 0.52 [0.42-0.64]；阿来替尼 300 BID 0.16 [0.08-0.33]；阿来替尼 600 BID 0.23 [0.17-0.30]；布加替尼 0.23 [0.15-0.35]），而阿来替尼和布加替尼改善了与克唑替尼和塞瑞替尼相比的 PFS（阿来替尼与克唑替尼相比，0.34 [0.17-0.70]；阿来替尼与塞瑞替尼相比，0.30 [0.14-0.64]；布加替尼与克唑替尼相比，0.49 [0.33-0.73]；布加替尼与塞瑞替尼相比，0.43 [0.27-0.70]）。与化疗相比，阿来替尼改善了 OS（HR 0.57 [95% CrI 0.39-0.83]）和克唑替尼（0.68 [0.48-0.96]）。与化疗相比，使用克唑替尼（比值比 2.08 [95% CrI 1.56-2.79]）和阿来替尼（1.60 [1.00-2.58]）而非塞瑞替尼（1.25 [0.90-1.74]）增加了严重不良事件的风险。在治疗经验丰富或初治患者中，结果基本一致。
ALK 阳性 NSCLC 患者的治疗相关死亡较为罕见。与其他 ALK 抑制剂相比，阿来替尼和布加替尼可能改善 PFS；然而，OS 的评估可能受到治疗交叉的影响，应谨慎解读。
